Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
34 Cards in this Set
- Front
- Back
|
Learning objectives
|
Understand the causes and composition of proteinuria
Know the clinical features of the nephrotic syndrome Understand the pathophysiology of the major disease entities that cause the nephrotic syndrome |
|
|
Proteins in urine
|
Proteins in the urine consist of:
-Secreted proteins from the nephron (Tamm-Horsfall mucoprotein) -Filtered albumin -Filtered globulins (Bence-Jones proteins) 2 theories exist regarding the filtered proteins: -The GBM is essentially impermeable to plasma proteins and very small amounts are filtered (most widely held) -The GBM is permeable to plasma proteins and large amounts are filtered and reabsorbed by the tubules |
|
|
Proteinuria definitions
|
Normal amounts of proteinuria:
-Children: < 100 mg/m2/day -Adults: < 150 mg/day Pathologic proteinuria: -150 mg – 3 grams = proteinuria -> 3-3.5 grams/day = nephrotic range proteinuria Albuminuria: -< 30 mg/day = normal -30-300 mg/day = microalbuminuria -> 300 mg/day = macroalbuminuria |
|
|
Selectivity of proteinuria
|
Highly selective:
-Mostly low molecular weight proteins -(albumin = 70 kD; transferrin = 76 kD) Poorly selective: -Includes more high molecular weight proteins -(globulins) |
|
|
Causes of proteinuria (3)
|
1. Transient or isolated: occurs intermittently due to stress which alter renal hemodynamics:
-Fever, vigorous exercise, exposure to extreme cold 2. Orthostatic or postural: occurs in children, >60% of all cases of childhood proteinuria -Proteinuria when upright > supine -Normal variant, subtle glomerular disease, altered renal hemodynamics, left renal vein entrapment 3. Persistent: -Glomerular source --Increased movement of proteins across GBM -Tubular source --Decreased re-absorption of proteins in the proximal tubule (Fanconi syndrome) -Overflow --Increased production of plasma proteins (paraproteinemias) overwhelms GBM filtering capacity/tubular re-absorption |
|
|
Nephrotic syndrome: definition
|
Clinical syndrome caused by pathological glomerular protein losses
Hallmarks: -Proteinuria (> 3-3.5 grams/24 h) -Edema -Hypoalbuminemia -Hyperlipidemia Most causes of nephrotic syndrome are diseases of the glomerulus |
|
|
Nephrotic syndrome: sequelae (6)
|
Elevated production/abnormal transport/decreased catabolism of lipids, hyperlipidemia → atherosclerotic disease, progression of CKD
Loss of ATIII, fibrinolytic factors → hypercoagulable state (Deep vein thrombosis, renal vein thrombosis) Loss of TBG (thyroid binding globulin), thyroxine → hypothyroidism Loss of vit D binding protein → hypovitaminosis D Loss of transferrin, erythropoietin → anemia Loss of immunoglobulins → relative increased risk of infection (staphylococcal, pneumococcal) |
|
|
The glomerular basement membrane: the size and charge barrier
|
Fenestrated capillary endothelium (size barrier)
Fused basement membrane with heparan sulfate (negative charge barrier) Epithelial layer consisting of podocyte foot processes |
|
|
Minimal change disease: histology
|
LM: normal
IF: negative EM: foot process effacement Other: proximal tubule cells laden with lipids (lipoid nephrosis) |
|
|
Minimal change disease: pathogenesis
|
Hallmark is visceral epithelial cell (podocyte) damage
? Immunologic dysfunction → cytokine elaboration → visceral epithelial cell damage Inherited defects in podocyte structural proteins (nephrin – NPHS1 variants) in congenital nephrotic syndrome of Finnish type produces MCD morphology Loss of charge barrier, but unclear how proteins traverse |
|
|
Minimal change disease: etiology
|
Primary (idiopathic)
-Observations that suggest immunologic cause: --Clinical association with respiratory infection --Response to immunosuppressive therapy --Association with other atopic disorders --Increased prevalence of certain HLA haplotypes that are associated with ectopy --Increased incidence in T-Cell lymphoma --Proteinuria inducing factors in the plasma of patients Secondary -NSAIDs, lymphoma |
|
|
Minimal change disease: epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-Most common cause of nephrotic syndrome in children -NS prevalence: children (65%) adults (10%) Clinical Presentation -Sudden onset of massive proteinuria and nephrotic syndrome Treatment -Corticosteroids, cyclosporine, cyclophosphamide Prognosis -1/3 remit, most relapse/remit, HTN and ESRD are rare |
|
|
Focal and segmental glomerulosclerosis (FSGS): histology
|
LM: focal and segmental sclerosis and hyalinosis
IF: focal IgM, C3 in sclerotic areas/mesangium EM: foot process effacement |
|
|
FSGS: pathogenesis
|
Hallmark is degeneration and disruption of visceral epithelial cells similar to MCD (? disease spectrum/continuum)
Circulating cytokines, genetically determined defects of the slit diaphragm complex likely contribute Hyalinosis and sclerosis result from hyperpermeable areas of the GBM and extracellular matrix deposition |
|
|
FSGS: etiology
|
Primary (idiopathic)
-Proteinuria can recur within 24 hours after transplant, suggesting circulating factor -Leading candidate: soluble urokinase plasminogen activator receptor (suPAR) Hereditary/genetic: associations with mutations in podocyte proteins -NPHS2 (podocin) – childhood steroid resistant FSGS -Alpha-actinin 4 – autosomal dominant FSGS -TRPC6 (podocyte ion channel) – adult onset FSGS -CD2 associated protein (CD2AP) -APOL1 (apolipoprotein 1) variants – kidney disease in African Americans Secondary -HIV -Hyperfiltration (unilateral renal agenesis, oligonephronia from premature birth) -Toxins/drugs (pamidronate, heroin) -Reflux nephropathy |
|
|
FSGS: epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-Common in adults -NS prevalence: children (10%) adults (35%) Clinical Presentation -Indolent, full nephrotic syndrome rare in secondary Treatment -ACEI, ARB. Primary with persistent nephrotic syndrome: corticosteroids, cyclosporine, mycophenolate mofetil Prognosis -Spontaneous remission rare (1⁰), common cause of ESRD, 50% of patients with persistent nephrotic proteinuria are ESRD within 5 years -Can recur within days to weeks in transplant |
|
|
HIV associated nephropathy: Pathology, etiology/pathogenesis
|
Pathology
-Collapsing variant FSGS – sclerotic glomerular tuft is retracted with proliferation of overlying visceral epithelial cells -Cystic dilation of tubule segments -Tubuloreticular inclusions in endothelial cells Etiology/pathogenesis -Direct infection of glomerular/tubular cells with HIV -HIV gene products vpr and nef are implicated |
|
|
HIV associated nephropathy: epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-More common in blacks than whites (association with APOL1 variants) Clinical presentation -Usually seen in uncontrolled HIV, but can precede AIDS -Nephrotic syndrome common Treatment -Highly active anti-retroviral therapy (HAART) Prognosis -Poor, common cause of ESRD in HIV patients |
|
|
Membranous glomerulopathy: histology
|
LM: diffuse capillary wall and GBM thickening, “spikes and holes” on silver stain
IF: granular staining in GBM (IgG, C3) EM: foot process effacement, sub-epithelial immune deposits |
|
|
Membranous glomerulopathy: pathogenesis
|
In situ immune complex formation against various antigens
Complement activation and formation of the MAC activates glomerular epithelial and mesangial cells → capillary wall injury and protein leakage Lesions are similar to Heymann nephritis model (antibodies to megalin). Susceptibility of rats to Heymann nephritis is linked to MHC locus variants, suggesting a genetic susceptibility in the human disease also |
|
|
Membranous glomerulopathy: etiology
|
Primary (idiopathic)
-Thought to be genetic susceptibility + antibodies to renal autoantigen -Antigen in neonates: neutral endopeptidase -Antigen in adults: likely phospholipase A2 receptor (PLA2R) Secondary -Drugs (penicillamine, captopril, gold, NSAIDs) -Solid tumor malignancies (lung, colon carcinomas) -Autoimmune disease (SLE, autoimmune thyroiditis) -Infections (hep B, hep C, syphilis, schistosomiasis, malaria) IMPORTANT |
|
|
Membranous glomerulopathy: epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-Think middle aged white males -NS prevalence: children (5%) adults (30%) Clinical Presentation -Variable – sudden onset proteinuria with nephrotic syndrome, more subtle onset with secondary Treatment -Age/sex appropriate cancer screening -Corticosteroids alt. cytotoxic agents, cyclosporine Prognosis -1/3 spont remit, 1/3 persistent, 1/3 progressive |
|
|
Membranoproliferative GN type 1: histology
|
LM: endocapillary proliferation, “tram-track” appearance due to GBM
splitting from mesangial inflitration, mesangial expansion/hypercellularity IF: granular staining in GBM and mesangium IgG, C3, C1q/C4 EM: subendothelial immune complexes |
|
|
MPGN type 1: pathogenesis
|
Hallmark: immune complex deposition in the subendothelial and mesangial compartments
Results in GBM alterations, endocapillary proliferation, leukocyte infiltration, mesangial proliferation Circulating antigens result in immune complex formation |
|
|
MPGN type 1: etiology
|
Primary (idiopathic)
-Inciting antigens unknown Secondary -Infection: hepatitis B, hepatitis C (usually with cryoglobulinemia), endocarditis, infected ventriculo-peritoneal shunts, chronic visceral abscesses, HIV, schistosomiasis --(immune complexes form from circulating virion particles, bacterial antigens, etc) -Alpha-1 antitrypsin deficiency -SLE -Malignancy: chronic lymphocytic leukemia, lymphoma |
|
|
MPGN type 1: epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-Rare -NS prevalence: children (10%) adults (10%) for all MPGN Clinical Presentation -Mixed nephrotic/nephritic syndrome Treatment -Treatment of underlying disease -Corticosteroids, immunosuppressive agents Prognosis -> 50% progress to ESRD for all MPGN |
|
|
MPGN type 2 (Dense deposit disease): histology
|
LM: endocapillary proliferation, “tram-track” appearance due to GBM splitting from mesangial inflitration, mesangial expansion/hypercellularity
IF: granular or linear staining of C3 in the GBM (but not in the deposits) EM: irregular, ribbon-like, electron dense deposited material in the GBM |
|
|
MPGN type 2 (Dense deposit disease): pathogenesis
|
Disorder of complement activation
Alternate pathway is being constantly activated due to pathologic stabilization of the C3 convertase -C3 nephritic factor (C3NeF) – circulating Ab which binds and stabilizes C3 convertase -Genetic defect in factor H – which usually degrades C3 convertase Glomerular damage occurs due to recruitment of inflammatory cells similarly to MPGN type 1 |
|
|
MPGN type 2 (dense deposit disease): epidemiology, clinical presentation, treatment, prognosis
|
Epidemiology
-Rare – usually young adults Clinical Presentation -Variable, nephrotic syndrome with hematuria or insidious proteinuria Treatment -Eculizimab (antibody against C5), plasma exchange, immunosuppression Prognosis -> 50% progress to ESRD for all MPGN |
|
|
Diabetic nephropathy: histiology
|
LM: 1) afferent & efferent arteriolar hyalinosis; 2) mesangial expansion; 3) GBM
thickening; 4) nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) IF: can have nonspecific focal IgG EM: foot process effacement, GBM thickening |
|
|
Diabetic nephropathy: pathogenesis, epidemiology, clinical presentation, treatment, prognosis
|
Pathogenesis
-AGEs, cytokine activation → GBM tvascular damage -hyperfiltration → glomerulosclerosisa Epidemiology -Most common cause of ESRD in U.S. -Longstanding (> 10 yr) history of T1DM (>20 years rare) -5-10 year history of T2DM Clinical Presentation -HTN, large kidneys early -Microalbuminuria with high GFR → macroalbuminuria with GFR decline Treatment -Tight glycemic control, ACEI/ARB -BP < 130/80 in DM and 125/75 in PCR > 1 g Pr/g Cr Prognosis -T1DM with DN, usually ESRD 15-30 years after DM diagnosed |
|
|
Amyloidosis: histology
|
LM: fluffy “cotton candy” deposition in mesangium, apple-green
birefringence on Congo Red staining IF: usually negative EM: randomly arranged fibrils |
|
|
Amyloidosis: pathogenesis, epidemiology, clinical presentation, treatment, prognosis
|
Etiology/pathogenesis
-Extracellular tissue deposition of protein fibrils in beta pleated sheets -AL: plasma cell dyscrasia → light chain fragments -AA: inflammation → serum amyloid A (acute phase reactant) -AF: inherited protein deformities such as transthyretin (prealbumin) Epidemiology -Rare Clinical Presentation -Proteinuria and renal dysfunction are severe, NS in 25% at presentation Treatment -Chemotherapy (AL), control of underlying inflammation, colchicine (AA), liver transplant (AF) Prognosis -Variable |
|
|
Lupus nephritis: pathogenesis, epidemiology, clinical presentation, treatment, prognosis
|
Etiology/pathogenesis
-Immune complex deposition causing proliferative glomerulonephritis -Nephritogenic antigen has not been indentified Epidemiology -Of patients with SLE: 75% will have abnormal U/A, 1/3 lupus nephritis Clinical Presentation -Variable: asymptomatic proteinuria/hematuria to edema to RPGN -Lupus nephritis can change classes over time Treatment -Class I-II: monitor, ACEI/ARB -Class III-IV: monthly IV cyclophosphamide x 6 months, then q3 months x 2 years; MMF may be equivalent as induction agent -Maintenance therapy: MMF, azathioprine Prognosis -Lower GFR, severity of disease on biopsy, interstitial fibrosis, crescents, black race predict worse outcome -Mortality rate of proliferative lesion: 10-20% at 10 years -ESRD rate in proliferative lesion: 25% |
