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581 Cards in this Set
- Front
- Back
What are the roles of the kidney?
|
Regulatory organ
Volume and blood pressure control (infinite gain – Guyton hypothesis) Composition regulation of ions, pH Endocrine organ (distant and local): Renin-angiotensin system, Endothelin, Prostaglandins, Growth factors Excretory organ |
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Where does most sodium reabsorption occur?
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The proximal tubule.
~67% ~25% is then absorbed in the thick ascending limb of the loop of Henle. |
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How do we calculate filtered sodium load?
|
Plasma [Na]mEg/LxGFRL/Min
~24,000 mEq/day We reabsorb about 99% of the sodium filtered. |
|
What happens in the proximal tubule?
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Isotonic reabs of Na+ along with HCO3, phosphate, glucose, K+ and Cl-
Reabsorption or secretion of organic compounds Activation of Vitamin D |
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What happens in the loop of henle?
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Variable water and solute permeabilities between segments
Generation and maintenance of concentrating gradient in medullary interstitium [NaCl, urea] High capacity NaCl transport in thick ascending limb (TALH) |
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What happens in the early cortical distal tubule?
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Low water permeability with NaCl reabsorption contributes to making tubule fluid dilute (hypoosmotic)
|
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What happens in the late distal tubule /collecting duct?
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Variable water permeability through aquaporin channels that are regulated by vasopressin
Na+ and K+ transport regulated by aldosterone Site of regulation of K+ excretion secretion Intercalated cells contribute to regulation of urine pH through secretion of H+ and HCO3 |
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What specialization do proximal tubule cells have?
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Thick brush border with invaginations to increase surface area.
|
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What channels are found in the early convoluted proximal tubule?
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Apical side:
Na+/H+ Exchanger Basolateral side: Na+K+ ATPase HCO3- transport coupled to K+ |
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What channels are found in the late convoluted proximal tubule?
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apical side:
Na+, Glc symport Amino acids, lactate, PO4 Basolateral side: Glc transporter coupled to K+ |
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What channels are found in the straight proximal tubule?
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Na+ Cl- Passive Diffusion-
Paracellular Reabs Na+ H+ Ex- Transcellular Reabs |
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Why does water flow from an isotonic lumen into an isotonic peritubular capillary?
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Key is the lateral intracellular space (LIS) between the cells
Basolateral transport makes for a hypertonic gradient in the LIS High Cl- in lumen creates a positive transepithelial voltage which facilitates Na+ diffusion across tubular tight junction |
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What transport processes occur in the loop of henle?
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20% of H2O
Isoosomotic to Hyperosmotic TF (tubular fluid) 20% of Na+, K+, Cl- Impermeable to H2O TF is !hypoosmotic! |
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What does furosemide inhibit in the loop of henle?
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Luminal (apical) Na+, K+, 2Cl- symporter.
|
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The macula densa is in contact with what parts of the nephron?
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Glomerulus
AND Early distal tubule |
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What is the cortical early distal tubule?
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Starts at the macula densa
Moderate capacity for NaCl transport with low water permeability helps dilute tubule fluid further Luminal Na/Cl symporter (NCC) inhibited by thiazide-like drugs (diuretic) Ca2+ and Mg2+ are reabsorbed here NaCl reabsorption support medullary gradient |
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What is the Late distal tubule / collecting duct?
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Principal cells:
reabsorb Na+, secrete K+ regulated by aldosterone Water reabsorption depends on vasopressin Spironolactone, triamterene and amiloride are K+-sparing diuretics Intercalated cells: secrete H+ or HCO3 to regulate pH; Inner medullary CD becomes permeable to urea backflux with vasopressin. |
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What is vasopressin?
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Potent anti-diuretic hormone (ADH)
Targeted to secretory pathway in PVN and SON neurons of the hypothalamus Released at the nerve terminal of the posterior lobe of the pituitary into the blood Similar to POMC, pre-provasopressin undergoes extensive proteolytic processing Circulating AVP activates V2 receptor subtypes (↑cAMP) on the renal distal tubules and collecting duct to stimulate AQP-2 (aquaporin 2) insertion and synthesis. |
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How does the kidney make a concentrated or a dilute urine?
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Key features:
Anatomical arrangement of hairpin loop Selective permeabilities to NaCl, urea, water Active NaCl transport in thick ALH Recycling of urea High medullary osmotic gradient (urea, NaCl) Required AVP stimulation of aquaporins Slows blood flow through vasa recta to preserve gradient |
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How do extracellular and intracellular fluids differ in ion content?
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Extracellular fluid is a high sodium, low potassium solution, whereas intracellular fluid is the opposite.
Osmolality is the same throughout all the body fluids. |
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What regulates the renal response to acute ingestion of a water load?
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antidiuretic hormone secretion
The ingested water lowers serum osmolality, which in turn reduces ADH secretion by the posterior pituitary. |
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What are the major physiological factors that regulate renal sodium excretion in response to changes in blood volume?
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GFR
Tubular sodium reabsorption. |
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How does GFR affect sodium excretion?
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Changes in GFR cause proportional changes in sodium excretion if the fractional reabsorption in the different nephron segments remains relatively constant.
|
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What is pressure natiuresis?
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an increase in renal perfusion pressure increases renal sodium excretion.
inhibition of renal nitric oxide (NO) reduces pressure natriuresis. |
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What is fractional excretion?
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the fraction of filtered Na excreted
FENa % = [UNaV / PNa X GFR] X 100 UNa=urine Na concentration (mEq/L); V=urine flow rate (ml/min); PNa=plasma Na concentration (mEq/L); GFR=glomerular filtration rate (ml/min) If one estimates GFR by creatinine clearance, this equation reduces to: FENa% = [UNa/PNa]/[UCr/PCr] x 100 |
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How does sympathetic stimulation affect tubular Na Reabsorption?
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Direct stimulation of proximal Na reabsorption through Na/H exchanger
(α-1 receptor) Thus, an increase in sympathetic activity will cause an increase in proximal Na reabsorption, decreasing Na excretion. Sympathetic tone also increases renin release. |
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What is the effect of the Renin angiotensin system on Na?
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It is antinatiuretic.
|
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What is the renin angiotensin system?
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Renin is an enzyme secreted by the JG cells of the kidney which acts on angiotensinogen, a large protein synthesized by the liver, to produce Angiotensin I, a decapeptide.
Angiotensin converting enzyme (ACE), located in the pulmonary arteries, converts Ang I to an octapeptide, Angiotensin II by clelaving a 2 amino acid fragment. Ang II stimulates the adrenal gland to secret aldosterone, a steroid molecule syntheisized from cholesterol. Aldosterone secretion is also controlled by the serum potessium concentration (increased K concentration increases aldosterone secretion). |
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By what mechanisms is angiotensin II antinatiuretic?
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Afferent vasoconstriction*
-Decrease GFR Increase tubular Na reabsorption -increase Na/H exchange * Efferent arteriole more sensitive to Ang II than afferent, but both can be affected. |
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By what mechanism is aldosterone antinatiuretic?
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Increase tubular Na reabsorption
-Opens Na channel (ENaC) |
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How is renin release controlled?
|
Delivery of Na to macula densa chemoreceptor in the juxta-glomerular apparatus. (The more sodium comes down the tubule the less renin is secreted)
Sympathetic nervous system Renal perfusion pressure (baroreceptor): The higher the pressure the less renin is secreted. |
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Na reabsorption by the tubular epithelial cells in the macula densa sends a signal, via adenosine generation from ATP, through the extraglomerular mesangial cells, to the afferent arteriole. This signal regulates two physiological variables. What are they?
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afferent arteriolar tone
and renin secretion |
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What hormones are natiuretic?
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Circulating:
Atrial natriuretic factor (ANF) Digitalis-like factor (DLF) Intrarenal: Dopamine (DA) Nitric oxide (NO) |
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What is DLF?
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Digitalis like factor
Made by the brain in response to increased CSF [sodium]. Much like atrial natiuretic factor it causes increased Na and water excretion. |
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What regulates free water excretion?
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ADH (Vasopressin)
|
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What does ADH do in the nephron?
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Increases water permeability in the distal tubule and collecting duct.
This means more free water is reabsorbed and the urine becomes more hypertonic. |
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What is the maximum concentration of urine the human kidney can achieve?
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1200-1400 mOsm
|
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What are the main regulators of ADH secretion?
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Plasma osmolality:
Osmoreceptor in hypothalamus detects increased plasma osmolality and produces ADH Arterial volume: Decreased arterial stretch results in ADH secretion. |
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How do we respond to increased salt and water intake?
|
Decrease antinatriuretic and antidiuretic factors
Increase natriuretic factors |
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How do we respond to decreased salt and water intake?
|
Increase antinatriuretic and antidiuretic factors
Decrease natriuretic factors |
|
How do we define hyponatremia?
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Serum Na < 135 mEq/L
|
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What is the underfilling theory of CHF?
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Systolic failure causes decreased arterial stretch.
Activation of renin-angiotensin system as if there was volume depletion. (ACE inhibitor) Water and sodium retention leads to edema. |
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What causes arterial underfilling in hepatic cirrhosis?
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Fluid extravasation from liver surface due to increased portal pressure.
Decreased serum albumin. Arterial vasodilation. Underfilling and decreased arterial stretch activates renin-angiotensin system and leads to ascites etc. |
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What are the three types of hyponatremia?
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Hypovolemic
Hypervolemic Euvolemic |
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What is hypovolemic hyponatremia?
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High ADH due to decreased arterial volume.
Vomiting, diarrhea, hemorrhage, fluid loss etc. Hypovolemic hyponatremia is not possible without free water intake which can be iatrogenic or spontaneous. So if we give 1/2 normal saline to these patients we will likely cause hyponatremia. |
|
What is hypervolemic hyponatremia?
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Classic is CHF.
High ADH due to decreased “effective” arterial volume Free water intake will cause hyponatremia. |
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What is euvolemic hyponatremia?
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High ADH due to non-osmotic/non-volume stimulus
eg. SIADH |
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SIADH is often associated with...
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bronchogenic carcinoma
Pulmonary disorders (decreased lung compliance with increased ADH) CNS disorders (seizures; increased IP; meningitis) Infectious diseases (HIV) Drugs (stimulate ADH secretion) |
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How does SIADH work?
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Primary increase in ADH
Increase in plasma volume. Increase in Na excretion. Hyponatremia results from the combination of decreased free water excretion and free water intake. Definition of SIADH: Sustained increase in ADH secretion not due to changes in plasma osmolality or arterial volume and with normal endocrine and renal function. |
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What is the effect of hyponatremia on cells?
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They swell.
Cerebral swelling causes: Altered mental status Siezures/irreversible brain damage/death Falls (in elderly) Hyponatremia also correlates with: Increased mortality Osteoporosis |
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How do we treat hyponatremia?
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Restrict free water intake.
Treat volume disturbance. 3% NaCl for patients with altered mental status. V2 receptor antagonist for chronic hyponatremia. |
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What are the different ADH (vasopressin) receptors?
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V1 causes vasoconstriction
V2 controls water reabsorption V2 is on the antiluminal surface providing access to circulating hormone. The second messenger for V2 is adenyl cyclase and the mediator of the effect is aquaporin (AQP2), a protein that when inserted into the lulminal membrane functions as a water channel. |
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What does the protein aquaporin 2 do?
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Opens pores in membranes that allow the passage of free water.
Vasopressin controls the amount of water that passes through distal tubular cells by controlling the number of aquaporin-2 proteins inserted in the cell membrane. |
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What is nill disease? (aka minimal change disease)
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A glomerular disease in which the foot processes lose their glycoprotein.
Called nill didease because there are no gross changes. EM shows the abnormality of the podocytes though. Proteinuria and eventually nephrotic syndrome. Can be treated with steroids. (likely immune mediated) |
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What are the three components of nephrotic syndrome?
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Proteinuria (>3.5g/day)
Edema Hypoalbuminemia |
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Why is it significant that mesangium cells are contractile to some degree?
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When vasoconstrictors are released, the mesangium constricts too and this makes less surface area available for filtration.
|
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Ions of which charge are more readily filtered?
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Cations
Anions are repelled by the negatively charged podocytes. |
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What happens to the permselectivity of the membrane in nephrotic syndrome?
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Loss of negative charge on filtration barrier.
This lets albumin through. |
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What is the end result of chronically elevated glomerular pressure?
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Fibrosis.
|
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What is acute post-infectious glomerulonephritis?
|
Often occurs after steptococcal infection.
(most studied is redlake strain) Streptococcal infection can result in deposition of complement and complexes tha damage GBM. Protein and RBC can be found in urine. |
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What happens in diabetic nephropathy?
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Deposition of various complexes on GBM causes damage, protein leak, apoptosis and glomerulosclerosis.
GFR decreases. Similar process in Lupus Nephritis except that the deposition is largely immunologic. |
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What forces govern ultrafiltration?
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Hydrostatic pressure favors it.
Oncotic pressure opposes it. (this is the main thing that changes form the afferent to the efferent end of the glomerular capillary) |
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What happens if oncotic pressure rises enough to equal hydrostatic pressure in the glomerulus?
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Ultrafiltration equilibrium.
No net ultrafiltration occurs. |
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What are the disadvantages of inulin for measuring clearance?
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Assay not widely available,
may cause allergic reactions, must be infused at constant rate i.v. for several hours. Other available markers that are not secreted absorbed or metabolized by the kidney: I131-Iothalamate, EDTA, Creatinine (endogenous), Cystatin - C, |
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The units for clearance are...
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ml/min
MUST include a time unit. |
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What is the central premise of the clearance concept?
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Filtered amount=Excreted amount because it is not reabsorbed secreted or metabolized.
Clearance=Volume of Plasma Completely “Cleared” of Z per Unit Time. GFR=UV/P Clearance=UV/P |
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How do we use creatinine clearance to calculate whole kidney GFR?
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P(cr)xGFR=U(cr)xV
Clearance =UV/P |
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How do we estimation GFR from serum creatinine by Cockcroft-Gault formula?
|
Males:
GFR= [(140-Age)*lean BW]/(Serum creatinine*72) Females: GFR=male value*0.85 |
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What is the relationship between creatinine clearance and GFR?
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Reverse hyperbolic.
Biggest changes occur with a GFR< 80 |
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What is a major limitation of the MDRD equation?
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Very accurate but only works for sick patients.(GFR<60 or so)
Variables: serum creatinine • age • sex • African American or not |
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What are the ethnic disparities in risk for kidney failure?
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Risk compared to caucasians:
African Americans 3.8 X Native Americans 2.0 X Hispanics 1.5X Asians/Pacific Islander 1.3X |
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Why are ARB's and ACE inhibitors useful in slowing the progression of chronic kidney disease?
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Selectively dilate the efferent arteriole and thus reduce glomerular pressure and fibrosis.
|
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How can we physically measure renal blood and plasma flow?
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Electrical:
Electromagnetic flowmeter Doppler / ultrasonic flowmeter Chemical: Use of a chemical marker (Fick principle) |
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Why is PAH ideal for kidney fick principle calculations?
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It is cleared in one pass so we don't need to measure venous content.
Equation is thus: Clearance of PAH= (Urinary excretion of PAH)/(PAH plasma conctration) Clearance of PAH and similar substances provides an approximation of renal plasma flow. |
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What endogenous compounds and drugs are secreted in the proximal tubule?
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Anions:
cAMP, bile salts, oxalate, PGs, urate penicillin, most diuretics, salicylates, PAH, probenecid Cations: creatinine (slightly) DA, NE, epinephrine cimetidine, morphine, amiloride, quinidine, procainamide |
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What substances are constrictors in the kidneys?
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Adenosine
Angiotensin II Endothelin Norepinephrine Vasoconstrictor PG |
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What substances are dilators in the kidneys?
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Bradykinin
Nitric oxide Vasodilatory prostaglandins |
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What do we mean by tubuloglomerular feedback?
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In response to sodium chloride delivery, the tubular system signals the glomerulus through the macula densa cells of the JGA .
This can regulate glomerular pressure by altering afferent arteriolar resistance. |
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Why are NSAIDS potentially bad for the kidney?
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They block the production of the vasodilatory prostaglandins.
|
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Most potassium is kept...
|
Intracellularly (~150mEq/L)
Extracellular compartment ~4mEq/L Concentration create a logarithmic effect on membrane potentials so small changes have a big effect. |
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How is K homeostasis maintained?
|
Cellular distribution
Renal excretion (90%) GI excretion (10%) Normal diet consumption is ~100mEq/day |
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What three things greatly influence potassium distribution?
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Insulin
Catecholamines Acid-Base status |
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What is the effect of insulin on potassium?
|
Insulin binding to its receptor causes hyperpolarization of cell membrane which facilitates K uptake. It also activates Na-K-ATPase.
Pumping K into cells requires a lot of energy because it happens against such a large gradient. |
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What effect does somatostatin have on potassium?
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Blocks insulin release and thus causes an increase in ECF potassium.
|
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How do catecholamines (namely beta agonists) affect potassium?
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Increase cellular cAMP which increases the activity of Na/ATPase and allows more K to be pumped into the cells.
Propranolol and other beta blockers have the opposite effect and will cause higher plasma potassium concentrations. |
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The relationship between acidosis and potassium is that..
|
Acidosis=hyperkalemia.
Intracellular K is exchanged with hydrogen ions in an attempt to equilibrate with plasma pH. 0.6 mEq/L ↑K per 0.1 ↓ pH (not tested) |
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What is the MAJOR potassium regulating cell in the kidney?
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Principal cells in the collecting duct.
|
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What channels move potassium in the principal cell?
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Interstitial side:
Na potassium ATPase brings potassium into the cell. Potassium also moves from the cell into the interstitium passively. Luminal side: As sodium is reabsorbed from the lumen, potassium diffuses across to balance the relatively negative luminal charge. These channels are affected by aldosterone. |
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What is the net effect of aldosterone on the potassium and sodium?
|
Increased urinary sodium absorption
Increased urinary potassium secretion This makes sense as aldosterone is released when we are hypotensive and trying to maintain volume status. |
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How does sodium delivery to the distal part of the kidney influence potassium?
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A lot of sodium means more exchange and therefore more potassium secretion.
Furosemide which enhances distal sodium delivery be inhibiting uptake more proximally will cause increased potassium secretion. (hypokalemia) |
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How does a high serum potassium influence potassium secretion in the principal cells?
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Hyperkalemia means high interstitial potassium and influences the cell to secrete more potassium towards the lumen.
|
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How does urinary flow rate influence potassium secretion?
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Increased flow rate means more potassium secretion.
|
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So in summary, what influences kidney potassium secretion?
|
Mineralocorticoid activity (Major)
Distal delivery of Na (eg Lasix) Tubular flow rate (eg. oliguric ATN) Total body K |
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What are the signs and symptoms of hypokalemia?
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Muscle weakness, even paralysis
Cardiac arrhythmias Rhabdomyolysis Renal manifestations – impaired concentrating ability causing polyuria Ileus Hyperglycemia EKG changes: -decreased amplitude or inversion of the T wave - increased amplitude of the U wave - prolongation of the Q-U interval |
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What are some possible etiologies of hypokalemia?
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Movement into cells:
Too much insulin. Stress. K loss: Diarrhea Kidney issues Hyperaldosteronism etc. (urine potassium >20 is worrisome) |
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Why do we give magnesium in hypokalemia?
|
To preserve potassium
|
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What is the benefit of potassium citrate as a form of replenishing potassium?
|
Not commonly used but:
We use this in acidosis because the citrate can be used by the body to produce bicarbonate. Can also be used in kidney stones with low citrate. |
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What are the etiologies of hyperkalemia?
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Cells:
Acidosis Cell lysis β-blocker Digitalis overdose Urine: Renal failure Hypoaldosteronism K-sparing diuretics |
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What are the signs of hyperkalemia?
|
Muscle weakness, even paralysis (secondary to depolarization)
Cardiac arrhythmias (ventricular fibrillation, standstill) |
|
What are the EKG changes of hyperkalemia?
|
-increased amplitude of T wave with shortened Q-T interval
-widening of QRS complex, -decreased amplitude of P wave with eventual loss of P wave |
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How do we treat hyperkalemia?
|
Reversible depolarization:
Calcium infusion (1-3 minute onset) Shift K into cells: Insulin (15-30minutes) NaHCO3 infusion (15-60minutes) Beta agonist (30 minutes) Remove potassium: Kayexalate (1-2hours) Furosemide (start of diuresis) Hemodialysis |
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How does calcium infusion help in hyperkalemia?
|
Raises the threshold potential of the cells and decreases the risk of fatal arrhythmia.
|
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Why does volume depletion cause hyperkalemia?
|
Low tubular flow means less sodium in the distal tubule and thus difficulty secreting potassium.
|
|
What are the major classes of diuretics by nephron site of action?
|
Proximal tubule:
Carbonic anhydrase inhibitors Osmotic diuretics Thick ascending loop of henle: Loop diuretics Distal convoluted tubule: Thiazides Cortical collecting duct: K sparing diuretics Collecting duct: Vasopressin receptor antagonists |
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What are the MOA's of the two proximal tubule diuretic classes?
|
Carbonic anhydrase inhibitors:
Shuts down bicarbonate reabsorption in the proximal tubule. (~80% of total bicarbonate reabsorbed in the nephron) Osmotic diuretics: Eg. Mannitol Agents that draw in fluid by osmotic potential in the proximal tubule. In diabetics, glucose does this and explains the polyuria and polydypsia. Both can be limited or compensated for somewhat by the distal segments of the nephron. |
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What are the MOA's of the two proximal tubule diuretic classes?
|
Carbonic anhydrase inhibitors:
Shuts down bicarbonate reabsorption in the proximal tubule. (~80% of total bicarbonate reabsorbed in the nephron) Osmotic diuretics: Eg. Mannitol Agents that draw in fluid by osmotic potential in the proximal tubule. In diabetics, glucose does this and explains the polyuria and polydypsia. Both can be limited or compensated for somewhat by the distal segments of the nephron. |
|
What is acetazolamide (diamox)?
|
Carbonic anhydrase inhibitor.
Sulfanilamide prototype with –SO2NH2 excretion of Na, HCO3 and K ↑; Cl ↔ alkaline urine and systemic acidosis Use: ↑urine pH (aspirin intoxication), Helps ASA clearance. Usually given with bicarbonate. Correct severe metabolic alkalosis in patients with CHF, glaucoma, epilepsy, mountain sickness. Occasionally to potentiate other diuretics. S/E, limitations: allergy, tolerance, metabolic acidosis because it favors alternate H+/HCO3- pathways. |
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Why is it important that diuretics and other drugs much like PAH are secreted in the proximal straight tubule?
|
Loop diuretics and thiazides work form the lumen side and not the blood side and they have to get to the lumen to do this.
|
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What is the MOA of loop diuretics like furosemide?
|
Loop diuretics specifically
inhibit NKCC2, a sodium 2 chloride potassium transporter in the TALH. Less sodium transport, less water reabsorption. One of the secondary implications of the mechanism is that K is driven out into the lumen through the ROMK channel. This creates a luminal charge which then drives paracellular diffusion of calcium and magnesium. The end result is that loop diuretics can also cause hypomagnesemia and hypocalcemia along with Na, Cl, K and water depletion. |
|
What are some commonly used loop diuretics?
|
Furosemide (Lasix®),
bumetanide, torsemide, ethacrynic acid (oldest) mainstay treatments in kidney disease with ↓eGFR (CHF, edema), hypertension, pulmonary edema, hypercalcemia. Used alone or combined with other diuretics |
|
What are the side effects and limitations of loop diuretics?
|
short action,
volume depletion, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalcemia, hyperglycemia, hyperuricemia, may cause hyponatremia*. All but EA are sulfa derivatives – allergy potential Ototoxicity, esp with aminoglycosides and higher with EA |
|
What is the MOA of thiazides?
|
Inhibit NCCT in DISTAL convoluted tubule.
|
|
What are some commonly used thiazides?
|
Hydrochlorothiazide [HCTZ]
chlorthalidone indapamide metolazone Sulfonamide derivatives do have minor CAI activity and ↑bicarbonate excretion Slight renal vasoconstriction limits use below GFR <30 ml/min Ca retention especially with chronic use. (opposite of loop diuretics) |
|
What are thiazides used for?
|
Use:
First-line drug in hypertension, edema, ± other diuretics, hypercalciuria, nephrogenic DI. Several drugs are long acting and can be given 1x/day. S/E, limitations: hypokalemia, hyperglycemia, hyperuricemia, metabolic alkalosis, volume depletion Potential allergy to sulfas |
|
Why should thiazides decrease Ca+2 excretion while loop diuretics increase Ca+2 excretion ?
|
Loop diuretics in the TALH prevent the generation of a positive potential in the lumen which is what drives reabsorption of calcium and magnesium.
In the distal nephron, the opposite occurs. Inhibition of the transporter enhances calcium entry. |
|
What channels are responsible for exchanging sodium and potassium between the principal cell and the lumen?
|
Sodium from lumen into cell-ENac
K from cell into lumen-ROMK |
|
What factors influence DISTAL regulation of K excretion?
|
Aldosterone
Na delivery to the distal tubule Potential difference (lumen negative voltage) across the tubule Tubular fluid flow rate |
|
What do drugs like amiloride block?
|
ENac
There is thus less activity of ROMK even though it is not actually blocked. |
|
What is the effect of aldosterone on the principal cell?
|
Opens ENac
Enhances Na/K ATPase Overall, it encourages potassium secretion by enhancing sodium absorption. Adrenal tumor patients will often thus have hypokalemia. |
|
What are amiloride and triamterene?
|
K sparing
Do not depend upon aldosterone antagonism; Drugs are effective in adrenalectomized patients. Decrease luminal Na entry by blocking the ENaC on the apical membrane of the CCT. Weak natriuretic agents alone but useful in combination with other natriuretics to potentiate Na loss and reduce K loss. Often useful in treating “refractory” edema. !!Hyperkalemia possible!! |
|
What is spironolactone?
|
K sparing
Gynecomastia May be effective in low renin-low aldosterone hypertension, perhaps because of inhibition of aberrant mineralocorticoid other than aldosterone, or through mineralocorticoid-like receptors in the brain. |
|
If ion transporters are expressed in other epithelia, why are diuretics relatively selective for the kidney?
|
specific renal transporters are targets, most on apical membrane, and level of expression in kidney is high.
Drug concentration is higher in the kidney: Filtration of free vs. bound drug Secretion of drug stripped of binding protein. Luminal conc. ↑ by Na, water reabsorption Filtered albumin [nephrotic syndrome] can re-bind diuretics and ↓effect |
|
Why may loop and thiazide diuretics cause hypokalemia?
|
Increased delivery of Na, water, sometimes HCO3- (only with acetazolamide) to distal nephron enhances K secretion.
Volume depletion leads to secondary hyperaldosteronism Better dietary Na control means less diuretic required means less distal nephron Na delivery and therefore less K loss and hypokalemia. |
|
How may loop and thiazide-like diuretics cause metabolic alkalosis?
|
Diuretics increase distal Na delivery:
Increased Cl loss (relative to bicarbonate as an anion) Increased K loss (eventually transcellular K/H exchange also contributes to lower pH) Increased H loss (distal Na delivery and aldosterone contribute) Decreased ECV (Increased aldosterone to increase K, H loss) Hypokalemic, hypochloremic alkalosis corrected with KCl replacement. |
|
How does physiological compensation limit diuretic effects?
|
Increased downstream reabsorption may reduce the effect of more proximally acting drugs
(e.g., CAI are weak natriuretics) Increased proximal reabsorption can compensate for more distally acting drugs (e.g., ↑ proximal reabsorption in response to ECV contraction produced by loop or DT-acting drugs) Dietary salt intake |
|
What is a V2 receptor antagonist (aquaretic)?
|
The V2 receptor mediates the antidiuretic response of ADH.
The vasopressin receptor antagonists produce selective water diuresis without affecting sodium and potassium excretion. Will correct hyponatremia in SIADH. |
|
What are the V2 receptor antagonist drugs?
|
oral:
tolvaptan satavaptan lixivaptan Selective for V2 receptor. IV: conivaptan blocks both the V2 and V1a receptors. Tolvaptan and conivaptan are currently available in the United States |
|
Summarize the complications of diuretics.
|
Proximal Diuretics
(Carbonic Anhydrase Inhibitors): Hypokalemia, metabolic acidosis Distal Tubule Diuretics (NCCT inhibitors): Volume depletion, hypokalemia, metabolic alkalosis, hypercalcemia Loop Diuretics (NKCC-2 inhibitors): Volume depletion, hypokalemia, metabolic alkalosis, hypocalcemia, hypomagnesemia K+-Sparing Diuretics: (amiloride, triamterene, spironolactone) Hyperkalemia (especially with CKD), metabolic acidosis Spironolactone: gynecomastia, impotence, menstrual abnormalities (endocrine effects of non-selective MC antagonist) |
|
What is Gitelman’s Syndrome?
|
Loss of NCCT Function at the level of the distal tubule.
Symptoms are just like thiazide overdose: Renal salt wasting Hypokalemia Met. alkalosis Volume depletion Low BP All have salt craving. Inverse relationship between salt intake and BP. Higher salt intake in these patients associated with lower BP. |
|
What is Liddle’s syndrome?
|
Volume Expansion
Hypertension Hypokalemia Metabolic Alkalosis Cause: Inherited gain of function mutation of ENaC Example of monogenic hypertension Respond to amiloride and triemterine. |
|
What is the single best test for the evaluation of renal function?
|
Urinalysis
|
|
Cloudy urine is usually a sign of...
|
UTI
|
|
When do we preform a UA?
|
Sports physical
First complete history and physical Initial evaluation of hypertension Any systemic disease with renal involvement |
|
How do we obtain the best urine specimen for analysis?
|
First morning void
Adequate cleansing without betadine Examine ASAP For micro: collect 5-10 ml spin @ 2000 rpm for 5 min pour off all but 0.5ml and re-suspend gently |
|
UA dipstick tests for...
|
Nitrite
Glucose Heme pigment Protein Leukocyte esterase Bilirubin |
|
What can cause + heme pigment in the urine?
|
hemolysis
rhabdomyolysis (heme from myoglobin with no RBC's) hematuria |
|
How much protein needs to be in the urine to be called nephrotic proteinuria?
|
>3g/day
Suggests a glomerular disorder Small amount of urinary protein can occur from the tubule (< 3 g/day) |
|
What is an RBC cast?
|
Conglomeration of red cells in the shape of a tubule. Cells can be mad out in the cast.
Waxy casts are clear and seen in advanced kidney disease. |
|
Coca cola colored urine is a term associate with...
|
Glomerulonephritis
|
|
What is a WBC cast?
|
A cast made of white cells.
Associated with interstitial nephritis (inflammation) or with pylonephritis (kidney infection). Interstitial nephritis should also have eosinophils in the urine. |
|
What is a granular cast?
|
Ischemia cause pieces of tubule to slough off as coarse granular casts.
(Acute tubular necrosis) |
|
What is a hyaline cast?
|
Seen in the normal urine.
|
|
Where do we find waxy casts?
|
In the urine of advanced kidney failure patients.
|
|
What is an oval fat body?
|
Fat droplets seen in the tubular cells of the nephrotic syndrome.
Can also form casts. |
|
Oval fat body cast
|
|
|
Oval fat body cluster
|
|
|
The most common kidney stones are made of...
|
Calcium oxalate crystals
|
|
Rhomboid shaped crystals in the kidneys are usually made of...
|
Urate
|
|
Triple phosphate crystals are made of...
|
Magnesium, ammonium phosphate.
Only seen with UTI. (infected stones) Most common in the elderly. Coffin lid shaped. |
|
How do we localize renal failure?
|
Prerenal:
High Bun/Cre ratio Concentrated urine, Hyaline casts eg. volume depletion Intrinsic renal-Glomerular: Proteinuria Frequent hematuria (RBC Casts) eg. Post-streptococcal glomerulonephritis Intrinsic renal - Interstitial or Tubular: WBC’s on UA or granular casts eg. Rhabdomyolysis or Interstitial nephritis. Postrenal: Bland UA Eg. obstruction Consider foley or ultrasound |
|
Chronic renal failure is characterized by..
|
History of hypertension
History of high serum creatinine History of proteinuria Small kidneys on ultrasound Usually do not respond all that well to treatment. |
|
Acute renal failure is characterized by...
|
No history of hypertension
Active urinary sediment frequently ***Most likely to respond to treatment Normal sized kidneys Must be treated emergently. |
|
Nitrite on a UA dipstick can detect white cells by...
|
Nitrite
Leukocyte esterase |
|
Why is UA so important in HIV patients?
|
Red cell casts=RPGN
Lot of protein only=HIV nephropathy Granulocasts= Acute tubular necrosis (HIV patients particularly susceptible) |
|
What is the pathology of benign nephrosclerosis?
|
Associated with benign (essential) hypertension
Often superimposed on other primary kidney diseases Arteries and arterioles are involved Symmetrical small, atrophic kidneys Diffuse fine granularity on the surface Cortical scarring and shrinking of renal tissue |
|
What is the histology of benign nephrosclerosis?
|
Hyaline arteriolosclerosis:
Thickening of walls of small arteries and arterioles Medial hypertrophy and intimal thickening Homogenous, pink hyaline material Narrowing of vessel lumen Decreased blood flow → ischemia Global glomerular sclerosis Tubular atrophy with interstitial fibrosis |
|
What causes malignant HTN?
|
Uncommon compared to essential HTN
Untreated essential hypertension Withdrawal or non-adherence to anti-HTN therapy Underlying presence of renal artery stenosis Autoregulation failure: Markedly elevated levels of plasma renin Self perpetuating cycle Increased Angiotensin II → intrarenal vasoconstriction → renal ischemia → increased renin secretion Increased permeability of small vessels to fibrinogen and other plasma proteins (like complement 3b) Endothelial damage with platelet deposition. !Fibrinoid necrosis! of arterioles Intravascular thrombosis Intimal smooth muscle hyperplasia |
|
Fibrinoid necrosis with HTN makes us think...
|
Malignant HTN.
Kidneys are usually normal sized. Hyperplastic arterioles Glomerular sclerosis |
|
hyaline arteriolosclerosis with HTN makes us think of....
|
Benign nephrosclerosis
|
|
What is TTP-HUS syndrome?
|
Acute syndrome with multiple organ involvement.
Difficult to clinically distinguish between TTP and HUS. Acute neurological manifestation is dominant with TTP. Acute renal injury is dominant with HUS. In children: HUS is often associated with E.coli (O157:H7) related diarrhea |
|
How is VWF synthesized?
|
VWF synthesized by endothelial cells
Assembled in large multimers called unusually large VWF (ULVWF) Cleaved to normal sized VWF in circulation by ADAMTS 13 |
|
What are the pathogenesis mechanisms of TTP-HUS?
|
Acquired defect in VWF
Defective ADAMTS13 Inhibitory antibody to ADAMTS13 |
|
TTP-HUS is clinically associated with...
|
Shiga toxin producing E.Coli infection
Quinine use Cancer and chemotherapy with mitomycin C, cisplatin, bleomycin Hematopoietic cell transplantation Pregnancy and oral contraception Immunosuppressive drugs like cyclosporine Anti-platelet drugs like clopidorgel (Plavix) HIV infection Antiphospholipid syndrome- lupus Post cardiovascular surgery |
|
Pathologic changes of HUS in the kidney include...
|
Thrombotic microangiopathy
Fibrin thrombi: Glomerulus Arterioles Cortical necrosis Chronic scarring of glomerulus |
|
What are secondary causes of malignant HTN?
|
Pheochromocytoma
Renovascular HTN |
|
What is calcium important for?
|
Bone formation
Cell division and growth Blood coagulation Intracellular messaging |
|
How is calcium distributed?
|
99% bone
1% intracellular 0.10% extracellular Total calcium = protein-bound calcium + ionized calcium + complexed calcium Normally: 45% protein bound 50% ionized 5% complexed |
|
What factors affect serum calcium?
|
Albumin binding
(most important) Other protein binding pH |
|
How do we calculate corrected serum calcium?
(VERY important) |
[(4 – serum albumin) x .8]
+ serum calcium |
|
What releases calcium from bone?
|
PTH or Calcitriol
PTH also inhibits renal excretion of calcium. |
|
In the absence of PTH calcitriol and vitamin D, serum calcium would be...
|
Quite low (about 4mg/dL)
Normal serum calcium is about 8-10mg/dL. |
|
Where does most calcium reabsorption occur?
|
Proximal tubule.
Some in the TALH. |
|
How much sunlight is needed to make cholecalciferol?
|
Depends on skin color
Depends on latitude |
|
Where in the diet do we get Vitamin D?
|
Concentrated source:
liver of cold water fishes Supplementation in milk |
|
What is the activated form of vitamin D?
|
Vit D converted to 25 hydroxy Vitamin D in the liver
(not rate limiting) Calcitriol – made by conversion of 25 OH D to 1,25 OH D in proximal tubular cells of the nephron mediated by 25 hydroxy Vitamin D 1-alpha hydroxylase. So in kidney disease patients are missing 1, 25 bot not 25 form. |
|
What is the role of calcitriol? (1,25 form of vitamin D)
|
Steroid Hormone
Increases intestinal calcium absorption Increases intestinal phosphate absorption Increases calcium and phosphate absorption from bone |
|
What does vitamin D do to PTH secretion?
|
Decreases it.
|
|
What cells have PTH receptors?
|
Osteoblasts
!NOT osteoclasts! (Stimulate osteoclast resorption) Renal effects occur in the distal tubule: Stimulates calcium reabsorption Stimulates phosphorus excretion. So, PTH increases calcium and decreases phosphorus. If someone has a high serum calcium we check serum phosphorus: If serum phosphorus is low, PTH problem. If both calcium and phosphorus are high, we think vitamin D (calcitriol) |
|
What does hyperparathyroidism do?
|
Reabsorb calcium from the bones.
Blood calcium goes up, Blood phosphate goes down (excreted in urine). |
|
Where is most phosphorus reabsorbed?
|
The proximal tubule.
|
|
Ordinarily, what is the distribution of phosphorus?
|
86% in bone
14% intracellular .03% extracellular |
|
What does the hormone fibroblast growth factor 23 do?
|
Decreases proximal tubular phosphate reabsorption.
Decreases 1,25 hydroxy vitamin D production. Decreases PTH secretion. Tumors that produce this cause: Tumor induced osteomalacia Hypophosphatemia Phosphaturia Very low 1,25 OH Vtiamin D3 |
|
Stage III renal failure occurs at a GFR of about...
|
30-60
Leads to: DECREASED URINARY PHOSPHORUS EXCRETION DECREASED CALCITRIOL PRODUCTION Less calcitriol means more PTH becaus it acts as a chill pill in the parathyroid gland. |
|
In summary, the three things we get in chronic kidney disease are...
|
Decreased phosphorus excretion
Decreased 1,25 OH Vit D (calcitriol) Increased Parathyroid Hormone |
|
How do we treat chronic renal failure?
|
Treat Hyperphosphatemia:
Decrease phosphorus in diet (colas, dried beans, dairy products) Use phosphorus binders with meals.(Calcium carbonate, calcium acetate, sevelamer or lanthanum) Remove phosphorus with dialysis In addition: Give calcitriol or calcitriol analogs to make up for loss of calcitriol synthesis. Give cinacalcet to bind to calcium sensing receptor of parathyroid gland. |
|
What is guyton’s theory of hypertension?
|
Hypertension is a disorder of volume regulation caused by an impairment in renal sodium excretion.
Increased volume causes increased CO which is compensated for by an increase in peripheral resistance. Result is hypertension with normal CO which increases GFR and reduces ECF volume to near normal. High peripheral resistance remains though. |
|
What are the two main categories of essential hypertension?
|
salt sensitive or salt resistant
|
|
How do diuretics like thiazides help salt sensitive HTN besides lowering BP overall?
|
Straightens the curve somewhat and makes them "less" salt sensitive.
Recovery is diveded into phases which are a reverse mirror image of the Guyton theory. |
|
What are the two most common cause of secondary hypertension?
|
Renal artery stenosis (Goldblatt hypertension)
Primary Hyperaldosteronism |
|
Stenosis of the renal artery leads to...
|
Decreased afferent arteriolar pressure.
Increased renin-angiotensin-aldosterone system activity. (anti-natiuretic) Increased sodium and water retention. Right shift of pressure diuresis curve. Renovascular (goldblatt)Hypertension. Usually NOT salt sensitive. |
|
Primary hyperaldosteronism as in an adrenal adenoma leads to...
|
Increased Renal tubular sodium reabsorption.(ENaC)
Right shift in pressure diuresis curve. HTN Patients with primary aldosteronism are “ salt sensitive”, whereas those with renovascular hypertension are not. Can be teated with spironolactone and friends. |
|
What monogenic defects in tubular Na absorption are associated with essential hypertension? (not crucial)
|
Increased proximal Na,K ATPase activity (α-adducin gene)
Increased epithelial Na channel (ENaC) activity (Liddle’s Syndrome) Increased distal NaCl reabsorption (WNK kinase) (Pseudohypoaldoseronism Type II) Glucocorticoid remediable aldosteronism (GRA) Polygenic defects are thought to be associated with: Loci 2q, 5q, 9q |
|
What acquired defects are thought to possibly be related to essential hypertension?
|
Decreased nephron number (developmental defect in utero)
Primary intrarenal vascular disease Subtle renal injury induced by: hyperactive SNS stimulated renin-angiotensin low K diet hyperuricemia |
|
In summary...
|
All chronic hypertension is caused by a defect in renal Na excretion.
“essential hypertension” in humans is due to genetic and/or acquired defects in renal Na excreton Most effective antihypertensive drugs lower blood pressure by returning the “pressure-diuresis curve” toward normal i.e. correcting the defect in renal Na excretion. |
|
What is the problem with pure vasogenic antihypertensive drugs like alpha blockers?
|
Lowering blood pressure without shifting the pressure diuresis curve causes sodium retention. (lowered perfusion pressure)
The retention will cause volume increase and "escape" for the effect of the drug. |
|
A good rule of thumb for urine output is ~
|
0.5cc/kg/hour
|
|
Most dilute possible urine is...
|
~50mOsm/kg
Highest concentration is ~1200mOsm/kg Anything over 280 means water retention because normal serum is ~280mOsm/kg. |
|
A Urine specific gravity of 1010 in the urine correlates with a urine osm of about ...
|
280-300
Higher specific gravity means higher osm. |
|
What is in a bag of normal Saline? (NS)
|
0.9% (0.9g/dL) or 308osm(154mEq/L)
1 L bag is ~9g |
|
When we give fluids in SIADH, we must make sure that the fluid concentration in osms is higher than....
|
Urine osms.
|
|
What does pitting edema tell us about salt?
|
Too much salt
|
|
Hypernatremia means...
|
Free water deficit.
|
|
What are the two types of dibetes insipidus?
|
Central
(not making ADH in brain) Nephrogenic (kidney not responding to ADH) |
|
What constitutes microscopic hematuria?
|
Anything >2-3 RBC/Hpf
Dysmorphic cells and RBC casts usually means glomerular rather than extraglomerular origin such as ureters, prostate, bladder etc. |
|
Transient hematuria often occurs in the setting of...
|
UTI, Trauma, Fever
Older Age makes for less benign DX in both transient and persistent hematuria. |
|
Hematuria with dysuria and pyuria suggests...
|
UTI
|
|
Hematuria with history of recent infection suggests..
|
PIGN
|
|
Hematuria with family history of chronic kidney disease may suggest...
|
Genetic disease like Alport's
|
|
What is the differential for persistent isolate hematuria?
|
Ig A nephropathy
Hereditary Nephritis Thin basement membrane nephropathy |
|
What is nephritic syndrome?
|
Active urinary sediment
Inflammatory process: RBC casts, Dysmorphic RBC Proteinuria (1-3 grams; not as high as nephrotic syndrome) HTN Edema (Increased Na avidity of tubules) ARF |
|
What are the most common etiologies of nephritic syndrome?
|
PIGN (post infectious GN)
Ig A nephropathy (Most common GN worldwide) Hereditary Nephritis MPGN |
|
What are the most common causative agents of post-infectious glomerulonephritis?
|
!!Strep.!!!
Viral, Mycoplasma, S. Aureus, Strep Pneumo Most common in children 2-14 yrs old. 2:1 Male/female |
|
Period of latency before onset of PIGN in strep throat is about...
|
2 weeks
~4 weeks for skin strep infections. Infection often resolved on nephritic presentation |
|
How does post-streptococcal glomerulonephritis present?
|
SX:
Hematuria (tea colored) Oliguria Edema, HTN U/A: RBC and RBC casts Variable proteinuria Labs: Low Complement (C3) in > 90% Positive Streptozyme in > 80 % Acute Renal failure (elevated serum Bun, Cr) |
|
What causes post-streptococcal glomerulonephritis?
|
Immune process with complemnt involvement.
|
|
Biopsy is definitive diagnosis for PSGN. What do we see?
|
Diffuse proliferation in mesangium
Enlarged tuft PMN (exudative GN) C3, Ig M deposits most prevalent On immunofluorescence, one of three patterns: Mesangial pattern Starry-sky pattern (Deposits in mesangium and capillary loops) Garland pattern (Deposits in capillary loops) On EM: Subepithelial hump shaped deposits. |
|
How do we treat PIGN?
|
Supportive
Fluid, diuretics, dialysis if necessary. Prognosis is good |
|
What is IGA nephropathy (Buerger's disease)?
|
Mesangial deposits of underglycosylated IgA1
Most common GN worldwide Male:Female 3:1 Uncommon in African Americans Peaks in 2nd-3rd decade of life |
|
What causes IGA nephropathy (Buergers disease)?
|
Majority idiopathic
but Secondary causes include: RA Inflammatory Bowel DZ Ankylosing spond. Cirrhosis Psoriasis Dermatitis herpitiformis |
|
What are the clinical findings of IgA nephropathy?
|
Persistant hematuria
Synpharyngitic hematuria (1-3 day after viral illness) Usually < 1 gram proteinuria HTN/renal failure not present at time of DX Normal Serum Complement level |
|
What is the pathology of IgA nephropathy?
|
Elevated Ig A level:
Abnormal production by mucosa (Skin, GI tract) Defective handling by Kupfer cell in liver. Light Microscopy: Diffuse mesangioproliferative changes Mesangial hypercellularity Incresaed Matrix EM: mesangial deposits. |
|
What are prognostic factors for IgA nephropathy?
|
20% reach end stage renal disease in 20 years.
Gross hematuria actually carries a favorable prognosis HTN, older age , heavy proteinuria, and renal failure carry higher risk of progression Gender, Serum Ig A levels, intensity of deposits have NO impact on prognosis. |
|
How do we treat IgA nephropathy?
|
ACEI/ARB for proteinuric patients
Fish oil (Decrease production of cytokines) Immunosuppression (aggressive/progressive disease) Tonsillectomy (Lessens episodes of gross hematuria) |
|
What is Henoch-shonlein purpura(HSP)?
|
Pathogenesis similar to Ig A disease.
Systemic vasculitis with Ig A deposits in the: GI tract (Belly pain) Renal Tissue (hematuria) Skin (rashes) Common in children with more skin manifestations (rashes on extensor surfaces of lower extemities) Adults tend to have more renal involvement More common in winter Overall good prognosis with majority recovering normal renal function |
|
What is hereditary nephritis(Alport’s syndrome)?
|
Inherited progressive glomerular disease
Often associated with Hearing loss Ocular abnormalities Mode of inheritance: X-linked 80% AR 15% AD 5% Absence or abnormal distribution of Alpha-3,4,5 chains of type IV collagen found in eye, kidney and cochlea. Mutations in COL4A5 gene on X chromosome accounts for 80% of affected patients. AR arises from mutation in COL4A3, COL4A4 |
|
What are the typical clinical findings of Alport's syndrome (hereditary nephritis)?
|
Young male (< 10 years)
Persistant microscopic hematuria & deafness May have occular abnormalities HTN/Proteinuria develops later in the course > 90 % reach ESRD by Age 35 Carrier state: female with much less aggressive disease, variable presentation, 12% ESRD by Age 40 |
|
How do we diagnose Alport's syndrome?
|
Triad of RF/Deafness/Family HX
Renal biopsy, confirmatory: !!Laminated Basement Membrane on EM!! Immunostaining of Type IV collagen Skin BX: Commercial assay of Ab to alpha-5 chain of type IV collagen Absence of staining is diagnostic Genetic testing available for prenatal DX or absolute exclusion of carrier state |
|
How do we treat Alport's?
|
Conservative measures:
ACEI/ARB BP control Cyclosporine No convincing data Risk out weights the benefit Renal transplant: 3-5% of patient develop de novo Anti-GBM dz Males with X-linked type Ab to A-5 chain Nevertheless NOT a contraindication to transplant |
|
What is Thin Basement membrane nephropathy (TBMN)?
|
Benign Familial hematuria
Microscopic hematuria minimal proteinuria, No HTN Affects at least 1% of the population 2/3 will have FH of hematuria A lifelong nonprogressive disorder associated with family history uniform thinning of the GBM |
|
What is Membranoproliferative GN(MPGN)?
|
A waste basket of diseases with three subcategories.
Primary: Type I: (30% progressive disease ) Type II : C3 nephritic factor (worse prognosis) Type III ( course similar to type I) Secondary : Hepatitis C infection Chronic infections, Endocarditis Visceral abscess Malignancy Cryoglobulinemia All have low complement levels. |
|
How do we treat MPGN?
|
Treat secondary causes if possible (HCV)
Steroids for Idiopathic type I useful in kids Not as effective for adults Type II MPGN Many drugs studied (Dipyridamole, steroids) No definitive therapy |
|
In summary what are the causes of hematuria and nephritis?
|
Common causes:
PSGN- LOW C3 Recent phrayngitis (2 weeks) HTN, proteinuria RBC casts Ig A nephropathy Synpharyngitic hematuria episodes (1-3 day) Persistent microscopic hematuria No significant proteinuria Alport’s syd Family HX Deafness Younger age MPGN Other not so common causes: SLE Vasculitis RPGN |
|
The majority of structures in the kidney are derived from...
|
Epithelial cells
|
|
For the most part, supply of blood to the renal medulla is..
|
Post glomerular
|
|
Where are nephrons located anatomically?
|
A cortical nephron, the group that includes most nephrons, is in the outer cortex, furthest away from the medulla:
Its loop of Henle is short and does not extend into the medulla Its thin loop of Henle is short and does not extend past the bend into the ascending limb. Its capillaries are in the cortex and are called peritubular. A minority of nephrons are juxtamedullary, located in the inner cortex, near the boundary with the medulla It has a long loop of Henle that passes into the medulla Its thin segment extends into the ascending limb The capillaries surrounding it are called vasa recta, the term applied to all medullary capillaries |
|
What is the key feature to distinguish capillaries from the kidney tubules?
|
The appearance of the nuclei.
Tubes have round nuclei whereas vessels usually have flat nuclei from endothelial cells. |
|
The glomerular basement membrane is an important part of the initial filtration system. How is it specialized?
|
It is thicker than the typical basement membrane (0.3-0.35 µm) and is composed of a variety of extracellular matrix glycoproteins and type IV collagen.
Both podocytes and capillary endothelial cells contribute to its formation. It inhibits large proteins and other molecules (>70,000 Daltons) from passing through into the capsular space, but lets small proteins and molecules, like H2O, Na+, and K+, pass. However, because of the large concentration of proteins in the blood, some still get through this barrier and must be resorbed in the proximal convoluted tubule. Basement membrane and basal lamina refer to the same structure. |
|
What proteoglycan is found in the basement membrane of the glomerulus?
|
Heparan sulfate
|
|
What is the function of mesangial cells?
|
Physical support of the glomerular capillaries
Control of blood flow by contraction in response to angiotensin II Phagocytosis of debris, especially from the GBM |
|
Juxtaglomerular apparatus consists of
|
Juxtaglomerular cells:
Modified cells of the wall of the afferent arteriole that secrete renin and control blood pressure Macula densa cells: Modified cells of the wall of the distal convoluted tubule that are thought to detect salt ions in the fluid within the distal tubules and regulate glomerular perfusion rate Extraglomerular mesangial cells |
|
If we see glomeruli on a slide, we know we are NOT in the...
|
Medulla
Glomeruli are strictly cortical structures. |
|
What lines the luminal surface of the proximal tubule?
|
A simple, cuboidal epithelium with an elaborate brush border (microvilli) and glycocalyx.
|
|
What is a glycocalyx?
|
Sugar coating on the outside surface of the cell membrane.
Found in the proximal tubule. |
|
How do we identify proximal tubules on a micrograph?
|
The lumen looks almost occluded because of the microvilli.
|
|
Describe the loop of Henle..
|
Thick segments may be found in the cortex:
Thick descending segment resembles the proximal convoluted tubule Thick ascending segment resembles the distal convoluted tubule Thin segment is located almost exclusively in medulla: Diameter = 15-20 micrometers A simple, squamous epithelium Function is to resorb from filtrate in lumen additional Na+ and other cations. Only the descending portion is water-permeable. Distinguishing thin loops from capillaries of vasa recta is not always possible. |
|
What is the distal tubule?
|
Consists of straight portion (synonymous with thick ascending portion of Henle’s loop) and convoluted portion.
Straight portion located in medulla and medullary ray. Convoluted portion located in cortex. Simple, cuboidal epithelium without brush border or significant glycocalyx. Aldosterone, a mineralocorticoid secreted by the adrenal cortex, stimulates Na+ resorption in exchange for K+ secretion Parathyroid hormone stimulates Ca++ resorption Also acidify urine by excreting H+ |
|
How do we identify the distal tubules on a slide?
|
clear lumen with no filamentous material in H & E stained slide and no violet to purple stained material in PAS stained slide
Diameter similar to that of the distal tubule initially, then increases progressively towards tip of medulla Simple, cuboidal to low columnar epithelium which usually stains more lightly than cells of other ducts |
|
The walls of the calyx are lined by...
|
Transitional epithelium which is stratified.
Continues all the way to the terminal urethra. Called transitional because it is designed to increase in surface area as the ureters fill with urine (cells transition between stretched and unstretched states) Increase in surface membrane area is accomplished by reversible fusion of intracellular membrane vesicles with the plasma membrane |
|
How are the walls of the ureter organized?
|
Not as clearly defined into circular and longitudinal as the gut.
|
|
What is the prostate gland?
|
A group of compound, tubuloalveolar glandular units, encased in a tunic of smooth muscle, with numerous ducts passing into the prostatic urethra
Epithelium is variable, ranging from simple to pseudostratified columnar, except in aged men where it may regress to squamous The fluid secreted by the epithelial cells contributes to about 1/4 the volume of the semen and is ejected into the prostatic urethra during ejaculation Prostatic fluid adds a variety of enzymes and other components to the semen which facilitate sperm function |
|
What is the difference between hyperplasia and hypertrophy?
|
Hyperplasia is an increase in cell number.
In hypertrophy existing cells get bigger. |
|
What is the normal pH range?
|
7.35-7.45
7.0 or 7.7 is incompatible with life |
|
What does the equilibrium constant tell us about acids and bases?
|
The larger the K’ (and the lower the pK’), the stronger the acid, and vice versa.
|
|
How does the Henderson equation simplify in the context of bicarbonate?
|
[H+]=24PaCO2/[HCO3-]
|
|
Apart form bicarbonate what other important buffers are in the body ?
|
proteins
(mainly the histidine rich hemoglobin because of it's imidazole group) Phosphates (inorganic: major urinary buffers organic: intracellular buffers) Ammonium |
|
How is CO2 transported in the blood?
|
CO2 (7%)
Hgb-CO2 (23%) HCO3- (70%) |
|
What are the sources of acid and alkali gain or losses?
|
Dietary intake (acid gain)
Metabolism / catabolism (acid gain) Gastrointestinal H+ or HCO3- loss Renal HCO3- filtration (potential loss) Renal HCO3- reabsorption and generation Renal H+ secretion |
|
What percentage of buffering is done by bicarbonate?
|
~50%
Plasma and interstitial proteins ~1% Intracellular / bone (~49-50%) |
|
Why is the proximal tubule so important in regulating acid base balance?
|
reclaims ~ 90% of filtered HCO3-
generates NH3 generates “new” HCO3- via H+ secretion and NH4+ production |
|
In order to get form the tubular epithelial cells into the lumen they must ....
|
Be actively transported against both an electrical and chemical gradient.
H2CO3 in the lumen breaks down into CO2 and water. CO2 is absorbed from the lumen and combines with HCO3- in the cell to form H2CO3 which dissociates again. Free hydrogens are then actively transported into the lumen. (secondary active transport) The remaining HCO3- in the cell is reabsorbed from the basolateral side along with Na to maintain electrical neutrality. The whole process is driven by the sodium potassium ATPase in the basolateral membrane. (secondary active transport) |
|
How does the proximal nephron produce NH3?
|
From glutamine.
The reaction yields NH4+ and glutamate anions. This reaction is amplified in the setting of hypokalemia. |
|
What is the role of the distal nephron in regulating hydrogen ion balance?
|
reabsorbs any remaining HCO3-
generates “new” HCO3- via H+ secretion and titration of urinary buffers (HPO43-, NH3) Bicarbonate reabsorption in the distal nephron is dependent upon HCO3-/Cl- exchange. |
|
Normal urine pH is..
|
4.5-7
|
|
Compared to arterial measurements, venous blood gases have the following characteristics.
|
pH 0.02-0.04 units lower
PaCO2 6-8 mmHg higher HCO3 1-2 mEq/L higher PaO2 ~ 60 mmHg lower |
|
Some tips about drawing blood gases include....
|
Avoid excessive amounts of heparin (lowers PaCO2 by dilution).
Keep specimen on ice (continued anaerobic glycolysis by RBCs and WBCs will lower pH at room temperature). |
|
How do we determine whether there is appropriate compensation acidosis or alkalosis?
|
|
|
How do we calculate anion gap?
(unmeasured anions-unmeasured cations) |
Na+ - (Cl- + HCO3-)
Organic acids are what contributes the most to anion gap. Potassium is NOT included in anion gap because it changes very little in a living organism. Normal anion gap is ~10-12mEq/L |
|
A significantly elevated anion gap means...
|
Metabolic acidosis
Not all metabolic acidoses have elevated anion gap though. |
|
What is the differential diagnosis of metabolic acidosis with an elevated anion gap?
(vast majority of metabolic acidoses) |
MUDPILES
Methanol (Formic acid) Uremia Diabetic ketoacidosis Paraldehyde, propylene glycol Iron, isoniazid, inhalants, idiopathic Lactic acidosis Ethylene glycol Salicylates ( can cause concurrent resp.alkalosis) |
|
What is the differential diagnosis of metabolic acidosis with a normal anion gap?
|
Addition on any INORGANIC acid.
Loss of bicarbonate (GI): !!Diarrhea!!, ileal loop bladder Loss of bicarbonate or failure of acid secretion (renal): !!Renal tubular acidosis!!, adrenal insufficiency, carbonic anhydrase inhibitors Addition of hydrochloric acid E.g., ammonium chloride, arginine-HCl, lysine-HCl The two most common causes are diarrhea and renal tubular acidosis. |
|
How do we correct metabolic acidosis acutely?
|
Goal:
pH > 7.20 HCO3- > 12 mEq/L ------------------------------ Calculate HCO3- deficit (or H+ surplus) = (HCO3- desired - HCO3- measured) x 0.5 x body weight (kg) Administer alkali to titrate one-half of H+ surplus over 6-12 hours and the remainder over the next 12-24 hours (usually IV NaHCO3) Can give up to 150 mEq of NaHCO3 per liter of D5W |
|
What is the differential diagnosis of metabolic alkalosis?
|
Chloride-responsive
(Urine Cl- < 25 mEq/L): Gastric fluid losses (vomiting, NG suction) Diuretic therapy (post-chronic use) Post-hypercapneic state Low chloride intake (rare) Stool losses (rare causes like congenital chloridorrhea, villous adenoma) Chloride-resistant (Urine Cl- > 40 mEq/L): Primary hyperaldosteronism Bartter’s syndrome Gitelman’s syndrome Cushing’s syndrome Renal failure (with bicarbonate loading) Idiopathic Renal problems tend to be chloride resistant. Non-renal problems tend to have a low chloride (chloride responsive) |
|
How is metabolic alkalosis initiated and maintained?
|
Net loss of hydrogen ions (H+) via GI tract (e.g., vomiting, nasogastric drainage) or kidney (e.g., hyperaldosteronism)
Alkali loading (usually requires concomitant renal insufficiency; otherwise would need >1000 mEq HCO3-/day in normal individuals) Volume contraction with disproportionate loss of chloride (e.g., diuretics) Increased HCO3- absorption by the kidney: Sodium avidity coupled with diminished availability of chloride Mineralocorticoid excess |
|
Tetany and hypoventilation are associated with....
|
Metabolic alkalosis.
|
|
How do we manage metabolic alkalosis?
|
Goal:
pH < 7. 6 HCO3- < 45 mEq/L Chloride responsive alkalosis: Prevention- Cl- and K+ supplements H2-antagonists, proton pump inhibitors Antiemetics Correction- NaCl, KCl administration acetazolamide acidifying-agents (e.g., HCl--rarely used) Chloride-resistant alkalosis: treat underlying defect (primary hyperaldosteronism, Cushing’s syndrome, etc.) Ancillary measures include Na+ restriction, large amounts of K+ supplementation. |
|
Whenever PaCO2 <HCO3-, pH will be...
|
>7.60
|
|
The characteristic of acute kidney injury is..
|
abrupt decrease in GFR
Decline in urine output can be variable though. Precise correlations between changes in serum creatinine level and GFR do not exist |
|
What is the issue with BUN an creatinine as indicators of renal function?
|
Insensitive and late markers of renal dysfunction
Can also be affected by other confounding factors (i.e. steroids, GI bleeding, catabolic states, high protein diet, rhabdomyolysis, drugs) |
|
What are the commonly acepted criteria for acute kidney injury (ARF)?
|
An acute and sustained increase in serum Cr concentration of 0.5mg/dl if baseline Cr <2.5mg/dl OR an increase in serum Cr by 20% if baseline Cr>2.5mg/dl
OR An abrupt (within 48hrs) reduction of kidney function defined by an absolute increase serum Cr >0.3mg/dl OR a percentage increase of serum Cr>50% OR reduction of urine output (<0.5ml/kg/hr for >6hrs) OR RIFLE Classification |
|
What are the pathophysiological mechanisms of prerenal AKI?
|
True intravascular hypovolemia
Decreased effective circulatory volume Intrarenal vasoconstriction Renal artery disease |
|
Autoregulatory dilatation of afferent arteriole is maximal at a mean systemic arterial BP of...
|
~80
|
|
What does hypercalcemia do to renal arteries?
|
Constriction.
contrast dye, cyclosporine, tacrolimus also constrict and can all cause prerenal AKI. |
|
How do NSAIDs cause prerenal AKI?
|
Inhibition of NO synthesis.
|
|
How much GFR decrease is acceptable for ACEI and ARB's?
|
If serum creatinine goes up more than 30% there is major cause for concern and the drugs should be stopped.
<30% is still troublesome and should be closely monitored but is somewhat acceptable. |
|
In prerenal AKI, labs show...
|
Elevated BUN/Cr >20:1
FeNa <1% prerenal azotemia (FeNa= (Una x Pcr)/ (Ucr x Pna) x 100 ) FeUrea <35% (calculated same way but with urea and BUN; more useful for patients on diuretics) Monitor for complications of ARF (hyperkalemia, acidosis) Bland urinalysis. UNa <20 |
|
What are the cause of intrarenal AKI?
|
|
|
What drugs increase serum creatinine and can thus be confounding factors in diagnosing ARF? (AKI)
|
Steroids
Probenecid Cimetidine Bactrim Inhibit tubular secretion of creatinine. |
|
What is the RIFLE classification?
|
Stratifies AKI into Risk, Injury, Failure.
Also defines outcomes in terms of loss (>3 weeks dialysis) and ESRD (>3 months dialysis). |
|
How do we treat prerenal AKI?
|
Optimize renal perfusion and volume status by giving isotonic fluids, blood products, or pressor agents
Exception: low effective circulation due to heart failure requires diuretic therapy Stop any drugs that may exacerbate the condition (ACEI. ARB's, NSAIDS etc.) Treat underlying disease(s) |
|
ATN is the most common cause of intrarenal (intrinsic) AKI. What is it?
|
Acute tubular necrosis
Prolonged Pre-renal AKI will turn into ATN. |
|
What are the causes of ATN?
|
Ischemia:
Prolonged hypoperfusion Crush Injury & trauma Septic shock Pancreatitis Endotoxins: Hemaglobin & myoglobin Uric acid Immunoglobulin light chains Exotoxins: Heavy metals (lead) Ethylene glycol Contrast dye Antibiotics (aminoglycosides, amphotericin B) |
|
What are the phases of ATN?
|
Initiation:
Oliguric phase Inciting event damages tubular epithelial cells causing necrosis and blockage of tubular lumen by necrotic debris. This causes reduction in GFR and vasoconstriction by A2 and endothelin 1 resulting in prolonged ischemia. Maintenance: Ongoing renal failure; lasts 7-21days Recovery: Polyuric phase; regeneration of tubular epithelium, but unable to reabsorb H2O and electrolytes Recovery phase; gradual return of BUN/Cr to baseline or near normal levels. |
|
How do we diagnose ATN?
|
Serum Chemistry:
Elevated BUN/Cr <20:1 (Unlike prerenal AKI which is >20:1) Urine FENa >2% Urine Na >40 Urine osmolality <450 Impaired concentrating ability: UCr/PCr <20 H2O reabsorption poor Urine Sediment Classic “Muddy Brown Cast" |
|
What does biopsy look like in ATN?
|
Flattened tubular epithelium
Sloughed cells |
|
How do we treat ATN?
|
Largely supportive
Attempt to improve renal perfusion, maintain SBP>100mmHG Avoid nephrotoxic agents Remember to adjust doses of medication for CrCl<20 Correct volume status Treat electrolyte disturbances Treat acidosis Dialysis Diuretics (questionable) Low dose Dopamine (questionable) |
|
What are risk factors for contrast induced nephropathy?
|
Underlying renal insufficiency (PCr >1.5; GFR<60ml/min)
Diabetic nephropathy with renal insufficiency Advanced heart failure or other cause of reduced renal perfusion (such as hypovolemia) Percutaneous coronary intervention, which also promotes the development of atheroemboli High total dose of contrast agent Presentation: Renal failure apparent within the first 12- 24 hours after the contrast study. Non-oliguric with mild decline in renal function. Patients occasionally require dialysis (especially if baseline Cr > 4 mg/dL) MUST differentiate from atheroembolic disease: Presence of other embolic lesions (as on the toes) or livedo reticularis Transient eosinophilia and hypocomplementemia. Onset of renal failure that may be delayed for days to weeks after the procedure. Protracted course with frequently little or no recovery of renal function. |
|
How do we treat contrast induced nephropathy?
|
Volume expand if not contraindicated
Prior to and continued for several hours after contrast administration. Isotonic bicarbonate or isotonic saline. |
|
What causes acute interstitial nephritis?
|
Drugs
Infections Autoimmune disorders Idiopathic pattern of renal injury characterized histopathologically by inflammation and edema of the renal interstitium. |
|
How does AIN typically present?
|
Onset of disorder:
Up to several weeks after initial exposure 3-5days after second exposure Latent period up to 18months Classical Symptoms: Rash (15% at presentation) Fever (27%) Eosinophilia (23%) Triad (10%) DX: Clinical symptoms ARF improves with removal of offending agent. Eosinophilia Urine eosinophils Definitive: renal biopsy |
|
How do we treat AIN?
|
Remove offending agent.
Possibly corticosteroids. |
|
Atheroembolic disease presents with Blue toe syndrome, Livedo reticularis and Gastrointestinal manifestations.
What are the renal manifestations? |
Occurs primarily in older patients (mean age 66yrs)
Marked renal impairment with an acute onset, seen within one to two weeks of event Sub-acute presentation: renal dysfunction occurs in staggered steps, separated by periods of stable kidney function Not a rare cause of acute renal failure in elderly patients DX: Urine- Bland urine sediment, Eosinophiluria during the active phase, Proteinuria is usually not a prominent feature; however, nephrotic range proteinuria. Serum-Eosinophilia, Hypocomplementemia Definitive: Biopsy |
|
Post renal AKI is caused by...
|
UT obstruction
Hydronephrosis Renal dysfunction only seen if bilateral or if patient only has one kidney. |
|
What does the serum chemistry look like in post renal AKI?
|
Elevated BUN/Cr
FeNa>2%-4% HypoNa, HyperK Urine: Bland sediment Hematuria (Stones, tumors) Crystals |
|
Obstruction usually produces a post void residual (PVR) >
|
>200
|
|
What is the prognosis of post-renal AKI?
|
Extent of recovery after relief of obstruction depends on severity and duration of obstruction:
<1week: usually recovers completely <2weeks: 70% chance; <3weeks: 30% chance >12weeks: no recovery Post Obstructive Diuresis (polyuria): Osmotic diuresis caused by retain urea. Volume overload. Tubular concentration defect. |
|
How does BUN/CR ratio help us localize AKI?
|
BUN/Cr >20:1 prerenal
BUN/Cr <20:1 intrinsic BUN/Cr >15 and variable in post renal |
|
How does urinalysis help us localize AKI?
|
Bland sediment:
pre-renal, post renal Epithelial cells and muddy brown casts: ATN RBC cast: Glomerulonephritis Eosinophils: AIN Renal will often have isosthenuric urine because they are unable to concentrate. |
|
What are contraindications for renal biopsy?
|
Uncorrectable bleeding diathesis
Small kidneys, indicative of chronic damage Severe hypertension Multiple bilateral cysts Hydronephrosis Active renal/peri-renal infection Uncooperative patient Indications: Isolated glomerular hematuria with proteinuria or renal insufficiency Isolated non-nephrotic proteinuria (< 1-2gm/day) Nephrotic syndrome Acute nephritic syndrome Unexplained acute or sub-acute renal failure |
|
What formulations of amphotericin B are more kidney friendly?
|
Lipid formulations.
|
|
What contrast media are more kidney friendly?
|
Low osmolality contrast media
|
|
How do we dose aminoglycosides so they do the least renal damage?
|
Single dose.
|
|
What are the indications for dialysis?
|
Acidosis:
Persistent metabolic acidosis with pH<7.2 with bicarbonate therapy Electrolyte Abnormalities: Persistent hyperkalemia ± EKG changes despite medical therapy Intoxications: Drug intoxications Overload: Refractory volume overload despite diuretics Uremia: Signs of uremia (altered mental status, pericardial rub) AEIOU |
|
The clinical triad of nephrotic syndrome is...
|
>3 grams protein in 24 hours
Low albumin ( urinary loss and increased tubular catabolism of albumin) edema (Decreased plasma oncotic pressure in systemic capillaries due to low albumin levels; sodium and water retention by the kidney) |
|
What are the complications of nephrotic syndrome?
|
Hypoalbuminemia
Edema Hyperlipidemia Lipiduria Hypercoaguable state |
|
What causes hyperlipidemia in nephrotic syndrome?
|
increased hepatic synthesis of lipoproteins
Lipiduria-Lipids are absorbed by tubular epithelial cells and appear in the urine as oval fat bodies. The urine may also contain free fat and fatty casts that resemble maltese crosses under polarized light. |
|
What causes hypercoagulability in nephrotic syndrome?
|
Increased hepatic synthesis of coagulation factors and loss of regulatory factors
(anti-thrombin III, protein C and S in the urine) |
|
What are the clinical consequences of nephrotic syndrome ?
|
Predisposition to infection (especially gram positive) from low serum IgG levels
Increased risk of thromboembolism and renal vein thrombosis Possible predisposition to atherosclerotic vascular disease Urinary loss of hormone binding proteins (low total thyroxine and iron levels) |
|
How do we manage nephrotic syndrome?
|
Salt restriction
Diuretics ACEI/ ARB Lipid lowering agent For patients on extended therapy with corticosteroids: monitor bone density and supplement with calcium carbonate and vitamin D |
|
What is the most common cause of nephrotic syndrome in children?
|
Minimal change disease (nill disease)
90% of nephrotic syndrome in children less than 10 years of age. Presents as sudden onset of heavy proteinuria and edema. Usually idiopathic- can be associated with NSAIDs and Hodgkin’s Disease. Steroid sensitive nephrotic syndrome.>80% respond to corticosteroids or immunosuppressives Relapse is common though (>50%) Does not progress to renal failure LM: Normal Glomeruli IM: Negative EM: diffuse effacement of podocyte foot processes |
|
What is Focal and Segmental Glomerulosclerosis (FSGS)?
|
Unknown pathology in idiopathic FSGS
In Familial FSGS the podocyte appears to be the primary site of injury Secondary is associated with long standing nephron loss, sickle cell disease, reflux nephropathy, analgesics, IV heroin abuse and HIV (collapsing variant), obesity !!Most common cause of nephrotic syndrome in African Americans!! |
|
What are the pathological findings of FSGS?
|
LM:
scarring in portions of some of the glomeruli IF: IgM and C3 in scarred segments EM: effacement of foot processes !No immune complex deposits! |
|
What are the pathological findings of FSGS on electron microscopy?
|
Effacement of foot processes
No immune complex deposits. this means we cannot tell it from minimal change disease unless we see LM. If the LM is normal, minimal change. Abnormal, FSGS. |
|
How do we treat FSGS?
|
Present with Nephrotic syndrome and early onset HTN and renal failure-may have microscopic hematuria
Idiopathic-40% respond to prolonged course of steroids Secondary FSGS-use ACEI or ARB-if possible treat underlying disease |
|
What is collapsing glomerulapathy?
|
Most associated with HIV.
Reported assoc with parvovirus and pamidronate without HIV though. Pt present with explosive onset of massive proteinuria, severe hypoalbuminemia, rapidly deteriorating renal function: bp may be normal. More common in African Americans. HIVAN-CD4 count is frequently low. PX: Most progress to ESRD w/in 13 months of diagnosis. ACEI may reduce proteinuria/slow the disease. |
|
What are the pathological findings of collapsing glomerulopathy?
|
LM:
FSGS w/ collapse of the glomerular tuft IF: IgM and C3 in sclerotic lesions EM: Effacement of podocyte foot processes. |
|
What are the pathological findings of collapsing glomerulopathy?
|
LM:
FSGS w/ collapse of the glomerular tuft IF: IgM and C3 in sclerotic lesions EM: Effacement of podocyte foot processes. |
|
What is membranous nephropathy?
|
Autoimmune disease in which antibodies are directed against a podocyte protein
M-type phospholipase A2 receptor (PLA2R) Most common cause of idiopathic nephrotic syndrome in caucasians Peak incidence is 4-6th decades M:F=2-3:1 Present with nephrotic syndrome or asymptomatic proteinuria, may have microscopic hematuria (55%) and early HTN (30%) Can be associated with Lupus. May present w/ thromboembolic complications May present with nephrotic syndrome or asymptomatic proteinuria Renal function and BP are often normal at presentation |
|
What are secondary cause of membranous nephritis?
|
Lupus nephritis
Hepatitis B/ malaria Gold, penicillamine, NSAIDs Occult Carcinoma (colon, lung, kidney, breast) De novo in renal transplants |
|
What is the prognosis of membranous nephropathy?
|
40% spontaneous remission
30% progressive renal failure 30% persistent proteinuria with variable renal dysfunction Risk factors for progression: male gender, severe proteinuria(>10gm/24hr), HTN, azotemia, tubulointerstitial fibrosis and glomerulosclerosis. |
|
What are the pathological findings of membranous nephropathy?
|
LM:
the capillary wall is interspersed with spikes of GBM extending between and around subepithelial deposits IF: glomerular capillary wall deposits of IgG EM: !!subepithelial!! electron dense deposits separated by spikes of basement membrane |
|
How do we treat membranous nephropathy?
|
ACEI
Steroids/cytoxic agents |
|
What is MPGN?
|
Variable Clinical presentations:
microhematuria and non-nephrotic range proteinuria Nephrotic syndrome Acute nephritic syndrome Crescentic RPGN Peak Incidence is 2nd-3rd decades Type I-immune complex mediated (most common) Type II- dense deposit disease Type III subepithelial and subendothelial deposits All have a double contoured GBM LM: increased glomerular cellularity IF: C3 and C1q deposits highlighting the lobular architecture of the glomerulus EM: large subendothelial and mesangial deposits |
|
The key feature of MPGN is...
|
Double contoured glomerular basement membrane
|
|
What is MPGN type II ?
|
Also known as dense deposit disease
LM: accentuated lobulation and increased glomerular cellularity IF: capillary wall and mesangial deposits of C3 (exclusively) EM: Intramembranous and mesangial very dense deposits |
|
What is MPGN type III?
|
Rare-immune complex mediated
|
|
What are the clinical characteristics of MPGN?
|
HTN and decreased GFR may be present at diagnosis
> 80% w/ Type I have Hep C Slow progression to ESRD in Type I and II, more common in Type III Spontaneous remission rarely occurs. |
|
What is the defining pathologic feature of RPGN?
|
A glomerular crescent.
Represents final common pathway of severe glomerular injury. Results from disruption of glomerular capillaries; if no disruption, a proliferative phenotype of injury occurs Inflammatory mediators and leukocytes enter Bowman space They induce epithelial cell proliferation and macrophage maturation to form cellular crescents Crescents are the most aggressive structural phenotype in the continuum of injury that results from glomerular inflammation. Crescents can appear in any kind of inflammatory glomerulonephritis. Their presence indicates a severe injury. |
|
What are the three immunologic (anti-body mediated) mechanisms of RPGN?
|
Immune complex.
Anti-glomerular basement membrane antibody. Pauci-immune (ANCA associated). *stars in the diagram represent diseases that CAN appear as exclusively kidney diseases. |
|
What are the glomerular syndromes?
|
Acute nephritic syndrome
RPGN Nephrotic syndrome Chronic renal disease (now called chronic kidney disease-CKD) Asymptomatic hematuria or proteinuria Hypertension |
|
What are the clinical characteristics of RPGN?
|
Rapid loss of renal function over weeks to months
Often accompanied by oliguria or anuria Features of glomerulonephritis: dysmorphic RBCs in the urine, RBC casts, and proteinuria Differential diagnosis: Acute thrombotic microangiopathy Atheroembolic renal disease |
|
What is the main difference between RPGN and proliferative GN?
|
There are holes in the glomerular basement membrane in RPGN.
Inflammatory mediators pass into Bowman's capsule. |
|
What do we know about Immune complex-Mediated Crescentic Glomerulonephritis ?
|
Causes:
Idiopathic Associated with primary glomerulonephritis. Associated with systemic process. Majority (45%) of crescentic GN in children; minority (6%) in the elderly Of the three mechanisms, IC is least likely to have crescents 25% of patients with crescentic IC GN are ANCA positive and this suggests more aggressive disease. LM: Involved glomeruli have severe necrotizing injury; other glomeruli show pathology of underlying process eg. mesangial deposition in IgA nephropathy Crescents with epithelial cells>>macrophages IM: Immune complexes. EM: Immune complex electron dense deposits Location within the glomerulus depend upon the type of IC disease. Breaks in GBM can be seen. Tx: STEROIDS If rapid decline in renal function, add cytotoxic agents, but IC crescentic GN is less responsive than pauci-immune or anti-GBM types. Institute immunotherapy early to prevent advanced scarring. Treat underlying disease if not idiopathic eg. Lupus nephritis. |
|
What do we know about Anti-glomerular Basement Membrane Antibody Disease?
|
Accounts for 5-20% of crescentic GN but 97% of those affected have crescents.
Anti-GBM disease occurs in two forms: Renal limited anti-GBM glomerulonephritis. or As part of a pulmonary-renal vasculitic syndrome with lung hemorrhage (Goodpasture syndrome) Two peak disease Second and third decade in males males; Goodpasture Sixth and seventh decades in females; renal limited Persons with HLA DR2 have a genetic susceptibility to anti-GBM disease because HLA DR2 can present GBM well to to T-cells. Antibody is to an epitope in the NC1 domain of the alpha 3 chain of type IV collagen presumably exposed by environmental factors. Antibody cross reacts with pulmonary alveolar basement membrane to cause lung hemorrhage. Pathgnomonic pathological finding is linear staining of IgG, IgA, GBM or C3 on immunofloresence. EM shows no immune complexes because the disease is a direct attack on the BM. LM will likely show crescents. Lesions tend to be synchronous. There are no changes in arteries/arterioles; if present, think associated ANCA disease |
|
What does anti-GBM disease histology typically look like?
|
Slide title:
Fibrinoid necrosis in crescentic GN Glomerulus with fibrinoid necrosis of its tuft. The fibrinoid material is seen as brightly eosinophilic material in the hematoxylin and eosin (H&E)-stained section in the left panel and bright fuchsinophilic (red) material in the right panel. The blue material in the right panel represents a scarred crescent. |
|
What is the clinical course of anti GBM disease?
|
Renal limited:
Abrupt acute glomerulonephritis with nephritic syndrome, oliguria or anuria, and proteinuria May have arthralgias, myalgias Goodpasture syndrome: Severe pulmonary hemorrhage concurrent or preceding glomerulonephritis; often requires intubation. Diagnosis: the detection of circulating antibodies to alpha 3 chain of type IV collagen of GBM in the patients blood. 25-33% of patients with anti-GBM disease will be ANCA positive with small vessel vasculitis (SVV) present in other organs. Disease can be monitored by level of anti-GBM antibody in the serum. Tx: Plasmapheresis to remove anti-GBM antibody. Steroids. Cytotoxic therapy.(Cyclophosphamide) Treat more aggressively if ANCA+ because of vasculitis. Once anti-GBM antibody is cleared, recurrence is rare, so if ESRD, can proceed with transplant. |
|
What is Pauci-Immune Crescentic Glomerulonephritis?
|
Usually a component of a systemic small vessel vasculitis such as Wegener granulomatosis, microscopic polyangiitis or Churg-Strauss syndrome
May be a primary, renal-limited process in 1/3 of patients Most common cause of RPGN in adults Whites>blacks Women=men Indistinguishable from anti-GBM disease on LM or EM. The distinguishing pathologic feature is the absence or PAUCITY of glomerular staining for immunoglobulins on IF. Known to be a disease of neutrophil activation. Auto-antibodies called anti-neutrophil cytoplasmic antibodies (ANCA) play a pathologic role. ANCA (cytoplasmic or perinuclear) are directed at myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA bind to externalized MPO or PR3 on neutrophil surface, leading to degranulation and release of lytic enzymes and toxic oxygen metabolites at vessel walls, producing a necrotizing inflammatory injury. ANCA antibodies can also enter endothelial cells and cause cell damage. |
|
What is the classical clinical triad of Wegeners granulomatosis?
|
Necrotizing granulomatous inflammation of the upper and lower respiratory tracts
glomerulonephritis systemic vasculitis. |
|
How does Wegeners Granulomatosis typically present?
|
Peak incidence in the fourth to sixth decades.
Usual presentation is malaise, fever, weakness, URT symptoms and renal involvement. May be fulminant RPGN needing dialysis. Typical RPGN course to renal failure is days to months Pulmonary hemorrhage and compromise often present. Usually part of small vessel ANCA associated systemic vasculitis (c-anca aka pr3-anca), and may present as pulmonary-renal, dermal-renal or multi-system disease. Usually nephritic urine; variable proteinuria Best predictor of survival: absence of pulmonary hemorrhage Best predictor of ESRD: initial serum Cr Nasal carriage of staph aureus increases relapse rate. Tx: Steroids Cyclophospamide (may switch to azathioprine) |
|
What are epidemiological risk factors for kidney stones?
|
Middle Aged
White Males Sedentary American diet Stone belt |
|
Number 1 risk factor for kidney disease is...
|
Low urinary volume.
Dilution is protective. |
|
What area of the U.S has the highest incidence of stones?
|
Southeast.
|
|
What are stone promoters?
|
Substances in the urine known to promote stone formation.
Stents Tam-Horsfall protein Uric acid (promotes Ca oxalate stones) |
|
What are stone inhibitors?
|
Substances that complex with stone constituents, increase solubility of small crystals and cover sites for further crystal growth.
!! Citrate !! Magnesium Glycosaminoglycans !Uropontin!. |
|
Why does a high sodium diet predispose to stones?
|
More sodium means tubular flow. This means less proximal reabsorption of calcium and therefore more calcium excretion in the urine.
Therefore, more stones. Thiazide diuretics decrease risk because they cause more PROXIMAL absorption of calcium. Loop diuretics increase urinary calcium. |
|
What can cause increased urinary calcium and therefore increased risk of stones?
|
Hyperparathyroidism
Sarcoidosis Antacids Vit. A or D intoxication Distal RTA Idiopathic is majority though. |
|
Where do we get oxalate?
|
Leafy greens, rhubarb, tea chocolate cocoa.
Glycine and vitamin C metabolism. Genetic hyperoxaluria. |
|
What does a low calcium diet do to risk of kidney stones?
|
INCREASED risk of stone formation.
Oxalate may be bound to calcium in the GI tract. Other factors associated with low calcium diet may be problematic. |
|
What pH favors each type of calcium stone?
|
Low pH favors calcium oxalate stones.
High pH favors calcium phosphate stones. |
|
How does a high protein diet favor stone formation?
|
Increased urine acid excretion which causes decreased urinary citrate (a stone inhibitor) excretion because it favors proximal citrate reabsorption.
Increased sodium intake increases excretion of the stone promoter uric acid. Decreased potassium content. Especially problematic with the Atkins diet and protein supplements. !!!A low calcium diet is associated with a greater rate of stone formation than a low protein diet!!! |
|
How can urinary oxalate be decreased?
|
Decrease exogenous oxalate.
Calcium supplementation. Magnesium supplementation. Cholestyramine. |
|
How does Allopurinol help for calcium oxalate stones?
|
Allopurinol lowers uric acid and thus calcium oxalate stones because uric acid is a promoter.
|
|
What are risk factors for uric acid stones?
|
Decreased urine volume
Increased uric acid production Urinary pH (Acidic) -Biggest factor -pKa ~5.7 -at a neutral pH most is sodium urate which is far more soluble. |
|
What causes increased uric acid production?
|
Dietary:
Sweetbreads, liver, pancreas Increased protein intake |
|
What is the problem with dietary fructose?
|
Increases urinary oxalate excretion
Increases plasma uric acid Increases urinary uric acid Bad for stones, bad for gout, bad for obesity! |
|
What is Cystinuria? (Not cystinosis and Not homocystinuria)
|
A defect in a transporter that carries:
Cystine Ornithine Arginine Lysine Not a huge problem except cysteine is relatively insoluble and causes cysteine stones. Cysteine is more soluble at higher pH’s. Thiola is a medication that binds to cysteine and makes it more soluble. Cysteine stones are hexagon shaped. |
|
What are struvite stones?
|
Frequently Staghorn calculi
(stones which get lodged between two calyxes) Magnesium Ammonium Phosphate Urease splitting bacteria release ammonium, and this leads to very high urinary pH Seen in the setting of chronic UTI Coffin lid shaped stones. |
|
What are treatment options for stones?
|
Endoscopic procedures
Placement of stent Open procedure Lithotripsy Indications: Infected stone Obstructing stone Painful stone |
|
What stones are invisible on x-ray?
|
Uric acid stones.
High resolution CT of the abdomen without contrast is best test at present. |
|
The recurrence rate of stones over ten years is ~
|
50%
|
|
What medical therapy is appropriate after passing a stone?
|
Thiazide Diuretics:
Increase Proximal Tubular Reabsorption of Calcium (for calcium stones) Allopurinol: Decreases urinary uric acid (for ca and uric acid stones) Increase urinary pH: For uric acid and cystine stones |
|
A “heart healthy” lower protein diet is preferred for kidney stones due to...
|
Decreased urinary acid
Decreased urinary uric acid Decreased urinary sodium Decreased urinary uric acid |
|
Why is beer bad for stones?
|
Guanosine in beer increases urine uric acid.
|
|
The risk of UTI with an indwelling catheter for longer than 48 hours is ~
|
1 in 50 (98%)
Next highest risk is hydronephrosis (85%) |
|
In descending order of prevalence, what organisms cause community acquired UTI's?
|
E.coli (~75%)
E.faecalis (~15%) Klebsiella Group B strept Other Nosocomial: E.coli (33%) Other GNR (33%) Enterococci (15%) Yeast (5%) |
|
What are the unique risk factors for cystitis (lower UTI) in women?
|
sexual activity leads to vaginal colonization with colon strains of E.coli
spermicides inhibit lactobacilli which inhibit E.coli The two above mentioned effects are synergistic. E.coli type 1 pili mediate attachment and invasion of bladder epithelial cells producing “bacterial factories” leading to sluffing of cells; also invade mucosa facilitating bacterial persistence and chronic inflammation. In older women, atrophic vaginitis leads to increased colonization that is reversible with local estrogen |
|
What are risk factors for pyelonephritis (upper UTI)?
|
!ureteral reflux!
Type 1 fimbriae mediate bladder attachment P fimbria mediate attachment to uroepithelial cells in the upper urinary tract via blood group determinants (P), glycolipids Tamm-Horsfall protein (secreted by uroepithelial cells) binds type 1 fimbriae (blocking attachment) Slide show pyelonephritis. Tubules filled with puss instead of clear urine. |
|
What are risk factors for indwelling catheter UTI?
|
!!duration of catheterization!!
technique Condom catheters lower risk than indwelling In/Out catheterization lower risk than continuous extralumenal - CNS, enterococci, yeasts, GNR intralumenal – GNR (pseudomonas is prototype) Biofilms, encrustations |
|
Accessing the port on a catheter without proper sterile technique...
|
Doubles the risk of infection.
|
|
What are risk factors for prostatitis?
|
BPH
stasis (prolonged sitting – bicycling, truck drivers) sexual activity instrumentation (catheters etc.) |
|
Flank pain, fever, rigors, nausea and vomiting suggest...
|
Upper UTI.
|
|
Loss of the psoas shadow on x-ray suggests..
|
UTI.
Gas in the kidney from a renal carbuncle or perinephric abcess is another sign. |
|
Chalmydial Urethritis or Vaginitis typically have...
|
negative bacterial cultures.
Chief complaint is also typically discharge and irritation rather than burning or frequency. |
|
What do we look for on U/A in a UTI?
|
>10 wbc/hpf
WBC casts are pretty much diagnostic of pyelonephritis (upper UTI) epithelial cells usually indicate contamination of specimen with vaginal contents. WBC's with no bacteria on culture could mean: Chlamydia Interstitial nephritis TB Other Pyuria (neutrophils) indicate: Cystitis or Upper tract infection or chlamydia |
|
What antibiotics can be used for prostate infections?
|
Poor penetration and long duration infections.
These antibiotics penetrate better than most. Quinolones Trimethoprim (resistance a problem) Erythromycin Tetracyclin when a foley catheter is in place, it should be replaced prior to treatment with antibiotics. Rx of asymptomatic bacteriuria in catheterized ICU patients with antibiotics and catheter change is not indicated. |
|
Why do we have to treat an infection before lithotrypsy?
|
Patients will become instantly septic.
|
|
Why do diabetics have increased risk of UTI?
|
Glucose in urine feeds bugs.
Diabetes impedes neutrophil function. |
|
Why is pregnancy an increased risk of UTI?
|
Ureteral reflux
|
|
What is ADPKD?
|
Autosomal dominant polycystic kidney disease.
Expanding cysts that ultimately destroy the renal parenchyma and cause renal failure. 15-fold more common than CF 10-fold more common than Sickle cell 50% of patients with ADPKD develop ESRD 4th most common cause for ESRD Accounts for ~10% of ESRD population There is no disease-specific treatment |
|
Where do cysts develop in ADPKD?
|
renal cysts develop along any portion of the tubule
each epithelial cell within the tubules harbors a germ line mutation for the ADPKD gene less than 5% of the nephrons are affected by the cystic growth. Requires a second hit for cyst to occur in the form of inactivation or somatic event in the allele from the healthy parent. |
|
What are the two mutations that cause ADPKD?
|
PKD1 gene on chromosome 16:
Accounts for 85 - 90% of all ADPKD in US whites. More severe disease due to development of more cysts at early age NOT faster rate of growth. Average age ESRD 54.3 years Gene product is Polycystin -1 PKD2 gene on chromosome 4: ESRD average age 74.0 Gene product is Polycystin-2 |
|
What cells in the nephron do NOT have primary cillium?
|
Intercalated cells of collecting duct.
|
|
What is the role of polycystin 1 and 2?
|
Polycystin-1 and 2 are localized to the primary cilium of epithelial cells lining tubules in the kidney and biliary tract
The cilium acts as a mechanosensor believed to be essential for maintaining differentiated state of epithelia lining Mechanical or flow-induced bending of the cilia is associated with a Ca2+ influx into the cell, which occurs through polycystin-2 This mechanosensory response is lost in polycyctin-1 deficient cells Defective flow sensing leads to tubular cell growth through lowered c-AMP. |
|
The resulting defect in ADPKD are...
|
Extracellular Matrix
Composition defects. Cell Growth defects Fluid Secretion (Role of Primary Cilium and Abnormal Cell Polarity) |
|
What is lost in polycystin-1 deficient cells?
|
Mechanosensory response
Ca2+ influx into the cell occurs through polycystin-2. |
|
What aspects of ADPKD cause cyst formation?
|
Cysts have decreased apical Na+ channels and increased Cl- channels:
The basolateral rather than the apical NKCC is activated Electrochemical gradient is favorable for movement of Na+ through paracellular channels into the cyst lumen. Water follows sodium into the cysts. Intracellular cAMP stimulates also apical CFTR Cl- channels and causes water to follow into the cyst lumen. Loss of Cl- into the cyst lumen further increases activity to NKCC. The cystic segment ultimately pinches off as fluid secretion contributes to accumulation of liquid in the cyst cavity. The cystic epithelium is associated with thickening of adjacent BM and an influx of inflammatory cells into the interstitium. |
|
What are some therapeutic targets for ADPKD?
|
Blocking V2 receptors can lower cAMP by alternate means and decrease both activation of the chloride channel and abnormal cell proliferation.
Somatostatin activation also inhibits cAMP. Studies are currently underway using V2 antagonists (Gi) and somatostatin/octreotide agonists (Gs). Sirolimus is also being clinically tried. |
|
How does cyst growth affect GFR in ADPKD?
|
Inverse correlation between the rate of increase in the kidney volume and the rate of decline in GFR.
Calculated GFR poor measurement of renal function in ADPKD The volume of an ADPKD kidney usually exceeds 1000mL before a fall in GFR is detectable (nl kidney volume 150mL) Serum creatinine is not a good measure (late marker) so we look at kidney volume on MRI. Kidenes that remain small (<1000-1500) are a sign of good prognosis. |
|
What are the complications of ADPKD?
|
Hypertension 60-100%:
Stretching of blood vessels around cysts leads to intrarenal activation of RAS Gross Hematuria 40-50%: Cyst hemorrhage, stone, infection, tumor Infection/UTI common: Result of cystitis, pyelonephritis, cyst infection, perinephric abscess E. coli, Proteus, Klebsiella Nephrolithiasis 20-25%: Decrease citrate in urine, distorted anatomy with urinary stasis Uric acid stones more common than general population Renal Failure 50% by age 60 for PKD1: Occurs on average 15-20 years earlier in PKD1 |
|
How do we diagnose ADPKD?
|
Dx of ADPKD relies principally upon imaging of the kidney .
Genetic testing not generally recommended except for prenatal screening and young living related kidney donors. age cutoff for imaging diagnosis: 30 y.o. ADPKD1; 40 y.o. ADPKD2 This means Pt. has to be 41 with no cysts to conform they dont have it. <30: 2 cysts in one or both kidneys 30-60: 2 or more cysts in each kidney or 4 or more total cysts >60: 4 or more cysts in each kidney |
|
What % of ADPKD are spontaneous mutations?
|
~5%
|
|
How do we manage PKD?
|
BP control with ACEI/ARB.
Early treatment of UTI with cyst penetrating drug (TMP-SMX, fluoroquinolone, chloramphenicol) |
|
What is ARPKD?
|
Autosomal recessive polycystic kidney disease.
Enlarged kidneys and biliary dysgenesis leads to portal fibrosis/congential hepatic fibrosis. Unlike ADPKD, enlargement is only in the collecting duct. High variable clinical presentation ranging from neonatal death (Potter’s phenotype) to later presentation with minimal kidney disease and portal hypertension. poorly functioning kidneys lead to oligohydramnios and pulmonary hypoplasia often incompatible with survival also a/w characteristic facies, deformities of spine and limbs Perinatal mortality 30 – 50 % Incidence 1 per 20,000 live births Caused by a mutation in PKHD1; protein: fibrocystin aka polyductin Fibrocystin/polyductin has been found in the same complex as polycystin-2 and has been localized to primary cilia as well |
|
What does the gross pathology o ARPKD look like?
|
Kidneys retain their reniform shape
Dilated collecting ducts extend through the cortex |
|
How do we diagnose and manage ARPKD?
|
Diagnosis:
fetal US at 16 and 20 weeks to evaluate kidneys and amniotic fluid Genetic testing able to identify approx 85% of mutation !!portal hypertension!! Management: BP control Dialysis/transplant Medical management of portal hypertension |
|
What diseases mimic polycystic kidney disease?
|
Von Hippel-Lindau :
VH1 gene senses hypoxia. Eyes and brain tumors. Cancer predisposition syndrome Retinal hemangiomas, cerebellar hemangioblastomas, renal cell cancer. All highly vascular tumors. Pheochromocytoma (pheo) Pancreatic cysts Tuberous Sclerosis: Hamartomas Renal cysts Angiomyolipomas (fat, smooth muscle and vessels on CT) Malignancy Adenoma sebaceum / facial angiofibroma on skin Mental retardation/seizures Tumor suppressor gene syndrome. TSC1(hamartin protein) or TSC2 (tuberin protein) |
|
What is Nephronophthisis (NPHP)?
|
5 genes (NPHP1 – NPHP5) have been identified
Code for proteins called nephrocystins Also located at the base of primary cilia of renal epithelial cells Accounts for 6 – 15% of ESRD in children and adolescents Infantile form: ESRD by 5 years of age Juvenile form: mean age of ESRD 13 !!!Polyuria, salt wasting and significant anemia!!! Associated with retinal defects (RP), mental retardation and cone shaped bone epiphyses. |
|
What does Nephronophthisis (NPHP) look like histologically?
|
clusters of atrophic tubules mixed with viable tubules that may show dilatation or compensatory hypertrophy, interstitial fibrosis surrounds atrophic tubules
|
|
What is medullary cystic disease?
|
Shares the same histopathologic features as nephronophthisis (tubular BM irregularities, tubular atrophy with cyst formation, interstitial cell infiltration with fibrosis) but a different inheritance mode
Juvenile NPHP: AR disorder that presents in childhood Medullary cystic disease: AD disorder that occurs in adults Type 1 progresses to ESRD after age 60 and type 2 at about 30 years of age Lack of extrarenal manifestations Mutations in the UMOD gene which codes for Tamm-Horsfall protein (aka uromodulin) identified as cause of Medullary Cystic disease type 2 Also associated with polyuria and salt wasting |
|
What is medullary sponge kidney?
|
Common disorder characterized by dilated medullary and papillary collecting ducts that give the renal medulla a spongy appearance
Affects 1 in 5000 and up to 20% of pt with kidney stones !!Asymptomatic radiographic finding unless complicated by nephrolithiasis, hematuria or infection!! Management is of complications and renal insufficiency is unusual. Hypercalcemia Urinary stasis Stones Multiple spherical or oval cysts measuring 1 – 8 mm in one or more papillae “Cysts” are often bilateral and contain spherical concretions of apatite (Calcium phosphate) Associated pyramids and calyces can be enlarged leading to nephromegaly |
|
What are simple cysts?
|
Increasingly common with age
Typically asymptomatic Usually an incidental finding On ultrasound: smooth walls, no septae, no intracystic debris On CT: homogenous attenuation, no contrast enhancement, thin and smooth walls, usually no calcification |
|
What tips us off to acquired cystic disease (Dialysis associated)?
|
Polycythemia without erythropoietin.
Usually dialysis patients are anemic. |
|
What percent of the U.S population have diabetes?
|
~7%
|
|
What is the leading cause of ESRD?
|
Diabetes
45% of incident ESRD was due to DM |
|
How do we define diabetic nephropathy?
|
Characterized by the presence of persistent microalbuminuria (>300mg/24 hour) on at least two occasions separated by 3-6 months
Microalbuminuria may regress or remain stable Less than half will progress to overt proteinuria |
|
What influences susceptibility of diabetics to ESRD?
|
Glycemic control
Genetics: Pima indians (outrageous 61%) Mexicans (x6) AA (x4) Gender: type 1 DM higher in females but Nephropathy higher in males. Age: Median time between the onset of proteinuria and ESRD- 14 years for those with diabetes diagnosed under the age of 12 8 years for those with diabetes diagnosed between the ages of 12 and 20 |
|
What are the stages of diabetic nephropathy in type 1 DM?
|
Renal hypertrophy and hyperfiltration with elevated GFR and UAER:
inc 20-40% over controls, RBF inc 9-14% Assoc with glomerular and tubular hypertrophy and enlarged kidneys on renal u/s Normoalbuminuria with an elevated GFR ( 5-10 years): Increased mesangial matrix Microalbuminuria (5-15 years): 30-300mg albumin/24 hours Increase in GBM thickness and mesangial volume Overt proteinuria (10-20 years): >300 mg albumin/g of creatinine Up to 66% will have microscopic hematuria Decline in GFR (15 to 25 years): 10ml/min/year ESRD-(5 -7years of nephrotic range proteinuria) |
|
What are some examples of diseases that can cause enlarged kidneys? (>10-12cm)
|
Diabetic nephropathy
HIV Amyloidoisis Interstitial nephritis Advanced CKD will often be small kidneys though. |
|
What is renal insufficiency?
|
Cr>2
|
|
Average decline in GFR in stage 5 DM nephropathy is ~
|
10ml/min/year
Varies with albumin excretion. The more protein you spill, the faster your kidney declines. |
|
How do we screen for diabetic nephropathy?
|
Normal UAER is 1.5-20ug/min
UAER increases with: Strenuous exercise Oral protein intake UTI infection UAER is 25% higher in the day then night and has about 40% variability from day-day. Test early morning urine sample Who to screen?: Individuals over the age of 12 with Type I DM for more than 5 years All Type II DM from the time of diagnosis of DM each year until age 70 Individuals with an elevated UAER should be screened every 6 months. UAER=Urine albumin excretion rate |
|
What conditions are associated with microalbuminuria/proteinuria in diabetics?
|
Diabetic microangiopathy:
Proliferative retinopathy and blindness increases with progressive albuminuria Peripheral neuopathy (21% normoalbuminuria, 31% microalbuminuria and 50% with macroalbuminuria) Cardiovascular disease: Independent risk factor for cardiovascular disease Hypertension Hyperlipidemia Increased urine protein correlates with mortality. |
|
How does diabetic nephropathy cause HTN?
|
Increased sodium and water retention.
Use ACEI/ARB if >130/80 Goal bp<125/75 each 10mm reduction in systolic pressure was assoc with a 12% risk reduction in diabetic complications. |
|
What is the target LDL in diabetic nephropathy?
|
LDL<100 or less than 70 if CV risk factors
|
|
What do we see in diabetic kidneys?
|
Enlarged gross appearance due to glomerular/tubular hypertrophy.
Thickening of the GBM Mesangial Matrix Expansion Glomerular sclerosis (Kimmelstiel- wilson nodules) Arteriolar hyalinosis (Affects both but efferent more specific for DM) Decreased number of podocytes |
|
How do we make the diagnosis of diabetic nephropathy?
|
Type I DM > years
(Type II DM may have proteinuria at the time of diagnosis of DM) Presence of Diabetic retinopathy Previous microalbuminuria No red blood cell casts/macroscopic hematuria Renal ultrasound !!Retinopathy and diabetic nephropathy have a concordance of 85-99% in Type I DM and 63% in Type II DM!! Consider biopsy if: Accelerated renal failure Absence of extra-renal end organ damage Macroscopic hematuria/active urine sediment Rapid decline in renal function with minimal proteinuria |
|
What other renal diseases are common in diabetics and thus important to keep in mind?
|
Glomerulonephrititis
(Nondiabetic causes of proteinuria in 4-25%) Renal papillary necrosis Renovascular disease Autonomic neuropathy of the bladder UTI Contrast nephropathy |
|
What is the pathogenesis of diabetic nephropathy?
|
Glomerular hyperfiltration
(afferent arteriolar dilatation-Use ACEI/ARB+low protein diet) Hyperglycemia and AGE (advanced glycosylation end products) Prorenin Cytokines Decreased Nephrin expression Decreased cell surface heparan sulfate may lead to increased permeability of the GBM to albumin. |
|
AGE’s mediate a variety of cellular actions through increased TGF beta.
What are they? |
Expression of cell adhesion molecules
Cell hypertrophy Synthesis of the ECM EMT of tubular cells Inhibition of NO synthesis Elevated plasma glucose levels are associated with increased levels of growth factors; IGF-1 EGF PDGF TGF-β |
|
What are risk factors for progression of diabetic nephropathy?
|
Hyperglycemia (keep HbA1c<7)
Hypertension (ACEI/ARB) Proteinuria Genetic Predisposition Male sex Hyperlipidemia (use statin) Tobacco use obesity low birth weight (lower total nephron mass) Best evidence of prevention of nephropathy is with insulin. |
|
What drugs work to reduce proteinuria in DM nephropathy?
|
ACEI + ARB
? Direct renin inhibitor (aliskiren) Nondihydropyridine calcium channel blockers (verapamil and diltiazem) Aldosterone antagonists: Spironolactone Eplerenone |
|
Do we currently recommend dietary protein restriction in diabetics?
|
No
Low salt diet Weight loss Smoking cessation Avoid nephrotoxins |
|
When do we get a biopsy on minimal change disease?
|
MCD is always an acute presentation.
and not an incidental finding. Biopsies are usually only done in adults. If we are truly dealing with MCD it should respond to steroids. However, if there is steroid resistance, relapse on steroid tapering or frequent relapses, maybe we are really dealing with FSGS. |
|
How much of the kidney is involved in FSGS?
|
Focal refers to involvement of some but not all (or at least not a majority of) glomeruli, by convention now this means involvement of > 50% of glomeruli; whereas segmental refers to involvement of part of but not the entire glomerulus.
|
|
The antibody associated with membranous glomerulopathy is...
|
IgG
Staining for C3 may or may not be present in the same pattern. Spikes seen in silver stained section. !!!Subepithelial!! electron-dense deposits separated by basement membrane spikes on EM |
|
What diseases are associated with membranous glomerulopathy?
|
Systemic Diseases:
Systemic lupus erythematosus Mixed connective tissue disease Sjogren syndrome Sarcoidosis Infections: Hepatitis B (especially in children) Syphilis Drug Toxicity: Penicillamine Gold salts Organic mercurial compounds Malignant Neoplasms: Carcinomas (colon, lung, kidney, breast) |
|
What conditions have C1q?
|
Type 1 MPGN
Lupus nephritis |
|
What does MPGN type 2 stain on IF?
|
C3
ring- and doughnut-shaped deposits Diagnostic |
|
What conditions can mimic MPGN?
|
Diffuse proliferative lupus nephritis
Hepatitis B and C Sickle cell disease Cryoglobulinemia Plasma cell dyscrasias Diabetic glomerulosclerosis Thrombotic microangiopathy (late stage) Chronic allograft nephropathy |
|
Starry sky of IgG sitting on top of the capillary wall in IF suggests..
|
Post-infectious GN
EM: Dome-shaped subepithelial and mesangial deposits. LM: Glomerular hypercellularity |
|
What are the pathological features of IgA nephropathy?
|
LM: Most often mesangial hypercellularity, but histology highly variable.
IF: Mesangial !!IgA!!! EM: Mesangial dense deposits HS purpura is systemic form and often seen in children. |
|
What are the other two genetic nephritis diseases?
|
Thin basement membrane nephropathy
(Benign familial hematuria) Alport syndrome: Frayed lamellated GBM (Basket-weave effect) Lenticonus Sensorineural deafness Gross hematuria in both these and IgA nephropathy is synpharyngitic. |
|
What is the prototypical crescentic glomerulonephritis?
|
Anti-GBM disease
|
|
Both anti GBM and goodpastures are characterized...
|
Linear IgG immunofluoresence.
|
|
What kidney syndromes are considered Systemic Vasculitides?
|
Wegener granulomatosis
Microscopic polyangiitis (MPA) Churg and Strauss syndrome |
|
What is the differential for crescentric glomerulonephritis?
|
|
|
How do we classify lupus nephritis?
|
Class I:
Minimal mesangial lupus nephritis Class II: Mesangial proliferative lupus nephritis. Class III: Focal lupus nephritis Endocapillary proliferation, segmental tuft necrosis, wire loop lesions, crescents and hyaline thrombi (involving up to 50% of glomeruli) Class IV: Diffuse lupus nephritis Same changes as above involving > 50% of glomeruli Class V: Membranous lupus nephritis Class VI: Advanced sclerosing lupus nephritis: =/> 90% of glomeruli globally sclerosed without residual activity. |
|
What does an IF ANCA test tell us?
|
Cytoplasmic ANCA (C-ANCA or PR3 ANCA). Seen in ~ 80% of cases of Wegener granulomatosis
Perinuclear ANCA (P-ANCA or MPO-ANCA). Seen in most cases of MPA and kidney-limited pauci-immune NCGN. |
|
What conditions are associated with adult polycystic kidney disease?
|
Berry aneurysm (worst headache)
Mitral valve prolapse (click murmur) Diverticulosis (Hemtaochezia) |
|
What are the characteristic findings of diabetic glomerulosclerosis?
|
Global expansion of the mesangium due, in particular, to the excessive deposition of mesangial matrix. Capillary wall thickening.
Nodules (Christmas balls) in advanced cases. aka Kimmelstiel-Wilson lesions. Uniformly thickened BM on EM. |
|
What are the two types of renal amyloidosis?
|
AA Amyloidosis:
complicates conditions associated with chronic tissue breakdown (chronic infections, rheumatoid disease, neoplasms) AL Amyloidosis: A complication of plasma cell dyscrasias. Myeloma cast nephropathy. Abnormal immunoglobulin deposition disease (light chain, heavy chain, light and heavy chain) |
|
What cells do we expect to find in Acute Drug-Induced Tubulointerstitial Nephritis (Acute Interstitial Nephritis)?
|
Eosinophils:
Suggestive but do not make or break the diagnosis. Granulomas: Their presence provides confirmatory evidence. Note eosinophils: binucleate nuclei with bright eosinophilic granules |
|
What are predisposing factors for UTI?
|
Female gender
Obstruction Vesicoureteral reflux Instrumentation Diabetes mellitus Culprit organisms: (Fecal flora) Esherichia coli Proteus Klebsiella Pseudomonas Serratia Aerobacte |
|
What can cause urinary tract obstruction?
|
Intraluminal:
Calculus Blood clot Sloughed renal papilla Posterior urethral valve Extraluminal: Gravid uterus Tumor Retroperitoneal fibrosis Aberrant renal artery Uretrocele Prostatic hypertrophy Iatrogenic |
|
What does a gross specimen of acute pyelonephritis look like?
|
Note yellow raised abscesses on the surface of this kidney from diabetic patient.
Note: This is the only acute setting in the kidney that involves neutrophils. |
|
In order for us to call something chronic pyelonephritis, there must be documented history of infection. What does it look like though?
|
Germinal center in a lymphoid follicle in a case of chronic pyelonephritis
|
|
What causes thyroidization? ( a form of tubular atrophy)
|
either chronic pyelonephritis or ischemic nephropathy
|
|
What is Xanthogranulomatous Pyelonephritis?
|
An inflammatory condition that enters to the differential diagnosis of renal cell carcinoma.
Zonation phenomenon is often present but is not required to make the diagnosis: Central suppurative inflammation (right). |
|
What do staghorn calculi look like?
|
Note the dilated calyces and markedly attenuated renal parenchyma.
|
|
What does atheroembolic kidney disease look like?
|
Cortical necrosis.
Note the relatively pale areas of the necrotic cortex and the markedly hyperemic medulla. |
|
Why does the kidney swell inside it's capsule in ATN?
|
|
|
What is the gross appearance of ATN?
|
Renal cortex is very pale but medulla is beetroot red.
Blood supply is shunted to the medulla depriving the more metabolically active cortex. |
|
What vascular changes are associated with hypertension?
|
Benign Hypertension:
Arteriolar hyalinosis Arteriolar and interlobular arteries medial hyperplasia Fibroelastic intimal thickening of interlobular arteries Malignant Hypertension: Arteriolar fibrinoid necrosis Myxoid intimal thickening (arterioles and interlobular arteries) Mesangiolysis |
|
What are commonly used urological imaging techniques?
|
Abdomen radiographs (a.k.a. KUB)
Intravenous urography (a.k.a. IVU, IVP) Cystograms (images of bladder) Urethrograms (urethra images) |
|
What is a KUB?
|
Abdominal plain film
Very limited specificity & sensitivity Requires radiation Poor contrast Most of urinary tract invisible Used to: Follow-up of radio-opaque stone Evaluate position of stents, drains Evaluate bowel gas pattern |
|
What is an Intravenous Urogram (IVU)?
|
Contrast media (iodinated benzene ring compounds) injected in any vein, followed by abdominal radiographs
Urine becomes opaque from the excreted contrast media Kidneys to bladder shown fairly well Familiar to most clinicians Readily available Requires radiation Requires contrast media (nephrotoxicity) Relatively slow Limited resolution compared to newer techniques (CT, US, MRI) Excellent visualization of ureters, calyces |
|
What are the advantages of renal sonography?
|
No toxicity.
Readily available. Real-time examination. Good visualization of kidneys. Great for differentiating solid vs. cystic masses. !!Best test for acute renal insufficiency work-up!! Disadvantages: Limited functional assessment. Ureters invisible. Operator dependent. Patient body habitus limitations. Less accurate than CT for detection of masses, stones. Indications: Evaluation for cause of renal insufficiency. Renal size. Renal transplants(obstruction, blood flow) Renal mass evaluation (simple cyst, or not) Simple cysts are black. Masses are white. |
|
What is renal CT?
|
Most accurate for renal masses.
Most accurate for staging cancer. Best test for stone diagnosis. Entire abdomen visible. Hematuria evaluation. 3D reconstructions possible. Disadvantages: Radiation Expense Contrast media sometimes needed Indications: Suspected stone disease Known or suspected renal mass (Diagnosis, Staging, Treatment Planning) Blunt trauma Hematuria |
|
How does MR compare to CT for renal imaging?
|
Similar strengths and indications as CT
More expensive Longer imaging time But…….. No nephrotoxic contrast needed No radiation Indications: Renal tumor in patient who cannot get contrast media. Imaging renal blood vessels & can’t get contrast media. Urethra/periurethral region. |
|
How do we do a cystogram?
|
Catheterize bladder
Fill with contrast media Radiographs Indications: Suspected bladder trauma Suspected ureter reflux Post operative evaluation |
|
How do we do a urethrogram?
|
Inject contrast into urethra
Radiographs Indications: Urethral trauma Suspected stricture disease Post operative evaluation |
|
What can interventional uroradiology do?
|
Percutaneous ablation of renal tumors
Image-guided abscess drainage Image-guided kidney drainage Image-guided biopsies |
|
55 yo man with acute renal failure. Serum creatinine = 3.7, minimal urine output in last 48 hours.
What imaging test should you order? |
US
Detects hydronephrosis Detects medical - renal disease |
|
In comparison to the liver, the kidney should normally be...
|
Less bright.
Brighter might indicate parenchymal disease. |
|
45 yo patient with acute left flank pain and microscopic hematuria
What imaging test should you order? |
CT
Look for stones.(95% accuracy) |
|
75 yo patient with acute left flank pain.
What imaging test should you order? |
CT
|
|
When we suspect kidney stone we should always beware of...
|
AAA
|
|
48 yo patient with a 3 cm right kidney tumor found on a CT stone study. Is it a simple cyst or not?
What test should you order? |
US
Ultrasound is extremely accurate in differentiating cysts from solid tumor in the kidney when they are > 1 cm |
|
30 yo man in an MVA, can’t void and gross blood seen at urethral meatus.
What test should you order to evaluate the urethra? |
Retrograde urethrogram will demonstrate whether there is a urethral tear, or not. If none, a catheter can be passed and a cystogram obtained.
Extravasation from urethra indicates a tear. |
|
30 yo man has diminished urine stream when voiding. He has a remote history of a straddle injury.
What test should you order to evaluate the urethra? |
Retrograde urethrogram will show if a stricture is present.
|
|
50 year old woman with congestive heart failure and an abdominal bruit. Had a kidney biopsy 3 years ago.
What test should you order? |
If normal renal function, order a CTA
If renal insufficiency, order an MRA. |
|
Dilatation of the renal vein might indicate....
|
A-V fistula
|
|
80 y.o. man with mild renal insufficiency (can’t give CT contrast)
Renal tumors detected but uncertain diagnosis with non contrast CT What imaging test should be used to characterize his renal tumors as benign or malignant? |
Due to renal insufficiency use MRI as MR contrast agents are not nephrotoxic at doses needed for imaging
MRI is highly accurate to diagnose renal tumors and for staging Good tumors (black): No enhancement Macroscopic fat (angiomyolipoma) Bad tumors (white): Enhancement (blood supply) No macroscopic fat |
|
What conditions are associated with chronic kidney disease?
|
Hypertension
Anemia Secondary hyperparathyroidism Metabolic acidosis Malnutrition Dyslipidemia |
|
At what point do we get into adaptive hyperfiltration?
|
Once the GFR falls below about half of the normal, kidney function tends to decline even if the initial insult has been eliminated.
Adaptive hyperfiltration: A process in which the kidney is able to adapt to the initial damage by increasing the filtration rate in the remaining normal nephrons. Results in long-term damage to the glomeruli of the remaining nephrons Manifested by proteinuria and progressive renal insufficiency. |
|
What are the stages of CKD?
|
Stage 1: GFR>90 (normal GFR)
Stage 2: GFR 60-89 (mild) Stage 3: GFR 30-59 (moderate) Stage 4: GFR 15-29 (Severe) Stage 5: GFR<15 (Failure) The must also be evidence of kidney damage for us to call a decline in GFR CKD. |
|
What are the risk factors for CKD?
|
Severity of proteinuria*
Degree of hypertension Type of underlying kidney disease African American race Males Obesity Diabetes Hyperlipidemia Smoking High protein diet Persistent metabolic acidosis *Strongest predictor of progression irrespective of BP control. |
|
How do we screen for CKD?
|
All who have increase susceptibility or inciting factor should be tested for markers of kidney disease
Imaging, proteinuria, hematuria, and abnormalities in urine sediment Assessment of kidney function: Estimated GFR with use of SCr and equations recommended (MDRD, CG, CKD-EPI) |
|
What are some markers of CKD?
|
Proteinuria (<200 normal)
Hematuria Urinary Sediment Radiologic evidence of damage Albuminuria is earliest sign usually: Alb/Cr ratio: < 30 normal 30-300 MICROALB >300 MACROALB TP/Cr: <0.2 normal 0.3 = 300mg, 1.2= 1200mg, 4.4= 4400mg/day protein excretion |
|
Which comes first? CKD or HTN?
|
It is thought CKD:
Sodium retention RAAS activation Sympathetic tone increase Secondary Hyperparathyroidism (rise intracellular calcium concentration leads to vasoconstriction) Increased blood viscosity and PVR from erythropoeitin treatment. Impaired nitric oxide synthesis and endothelium-mediated vasodilatation. !!Each increment of 20/10 mmHg over 115/75 doubles the risk of CVD!! |
|
How do we treat HTN in CKD patients?
|
GOAL BP < 130/80
Antihypertensive regimen 1st Line: ACEI/ARB May see Cr to rise due to inhibition of efferent vasocontriction Will tolerate 30% increase in SCr 2nd Line: Diuretic- Thiazide (GFR> 40ml/min); Loop (GFR < 40ml/min) 3rd Line: CCB (nondihydropyridines) Therapeutic lifestyle changes: Limit Sodium intake to < 2300 mg daily (< 100mEq) Avoid NSAID and sympathomimetics (sudafed, cocaine) Smoking cessation, limit EtOH use, reduce weight etc. |
|
How is anemia related to CKD?
|
With GFR < 60ml/min/1.73m2, the prevalence of anemia increases dramatically.
EPO(90%) is produced in the peritubular cells in kidneys of the adult. It acts to rescue erythroid cells from apoptosis and increases survival of RBC. |
|
So what CAUSES anemia in CKD?
|
Reduced EPO production because of reduced nephrons.
There is also an absolute iron deficiency even in predialysis patients because of reduced hepcidin. ACEI can also cause anemia. Workup: Anemia of chronic kidney disease is normocytic normochromic. (♂♂ Hb<13.5; ♀♀ Hb<12.0) MUST exclude iron deficiency with Iron panel. (Tsat<20% and Ferritin<100 =deficiency) Also rule out any other anemia causes. Measurement EPO levels NOT necessary. Correct iron deficiency Goal Hemoglobin 11 – 12 g/dL (>13 increased risks) ESA therapy when Hb<11 g/dL (Epoeitin or Aranesp) Monitor hemoglobin every two weeks until both hemoglobin and EPO dose are stable, then monitor hemoglobin monthly |
|
How does secondary hyperparathyroidism work?
|
Starts early in CKD
Decline in GFR leads to Increased phosphorus retention and decreased calcitriol production. Decreased Calcitriol: Decreases Ca reabs in gut Decreases Ca mobilization from bone. Increase Phos retention: Ca-Phos binding occurs which lowers Ionized Ca Result is Hypocalcemia which causes increased PTH production. Under normal conditions, PTH will go to the kidneys and stimulate production of vitamin D for gut calcium absorption and decrease calcium spillage into urine. It will also go to the bone and encourage calcium release. In kidney disease patients who are unable to make vitamin D and reabsorb calcium, the brunt of the PTH burden lies on the bones. (bone disease). Results in hypocalcemia PTH secretion is able to maintain [Ca++] and Phos] within normal range in CKD stages 3 and 4. At the expense of bones. |
|
What are the complications of secondary hyperparathyroidism?
|
Renal Osteodystrophy
Adynamic Bone Disease (low bone turnover state) which alternates with Osteitis Fibrosa Cystica (high bone turnover state) Soft tissue calcification: Coronary arteries Heart valves Other major arteries – can lead to amputations Proximal myopathy Pruritus (very severe) Skin ulceration and soft tissue necrosis (calciphylaxis or calcific uremic arteriolopathy) |
|
When do we start checking for secondary hyperparathyroidism?
|
From Stage 3 CKD onwards.
Check PTH, Ca , Phos at least every year for stage III. PTH, Ca and Phos every 3 months for stage IV. PTH every 3months, Ca, Phos every month for stage V. PTH goals are: Stage III- 35-70 pmol/L Stage IV-70-110 pmol/L Stage V-150-300 pmol/L Shoot for Ca of ~8.4-9.5 mg/dL in stages IV and V. |
|
How do we treat secondary hyperparathyroidism?
|
GFR< 60 (Stage 3):
√Check Vit 25 D, PTH, Ca, Phos Replete Vit 25 D if insufficient (Ergocalciferol x 6mo) Once Vit 25 D repleted, if PTH still elevated above target, start active vitamin D supplementation Dietary restriction to maintain serum levels of Phosphate and PTH levels at goal: 800- 1,000 mg/day Phosphorus restriction. Protein restriction. Phosphate Binders: Decrease phosphate stimulation of PTH secretion. Binds phosphate in foods to a cation in the intestinal lumen and excrete without being absorbed. MUST be taken with food to work!! |
|
What are the different binder types we use for treating secondary hyperparathyroidism?
|
Basically calcium binders and non-calcium binders.
!!Not important!! Calcium: Calcium carbonate (Oscal, Tums) Calcium acetate (Phos-Lo) Calcium citrate (Citrical) Aluminum: Aluminum hydroxide (Alu-Tab, Amphogel) Aluminum carbonate (Basagel) Lanthanum Lanthanum carbonate (Fosrenol) Polymers Sevelamer (Renagel, Renvela) |
|
What is the goal of active vitamin D supplementation in secondary hyperparathyroidism?
|
Increased gut absorption, Increased bone efflux, ↓Ca/Phos tubular excretion to increase serum Ca levels/decrease phos levels
Decrease PTH stimulation Stop vitD if Ca>9.5 or PTH below goal. |
|
What are some examples of active vitamin D supplements?
|
Calcitriol (natural form)
Paricalcitol Doxercalciferol |
|
What do we do for PTH secretion refractory to therapy with VitD & Phos binders?
|
Cinacalcet (Sensipar):
increases the sensitivity of the calcium-sensing receptor on the parathyroid gland thereby inhibiting PTH. Subtotal Parathyroidectomy: Indications- Persistent serum levels of intact PTH >800 pg/mL. Severe hypercalcemia. Progressive and debilitating hyperparathyroid bone disease. Pruritus that does not respond to medical or dialytic therapy. Progressive extraskeletal calcification or calciphylaxis. Symptomatic myopathy. |
|
When does chronic metabolic acidosis usually begin in CKD?
|
when GFR<40ml/min/1.73m2
Acidosis tends to be mild Consequences: Increases bone resorption. Weakens bone structure. Increases risk of fractures. Enhances protein catabolism, contributing to malnutrition. Treatment: Oral Sodium Bicarbonate tablets Maintain HCO3>22 |
|
Why do we restrict protein in CKD and dialysis patients in general?
|
Low-protein diets (0.8-1g/kg) reduce the generation of nitrogenous wastes and inorganic ions.
Diminish the ill effects of hyperphosphatemia, metabolic acidosis, hyperkalemia Retard progression of underlying kidney disease. Disadvantage: Malnutrition. GFR<30 is an independent risk factor for malnutrition. |
|
What is the goal lipid profile for CKD patients?
|
LDL<100, nonHDL <130 (nonHDL=Total Cholesterol – HDL)
|
|
Summarize the management of CKD...
|
Control BP < 130/80 and control proteinuria:
ACEI, ARB Diuretic Correct severe anemia, (Hb11-12) RULE OUT Fe deficiency and correct if necessary. Control high phosphorus and PTH Use NaHCO3 to correct acidosis (HCO3>22) Control cholesterol (LDL<100, nonHDL<130) Lifestyle Modifications: 2 - 3 gm Sodium diet Control Protein intake but avoid malnutrition. Avoid NSAIDs, fleets, IV contrast and gadolinium. Smoking cessation. Reduce obesity. |
|
The most sensitive stain from Amyloid is....
|
Thioflavin T-stained section (under fluorescent light).
Congo red that stains apple green is most commonly used. Both are ordinary histochemical stains. NOT immune On EM, almost complete replacement of the glomerular basement membrane . |
|
What does myeloma cast nephropathy look like?
|
characteristic fractured casts with surrounding multinucleated giant cells.
|
|
What complications can occur from horseshoe kidney?
|
Complications, when they occur, are mostly related to a true obstruction at the ureteropelvic junction. (kinking of the ureter)
Stasis, stones, infections etc, |
|
What is the most common cause of ESRD in childhood?
|
Multicystic dysplasia.
(NOT polycystic kidney disease) Related to lower UT obstruction. Can be bilateral, unilateral or segmental. Primitive ducts and cartilage seen on histology. |
|
What is the distribution of the various cysts in polycystic kidney disease?
|
In infantile or ARPKD, collecting ducts or ducts of Bellini.
(explains distribution) Medullary cystic disease complex is actually a misnomer. They don't necessarily have cysts. They have an abnormality in the secretion of uromodulin by the TALH. Medullary sponge kidney, cysts occur in the papillae. Relatively benign, can be incidental finding. Can also form stones or get UTI's. Simple cysts are typically benign. |
|
The most common adult kidney neoplasia is....
|
Renal cell carcinoma.
Bright yellow (high lipid) Bleeding causes bright red and brown colors. Scar tissue formed is gray. |
|
What does the clear variant of Renal cell carcinoma look like?
|
Graded based on nuclear features with larger nuclear size and prominence of nucleoli correlating with higher nuclear grade (Fuhrman system)
|
|
What does the papillary form of renal cell carcinoma look like?
|
|
|
What does the papillary form of renal cell carcinoma look like?
|
|
|
What are some unique features of papillary variant renal cell carcinoma?
|
Foam cell cores and the psammoma bodies.
|
|
The most aggressive form of renal carcinoma is....
|
Collecting duct carcinoma also related medullary carcinoma
Dismal prognosis. More common in sickle cell. |
|
Is there such a thing as renal cell adenoma?
|
Yes, this term can be used but it has to be a papillary lesion less than 0.5cm. Such a small lesion has a low risk of metastasis.
A clear cell tumor is always a carcinoma. |
|
What is the most common malignant neoplasm of childhood?
|
Wilm's tumor.
|
|
What are the three components of a Wilm's tumor?
|
The undifferentiated blastema,
Epithelial component Mesenchymal component. Based on presence or absence of anaplastic nuclear features a particular case is classified as have a poor or good prognosis, respectively. |
|
What benign tumor is sometimes seen in adults?
|
Oncocytoma.
Hard to distinguish from chromophobe renal cell carcinoma. Use cytokeratin stain, the carcinoma will have extensive staining along the cell membranes whereas the oncocytoma will have small groups of cells staing through the cytoplasm. |
|
What are the various forms of cystitis?
|
Hemorrhagic (cyclophosphamide)
Bullous Emphysematous (gas formers) Encrusted (Schistosoma) Follicular (Strong lymphoid reaction) Papillary (might be neoplasm) |
|
What are the malignant urinary tract tumors?
|
Epithelial:
Transitional cell Carcinoma Squamous cell carcinoma Adenocarcinoma Stromal: Sarcoma botroydes Mixed mullerian tumors Other sarcomas |
|
What is carcinoma in-situ in the UT?
|
Refers to neoplasia involving flat urothelium.
We cannot use the term if there are papillae or villi. |
|
Why should we be concerned about Stage V CKD?
(Typical GFR<15 but no hard and fast rule for starting dialysis) |
Number of patients with ESRD are increasing (increasing Incidence).
Dialysis saves lives but is a costly therapy. Survival of patients with CKD not as good as we would like it to be. |
|
What is the leading cause of ESRD?
|
Diabetes
Incidence rates highest in elderly patients, highest in AA. Average age of new dialysis patients is increasing. Prevalence is highest in age 45-64 but incidence is higher in older patients because of survival and comorbidities. Same applies to race. Whites have higher prevalence but AA higher incidence. |
|
Summarize the epidemiology of stage 5 CKD concisely?
|
Runs in families
ESRD Most commonly due to Diabetes Most Often seen in elderly with comorbidities Highest incidence rates in African Americans |
|
What are contraindications for hemodialysis?
|
Absolute:
No access Fresh intracranial bleed (can dialyse without anticoagulation though) Relative: Hemodynamic instability/CVDz Carotid disease Difficult disease GI bleeding |
|
What is the typical hemodialysis schedule?
|
Typical treatment = 4 hours - 3/week
The more dialysis the better patients do.(Easier to control BP) The higher phosphorus gets the higher the risk of death. |
|
What are the contraindications for peritoneal dialysis?
|
Absolute:
Cannot/will not learn No partner, home not suitable Unusable abdomen (no PD surface area) Ostomy (colostomy>>ureterostomy) Relative: Social instability, Malnutrition, Large body weight (BSA, V) Fresh intraabdominal foreign body (AAA graft) Inflammatory bowel disease |
|
How does peritoneal dialysis typically work?
|
Usually a daily (7 days a week) therapy
Two major forms of PD: CAPD -- do all manual exchanges (3 during day, 1 overnight) APD -- use a cycler to do automated exchanges at night (3 exchanges) while sleeping with a daytime dwell. Blood Flow Independent Blood supply - mesenteric vessels Membrane - peritoneal, mesothelial cells. |
|
In summary, stage VCKD patints have the following options:
|
Conservative therapy
Transplantation Hemodialysis Peritoneal dialysis MOST PATIENTS WILL LIKELY NEED A COMBINATION OF MANY OR ALL REPLACEMENT THERAPIES IN THEIR LIFETIME |
|
What is the difference between hemodialysis fluid and peritoneal dialysis fluid?
|
HD: non sterile, must
be locally produced* PD: sterile, shipped |
|
Dialysis is driven by two physical processes. What are they?
|
Diffusion
(The smaller the molecular weight, the easier it is to increase diffusion by increasing flow rate) Convection |
|
How do we increase solute clearance in hemodialysis?
|
Can pick different dialyzers (membranes, surface area) to augment clearance
Increase blood flow as tolerated Increase time per treatment |
|
How do we increase solute clearance in peritoneal dilaysis?
|
All patients have different peritoneal membrane transport characteristics (mostly depending on vascularity)
You can not pick membrane type Must adjust dwell time per exchange to match peritoneal membrane transport type Increase instilled volume/exchange Increase number of exchanges |
|
How do we control ultrafiltration (salt and water removal) in dialysis?
|
HD -
due to adjustment of trans-membrane pressures. Increase by changing positive or negative pressure forces. PD - due to osmotic pressure gradients. Increase by adjusting % glucose in fluids (increase osmotic pressure gradient) |
|
Convection (ultrafiltration) is important for removing...
|
Middle molecules.
Can increase convective clearance by increasing UF volume In HD one can intentionally manufacture synthetic membranes with a high UF intrinsic ultrafiltration rate in order to optimize middle molecule removal Can not do this with PD. |
|
Diffusive clearance is important for...
|
Very effective for small molecular weight solutes removal
Not as effective as increasing convective clearance would be for middle molecule removal |
|
What sort of access is used for dialysis?
|
HD:
-natural a-v fistula preferred -a-v graft (gortex) next best -temporary catheters (IJ) most are gortex grafts PD: Tenckhoff |
|
What sort of access related infections are associated with dialysis?
|
HD:
Can have exit site infections. Can have bacteremia, line sepsis Highest risk Tunneled catheter > Graft > AVF Bacteremia occasionally complicated by endovascular infections (SBE) or joint infections PD: Can have exit site infection (1/6 years on average) Can get peritonitis (On average about 1 in 3.5 years) Almost never have bacteremia |
|
To what degree does dialysis replace normal kidney function?
|
Efficient regimens only provide 10-12% of the small-solute clearance of two normally functioning kidneys
|
|
The patients who benefit the most from early kidney transplant are...
|
Young caucasian diabetics
|
|
When should a patient be referred for transplant?
|
GFR < 30 cc/min
Rapid decline in renal function Diabetics- early |
|
Is HIV a contraindication for renal transplant?
|
Not any more.
Stable HIV can get a transplant. |
|
What are the general exclusions for renal transplant?
|
Severe cardio-vascular disease
Malignancy within the past two years Active infection Morbid obesity Poor functional status Lack of adequate social support Uncontrolled psychiatric disease Active substance abuse Non-adherence to medical regimen |
|
What phenotypes are matched for renal transplant?
|
HLA -A, -B, -DR
Millions of combinations exist Unique combinations more common in non-Caucasian groups The immune response is directed one way, from recipient to donor. GVHD very rare in solid organ transplant. Random sibling 25% will be 1/6 match. 25% will be no match. 50% will be 3/6 match. There is a clear survival advantage to a well matched kidney. |
|
How do you accrue points on the UNOS list?
|
Time on waiting list.
HLA DR matching. Pediatric recipient (Age < 18 years) gets four automatic years. Prior living donor gets four automatic years. Panel reactive antibody >80 % Medical urgency is NOT a factor for the national waiting point system |
|
What is PRA?
|
Essentially susceptibility to rejection.
the higher the PRA the more you need a perfect match. PRA >20 % means Higher risk for rejection Predicts waiting time for deceased donor organ. UNOS assigns additional points for PRA >80 % |
|
Logistically, kidneys are allocated...
|
Locally first, then regionally, then nationally
UNOS requires ABO identity (i.e. Group O for O), this is for fairness. |
|
Who typically waits longest for transplant in descending order?
|
B
O A AB |
|
The recent trend has been...
|
A decrease DD kidneys and an increase in LD kidneys.
This probably due to more relaxed LD exclusion criteria. |
|
Who is a deceased organ donor?
|
Known irreversible brain injury
Normothermic, non-sedated, comatose patient Absence of brain stem reflexes, motor responses, respiratory drive Physician and family intend to withdraw life support Required to contact the organ procurement organization (OPO) in a timely fashion: Before brain death occurs Prior to withdrawal of life support With family consent, OPO may proceed and determine suitability of donor: OPO will discuss donation with the family in a private setting, separate from pronouncement of brain death Precludes donation: Active infections Overwhelming sepsis Specific systemic infection (i.e. rabies, HIV, TB) Current malignant neoplasms |
|
What are the criteria for live kidney donors?
|
What are the criteria for live donors?
Age >18 and usually <65 years Healthy, willing Common contraindications: Proteinuria Reduced kidney function Diabetes Hypertension (relative) Evaluation is extensive and time-consuming Cost is covered by the recipient’s medical insurance |
|
What are the causes of early graft dysfunction?
|
Hypovolemia
Urinary obstruction Acute pyelonephritis Drug toxicity Calcineurin inhibitor*-related Acute rejection: Antibody-mediated Cell-mediated |
|
How does acute rejection in kidney transplant recipients present?
|
Uncommon after the first 6 months post-transplant
Presentation: Asymptomatic rise in the serum creatinine If abrupt discontinuation of anti-rejection medications, may present with a painful swollen allograft. Diagnosed by renal transplant biopsy Excellent response rate when treated early Consequence: scarring, loss of function |
|
What are the causes of late (>3months) graft rejection?
|
Intrinsic renal process:
Chronic rejection Chronic drug toxicity Late acute rejection Recurrent and de novo renal diseases Transplant pyelonephritis Mechanical: Ureteral obstruction or stricture |
|
What is chronic allograft dysfunction?
|
Common endpoint for renal allografts
Progressive decline in function over months-years A non-specific, multi-factorial disorder: Immunologic injury Chronic rejection Non-immunologic causes Poorly controlled blood pressure Diabetes mellitus Dyslipidemia Immunosuppressive drugs (i.e. cyclosporine and tacrolimus) Pathology: vascular obliteration, interstitial fibrosis and tubular atrophy. |
|
Rejection drugs increase the risks of...
|
Non-melanoma skin cancers:
Account for more than 50% of all malignancies in transplant recipients Post-transplant lymphoproliferative disorder: Usually arises after primary infection or reactivation of latent Epstein-Barr Virus infection |
|
What sorts of infections are transplant patients susceptible to?
|
1st month:
Similar infections to non-immunosuppressed surgical patients Wound infections Line-related infections Month 1-6 post-transplant: Immunomodulating viruses Cytomegalovirus Urinary tract infections Greater than 6 months post-transplant Urinary tract infections, community acquired pneumonia Opportunistic infections: Listeria Monocytogenes, Nocardia sp, mycobacteria |
|
How does cellular (T-cell rejection) work?
|
Transplantation
Recognition: Antigen Presenting Cells interact with CD4 T-lymphocytes Stimulation: CD4 T cells release IL-2 (a cytokine), key growth factor for T cell proliferation. Activation: Cytokines trigger cytotoxic T-cells (CD8), trigger further proliferation Rejection: Cytotoxic T-cells attack tissue, activate other cell responses |
|
How does Acute Humoral (Antibody-Mediated) Rejection work?
(B-cell rejection) |
Transplant recipients may produce antibody to the donor’s HLA antigens
Acute humoral rejection may occur on its own or may co-exist with cellular rejection May result in chronic rejection, an irreversible process causing vascular damage Occurs months to years after transplant. |
|
What principles guide the prevention of rejection in solid organ transplant?
|
Combination Immunosuppressive Therapy
Complementary mechanisms of action without overlapping toxicity Induction Therapy Therapeutic Drug Monitoring Compliance with medication regimen and follow-up |
|
What factors influence the immunologic rejection risk?
|
LOW:
First Renal Transplant Non African-American PRA ≤20 % Elderly Recipient HIGH: Repeat Renal Transplant African-American PRA >20% Pediatric Recipient |
|
What are indications for induction immunosupression?
|
Lower degree of HLA matching
i.e. Deceased or living unrelated donor Higher immunologic risk patients |
|
What are two main categories we can categorize transplant immunosupression drugs into?
|
Lymphocyte depleting (very potent):
-Polyclonal antibody preparation- Rabbit Anti-thymocyte globulin or r-ATG (Thymoglobulin) -Monoclonal antibody preparation- Alemtuzumab (Campath 1-H) Muromonab-CD3 (OKT3 Non Lymphocyte depleting (Better tolerated): -IL-2 Receptor Antagonists- Basiliximab (Simulect) Daclizumab (Zenapax) |
|
What are side effects of rATG (Thymoglobulin)?
|
Polyclonal so not very specific.
Infusion-related reactions: Fever/chills. Anaphylaxis including hypotension and respiratory distress are rare. Prevent or reduce infusion-related reactions by pre-medication with corticosteroids ± acetaminophen ± diphenhydramine. Slowing the infusion rate. Side effects Thrombocytopenia and/or neutropenia Increased risk of infection in the months following the use of rATG. |
|
What is Alemtuzumab (Campath 1-H)
|
Humanized monoclonal antibody:
Targets CD52 antigen present on all lymphocytes Includes B-cells AND T-cells Approved for use in treatment of B-cell chronic lymphocytic leukemia: Role in transplantation is induction therapy (Select centers including WFU) Given as one intravenous dose intra-operatively. |
|
What adverse events are associated with alemtuzumab?
|
Infusion-related reactions:
Fever, chills, hypotension, bronchospasm Pre-medication may prevent/decrease infusion related reactions Others: Bone marrow suppression. Leukopenia is frequent. Increased risk of infection for months after administration. |
|
What are IL-2 receptor antagonists good for? (Basiliximab
and Daclizumab) |
Bind with
high affinity to the alpha subunit of the IL-2 receptor (CD25) Indicated for the prophylaxis of acute rejection in lower immunologic risk patients NOT effective treatment for acute rejection Mechanism of Action Target: CD25, saturates the receptor for weeks Inhibits IL-2 binding, competitively inhibits IL-2 mediated activation of lymphocytes. Adverse events: Good tolerability No pre-medication necessary |
|
What drugs are used for maintenance immunosupression?
|
Calcineurin Inhibitors (CNIs):
Tacrolimus (FK-506, Prograf) Cyclosporine (Neoral, Gengraf) mTor Inhibitors: Sirolimus (Rapamycin) Anti-Proliferative Agents: Mycophenolate Mofetil (Cellcept) Azathioprine (Imuran) Corticosteroids: Prednisone |
|
How do calcineurin Inhibitors (Tacrolimus and Cyclosporine) work?
|
Act at an early stage of T-cell activation
Inhibits transcription of interleukin-2 and other cytokines Inhibits T-cell activation The cornerstone of most immunosuppressive regimens in the United States Two drugs in this class Cyclosporine: Binds to cyclophilins (hirsutism and gingival hyperplasia) Tacrolimus: Binds to FK-binding protein (worse on glucose, hair loss and neurologic side effects) Pharmacokinetic monitoring is required |
|
How does Sirolimus (Rapamune) work?
|
Place in therapy:
Prevent acute rejection Potentially less nephrotoxic than the CNIs May be used in place of the CNI Binding: mTOR (Mammalian Target of Rapamycin) Mechanism of Action: Binds later in the T-cell activation pathway than the CNIs Interferes with IL-2 signaling Markedly suppresses T-cell proliferation. Adverse effects: Anemia, leukopenia, thrombocytopenia Delayed wound healing Lymphocele formation Increased cholesterol and triglyceride levels. Edema Diarrhea |
|
How does azathioprine work?
|
Anti-rejection therapy
Mechanism of action: Metabolized to 6-MP in the liver 6-MP inhibits DNA and RNA synthesis Interferes with proliferation of T- and B- cells Toxicity: Bone marrow suppression (especially leukopenia) Pancreatitis. NEVER use with allopurinol!!! |
|
How does Mycophenolate Mofetil(Cellcept, MMF) work?
|
Anti-rejection therapy
Commonly used in combination with a CNI or sirolimus, rarely by itself. Mechanism of action: Inhibits de novo guanine synthesis Blocks proliferation of T- AND B- cells Adverse effects: Diarrhea Leukopenia, anemia |
|
How do steroids help in transplant rejection prevention?
|
Interfere with macrophage function
Inhibit synthesis and release of IL-1 Inhibit IL-2 secretion from T-cells Non-specific anti-inflammatory effects LOTS of side effects. Withdraw as early as possible. |
|
So how do we treat acute rejection?
|
Mild Cell-mediated Rejection:
Bolus intravenous corticosteroids X 3-5 days Severe Cell-mediated Rejection: Lymphocyte depleting agent X 5-10 days via a central line Antibody-Mediated Rejection: Plasmapheresis followed by Intravenous Immune Globulin X 3-9 treatments |
|
How does CMV present?
|
Presentation:
Acute viral syndrome with leukopenia Tissue invasive disease: hepatitis, pneumonitis, pancreatitis, colitis Risk Factors: CMV sero-negative Recent treatment with lymphocyte depleting agent. Diagnosis. Demonstration of CMV viremia by PCR Treatment: IV ganciclovir or oral valganciclovir (prodrug) Reduce dose if renal insufficiency |
|
What drugs interact with calcineurin inhibitors?
|
P450 Enzyme Inducers:
(Lower CNI Level) Antituberculosis drugs- Isoniazid Anticonvulsants- Phenytoin (Dilantin) P450 Enzyme Inhibitors: (Raise CNI Level) -Calcium channel blockers- Diltiazem Verapamil -Antifungal agents- Fluconazole Ketoconazole -Antibiotics- Erythromycin Clarithromycin (Biaxin) |
|
What drug is contraindicated in dialysis patients?
|
Demerol
|
|
What size are amyloidosis patients kidneys?
|
Big
|
|
Causes of nephrotic syndrome....
|
Membranous nephropathy
Minimal Change disease FSGS IgA Nephropathy Lupus HIV Amyloidosis Diabetic Nephropathy MPGN C1q nephropathy |
|
How do we treat hyperkalemia....
|
Emergent hemodialysis treatment
IV calcium, insulin, glucagon, and sodium bicarbonate Kayexalate 60 gm po or pr times one |