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330 Cards in this Set

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Know healthy, under- and overweight, and obesity BMI definitions.
Underweight BMI: <18.5
Healthy BMI: 18.5-24.9
Overweight BMI: >= 25
Obesity BMI: >=30
Extreme Obesity >=40
Leptin

source, genetics, 2 fnx, loss of fnx mutation
Source: adipose tissue
ob gene = leptin
db [diabetes] gene = leptin receptor [JAK-STAT]
Fnx: high [leptin]
1) suppresses neuropeptide Y --> inhibits anabolic circuits
2) stimulates leptin-melanocortin circuit POMC/CART --> stimulates catabolic pathways, important in thermogenesis

Loss of fnx mutation --> early onset severe obesity

[3] pro-inflammatory cytokine, regulates hepatopoiesis & lymphopoiesis
[4] involved in puberty
ob gene

product, fnx
gene for leptin

1) suppresses neuropeptide Y --> inhibits anabolic circuits
2) stimulates leptin-melanocortin circuit POMC/CART --> stimulates catabolic pathways, important in thermogenesis
db gene

fnx
JAK-STAT leptin receptor

1) suppresses neuropeptide Y --> inhibits anabolic circuits
2) stimulates leptin-melanocortin circuit POMC/CART --> stimulates catabolic pathways, important in thermogenesis
MC4R mutation
important receptor in leptin-melanocortin circuit POMC/CART, normally stimulates catabolic pathways, important in thermogenesis

MC4R mutation in Leptin-POMC pathway --> no satiety signal --> 5% of massive obesity
Adiponectin

Source, Fnx
adipose tissue, produced more in lean individuals

Fnx
1° Directs FA to muscle for oxidation
2° Acts on Liver to inhibit metabolic syndrome: decreases FA influx in liver, decreases TAG content, decreases Gluocse prodxn
Ghrelin

Source, Fnx
THE ONLY GUT HORMONE THAT INCREASES FOOD INTAKE
Source: arcuate nucleus of hypothalamus + empty stomach
Fnx: binds growth hormone secretogoge receptor
obese individuals not able to fully suppress ghrelin
Gut homrone which increases food intake

Source, Fnx
Ghrelin is the only one

Source: arcuate nucleus of hypothalamus + empty stomach

Fnx: binds growth hormone secretogoge receptor
obese individuals not able to fully suppress ghrelin
Peptide YY

Source, Fnx, Loss of Fnx
Fnx: ↑ after food intake --> stims POMC/CART neurons in hypothalamus -->satiety signal;

Lost in Prader Willi syndrome --> hyperphagia & obesity
Prader Willi syndrome
Loss of Fnx in Peptide YY

Normally ↑ after food intake --> stims POMC/CART neurons in hypothalamus -->satiety signal;
Leptin: melanocortin circuit: catabolic pathway
POMC/CART [Pro-opiomelanocortin/Cocaine-Amphetamine regulated transcipts] neurons: within hypoathalamic arcuate nucleus. Stimulated by Leptin, Peptide YY to produce alpha Melanocyte-stimulating hormone. aMSH + Melanocortin Receptor 4 MC4R on endocrine/ANS cells --> TRH, CRH --> increases SNS tone, energey expenditure decreases food intake

MC4R mutation in Leptin-POMC pathway --> no satiety signal --> 5% of massive obesity
NPY/AgRP pathway
[Neuropeptide Y, Agouti-related peptide]
ypothalamus stimulated by ghrellin, inhibited by Leptin and Peptide YY; Produce Neuropeptide Y which increases appetite and decreases energy utilization
3 consequences of hyperinsulinemia
→ ↓ [adiponectin] → ↑ [insulin] (+feedback)
→ ↓ IGFBP-1 & -2, (binding proteins) → ↑ free IGF-1 → aging
→ both IGF-1 & Insulin ↑ cell proliferation & ↓ apoptosis --> CA
→ sex hormonal changes: ↑ peripheral aromatas activity, estrogen bioavailability, ovarian androgen, ↓ SHBG prodxn --> endometrial & breast CA
List all cardiovascular health risks of obesity.
Coronary Artery Disease ( htn & hyperlipidemia)
CHF: (htn) major cause of death in obese pts
Thrombi: htn + inactivity + visceral adipose tissue produces TNFa, IL1, IL6 --> ↑ C reactive protein, ↑ prdxn of PAI plasminogen activator inhibitor + ↑ platelet activation
5 features of metabolic syndrome.
Central Obesity
Insuline Resistance
HTN
Dyslipidemia: high cholesterol, high TAGs, low HDL +- increases LDL
Impaired Glucose Tolerance
What is the pathogenesis of hypertension and of thromboembolism related to obesity?
excess insulin →
retention of sodium --> expansion of blood volume
↑ NE
↑ Smm proliferation w/in arterioles ↓ artery distendability

visceral adipose tissue produces TNFa, IL1, IL6 → ↑ C reactive protein, ↑ prdxn of PAI plasminogen activator inhibitor + ↑ platelet activation
What are the gastrointestinal risks of obesity?
Gallstones--> cholecystitis, pancreatitis, gallbladder CA
unfavorable lecithin:cholesterol ratio --> precipitation into gallstones

Hernias: Umbilical, abdominal incisional, inguinal, hiatal

GERD --> Barret's --> Adenocarcinoma

Hemorrhoids

Non-EtOH Fatty Liver Disease; Steatosis --> Steatohepatitis --> Cirrhosis
What pulmonary and sleep disorders are related to obesity? Describe the sleep disorders.
Asthma 2* to inflammatory cytokines of abdominal fat
Restrictive Lung Disease --> Pickwickian hypoventilation syndrome
Sleep Apnea 2* to neck circumference >=17" M, >=16" F
Additl Drowsinesss due to meatbolic change
Pickwickian Syndrome
extreme fat restricts lung expansion --> hypoventilation --> twitching, cyanosis, periodic breathing, 2* polycythemia, Right Heart failure
Obstructive Sleep Apnea:
best predictor & complications
50% 2* to neck circumference >=17" M, >=16" F
predisposes to htn, sudden death, postop edema, ARDS
What are the musculoskeletal, including Osteopathic complications of obesity?
Gouty Arthritis
+
Osteoarthritis 2* to weightbearing
Knees in women
Hips in men
Feet & Ankles in both

Flattened Thoracic & Lumbosacral curves
Sacral extension, L5 anterior to S1
--> bilateral intermittend lumbar radiculopathy
--> lumbostacral instability --> pain, weakness in legs
--> constant low back pain
--> atlanto occiptal muscle contracture headaches
Female reproductive risks of obesity
Menstrual irregularity and amenorrhea
ovulatory infertility
polycystic ovarian syndrome
increased maternal morbidity
-gestation htn, diabetes
-increased C section rate
-increases risk of pre-eclampsia

Increased fetal morbidity
-congenital malformations esp NT and heart
-macrosomia 2* to daibetes
Male reproductive risks of obesity
Impotence & Infertility
Renal Effects of Obesity
DM is the most common cause of renal failure in adults
Htn: 2nd most cause of renail failure in adults
Renal insuffieincy not 2* to htn/DM
What are psychosocial affects of obesity?
Depression, worse w/ childhood onset
Bing eating disorder
Poor body image, esp white females -- tendency to OVERestimate body size correlates with adolescent obesity
Fale expectations for weight loss
Social stigmatization for "poor self control"
Discrimination: employment, college application, rental, dating
What cancers are strongly associated with Obesity? Describe the pathogenesis of obesity-related cancer risk.
Insulin stimulates growth & IGF-1 release
IGF-1 is mitogenic, anti-apoptotic
estrogen syntehd in fat from androgens
androgen syned in ovaries, adrenals
↓ sex hormone binding protein prodxn
↓ adiponectin (licenses hyperinsulinemia)

Distal Colon
Endometrial
Prostate
Esophageal adenocarcinoma (2* to GERD)
Gallbladder (2* to stones)
Renal Cell Carcinoma (esp women)
What is the overall impact of obesity on mortality
Increase of all cause mortality 50%+ at BMI >30
13 year reduction in life expectancy
What skin lesions are more frequent in obesepatients?
psoriasis
Funcal infections of skin folds esp taenia cruris (groin-perineum of obese men)
panniculitis: bacteiral infection in subcu abdominal fat
fourneir's gangrene: necrotizing fasciitis of scrotum
What are the diagnostic criteria for diabetes Mellitus?
Fasting
Normal: <=100 mg/dL
Impaired Tolerance 100-125
Diabetic: >126 mg/dL

Random
Normal: <=140
Impaired 140-199
Random: >=200 mg/dL

Hemoglobin A1C
Normal: 5%
DM: >=6.5
How does HbA1c correlate to average fasting glucose
Start with HbA1c of 5 ~= average blood sugar at 100
add 35 glucose/1% A1c
What is HbA1c

When is it not usefule?
Glycohemoglobin, glycosylated/glycated hemoglobin
monitoring lab test for average glucose levels over previous few months
decreased in sickle cell anemia (HbF) & thalassemia (decreased HbA1
List all causes of diabetes mellitus
Type 1: Beta Cell Destruction

Type 2: IR w/ relative insluin deficiency

Genetic defects of Beta cell fnx: MODY & Mito dysfnx
---MODY = Maturity Onset Diabetes of the Young genes

DM 2* to
--Pancreatic damage: chronic pancreatitis, CF, pancreatectomy, heomchromatosis
--Endocrinopathies: Cushings
--Infx : Coxsackie B, CMV
--Drugs: glucocorticoids, protase inhibitors, thiazides, beta adrenergics
Describe the pathogenesis of type I diabetes mellitus.

What genes are involved
The fundamental abnormality is a failure in T cell regulation

Insidious autoimmune process presents abruptly after 90% destroyed
autoantibodies found in serum, actual damage done by CTL's

Genetic susceptibility: 70% twin-corcordance & 6% of 1st degree relatives
20 genes
--insulin polymorphism
--95% have HLA-DR3, DR4 or both; Class 2 MHC Chrom 6; [DQ8 strongly assoc as well]
--CTLA4; PTPN-22 KO's → ↓ T cell inhibition
--CD25 ie IL2R KO → ↓ T reg population

Coxsackie B, M, M, R, CMV & EBV
Hygeine hypothesis
What are clinical features of insulin resistance?
Acanthosis nigricans of skin
Polyps of the skin
polycistic ovary syndrome, anovulation, hirsutism
high BP
↑ visceral fat in vast majority of IR & majority of BMI>50 have IR
Describe the pathogenesis of type II diabetes mellitus.
Multifactorial: Genetic + Environment
twin concordance > than Type 1(70%), 40+ loci, most strongly beta cell fnx/insulin secretion, NO HLA's
Altered insulin signalling pathway --> IR --> postprandial hyperglycemia

↑ visceral fat in vast majority of IR & majority of BMI>50 have IR
NEFA's: non-esterified fatty acids; build up and ↓ responsiveness to insulin → , loss of inhibition of hepatic Gng
Prohyperglycemia adipokines retinol binding protein 4 RBP4 & resistin
Lack of antihyperglycemic adipokines: leptin, adiponectin which normally enhance hepatic & skm AMP-activated protein kinase AMPK to promote FA oxidation. Targetted pathway of metformin
Proinflammatory cytokines: TNF, IL6 & M∅ chemoattractant protein 1; create cellular "stress" activates multiple signalling cacades to antagonize insulin
Peroxisome proliferator- adtivated receptor gamma PPARG: receptor/transcription factor --> adipocyte differentation, deposition of NEFA in adipose (not liver Muscle) + adiponectin secretion; KO = monogenetic diabetes; stimulated by thiazolidinediones

Beta cell dysfnx: genetic predisposition, lipotoxicity from increased NEFA's, accumulation of toxic amyloid in iselts
NEFA's
non-esterified fatty acids; build up in obesity and ↓ responsiveness to insulin → , loss of inhibition of hepatic Gng
RBP4
retinol binding protien 4

prohyperglycemic adipokine produced during IR
resistin
prohyperglycemic adipokine produced during IR
AMPK
AMP activated Kinase.

stimulated in liver & SkM by adiponectin and leptin

promotes FA oxidiziation

leptin, adiponectin signals lost in IR
targetted pathway of metformin
cellular "stress" of IR
TNFa, IL1 & M∅ chemoattractant protein 1 induce cellular stress antagonizes insulin
PPARG
Peroxisome proliferator- adtivated receptor gamma PPARG: receptor/transcription factor → adipocyte differentation, deposition of NEFA in adipose (not Liver, Muscle) + adiponectin secretion;

KO = monogenetic diabetes;

stimulated by thiazolidinediones
pathway targeted by metformin
AMPK: AMP activated Kinase.

normally stimulated in liver & SkM by adiponectin and leptin

promotes FA oxidiziation

leptin, adiponectin signals lost in IR
pathway targetd by thiazolidinediones
Peroxisome proliferator- adtivated receptor gamma PPARG: receptor/transcription factor → adipocyte differentation, deposition of NEFA in adipose (not Liver, Muscle) + adiponectin secretion;

KO = monogenetic diabetes;
Define MODY, describing genetics, clinical features and characteristics of MODY.

Describe MODY2
Maturity onset Diabetes of the Young
Autosomal dominant genes, onset <25yo
not correlated with: obesity, IR, islet cell autoantibodies
6 genetic defects not relating to T2DM

MODY2: glucokinase deficiency: first & RLS of glucose metabolism, transferring P to glucose; mild, non-progressive chronic hyperglycemia
half --> gestational DM, accts for 5% of gestational DM

remaining MODY's control insulin expression, B cell mass
MODY2
glucokinase deficiency: first & RLS of glucose metabolism, transferring P to glucose; mild, non-progressive chronic hyperglycemia
half --> gestational DM, accts for 5% of gestational DM
glucokinase deficiency
MODY2

glucokinase deficiency: first & RLS of glucose metabolism, transferring P to glucose; mild, non-progressive chronic hyperglycemia
half --> gestational DM, accts for 5% of gestational DM
Advanced Glycation End Products
intracellular glucose derived dicarbonyl precurosors + amnio groups of proteins; resistant to protesolytic degredation, rate of prodxn increases in hyperglycemia

AGE can directly crosslink polypeptides, decreases large vessel elasticity, & makess it sticky, trapping LDL's --> atherogenesis

Receptors = RAGE; Rage-AGE -->
-M∅ release cytokines, growth & procoagulant factors
-endothelial cells produce ROS's & procoagulant activity
-VSMC proliferate & synth ECM

AGE in capillaries & glomeruli traps albumin in basement membrane = diabetic microangiopathy
DAG
metabolic intermediate in the breakdown of FA, backup excess serves as a signalling molecules, activates Protein Kinase C →

increased VEGF (diabetic reitnopathy)
decreased NO → vasoconstriction, increasess endothelin
deposition of ECM & BM
Increased PAI plasminogen activation inhibitor
proinflammatory endothelium
Polyols
Ts which do not req insulin for glut transport: nerves, lenses esp

NADPH used in reaction aldose reductase glucose --> sorbitol; NADPH not available regenerate GSH --> ROS damage; glucose neurotoxicity.
Pancreatic Morphology

T1DM vs T2DM
Type 1: reduced size & number of islets, leukocyte infiltration (insulitis)

Type 2: amyloid replacement of islets, subtle reduction in islet cell mass (not readily apparent)

Infants of diabetic mothers: increased islet cells
List the macrovascular complications of DM
Accelerated atherosclerosis is the hallmark of DM & most common cause of death M=F
---Metabolic syndrome = independent risk factor
MI
Strokes
Renal artery atherosclerosis --> stenosis --> renovascular htn --> renal failure
Hyaline arteriolosclerosis (if severe DM)
Gangrene of LE
most common cause of death in DM
accelerated atherosclerosis

(DAG activated PKC → activated endotherlium, AGE's crosslink peptides: reduce elasticity, trap LDL's)
What is the frequency and significance of coronary artery disease in DM?
80% of T2DM deaths
Diabetes same risk as prior MI

(DAG activated PKC → activated endotherlium, AGE's crosslink peptides: reduce elasticity, trap LDL's)
List the consequences of diabetic microangiopathy
AGE & PKC
Diffuse thickening of BM's in capillaries and renal tubules.

Diabetic capillaires leak plasma proteins causes //this seems backwards, why would thickened BM be more prone to leakage?
retinopathy, nephropathy, accelerates neuropathy (diseased vascularization of nerves)

Describe the morphologic features and clinical consequences.
What are all features of diabetic nephropathy?
Earliest marker for nerphropathy: Microalbuminuria: albumin in urine >30mg/day but <300 mg/day;

Glomerular lesions produce nephrotic syndrome
diffuse mesnagial sclerosis
nodular glomerulosclerosis/Kimmelstiel Wilson lesion specific for DM 30% of DM
renal atherosclerosis
hyaline arteriolosclerosis (nephrosclerosis), both afferent and efferent
pyelonephritis with risk for papillary necrosis

~40% of diabetics dvlpt nephropathy. 20 years to renal failure
BP control req'd to prevent progression

Tx: ACE inhibitors decreases nephropathy & correlated cardiovascular events
Hyperglycemia + Microalbuminuria
Earliest marker for nerphropathy: Microalbuminuria: albumin in urine >30mg/day but <300 mg/day;
What are the neurologic consequences of DM?
Describe pathogenesus
Symmetric peripehral neuropaty
both sensory and motor, LE most affected --> diabetic foot ulcers --> infx
Charcot joint: lysis of injured bone
ANS neuropathy --> sexual impotence, bowel and bladder dysfnx

Impaired cognitive fnx from degeneration of brain and cord
mononeuropathy affecting one single nerve: obturator, femoral, scietic etc
strokes from htn & microangiopathies
Hypoglycemic CNS injury
Charcot joint
lysis of injured bone as seen in DM nephropathy
List GI complications of diabetes mellitus.
Strongly correlated with glycemic control
--> GI dysmotility, constipation/diarrhea; abd pain, N/V dysphagia, heartburn
gallbladder dysfnx: delayed emptying, larger volumes

[Pathogenesis: multifactorial]
What is the frequency and types of infections in DM? What is the pathogenesis?
Skin esp foot ulcers
TB/Fungal infx esp necortizing mucor of sinuses
pneumonia
pyelonephritis (accelerating factor of diabetic nehpropathy)
Fournier's gangrene
5% of DM die of infx
Ketoacidosis
glycogen stores depleted, fat metabolism increases --> ketone bodies
counterregulatory hormone actions, glucagon, growth hormone, epinephrine → glucose formed from GNG of AA → hyperglycemia + negative energy balance --> polyphagia;
epinephrine blocks residual insulin release, stimulates glucagon. plasma glucose 500+;

glycosuria @ >=160 mg/dL --> osmotic duriesis --> polyuria, polydipsia

Acetoacetic acid and beta-hydroxybuterate formed more quickly than can be used --> ketonemia, ketonuria; osmotic diuresis --> increases [H+]
Nausea/Vomiting, Kussmaul
pathogenesis of polydipsia, polyuria, polyphagia
glycosuria @ >=160 mg/dL --> osmotic duriesis --> polyuria, polydipsia

glycogen stores depleted, fat metabolism increases --> ketone bodies
protein metabolism of muscle mass releases amino acids negative energy balance --> polyphagia
T1DM correlated disease

(not causal, not complication)
14 genes shared with Celiac Disease
Tx T1DM
Insulin is only pharmacologic therapy. Must be coupled with well regulated diet and regular exercise.
Clinical Presentation T1DM
polyuria, polydipsia, polyphagia, weight loss, ketoacidosis
Most new cases <18yo w/ abrupt onset usually 2° to infx
1 year honeymoon

"Brittle" glucose intolerance affected by minor changes in diet, physical activity, stress, inefction, vomiting, fluid in/outflow.
Risk Ketoacidosis and Hypoglycemic Episodes
Hyperosmolar Nonketotic Coma
failure to adequately compensate for fluid lost through osmotic diuresis;
typical pt elderly, disabled by stroke/infx, unable to drink enough water
no nausea, vomiting, respiratory difficulties
Tx T2DM
10% weight loss reverses new onset T2DM
Diet & excersize delay impaired GT

Oral Agents:
sulfonyrea, glitinides: increases release of insulin
metformin: decreases hepatic glucose prodxn
thiazolidinediones: decreases insulin resistance
GLP1: increases insulin, decreases glucagon, delays stomach emptyig; Glucose control w/o hypoglycemia.
± needs insulin
GIP Gastroinhibitory peptide
GLP glucagon like protein -1
enhances inusline relase
metabolized by DPP-4
blocked by sitagliptin --> prolonged elevation of GLP-1 increases insulin release
exenatide: GLP-1 like drug from Gilamonsters
What are the definition, features and complications of gestational diabetes?
Definition: Hyperglycemia/Diabetes detected when pt is pregnant
>10% of all pregnancies, most common complication, hispanics more at risk
Diagnostic criteria: LOWER THAN FOR DIABETES
Fasting 105

Maternal Risk for Post Partum Overt DM ~50% at 5 years

Aggressive Tx to Protect Fetus & Mother
screen all increased risk for T2DM before pregnancy
screen all pregnant women at during 7th month of pregnancy

Highest risk:
excessive maternal weight gain
UA positive for glucose
Hx large babies, unexplained fetal loss, family Hx

Fetal complications merit their own card
Fetal complications of Gestational Diabetes
childhood obesity & cognitive impairment, metabolic syndrome & T2DM as adult;
macrosomia 2* to growth hormone: risks at delivery: dystocia, fractures, nerve palseis, IUGR (pre-eclampsia)
stillbirth
malformations: neural tube, cardiac
neonatal hypoglycemia 2* to islet hyperplasias
increased risk hyaline membrane disease
What are the general features of pancreatic endocrine neoplasms?

When are they considered malignant?

What is the most common type
Rare, Adults, Anywhere along Pancreas or in Ectopic Ts;
Carcinoid;
± single/multiple, ± benign/malignant ± hormone prodxn

Malignancy if
-mets
-vascular invasion
-gross invasion of adjacent viscera

most common islet cell tumor is insulinoma
Insulinoma
Frequency, morphology, Sx, lab findings, DDX, Tx
most common islet cell tumor
gross:solitary, small benign, w/in pancreas
micro: monotonous carcinoid cells w/ amyloid deposition

Sx: hypoglycemia, Altered mental status, hypoglycemic attacks relieved by glucose

lab finding: low fasting blood sugar, high insulin and C peptide
Gold standard: 3 day fast w/ glucose insluin & C peptide levesl q6h

DDx: diffuse hyeprplasia of islets, hypoglycemia in infants of diabetic mothers; fibrosarcoma paraneoplastic insulin;

Tx: surgery
Hypoglycemia without hyperinsulinemia

DDx
Hypoglycemia w/o hyperinsulinemia
diffuse, endstage liver disase
inherited glycogenoses
drugs- self-induced hypoglycemia
Zollinger Ellison syndrome

Sx, Dx, Tx, Px
Gastrin producing tumor in duodenum, peripancreatic ts or pancreas
peptic ulceration in 90%, intractible to Tx, in unusual locations like jejunum, [duodenal > gastric,]

multiple, 1/2 are malignant, 1/2 present with diarrhea

Dx: increased serum gastrin (also elevated in atrophic gastritis)
Tx: H2 receptor blockers, surgical exision of possible
Px: 1/2 invasive metastatic at discovery --> mets to liver, liver fialure in 10 years
25% assoc w/ multiple endocrine neoplasia
Glucagonoma
alpha cell tumors
DM, Migratory necotizing skin erythema, Anemia
Perimenopausal women, high plasma glucoagon
[rare]
Somatostatinoma
delta cell tumors
DM, Cholelithiasis, Steatorrhea, Hypochlorhydria
Hard to localize
high serum somatostatin (an IGF)
VIPoma
diarrheogenic islet cell tumor
Vasoactive Peptide
Watery diarrhea, hypokalemia, achlorhydria
tumors may be invasive &/ metastatic
may be caused by neurocrest tumors-neuroblastoma
DM, Migratory necotizing skin erythema, Anemia
Perimenopausal women
Glucagonoma
alpha cell tumors
DM, Cholelithiasis, Steatorrhea, Hypochlorhydria
Somatostatinoma
delta cell tumors
Hard to localize
high serum somatostatin (an IGF)
Watery diarrhea, hypokalemia, achlorhydria
VIPoma
diarrheogenic islet cell tumor
Vasoactive Peptide
tumors may be invasive &/ metastatic
may be caused by neurocrest tumors-neuroblastoma
In general, what labs reflect glomerular function, tubular reabsorption (concentrating ability)?
GFR: Glomerular filtration
Proteinuria: Glomerular filtration
Urine specific Gravity: Tubular reabsportion (concentrating ability)
BUN
increases before creatinine,
high sensitivity, low specificity; not increased in early nephrotic syndrome
Increased in: Dehydration ("pre-renal"), GI bleeding, excess destrxn of cellular proteins ( fever, DM, catabolism --incl. exercise)
[From Phys: about half the filtered urea is reabsorbed, and resporption increases when GFR is low]
Creatinine
catabolic end product of creatine in SkM which gave up ATP; prodxn is constant and proportional to muscle mass.
high specificity, low sensitivity for decreased GFR
Increased in: dehydration, poor reanl perfusion, most renal disease;
[From Phys: freely filtered, almost no resorption/secretion: what you see is what you filtered]
Cause of Hyponatremia
salt wasting renal tubular defect
Cause of Hyperkalemia
decreased renal excretion in endstage kidney disease or acidosis
Cause of Metabolic Acidosis
renal tubular acidosis: tubular loss of bicarbonate OR decreased tubular excretion of organic and inorganic (phosphates) acids
Casts
form in tubules of kidney, indicative of renal disease or dehydration
Specific gravity
concentrating ability of kidney, lost in renal tubular disease
Proteinuria
ALL glomeular disease results in proteinuria. Urinary protein:Cr ratio >1000mg/g ~= glomerular disease Proteinuria reflects glomeular pressure. Timed urin sample is gold standard for quantitative assessment.
Albuminuria
early sensitive marker for many types of kidney disease
"Spot" urine
ratio of albumin to creatinine: corrects of hydration. Normal <10mg/g
compare/contrast nephritic vs nephrotic syndromes utilizing labs
Nephritic: gross hematuria, <= moderate proteinuria, htn

Nephrotic: >= 3.5g/24h in urine --> hypo-albuminemia, severe edema;
hypoproteinemia --> hyperaldosteronemia --> Na+, H2O retention --> worsens edema
Lipiduria & hyperlipidemia incl. lipoprotein synth by liver, abnormal transport & decreased catabolism --> increased choleesterold, hyperTAGemia
GFR initially increased, BUN & Creatinine normal
eventually GFR decreases --> renal insufficiency --> failure
proteinuria delivers concentrated cytokines, growth factors, et al mediators to tubules --> interstitial inflam & fibrosis --> tubular/vascular dysfnx
selective vs poorly selective proteinuria
selective: mostly albumin & transferrin
poorly selective: albumin + globins --> lost IgG = Infx, lost AT3 & antiplasmin --> thrombosis/thromboembolism
What two labs predict chronic kidney disease and its progression? What is the GFR that defines chronic kidney disease, stage 2?
-proteinuria + creatinine (? I guess)

GFR = best measurement of renal fnx, estimated by Creatinine clearance or estimated Cr clearance from serum Creatinine

Chronic kidney disease defined as reduced kidney fnx for >3 mo
stage 1: kidney damage + proteinuria, GFR >=90
stage 2: GFR <90
stage 3: GFR< 60
Stage 4: GFR <30
Stage 5: GFR <15 = Kidney Failure, req's dialysis

[there is a lot more about staging, not in obj]
Define azotemia. How is renal azotemia differentiated from pre- and postrenal azotemia? What are causes of pre-renal azotemia? Postrenal azotemia?
Azotemia: elevated BUN + Creatinine: indicative of decreased GFR
Renal cause BUN:Cr ratio 12-20:1; if disproportional, look for non-renal cause of increased BUN;

Prerenal azotemia: hypeoperfusion w/o parenchymal damage
BUN/Cr >
Causes: hemorrhage, shock, dehydration, CHF

Postrenal azotemia: outblow obstrx
Causes: Stones, prostate, tumor etc. Relief of obstrx corrects azotemia.
Uremia labs
Hct ↓, Cr ↑, BUN ↑, Ca2+ ↓ Uric acid ↑, Proteinuria
--Hyperphosphatemia (normally excreted), hypocalcemia (normally absorbed) --> stones & also 2* increased PTH w/--> renal osteodystrophy
--Anemia: normocytic normochromic w/ burr cells (NcyNch Acanthrocytes); EPO low, serum iron low; Bleeding due to platelet dysnfx --> low Hct
--uremic retinopathy: atherosclerotic (silver wire arteries, hemorrhages) hypertensive: cotton wool exudates, flame shaped hemorrhages, papilledema)
--Uremic respiratory disease: hilar pneumonitis "bat wint" opacity on x ray" Kussmall respiration, urine smell to breath, plural effusions
--CV: HTN --> CHF --> Pulmonary Edema, Fibrinous Pericarditis
--GI: N/V, inflammation w/ ulcerations: Bleeding (low platelets), constipation <--> diarrhea; Coated tongue ammoniacal/unpleasant taste
--Neuromuscular: myopathy, peripheral neuropathy, encephalopathy
--Dermatologic: Sallow (grey-yellow), pruritis, dermatitis, edema, purpura, exocriations (sloughing), rarely "uremic frost"
--CNS: HA, drowsiness/insomnia, muscle fasiculation/weakness, convulsions, coma
Cardio: Htn, dizziness, friction rub, cardiomegaly
GI: N/V, hematochezia/melena
Respiratory: dyspnea on exerction, burning retrosternal pain worse on inspiration; rales
Dermal: sallow, excoriations, bruises, pitting edema`
Uremia
--Hyperphosphatemia (normally excreted), hypocalcemia (normally absorbed) --> stones & also 2* increased PTH w/--> renal osteodystrophy
--Anemia: normocytic normochromic w/ burr cells (NcyNch Acanthrocytes); EPO low, serum iron low; Bleeding due to platelet dysnfx --> low Hct
--uremic retinopathy: atherosclerotic (silver wire arteries, hemorrhages) hypertensive: cotton wool exudates, flame shaped hemorrhages, papilledema)
--Uremic respiratory disease: hilar pneumonitis "bat wint" opacity on x ray" Kussmall respiration, urine smell to breath, plural effusions
--CV: HTN --> CHF --> Pulmonary Edema, Fibrinous Pericarditis
--GI: N/V, inflammation w/ ulcerations: Bleeding (low platelets), constipation <--> diarrhea; Coated tongue ammoniacal/unpleasant taste
--Neuromuscular: myopathy, peripheral neuropathy, encephalopathy
--Dermatologic: Sallow (grey-yellow), pruritis, dermatitis, edema, purpura, exocriations (sloughing), rarely "uremic frost"
--CNS: HA, drowsiness/insomnia, muscle fasiculation/weakness, convulsions, coma
bilateral renal agenesis
Potter's syndrome: bilateral total agensis, incompatible with life; failure to produce urine --> oligohydramnios --> flat facies, limb defects, hypoplastic lungs; amnion nodosum
unilateral renal agenesis
hypertrophied singular, risk for glomerular sclerosis
renal hypoplasia
bilateral hypoplasia --> childhood renal failure
unilateral hypoplasia, usuallyl atrophy 2* to infx
Ectopic Kidney
Ectopic: commonly in pelvis or just above pelvic brim
Risks: UTI, obstrx 2* to tortuous ureter
Horseshoe kidney
fusion of poles acorss midline; 1/500; risks: UTI, obstrx 2* to tortuous ureter;
Multicystic renal dysplasia:
sporatic
enlarged cystic kidney/flank mass, present at birth
disorganized architecture: cartilage, undifferentiated mesenchyme, immature collecting ductules, abnormal lobular organization;
unilateral or bilateral, assoc with abnormalities lower down
adult polycystic kidney disease

genetics, pathogenesis, morphology, progression, presentation, complications, comorbidities, dx, Px
- Inheritance: AD, Penetrance increases with age, Frequency: Common 1/700; 10% of transplants
- Morphology: Large, multicystic kidney, liver cysts, berry aneurysms
- Outcome: chronic renal failure beginning ~50 ± 10, Initially focal always progress to bilateral.
- Polycystin located in primary cilium of tubule cells & influences mechanocensing --> intracellular Ca2+ --> influences cell-cell & cell-matrix interactions --> altered tubular growth --> cyst --> cysts detach and enlarge by fluid secretion --> glomerular vascular damage, interstitial inflam/fibrosis.
3 separate genes: Majority are PKD1 on Chrom 16 which produces polycystin 1, PKD2 ≈ delayed onset
- Presenting sx: 50 yo w/ renal colic from passing clots 2* to dilation & hemorrhage; bilateral abdominal masses, hematuria, proteinuria, polyuria, htn
- Complications: Hematuria, flank pain, UTI, Stones, HTN
Comorbidities: defective basement membranes: 40% have polycystic liver disease, 30% have berry aneurysm in circle of willis, mitral valve prolase
- Dx: US, CT Px: Slowly progressive azotemia → death from HTN: CVA, Ruptured aneurysm
50 yo, renal colic, bilateral abdominal masses
hematuria, proteinuria, polyuria, htn
Adult Polycystic Kidney Disease
- Inheritance: AD, Penetrance increases with age, Frequency: Common 1/700; 10% of transplants
- Morphology: Large, multicystic kidney, liver cysts, berry aneurysms
- Outcome: chronic renal failure beginning ~50 ± 10, Initially focal always progress to bilateral.
- Polycystin located in primary cilium of tubule cells & influences mechanocensing --> intracellular Ca2+ --> influences cell-cell & cell-matrix interactions --> altered tubular growth --> cyst --> cysts detach and enlarge by fluid secretion --> glomerular vascular damage, interstitial inflam/fibrosis.
3 separate genes: Majority are PKD1 on Chrom 16 which produces polycystin 1, PKD2 ≈ delayed onset
- Presenting sx: 50 yo w/ renal colic from passing clots 2* to dilation & hemorrhage; bilateral abdominal masses, hematuria, proteinuria, polyuria, htn
- Complications: Hematuria, flank pain, UTI, Stones, HTN
Comorbidities: defective basement membranes: 40% have polycystic liver disease, 30% have berry aneurysm in circle of willis, mitral valve prolase
- Dx: US, CT; Px: Slowly progressive azotemia → death from HTN: CVA, Ruptured aneurysm
childhood polycystic kidney disease

frequency, inheritance, pathogenesis, morphology, Px
Rare, AR
PKHD1: fibrocystin: membrane protein of primary cilium of tubular cells; most cases are compound heterozygotes;

Morphology: parallel cylindrical cysts in cortex and medulla at right angles to cortical surface

Perinatal most common: rapid renal failure
Infantile assoc w/ congenital
Juvenile: hepatic fibrosis, liver disease w/ increasing age
medullary sponge kidney

morphology, complications
Morph: multiple small cystic dilations of cuboidal transitional/cell lining in medullary collecting ducts
Complications: calcifications in dilated ducts, hematuria (presenting sx)
Renal fnx: normal
Sulfanamides
Trimethoprim/Sulfamethoxazole (Bactrim, Septra)
Sulfisoxazole (Gantrisin)
Sulfisoxasole/Erythromycin (Pediazole)
Silver Sulfadiazine (Silvadene) **Topical form
Sulfacetemide (Cetamide) **Opthalmic drops
Use:
broad spectrum, use for UTI, increase fluids

SE:
GI, skin rash, phototox, super-infections, hyperkalemia, blood dyscrasias, stevens johnson syndrome, anaphylaxis
Adult onset medullary cystic disease

inhereitance, morphology, complications, Px
Inheritance: AD
Morph: corticomedullary jxn cysts, corticotubular atrophy & interstital fibrosis, shrunken kidneys
Complications: salt wasting polyuria
Outcome: chronic renal failure beginning in adulthood
most common genetic cause of endstage renal disease in children, young adults
Complex variants of Nephronophthisis
Familial or sporadic
familial AR manifests in chilhood
familial AD in adults
Gene: NPH (7 variants) for nephrocytin = ciliary protein

sodium wasting polyuria with tubular acidosis --> terminal renal failure in 5 years
Dx: biopsy shows chornic tubulointerstitial nephritis
What are the features of dialysis-associated acquired cystic disease?

inhereitance, morphology, complications, outcome
Inhertiance: None
Morph:Cortical and Medullary Cysts
Tubules obstrcted by interstital fibrosis or oxalate crystals
Complications: increased risk of renal cell tumors, +-hematuria
Outcome: dialysis
simple cysts

inhereitance, morphology, complications, outcome
Freq: common
Inheritance: None
Morph: 1+ cysts in normal sized kidney up to 10cm
Complciations: microscopic hematuria, occasional hemorrhage: rapid distention & pain, DDX: cystic renal cell carcinoma
Outcome: benign
Recognize the gross and microscopic morphology of benign nephrosclerosis. Know associations and significance.
Kidney of benign htn: sclerosis of renal arterioles & small arteries
assoc w/ age, diabetes, htn & African Americans
Pathogenesis:
intimal thickening + Hyaline deposition from extravasated plasma --> narrowing of lumens --> patchy ischemic tubular atrophy with intestitial fibrosis; glomeruli become sclerotic
Finely granular cortical surface
Clinical presenation: GFR >= Normal, mild proteinuria, increased risk of renal failure
What are the clinical and morphologic features (gross and microscopic) of kidney and of retina in malignant hypertension. Define malignant hypertension and list causes.
Malignant HTN: BP >200/120
Causes: complication of any htn; most likely htnsive young black men, or scleroderma with nephropathy
essential htn
2* htn:
--endocrine disease: pheochromocytomas
--renal vascular disease
--acute and chronic renal disease
What are common complications of hypertension?
Concentric LV hypertrophy: CHF
MI, Strokes, Cerebral Hemorrhage, Aortic dissection, Chronic renal failure

Morphology: fibrinoid necorsis of arterioles --> onionskin hypertorphy

Renal vascular damage --> fibrosis & low perfusion --> AT2 secret'n --> renal vasoconstrxn --> further injury
also low perfusion --> aldosterone --> salt retention -->

Focal hemorrhages = "flea bitten"
shrunken overtime

Retinas: flame-shaped hemorrhages, cotton wool exudates, papilledema
Causes of HTN w/ Hypokalemia
Malignant hypertension
Primary hyperaldosteronism
hyperaldosteronism 2* to renovascular disease
Cushing syndrome
Endocrine
Thiazide/diuretic Rx's

Rule out renal vascular disease with duplex US
[Pheochromocytoma --> VMA/metanephrines in urine from catecholamines]
Describe the pathogenesis of renovascular hypertension using unilateral stenosis model.
Constriction of artery --> ischemic kidney --> renin secretion increased --> AT2, Aldosterone --> maintenance of HTN by sodium
Shrunken "Goldblatt" Kidney
What diseases cause renovascular hypertension and what are the features and morphology of each?
Causes:
-Majorty are Atherosclerosis: atheromatous plaque at origin of renal artery
-Fibromuscular dysplasia Women 20-40 yo: beaded appearang vessel on x ray from fibro-eslatic ts or VSMC thickening

Morphology:
-Contralateral hyaline arteriosclerosis
-End stage kidney shrunken, inflammed atrophied, fibrotic

Clinical features:
HTN with hyperreninemia, responds to ACE inhibitors
Dx via arteriography Tx via interventional radiology
Review the pathogenesis and list of thrombotic microangiopathies.
Typical HUS: childhood HUS following bloody diarrhea
Atypical huse: no diarrhea, acquired or familial
TTP: Idiopathic trhombocytic throbocytoepnic purpura
What are the peripheral blood and renal morphologic findings of these thrombotic microangiopathies?
Thombosis in capillaries and arterioles
microangiopathic hemolytic anemia
thrombocytopenia
+- renal failure

Morphology:
platelet/platelet fibrin thrombi in small arteries and glomeruli:
What are the causes/clinical features of typical HUS?
Typical HUS:
-follows diarrhea or "flu" +- hematemesis, melena
Shiga toxin damages endothelium --> intravascular thrombosis --> schistocytes
Sudden onset of oliguria w/ hematuria, microangiopathic hemolytic anemia, +-nerologic disease
Tx: dialysis
Px: 5% mortality, high % persistent abnormal renal fnx --> chronic renal failure
What are the causes/clinical features of atypical HUS?
adults with inherited deficiency of complement regulatory proteins, esp factor H
else:
-antiphospholipid syndrome, post-partum renal failure, renal vascular disease 2* to malignant htn or systemic sclerosis, CA chemotherapies or renal radiation
[?Sudden onset of oliguria w/ hematuria, microangiopathic hemolytic anemia, +-nerologic disease
Tx: dialysis
Px: poor
What factor is deficient in TTP?
Nerologic Sx! + microangiopathic hemolysis thrombocytopenic purpura; renal failure; fever
Activated vWF multimers 2* to deficiency of protease ADAMTS-13: acquired or familial, familial is chronic/relapsing
Females <40
What renal diseases are related to atherosclerosis? Atheroemboli (recognize morphology 20-43)
Atherosclerotic ischemic renal disease
bilateral --> renal insufficiency +- htn

Atheroebolic enral disease --> acute renal failure, cholesterol crystals in lumen
What are all associations of papillary necrosis of the kidney (table 20-9).
See table, have made chart

Sickle cell disease nephropathy: papillary necoris, hematuria, diminished concentration
Homozygoes 30% have proteinuria, +- nephrotic w/ glomerular lesions
What are associations and consequences of diffuse cortical necrosis?
follow septic shock & abruptio placenta ie obstretric emergencies.
Sudden onset aneuria + uremia
Bilateral = poor prognosis
What are causes and morphology of renal infarcts?
Kidney is the most common site of infraction, mostly due to embolism
Infarcts are wedge shaped, pale & produce scare
silent infarct presents as costovertebral angle pain & hematuria
may cause htn
What are the seven categories of systemic manifestations for chronic kidney disease and uremia
Fluid & Electrolytes
Calcium Phosphate & Bone
Hematologic
Cardiopulmonary
GI
Neuromuscular
Dermatologic
What are the four stages of renal failure?
1. Diminished renal reserve- GFR 50% normal; no increase in BUN, Creatinine, aSx
2. Renal insufficiency- GFR 20-50% normal; azotemia w/ anemia and hypertnesion, polyria, nocturia
3. Renal Failure GFR <25% normal +- edema, acidosis, hypocalcemia, uremia
4. End Stage Renal Disease GFR <5% normal, uremia
What are the three groups of glomerular diseases? (Table 20-2)
Primary glomerulopathies- kidney predominate as only organ
2ndry--due to systemic disseases
Hereditary disorders
What are the five major glomerular syndromes? (Table 20-3)
Nephritic Syndrome: hematuria, azotemia, +- proteinuria, oliguria, edema, htn
Rapidly progressive Glomerulonephritis: acute nephritis, proteinuria, acute renal failure; Nephrotic Syndrome: >3.5 gm proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria
Chornic rneal fialure: Azotemia --> uremia
Isolated urianry abnormaliteis: glomerular hematuria, subnephrotic proteinuria
What are the four basic tissue reactions in glomerulonephritis?
Glomerular hypercellularity: proliferative: mesangial, endothelial, infiltrative: PMN, M0, lymphos

Crescents: accumulation of cells composed of proliferating epithlial cells and infiltrating lymphos

Basement membrane thickening:
--LM: thicked capillary was
--EM: thickened BM's, depsoition of amorphous electron dense material

Hyalinization and Sclerosis
--LM: accumulation of homogenous eosinophilic mateiral
--EM: extracellular amorphous substance
Define wrt the Glomerulus
Diffuse, Global, Focal, Segmental
Diffuse- involving all glomeruli
Global- involving the entire glomerulus
Focal- involving a certain portion of the Segmental- involving only certain portions of each glomerulus
Diffuse, linear immunofluorescent pattern of glomerular immune complex despition
Anti-GBM nephritis: Goodpasture Syndrome: Severe damage & Rapid renal failure
Antibodies directed against intrinsic GBM antigens
Cross reacts with other BM's esp lung alveoli
immunofluorescence pattern is granular and interrupted of glomerular immune complex despition
Heymann's nephritis
antibodies to bursh border antigens
EM: numerous electron dense depsoits in subepithelial aspect of BM
granular heterogenous pattern on immunofluroescence of glomerular immune complex despition
Planted Antiens
ab's react in situ with non-glomerular ag's
granular deposits on BM &/ on mesangium of glomerular immune complex immunofluorescence
Circulating Immune Complex Nephritis
Trapping of cirgulating immune complexes within glomerul --> complement activation --> damage
EM: electron dense deposits in mesangial, subendothelial (between endothelial cells & GBM), subepithelial (btw podocytes & outer surface of GBM, rare)
Using figure 20-5 identify the four areas of localization of immune complexes.
?
What happens when glomerular epithelial cells are injured
Morphologic changes: loss of food processes, vacuolization, etraction and detachement from GBM; functional proteinuria
focal segmental glomerulosclerosis
due to adaptive change in unaffected glomeruli --> compensatory hypertrophy & hemodynamic changes. Htn + increased permeability --> accumulation of proteins in mesangial matrix, proliferation of mesangial cells, infiltration by macorcytes, ECM deposition. --> sclerosis --> proteinuriaglobal

[podocytes unable to increase in number, streteched too thin --> unopposed intracapillary pressure --> fibrous attachemnt of bulgin gcapillary to bowmans capsule --> contineud sclerosis]
tubulointerstitial ifnalmmation and fibrosis:
better correlated with decline in renal fnx than severity fo glomerular damage
protein causes direct injury to and activation of tubular cells.
Explain renal ablation focal segmental glomerulosclerosis (Fig. 20-8).
(Fig. 20-8).
Know the entire table 20-5 with the summary of major primary glomerulonephritides except for the pathogenesis column.
I made a chart!
Syndrome of Acute Nephritis
Hematuria, red cell casts, azotemia, oliguria, mild to moderate htn; proteinuria and edema lesss than in nephrotic syndrome; may occur in multisystem disease; typically characteristic of acute proliferative glomeulonephritis and srescentif GN;
Acute proliferative GN
Poststreptococal, Postinfectious
immunologically mediated GN w/in a mo after certain GABHS strains;
enlarged hyperceullar glomeruli, diffuse proliferation of mesangial, endotheial cells, diffuse infiltration of PMN,s M0's;

tubules will have RBC casts, +- interstitial edema/inflam
IF: granular deposits of IgG, IgM and C3 in mesangium and along BM
EM: discrete amorphous electron dense deposits on epithelial side of BM --"humps" of C3

Clinical: young child w/ abrupt onset of malaise & hematuria w/in mo after recovering from sore throat
RBC casts, milkd proteinuria, periorbital edema, mild htn
adult onset atypical

Lab findings: elevated anti-streptococcal ab titers, low serum C3, cryoglobins in serum
Most children recover totally. 2% slow progression to chronic GN, <1% rapidly progressive GN
Only 2/3 adults recover completely
Rapidly Progressive Glomerulonephritis = RPGN
Crescents of proliferted parietal cells and infiltrating M0 into Bowman's space (obliterate space); Fibrin between layers of crescent;
EM: rupture in GBM +- deposits
ImmunoF:
Post-infx: granular
Goodpasture: linear
Ideopathic: granular, linear or none
Serum analysis for Anti-GBM, antinuclar ABS' and ANCA's

Clinical: Hematuria w/ red cell casts, proteinuria
variable htn & edema
rapid loss of renal fnx w/ oliguria, death w/in weeks if unTx
Goodpasture: recurrent hemoptysis or life trheatening pulmonary ehmorrhage

Tx: goodpastrues: plasmapharesis, cytotoxic agents, steroids
Non-goodpasture: steroids, cytotoxic agents
Types of Rapid Progressive glomerulonephritis
Type 1: Goodpastures: Antibodies vs BM, esp glomerulus and lungs
IF: linear; tx: plasmapheresis, cytotoxic agents, steroids

Type 2: IC mediated
IF: granular pattern
Tx: underlying disease

Type 3: pauci-immune type: Most C-ANCA or P-ANCA, lack of anti-GBM abs/IC's, either idiopathic or part of systemic vasculitis
Tx: steroids, cytotoxic agents

Idiopathic RPGN: IF: granular, linear or none
1/4 = Type 1, 1/4 = Type 2, 1/2 = Type 3
Define the nephrotic syndrome (four features). What are the major primary glomerular diseases that present with the nephrotic syndrome (Table20-7)? Which is most common in children? In adults?
Massive proteinuria >3.5 g/day
hypoalbuminemia <3g/dL
generalized edema
hyperlipidemia & lipiuria

assoc. w/ primary & systemic GN
most common in children: minimal change disease
most common in adults: focal segmental glomerulosclerosis
membranous GN

LM, EM, IF
Causes, Px
LM: diffuse, uniform thickening of capillary wall; silver stain shows spikes of BM between deposits
IF: granular deposits of IgG and C3
EM: irregular dense subepithelial deposits, foot processes lost

Causes: 85% idiopathic; rest: drugs, malignant tumors, SLE, infx, autoimmune disorders
Clinical: insidious onset of nephrotic syndrome, indolent; proteinuria does not repsond to steroids; proteinuria persists in 60$; 40% dvlp renul insufficiency in 10 years. only 10% reach renal failure in 10 years.
Minimal change disease
aka lipoid nephrosis
most common cause of nephrotic syndrome in children
LM: lipid in tubles
EM: no deposits, uniform and diffuse effacement of food processes
Rapid repsonse to steroids
nephrotic phase may recurr

(come back to the rest)
What are the two hereditary syndrome of isolated hematuria?
Alport Syndrome
Thin Membrane Disease-- most common cause of benign familial hematuria
What are the manifestations of Alport Syndrome and the clinical course?
Defective GBM syntehsis is 1* lesion
Nephritis + nerve deafness & eye disorders
males more freq & severe, heterogenous inheritance
EM: GBM shows irregular foci of thickening or attenuation, pronounced splitting
ClinicaL: hematuria starting age 5, renal failure sometime after age 20
What are the clinical and morphologic features of Thin Basement Membrane Disease? What is the other name for Thin Basement Membrane Disease?
most common cause of benign familial hematuria
diffuse thinning of GBM
renal fnx normal, prognosis good
Which GN’s are likely to progress to chronic GN? Not likely to progress? (Figure 20-21). What are the gross and microscopic features of chronic GN? What is the clinical course?
Kidneys symetrically contracted, diffusely granular cortical surfaces
hyaline obliteration of glomeruli, acellular eosinophilic PAS positive masses
atrophy of tubules, interstitial fibrosis, lymphocytic infiltrate
Extrarenal morphology:
uremia: pericarditis, gastroenteritis, 2* hypoparathyroidism w/ neprhocalcinosis & renal osteodystrophy;
LV hypertorphy 2* to htn, Pulmonary DAD

Clincial: insidious progression to death
most pts htn, clinical manifestation may be cerebral or cardiovascular
must be maintained on dialysis or receive transplant

Most likely to progress:
Crescentic GN, PSGN, membraneous, Focal Segmental Glomeruloscleorsis, Membranoproliferative GN, IgAN
What are the three morphologic changes that occur in the glomeruli of diabetics? What is the other term for nodular glomerulosclerosis? Describe the clinical progression of renal disease in diabetics?
arteriolar sclerosis, papillary necoris, tubular lesions

AGE's --> thicken GBM & increase mesangium
Hemodynamic htn --> glomerular hypertrophy --> diffuse mesangial sclerosis
nodular glomerulosclerosis: aka Kimmelstiel Wilson Disease = spherical laminated hyaline masses at periphery; PAS+, lipid, fibrin

Clincal progression
increased GFR --> microalbuminuria
proteinuria --> nephrotic
progressive loss of GFR --> end stage renal filure
systemic hypertension
dialysis, transplants, may recur

Preventable w/ control of blood sugar; delayed progression w/ ACE inhibitors
spherical laminated hyaline masses at periphery; PAS+, lipid, fibrin
Kimmelstiel Wilson Disease

aka nodular glomerulosclerosis:
What are the two major groups of processes which affect the tubules and interstitium?
1. Ischemic/toxic tubular injury = acute kidney injury aka actue tubular necrosis AKI/ATN

2. Inflam rxn of tubules & interstitium: tubulointerstitail nephritis
FIGURES:
20-23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37

TABLES: 20-8, 9, 10
What are the major morphologic and clinical features of acute kidney injury? What is the most common cause of acute renal failure? Is AKI reversible? What are the two patterns of AKI? What are the two critical events in AKI?
Morph: destrx of tubular epithelial cells
Clinical: acute suppressed renal fnx, most common cause of acute renal failure

Diagnostic criteria: an absolute increase in serum Creatinine >= 0.3 mg/dl, a percentage increase in serum creatinine of >= 50% or a reduction in UO < 0.5 ml/kg/h for >6h

AKI is by definition a reversible lesion
Two types of AKI: Ischemic & Nephrotoxic
Two critical events: tubular injury + persisten & severe disturbance in blood flow ( decreased GFR)
Acute renal failure:
acute suppression of renal function and urine flow falling w/in 24 h to less than 400 ml
What are the two main morphologic features of both types of AKI (Fig. 20-24)?
Ischemic morphology:
focal tubular epithelial necoris + apoptosis at multle points along nephron with skin areas, +- reuptured BM's, occlusion of tubular lumens by casts
affects traight portion of proximal tubule adn ascending thick limb of Henle

Toxic morphology:
acute tubular injury in proximal convoluted tubules
distinctive patterns with ?[mercuric chloride, carbon tetrachloride, ethylene glycol, calcium oxalate]

Both types +- eosinophilic hyaline casts & pigmented granular gasts in distal tubules & collecting ducts; casts principally Tamm-Horsfall protein-urinary glycoprotein secreted by cells of ascending thick limb & distal tubules
+- interstitial edema/inflam
epithelal regeneration = flattened epithelal cells w/ hyperchormatic nuclei & mitotic figures
What are the three phases of classic AKI? Describe each phase. What is the prognosis for AKI?
1. Initiating: slight decline in urine 36 hours after inciting event
2. Maintenance: sustained decrease to 40-400 ml/day, Na+H2O overload, rising BUN, hyperkalemia, metabolic acidosis; keep pt alive with dialysis
3. Recovery: steady increase in urine volume to 3L/day; tubules still damaged, w/ Na+H2O wasting & increased risk of infx
Px: 50% mortality with burn or spesis related shcok; recovery if other organs not seriously damaged
Nonoliguric ATN
more benign clinical course
What features distinguish acute and chronic tubulointerstitial nephritis? What distinguishes TIN from glomerular disease?
Acute: acute onset, focal tubular necrosis, w/ inflam & edema
Chronic: Mononuclear cells, fibrosis, widespread atrophy

Tubuloinsterstial Nephritis will not have nephritic/nephrotic syndrome, and will have defects in tubular fnx manifest as:
impaired concentration: polyuria, nocturia
salt wasting
metabolic acidosis
isolated defects in tubular resorption of secretion
What parts of the kidney does pyelonephritis affect? What are the two forms of peylo? Characterize each. What is the most common organism causing urinary tract infections? Where do the infecting organisms come from?
Bacterial infx 2* to UTI
Tubules, Interstium & Renal Pelvis
Forms: Acute & Chronic
Acute:
Chronic: + other factors (?the hell does that mean)

1* Gram Negative Bacilli: E Coli, Proteus, & Kleb (by freq respectively)
Organisms from GI tract, reflux up UTI

Tranplanted Kidneys at risk for Polymoavirus, PMV, & Adeno
What are the two pathways by which bacteria can reach the kidney? (Fig. 20-26) What are the five steps in ascending infection of the kidney? What is vesicoureteral reflux (Fig. 20-27)? What is it most often due to?
Ascending (most common) & Hematogenous

1. Colonoization of distal urethra and intraoitus by coliform bacteria, req's P fimbrae w/ ability to adhere to uroepithelium
2. Entry to bladder via instrumentation or women (shorter urethras, no antibacterial prostatic fluid, hormanal influence on adherence, intercourse)
3. Multiplication in bladder; Usually flushed out. Req's stasis: BPH, tumors, calculi
4. Vesicoureteral reflux: incompetance of vesicoureteral valve: most often congenital inherited absense or shortening of intravesical portion of ureter; acquired due to spinal cord injury --> spinal cord injury
5. intrarenal reflux through papillae into poen ducts: demonstrate with voiding cystourethrogram. w/o reflux infx remains localized to bladder
What are the three hallmark morphologic features of acute pyelonephritis? What are three serious complications which may occur with acute pyelo?
Morphology: patchy interstitial suppurative inflam, intratubular aggregates of PMN's and tubular necrosis

Complications:
Papillary necorsis esp in diabetics & obstrux, usually bilateral, affects any number ofpyramids, tips of pyramids have grey white necrosis grossly, on micro: coagulative infarct necrosis

Pyelonephrosis: supprative exudate can drain & fills renal pelvis --> total or complete obstrx

Perinephric abscess: extension of suppurative inflam through capsule into perinephric tissue

[Healing pyelo: scarring w/ fibrous depressions on cortical surface w/ fibrosi & deformation of underlying calyx & pelvis]
What are the predisposing conditions for acute pyelo?
Obstrx
Pregnancy
Preexisting renal lesions
Immunovulnerable
Vesicoureteral reflux
1st year = anatomical anomolies, after 1 year; Women <40, Men >40 (prostatic hypertrophy & instrumentation)
DM
Sudden onset CVA pain, fever, malaise
dysuria, frequency, urgency, Pyuria; wbc casts
acute pyelo
Tx: antibiotics
Px: generally benign course
What pathogen may cause pyelo in kidney allografts? Treatment?
Polyoma virus: latent infx widespread in general, takes advantage of immunosuppression; Tx: back off immunosuppression.
What are the two forms of chronic pyelo? Which is more common?
Chornic pyelo: chronic inflam & scarring w/ involvement of calyces & pelvis

2 forms: chronic obstructive & reflux nephropathy

Chronic obstructive: recurrent infx superimposed on obstructive lesions

Reflux nephropathy is more common form: early childhood superimposed UTI's on congenital vesicoureteral & intrarenal reflux
What are the gross morphologic features of chronic pyelo? What part of the kidney is involved by chronic pyelo which leads to distinctive changes (Fig. 20-32)?
Morph:
Kidneys are irregularly scarred, asymmetrically so if bilateral (contast w/ GN)
Hallmark is coarse, discrete corticomedullary scar overlying blunted dilated calyx
Tubules shot atrophy * hypertrophy +- colloid casts (thyroidization); fibrosis in cortex and medulla;
How do chronic pyelo patients present? What complication may occur which leads to proteinuria?
Insidiously else acute w/ back pain, fever, pyruia and bacturia
Reflux neuropathy = the common cause of htn in children
if proteinuria, mild
focal segmental glomerulosclerosis = poor prognositc change
In what three ways can toxins and drugs produce renal injury?
1. Trigger Immune Reaction
2. Acute Renal Failure
3. Subtle, cumulative injries --> chronic renal insufficiency
What groups of drugs cause acute drug-induced interstitial nephritis (ADIIN)? What are the four clinical features? When do they occur after drug exposure? What complication occurs in 50 % of cases? What types of leukocytes are present in the interstitium?
synthetic penicillins, sulfonamides
onset 15 days after exposure
fever, eosinophilia, rash + renal: hematuria, eosinophil leukocyturia, mild proteinuria
50% dvlp rising creatinine or Acute Renal Failure

interstitial edema w/ mononuclear infiltrate +- large # eosinophils & PMNs.
Is the immune response in ADIIN dose related? Does withdrawal of the drug always lead to recovery?
most likely hapten in combo w/ tubular cells
onset not dose related
withdrawal of drug always followed by recovery (check this fact-cat on book right now)
Analgesic nephropathy is caused by what? What are the two morphologic features? What analgesic is implicated ? In what sequence do the morphologic features occur? What do the papillae show microscopically?
excessive intake of analgesics
morph: chronic tubulointerstitial nephritis w/ renal papillary necrosis

papillary necrosis occurs first then cortical tubulointerstitial nephritis

acetaminophan injurs by covalent binding and oxidative damage
aspirin potentiates by inhbiting vasodilatory effects of prostaglanding

gross: depressed areas of cortical atrophy overlying necrotic papillae in various stages of necosis --> calcification --> fragmentation --> sloughing

microscopically papillae show patchy to full necosis; cortex tubular atrophy, interstitial iflam/fibrosis
Analgesic nephropathy is prevalent in what group of patients? Does drug withdrawal lead to recovery? What complication may occur in a small percentage of patients? Is papillary necrosis specific for analgesic nephropathy (Table 20-9)?
women with recurrent headaches & muscle pain: factory workers,, psychoneurotic pts
[inability to concentrate urine, HA, anemia, GI sx, htn, UTI in 50%
entire tips of necortic papillae may be excreted: gross hematuria w/ renal colic]
drug withdrawal and proper infx tx may stabalize or improve else chronic renal failure;
rare complication: transitional papillary carcinoma
What are the NSAID associated renal syndromes?
Hemodynamically induced acute renal failure
actue hypersensitivity interstitial nephritis
acute intersitial nephritis and lipoid nephrosis
Membranous GN

[slide on chinese herb nephropathy]
What three types of nephropathy can occur in patients with hyperuricemic disorders?
Acute uric acid nephropathy: precipitation of uric acid crystals in renal tubules, obstrx of nephrons, actue renal failure, esp in leukemia lymphoma pts during chemo

Chronic urate nephroathy (gouty nephropathy)
depsoition of monosodium urate n distal tubules: microscopically distinctive bireringement needlelike cyrstals in tubular lamina/intersitium --> giant cell enclosed trophus

Nephrolitiasis: uric acid stones
What four factors contribute to renal damage in multiple myeloma? What are the clinical renal manifestations?
Bence Jones Light Chains directly toxic to epithelium, combine with Tamm Horsfall urinary glycoprotein to form tubular casts that obstruct lumin and induce peritubular inflam

Amyloidosis
Light chain nephropathy
hyhpercalcemia, hyperuricemia

morphology: pink-blue amorphous masses of Benc Jones tubular casts filling & distending tubular lumens ± multinucleated giant cells

Clinical: mostly chronic renal failure, some acute renail failure; bence jones proteinuria in 70%
[ Hypercalcemia and Nephrocalcinosis, Acute phosphate nephroapthy, Renal involevement by nonrenal neoplasms]
Hypercalcemia --> stones --> tubulointerstitial
What are three consequences of urinary tract obstruction?
infection
calculus
hydronephrsosis, hydroureter --> kidney atrophies under pressure
List congenital anomalies causing obstruction.
stricture, meatal stenosis
posterior ruerthral valves in male infants: valves arise from verumontanum, bladder wall hypertrophy; mucosal surface trabeculated.
ureteral pelvic jnx narrowing --> veicourteral reflux
1st sign may be pyelonephritis
What other conditions cause obstruction? Which are most likely to cause bilateral obstruction?
urinary calculi; in bladder will cause bilateral obstrx
benign prostatic hyperplasia -bilateral obstrx
inflamation: prostatisis, ureteritis, urethritis w/ strix, retroperitoneal fibrosis
Tumors: prostate, urothelial, lymphoma, cervical carcinoma
Pregnancy
uterine prolapse & cystocele
retroperitoneal fibrosis
Papillary necrosis: diabetes, pyelonephritis, sickle cell, analgesic abuse nephroapthy (phenacetin), obstrx w/ infx
Blood Clots
Functional Disorders: neurogenic (spinal cord injury), diabetic neuropathy
pain
renal colic
back pain at costophrenic angle

Dx, Tx, Px
clinical presentation of urinary tract obstruction


renal colic: due to stone, clot, papillae in distended ureter
back pain at costophrenic angle from renal capsular distention
nocturia and urgency if prostatic enlargement
Dx: US/Imaging
urinary obstrx

complete vs partial, unilateral vs bilateral
Unilateral or partial: may be silent until irreversible hydronephrosis
Partial bilateral-->tubulointerstitial lesions:
--decreased concentrating ability, salt wasting --> distal tubular acidosis, htn
--calculi form in stagnant urine
--scarring

Complete bilateral obstrx
Causes: prostatic hyperplasia, posterior urethral valves, urethral strix, bladdder stones, neoplasms of bladder/pelvis
Sx: oliguria/anuria
MUST BE RELIEVED TO PREVENT DEATH, Relief => Massive Diuresis
List 4 types of common urinary calculi. Which is most common. Know causes of each, listing by frequency. Contrast as to:
pH of urine in which they form
radiolucent vs radio-opaque on plain film of abdomen
Know any unique morphology
calcium oxalates/Calcium Phosphates, highest frequency, pH ~7, radioopaque

Magnesium ammonium phosphate stone, urease bacteria alkaline urine, Radio-opaque, staghorn calculi

Uric Acid Stones Acid Urine Radio-lucent

Cystine Stones Urinary pH: Acidic, Mildly Radiodense (visible)
calcium oxalates/Calcium Phosphates
Frequency: Majority of stones
Urinary pH: near neutral/acidic pH
Radio-opaque
Morphology:
Causes by freq: Ideopathic hypercalciuria, uric acidemia, no metabolic defect, hypercalciuria 2* to hypercalcemia, hypercalciuria 2* to renal tubular reabsorption defects, familial/vegan hyperoxaluria, hypocritraturia 2* to chornic diarrhea/acidosis
Magnesium ammonium phosphate stone
Causes: urea splitting proteus or staph --> ammonia --> alkaline urine
Urinary pH: alkaline
Radio-opaque
Morphology: any size/location --> grow to staghorn calculi: large, branching, take shape of calyces & pelvis
Uric Acid Stones
Causes: mostly from elevated uric acid: gout, leukemia/lymphoma
, else hyperuricemia, uricosuria 2* to Rx's: Vitamin C, thiazides, etc
Urinary pH: Acid Urine
Radio-lucent
Morphology
Cystine Stones
Genetic defect in renal reabsorption of Amino-Acids
Frequency: Uncommon
Urinary pH: Acidic
Mildly Radiodense (visible)
Morphology
Staghorn calculi
Magnesium ammonium phosphate stone
Causes: urea splitting proteus or staph --> ammonia --> alkaline urine
Urinary pH: alkaline
Radio-opaque
Morphology: any size/location --> grow to staghorn calculi: large, branching, take shape of calyces & pelvis
Stone in alkaline urine
Magnesium ammonium phosphate stone
Causes: urea splitting proteus or staph --> ammonia --> alkaline urine
Urinary pH: alkaline
Radio-opaque
Morphology: any size/location --> grow to staghorn calculi: large, branching, take shape of calyces & pelvis
Radio-lucent kidney stones
Uric Acid Stones
Causes: mostly from elevated uric acid: gout, leukemia/lymphoma
, else hyperuricemia, uricosuria 2* to Rx's: Vitamin C, thiazides, etc
Urinary pH: Acid Urine
Radio-lucent
Morphology
Most common kidney stones
calcium oxalates/Calcium Phosphates
Frequency: Majority of stones
Urinary pH: near neutral/acidic pH
Radio-opaque
Morphology:
Causes by freq: Ideopathic hypercalciuria, uric acidemia, no metabolic defect, hypercalciuria 2* to hypercalcemia, hypercalciuria 2* to renal tubular reabsorption defects, familial/vegan hyperoxaluria, hypocritraturia 2* to chornic diarrhea/acidosis
Causes and consequences of hypercalcemia:
- hyperparathyroidism
-carcinoma met'd to bone
-homrone producing lung/renal CA
-granulomatous disease: sarcoidosis, TB/Coccy
-Hypervitamin-A/D-oses
-Addison Disease
What are symptoms, labs, common locations of urinary calculi? Review consequences of obstruction.
Sx: hematuria w/ cramping, colicky pain
Consequences: obstrx assoc w/ smaller stones --> hydroureter, hydronephrosis
Ulceration & bleeding; obstrx & trauma --> Infx
Common sites: passing brim of pelvis, entry into urinary bladder
Review and recognize all consequences of lead toxicity. What are the nephrotoxicities of lead?
Pull out previous cards ofr led toxicity
Chronic tubulointerstitial renal disease
Acute Toxicity: damage to proximal tubules --> aminoaciduria, phosphaturia, glycosuria (Fanconi syndrome)
Chornic Toxicity: Diffuse interstitial Fibrosis: proteinuria, hyperuricemia, htn, gouty arthritis +- --> chronic renal failure
-Htn
-Renal Cell Carcinoma
What are the nephrotoxcity and the CNS toxicity of mercury?
methyl mercury & ethylmercury do not respond to chelation
acute expsoure: proximal tubular necorsis
chornic low dose exposure: mild renal dysfnx
CNS Toxicity: Minamata disease aka Mad Hatter: Muscle Tremors, Dementia, Gingivitis, Cerebral palsy, Mental retardation
What are the nephrotoxicity and malignancies associated with cadmium exposure?
pulmonary toxicity: obstructive lung disease
nephrotoxicity: concentrates in proximal convoluted tubules
acute toxicity: proteinuria
chornic toxicity: hypercalciuria, osteopenia, fractures, prostate and renal CA
Describe angiomyolipoma of the kidney by histology, behavior. What are characteristics of the associated syndrome?
blood vessesl, smm, fat
--> tuberous sclerosis
AD familal TSC1 or TSC2
Skin lesions: ash leaf macules, periungual fibromas
cerebral cortex lesions: siezures, +- retardation
~half have angiomyolipoma
What is the appearance and association of oncocytoma? Is it benign or malignant?
brown liver-like cut surface
cuboidal mitos rich eosinophlic cells
benign, tho may reach ~10 cm in size
Know risk factors for renal cell carcinoma. What two gene defects are associated with these neoplasms?
Males 50-70
Tob smoking
Obesity (unopposed estrogen)
asbestos
petroleum industry
Htn
chornic renal failure
dialysis (cystic kidney)
Genetics (1/20 of cases)
---Von Hippel Lindau: hemangioblastomas of cerebellum & retina; 2/3 develop multiple bilateral RCC
--Non-syndromal defects in VHL gene
--Hereditary papillary carcinoma = MET oncogene
Stratify the 4 listed types of renal cell carcinoma by 1) most frequent; 2) good prognosis; 3) poor prognosis; 4) origin
Clear Cell Carcinoma: most frequent, Origin: tubular epithelial cells

Papillary adenocarcinoma

Chromophobe renal cell carcinoma; best prognosis
Prognosis Excellent
Origin collecting duct intercalated cells

(Bellini) Collecting Duct Carcinoma: Least Frequent, worst prognosis
Origin: renal medulla,
VHL gene
tumor suppressor [ubiquintin ligase complex:] normally downregulates downregulates HIF-alpha, promotes VEGF, EPO & other growth factors--> pro-angiogenic [hemangioblastomas, polycythemia vera, renal cysts & renal cell carcinoma] assoc w/ 80% of RCC Clear Cell type; chrom 3
VHL inhibits insulin like growth factor (anti-apoptotic)
What is the gross and microscopic appearance of clear cell carcinoma of the kidney?
solitary, unilateral if psortaic
multiple bilateral in VHL
Spherical 9 cm (+- 6)
yellow mottled surface w/ gray-white necrosis
Vascular w/ areas of hemorrhage

histology: clear/granular cytoplasm + for glycogen
What are the clinical presentation; paraneoplastic syndromes, pattern of metastases of renal cell carcinoma.?

to where is it most likely to met?
Hematuria (not paraneoplastic) +
Polycythemia, Hypercalcemia, Htn

metastatic sites: most to lungs by renal vein extension
33% to bones: osteoclastic "lytic" mets

[Endocrine dysnfx: cushings; feminization/masculinization
Hepatic dysfnx
eosinophilia, leukemoid rxns]
[else Mets regional LN's, Liver, Adrenals, Brain]

5 years survival ~half, better if no mets on discovery (present in 1/4)
Hematuria, Polycythemia, Hypercalcemia, Htn
paraneoplastic syndromes, pattern of metastases of renal cell carcinoma.

metastatic sites: most to lungs by renal vein extension
33% to bones: osteoclastic "lytic" mets

5 years survival ~half, better if no mets on discovery (present in 1/4)
What are the risk factors, growth pattern and presenting symptoms of urothelial carcinoma of the kidney? What diagnostic studies are employed; how does the prognosis compare with renal cell carcinoma? What is the gross and microscopic morphology?
Arises from renal pelvic transitional cell epithelium

Presenting sx: may be multiple locations along urinary tract, 10% of kidney carcionma

prsesenting sx: hematuria, obstrx (flank pain, hydronephrosis),

Risks: Tob, analgesic nephropathy, balkan nephropathy

Diagnostic procudres:
Urine cytology for atypical cells
[imaging, retrograde pyelography, cytbrush of lesion]
Morphology: papillary transitional cell carcinoma [or invasive]
prognosis dependent upon depth of invasive
Superficial >50%, Invasive ~10% at 5 yr,
Tx: nephrectomy
Where do calculi lodge in ureters?
Points of narrowing: ureteropelvic jnx, crossing iliac arteries, entry to bladder
Review list of causes of ureteral obstruction. (Table 21-1)
Calculi, strictures, tumors, blood clots, neurogenic
pregnancy, periureteral inflam, endometriosis, tumors
Define and list complications of :
Exstrophy of the urinary bladder
Bladder opens anteirorly through abdominal wall. high risk for infection, intestinal metaplasia with risk for adenocarcinoma, surgically correctable.
Define and list complications of :
Patent urachus
fistulous tract from bladder to umbilicus may closet to bladder diverticulum, may persist as urachal cyst.
Site of adenocarcinoma of the bladder
Define and list associations and complications of sclerosing retroperitoneal fibrosis?
fibrous proliferative inflammation which bilaterally obstructs ureters and causes hydronephrosis;
>= middle age, assoc. w ergot, beta adrenergics & beta blockers, fibrosis elswhere: Reidel's struma (thuroid).
most are idiopathic possbly autoimune
List types of cystitis.
Bacteira
Schistosoma haematobum in middle east
Cyclophosphamide: hemorrhagic cystitis
radiation cystits +- hemorrhagic

Hemorrhagic & Intersitial
What are the characteristics of interstitial cystitis?
painful form of chronic cystitis associated with SLE & autoimmunities, (females)
Intermittent severe suprapubic pain, frequency, urgency, dysuria, hematuria
Sterile urine
hunner ulcers in mucosa
inflammation with mast cells & fibrosis of all layers
What is malakoplakia and its associations?
chronic e coli infx in an immunosuppressed pt
gross: soft, yellow raised mucosal plaques
micro: infiltrate of foamy M0 w/ PAS+ cytoplasm
List associations of urethritis.
gonococcal: urethritis is 1st manifestation, produces uretheral strictures in males
nongonococcal: e coli, other coliforms; venereal: chlamydia trachomatis, mycoplasma
assoc. prostatitis in males, cystitis in females
Metaplastic lesions of urothelium:
Metaplastic: common w/ no adverse associations
--Cystitis cystica, cystitis glandularis
Metaplastic 2* to injury:
--squamous emtapolasa, nephrogenic adenoma (forms a nodule)
List the spectrum of urothelial neoplasms. Compare morphology, risk of recurrence, survivals. What is the most important determinant of prognosis for urothelial carcinoma?
Papilloma = benign
Non invasive papillary (//sessile) tumors range form low malignant potential to high
carcinoma in situ: flat but high grade

Low grade papillary urothelial carcinoma aka Grade I papillary transitional cell carcionma
mild nuclear atypia/pleomorphism; 50% risk of recurrence, low 10% invasivenss, low risk progression, excellent prognosis.

high grade urothelial carcinoma: may be papillary, nodular, flat (in situ) or flat invasive;
pleomorphic anaplastic cells with frequent mitoses, loss of polarity and cohesions. Px ~= depth of invasion; muscularis = worst. "superficial" tumors likely to have invasive areas. high risk of recurrence 40% 10 year survival.

Carcinoma in situ: high grade flat neoplasm within epithelium. usually accompanies other transitional cell carinoma. aggressive with high risk for invasion, 60% invade if unTx.
Papilloma = benign
Non invasive papillary (//sessile) tumors range form low malignant potential to high
carcinoma in situ: flat but high grade
Low grade papillary urothelial carcinoma aka Grade I papillary transitional cell carcionma
mild nuclear atypia/pleomorphism; 50% risk of recurrence, low 10% invasivenss, low risk progression, excellent prognosis.
high grade urothelial carcinoma
may be papillary, nodular, flat (in situ) or flat invasive;
pleomorphic anaplastic cells with frequent mitoses, loss of polarity and cohesions. Px ~= depth of invasion; muscularis = worst. "superficial" tumors likely to have invasive areas. high risk of recurrence 40% 10 year survival.
Carcinoma in situ
high grade flat neoplasm within epithelium. usually accompanies other transitional cell carinoma. aggressive with high risk for invasion, 60% invade if unTx.
What are the causes and significance of squamous cell carcinoma of the urinary bladder?
chronic bladder irritaiton, eg schistosoma haematobum; deeply invasive ad discovery, poor prognosis: 70% mortality at 1 year.
What conditions are associated with adenocarcinoma of the urinary bladder?
rare, histologically identical to GI tract tumors
arises from bladder epithlium: urachal remnants, exstrophy, etc.
What agents are risk factors for urothelial carcinoma?
Cigarette smoking
industrial arylamines: 2-naphthylamine strongest 10+ years after exposure;
pelvic radition
betel nuts
Shistosoma hematobium
analgesic abuse phenacetin
cyclophosphamide immunosuppressant long term heavy use cases hemorrhagic cystitis and risks transitional cell CA

[molecualr alterations not an objx]
What is the clinical presentation and behavior, in general, of carcinoma of the bladder?
painless hematuria is most common presenting complaint
+- obstruction --> pyelo, hydronephrosis;
50% are single localized to bladder, but likely to recur at any site along urinary tract, likely to crop up multifocally.
How is carcinoma of the bladder diagnosed?
Dx via cytoscopy w/ biopsy;
Retrograde pyelography w/ contrast (x ray procedure)
urine cytology: atypical cells w/ non-visualized tumor on cytoscopy suggests ureteral or kidney lesions
flow cytometry for DNA, other markers

[tx no in objex]
What mesenchymal tumors involve the urinary bladder
rarely benign leiomyomas
What is the nature of mesenchymal tumors that involve the urinary bladder
malignantly: embryonal rhabdomyosarcoma (sarcoma botryoides): occur in infnacy/childhood, large mass protruding into lumen of bladder

[no objx for 2ndry bladder tumors]
What are causes, clinical features and morphology of bladder neck obstruction?
Bladder neck obstruction, causes

congential narrowings, structures
prostate hyperplasia/prostatitis
immediately postpartum
fibrosis bladder
any tumor
bladder calculi, foreign bodies
neurogenic
cystocele in women

Clinical features: acute obstrx, distended bladder w/ thinned wall
chronic obstrx; hypertrophied wall, trabeculations & diverticula
Bilateral hydrophenosis in either
What two tumors involve the urethra of older females. What is the morphology of the more common?
urethral carbuncle: vascular proliferation w/ inflammatory cells produces small painful nodule at extenrla meatus. sx: local pain & bleeding; more common

squamous cell carcinoma. sx: local pain & bleeding, distal urethra w/ poor prognosis.
How many cell layers are the normal prostate glands lined by?
2 cell layers: basal layer of low cuboidal cells + columnar mucous secreting cells
What three pathologic processes affect the prostate with any frequency? Which is the most common?
Inflammation
Benign Nodular Enlargement - most common
Tumors
What three categories can prostatitis be divided into?
Acute Bacterial
Chornic - insidious, hx of UTI's
Chronic abacteiral - insidious no hx of UTI's
Granulomatous 2* to intentionall innoculation of BCG into baldder to tx CA
What causes acute bacterial prostatitis?
Acute Bacterial prostatitis
E coli & gram neg rods
fever, chills dysuria
clinically tender & boggy, dx via urine cultures & clinical features
What are the symptoms of acute bacterial prostatitis?
morpholgoy: minute disseminated abscesses, large coalescent areas of necrosis
diffsue edema, congestion boggy suppration of entire gland, eventual scarring
What are the clinical presentations of chronic bacterial prostatitis? What common clinical setting is found?
chronic: insidious presentation: low back pain, dysuria, aSx
Hx of recurrent UTI's w/ same organism
Dx: leukocytosis & positive bacteiral cultures in prostatic secretions
Why is chronic bacterial prostatitis difficult to treat?
Difficult to treat because antibiotics seed prostate poorly
How is chronic bacterial prostatitis diagnosed?
morphology: aggregates of lymphos, plasma cells, M0's & PMNs
What is the most common form of prostatitis ? What history is lacking as compared to chronic bacterial? How is it diagnosed?
Chronic abacterial
no recurrent UTI's
clinically same as chronic bacterial w/o Hx of UTI's: insidious presentation: low back pain, dysuria, aSx
Caused by Chlamydia trachomatis, ureaplasma urealyticum
prostatis secretions contain >10 WBC/high powered field
BPH is common in men over what age? What androgen is implicated? What drug is used to counteract the androgen?
50 yo
DHT, 5 reductase inhibitor will reduce conversion of testosterone to DHT, estorgens may aid process
What is the tension of prostate smooth muscle mediated by? How can alpha-adrenergic receptor antagonists help in BPH?
tension in prostate smooth muscle mediated by alpha 1 receptors
What are the gross features of BPH? What are the hallmark microscopic features?
hallmark feature is nodularity
prostatic nodules ~80 gms (+-20) originating in periurethral & transitional zones.

nodules may compress urethra
nodes easily identified on cross section
glandular: yellow, soft, milkey
fibrious- pale grey, tough no fluid
no true capsule

bilayered (inner columnar, outer cuboidal) epithlium predominates with aggregates of small & large cystically dilated glands

epithlium thrown into numerous papillary buds and infoldings
What two secondary effects account for the clinical symptoms of BPH?
compression of urethra: difficulty voiding
retention of urine: distention, hypertrophy & infections of bladder
What are the clinical symptoms of BPH?
LUTS:
-frequency
-nocturia
-difficulty stopping & starting
-overflow dribbling
-dysuria
-2ndry changes in bladder
Is BPH a premalignant lesion?
Hyperplasia is not a premalignant condition
What treatments are available for BPH?
Tx: alpha blockers decrease smooth msucle tone, 5alpha reductase inhibitors reduce DHT, estrogen antagonizes DHT: shrinks prostate.
Noninvasive: TURP, US, laser therpay, hyperthermia, stents & radiofrequency
What is the most common form of cancer in males? Where does it rank in terms of cancer death in men?
Prostate cancer: 1/6 men;
2nd leadign cause of CA death.

that said: 90% indicental at autopsy: most men die with cancer rather than from the cancer.
Prostate cancer is usually a disease of men over what age?
50's
What are the five risk factors of prostate cancer?
Ethnicity: Blacks
Age: 75% found >65
Family Hx
High Fat Diet
Genetics: androgen receptor AR gene amplification: related to CAG repeats: short repetaes ahve increased sensitivity to androgen (accts for ethnic variation)
What is the most common genetic alteration seen in prostate cancer?
>90% show hypermethylation of GSTP1 glutathione S transferase gene promotor 1; GSTP1 important to prevent damage from carcinogens, hypermethylation turns it off.
Where do most cases of cancer arise in the prostate?
70% posterior lcoations, palpable through rectum
Describe the gross features f prostate cancer?
gritty & firm
Describe the bony metastases of prostate cancer? What bone is most frequently involved?
spreads via direct invasion into seminal vesicles, bladder, spreads hematogenously to lumbar spine, spreads lymphatically to obturator nodes
What are the hallmarks of malignancy?
Hallmarks of malignancy: capsular invasion, perineural invasion
What are the histologic features of prostate cancer? How many cell layers are present?
Most are adenocarcinomas w/ well defined gland patterns
only one cell layer: outer basal layer absent;

malignant acini smaller & closely spaced w/ little intervening stroma, may see papillary cribiform pattern; nuclei large, vaculolated 2/ 1+ nucleoli
What is PIN?
Prostate intraepithelial neoplasia
Is PIN a presumptive precursor lesion to carcinoma?
Seen in 80% of CA's
architecturally benign prostatic acini lined by cytolicocally atypical cells w/ prominent nucleoli
no invasiaon, basal cell layer intact or fragmented
intraacinar proliferation of cells w/ nuclear anaplasia
similar molecular changes in PIN & invasive CA
presumptive precursor lesion for carcinoma
What is the best known grading system? How many grades are in the system?
Gleason grades 1-5
How is a score obtained?
assign primary grade to dominant pattern, 2ndry grade to subdominant pattern, add 2 together to get gleason score
Why is grading important?
Low score = well diffrentiated, high score = poorly differentiated
What staging system is used?
Grading is good predictor for prognosis
What is the significance of incidental cancers? What is the difference in outcome between a T1a and a T1b?
TNM staging system is important for Tx
T1 = incidental finding on TURP
T1a no progression over 10 years
T1b 40% progress w/in 5 years
Do most cancer patients present with urinary symptoms?
In CA urinary sx present late if at all
some present with back pain
The finding of osteoblastic bone mets in bone in virtually diagnostic of what?
finding osteoblastic mets is diagnostic for prostate cancer
How are the cancers detected? What is required to confirm the diagnosis ?
Digital rectal, transrectal ultrasound for early detection
transperineal/rectal biopsies to confirm
CT/MRI to evaluate extent of disase (nodes), bone scane
Is PSA produced by normal glands? What is a common laboratory cutoff value for PSA? Is PSA cancer specific? Organ specific?
produced by normal and neoplastic endoethlium
sensitive not specific for CA, also elevated in BPH, prostatitis, infarct, instrumentation

30% of pts w/ CA have psa <4
What things besides cancer can cause an elevated PSA?
PSA <4ng/ml normal
PSA 4-10ng/ml <50% risk for CA
10-20 >50% risk for CA
>20ng/mL = frank CA
What four refinements have been proposed in the estimation and interpretation of PSA values?
PSA density: takes ratio between serum SPA adn volume of prostate gland
PSA velocity: rate of change in PSA with time
Age specific range references
When is the use of per cent free PSA the most valuable? Are serial measurements of PSA useful?
Age specific range references
Ratio of free to unbound BSA: useful in discriminating when in 4-10ng/mL grey zone
What are the five types of therapy for cancer? What is the treatment for metastatic disease?
Watchful waiting
Surgery (radical, perineal, nerve sparing)
Radiotherpay (external or brachytherapy)
Cryotherapy
Hormonal manipulation - orchiectomy, agonists of LHRH, mainstay of tx for metastatic disease
What is the role of PSA in screening currently?
controversial
What is the expected specific gravity of first voided urine?
1.025
What is “low, fixed specific gravity” and what is the significance?
end stage renal disease produces low, fixed specific gravity ~1.010
What is the renal threshold for glucose? List causes of glycosuria.
180 +-20 = 160-200

Endstage kidney w/ normal blood sugar
DM
hyperglycemia: adrneal cortical/endocriend disease
renal disease alters renal trheshold
Rx: diuretics, birth control pills
fever in children
List causes of ketonuria
poorly controlled insulin dependent diabetes
anorexia nervosa/acute dieting
prolonged vomiting
GI diseases
What are the causes of proteinuria?
renal disease: glomerular, tubulointerstitial, vascular
microalbuminuria 30-300mg first sign of diabetes
Bence-Jones proteinuria of multiple myeloma only detected by immunoelectrophoresis, negative by dipstick

w/o disease: usually trace to 1+
strenuous exercise
exposure to extreme cold
psychologic stress

non-urinary disease: usually trace to 1+
hemorrhage
systemic infections
heart failure
dehydration, starvation
What defines nephrotic urine? What are the other lab findings of nephrotic
syndrome. List causes.
>3.5 gm protein/24 hours
oval fat bodies is the other cuase

other lab findings
lipiduria w/ fatty casts oval fat bodies
hyperlipidemia
hypoalbuminemia

most common cause in childhood: minimal change disease
other causes: henoch schonlein purpura

adutls:
daibetict neropathy
focal segmental glomerulaosclerosis
Systemic amyloidosis
membraneous glomeurlonephritis 1* or 2* to: NSAIDs, Penicillamine, carcinoma of lung or colon, Hep B & C, Syphilis, SLE
Urinary tract disease
What are the causes of hematuria / hemoglobinuria(by dipstick)?
hematuria:
strenuous exercise produces transient glomerular defect
disorders of uterus, vagina (menses)
prostatitis, prostatic CA (late sign)
disorders of urinary tract
--tumors both malignant and benign: renal cell carincoma, urothelial carcinomas
--glomerulonephritis
--pyelonephritis
--renal calculi
--polycystic kidney, medullary sponge kidney
--bleeding disorders incl anticoagulatnt herapy

False negative with vitamin C
What is the significance of RBCs plus casts in urine?
renal disease usually nephritic
RBC's without proteinuria?
bleeding distal to keyney
Dysmorphic RBCs are seen in:
suggestive of glomerulonephritis
When would urine demonstrate hemoglobinuria but no RBCs on microscopic
examination?
myoglobin:
after severe physical exercise
rhabdomyolysis of all causes

hemoglobin:
hemolysis of RBC's within urinary tract
intravascular hemolysis, hemolytic anemia, transfusion reaction
RBC casts
bleeding from kidney
WBC casts
pyelonephritis
RTE casts
renal tubular damage- toxic or ischemic ATN
Fatty casts-
lipiduria: nephrotic syndrome
Waxy casts:
acute & chronic renal failure w/ severe tubular destruction
Bile casts
hepatorenal syndrome
Red casts, no RBCs
Myoglobin: rhabdomyolysis of all causes, extreme exercise
What are the associations of positive nitrite? Can a UTI be present when nitrite
is negative?
bacteriuria: only certain species: E Koli, Kleb, proteus, staph pseudomonas
yes: yeasts, enterococci, false negative from low vegetable diet
What does esterase detect? What diseases are associated with positive esterase?
leukocytes pyuria
List causes of leukocyturia.
UTI, renal disease, renal calculi, ladder tumors, prostatitis urethririts
glitter cells:
PMNs in hypertonic solution
One or more photomicrographs of crystals will be presented on exam. Recognize morphology and correlate with urinary tract pathology. Use drawing as reference and know uric acid, calcium oxalate, cystine, triple phosphate
crystals.
shit
What is the significance of increased renal tubular epithelial cells in urine? When
is ethylene glycol poisoning suspected?
RTE + Oxalate = ethylene glycol
What is the significance of :
Atypical cells ?
malignant transitional epithelal cells = renal cell carcinoma, urothelal cell carcionma
What is the significance of > 8 / hpf Squamous epithelial cells
vaginal contamination of urine
What is the urinalysis of endstage kidney disease? Review all lab findings
of uremia/
low volume, low fixed specific gravity, proteinuria, glycosuria, grace blood few rbcs & wbc's waxy casts
GSPT1
the most common genetic alteration seen in prostate cancer?

>90% show hypermethylation of GSTP1 glutathione S transferase gene promotor 1; GSTP1 important to prevent damage from carcinogens, hypermethylation turns it off.
The most common cuase of htn in children
Reflux neuropathy
nodular prostate
hallmark feature of benign hypertrophy
embryonal rhabdomyosarcoma
malignant mesenchymal tumor in the bladder; occur in infnacy/childhood, large mass protruding into lumen of bladder
hunner ulcers
in mucosa of bladder assocaited with interstitial cystitis, mostly from autoimmunity aka chronic pelvic pain syndrome
EM: uniform diffuse effacement of foot processes
Minimal change disease aka lipoid nephrosis
most common cause of nephrotic syndrome in children
LM: lipid in tubles
EM: no deposits, uniform and diffuse effacement of food processes
Rapid repsonse to steroids
nephrotic phase may recurr

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Glomerular disease responds to steorids
Minimal change disease aka lipoid nephrosis
most common cause of nephrotic syndrome in children
LM: lipid in tubles
EM: no deposits, uniform and diffuse effacement of food processes
Rapid repsonse to steroids
nephrotic phase may recurr

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cystitis cytica
metaplastic cystic lesion with no adverse assocations
cystitis glandularis
metaplastic cystic lesion with no adverse assocations
liver toxicity with obstructive lung disease, bone disorder
cadium
Finely granular cortical surface
of benign nephrosclerosis.
Kidney of benign htn: sclerosis of renal arterioles & small arteries
assoc w/ age, diabetes, htn & African Americans
Pathogenesis:
intimal thickening + Hyaline deposition from extravasated plasma --> narrowing of lumens --> patchy ischemic tubular atrophy with intestitial fibrosis; glomeruli become sclerotic
Finely granular cortical surface
Clinical presenation: GFR >= Normal, mild proteinuria, increased risk of renal failure
Circulating IC Nephritis EM
Trapping of cirgulating immune complexes within glomerul --> complement activation --> damage
EM: electron dense deposits in mesangial, subendothelial (between endothelial cells & GBM), subepithelial (btw podocytes & outer surface of GBM, rare)
LM: diffuse uniform thickening of capullary wall
membranous GN
LM: diffuse, uniform thickening of capillary wall; silver stain shows spikes of BM between deposits
IF: granular deposits of IgG and C3
EM: irregular dense subepithelial deposits, foot processes lost

Causes: 85% idiopathic; rest: drugs, malignant tumors, SLE, infx, autoimmune disorders
Clinical: insidious onset of nephrotic syndrome, indolent; proteinuria does not repsond to steroids; proteinuria persists in 60$; 40% dvlp renul insufficiency in 10 years. only 10% reach renal failure in 10 years.
EM: irreglar dense subepithelial deposts, foot processes lost
membranous GN
LM: diffuse, uniform thickening of capillary wall; silver stain shows spikes of BM between deposits
IF: granular deposits of IgG and C3
EM: irregular dense subepithelial deposits, foot processes lost

Causes: 85% idiopathic; rest: drugs, malignant tumors, SLE, infx, autoimmune disorders
Clinical: insidious onset of nephrotic syndrome, indolent; proteinuria does not repsond to steroids; proteinuria persists in 60$; 40% dvlp renul insufficiency in 10 years. only 10% reach renal failure in 10 years.
granular deposits of IgG, IgM and C3 in mesangium along BM
acute proliferative (post-strep)immunologically mediated GN w/in a mo after certain GABHS strains;
enlarged hyperceullar glomeruli, diffuse proliferation of mesangial, endotheial cells, diffuse infiltration of PMN,s M0's;

tubules will have RBC casts, +- interstitial edema/inflam
IF: granular deposits of IgG, IgM and C3 in mesangium and along BM
EM: discrete amorphous electron dense deposits on epithelial side of BM --"humps" of C3

Clinical: young child w/ abrupt onset of malaise & hematuria w/in mo after recovering from sore throat
RBC casts, milkd proteinuria, periorbital edema, mild htn
adult onset atypical

Lab findings: elevated anti-streptococcal ab titers, low serum C3, cryoglobins in serum
Most children recover totally. 2% slow progression to chronic GN, <1% rapidly progressive GN
Only 2/3 adults recover completely
humps of C3
acute proliferative (post-strep)immunologically mediated GN w/in a mo after certain GABHS strains;
enlarged hyperceullar glomeruli, diffuse proliferation of mesangial, endotheial cells, diffuse infiltration of PMN,s M0's;

tubules will have RBC casts, +- interstitial edema/inflam
IF: granular deposits of IgG, IgM and C3 in mesangium and along BM
EM: discrete amorphous electron dense deposits on epithelial side of BM --"humps" of C3

Clinical: young child w/ abrupt onset of malaise & hematuria w/in mo after recovering from sore throat
RBC casts, milkd proteinuria, periorbital edema, mild htn
adult onset atypical

Lab findings: elevated anti-streptococcal ab titers, low serum C3, cryoglobins in serum
Most children recover totally. 2% slow progression to chronic GN, <1% rapidly progressive GN
Only 2/3 adults recover completely
flea bitten kidney
focal hemmorhages
complications of htn
fibrocystin
childhood polycystic kidney disease
parallel cylindrical cysts at right angles to cortx
childhood polycystic kidney disease
MET oncogene & renal CA
papillary carcinoma
gut hormone binds growth hormone secretogogue receptor
Ghrelin
THE ONLY GUT HORMONE THAT INCREASES FOOD INTAKE
Source: arcuate nucleus of hypothalamus + empty stomach
Fnx: binds growth hormone secretogoge receptor
obese individuals not able to fully suppress ghrelin
Stones caused by thiazides
uric acid
patchy interstitial suppurative finlam, intratubular aggreagates of PMN's and tubular necrosis
hallmark morphology of acute pyelonephritis
stone caused by too much vitamine C
acidic Ca2+ oxalate
stones caused by uric acidemia
uric acid
Ca2+ oxalate (acidic & forms nidus)
CA originating from Tubular epithelial cells
Clear Cell Carcinoma
CA originating from duct intercoloating cells
Chromophobe
CA originating from Collecting Ducts
Belllini Collecting Duct Carcinoma