Nephrotic & Nephritic Syndromes

By:Dawit AyeleMD,Internist

objectives

• Understand the difference betweennephrotic and nephritic syndrome• Understand the biology of the glomerularfiltration barrier• Differentiate primary from secondarynephrotic syndromes• Approach to management of nephroticsyndromes

• WHAT MAKES THESE DISORDERS DIFFERENT?

Normal glomerular BM• Arteriolar lumen contains-

Albumin –negatively charged,small

Immunoglobulins -positively charged,large

*Endothelial fenestrae – Negatively charged*Basement membrane – Negatively charged*podocyte- --Bowman’s space- - - -

How do we make a diagnosis?

• Clinically, at thebed side?• Investigations?

Nephrotic syndrome

• Proteinuria > 3g/day (adult)• Proteinuria >40mg/h/m2 (child)• Hypoalbuminemia• Edema• Hyperlipidemia• Lipiduria

Nephrotic syndrome• Diagnose type by renal biopsy• Histologic hallmark of

proteinuric states– simplification/ effacement of

visceral podocyte foot processes

• Classically non-inflammatory• Lack of inflammation is

consistent with:– Absence of “active” urine (casts

and cells)– Creatinine may not be very

elevated

Proteinuria

Depends on charge and size of molecules• Small negatively charged molecules e.g..albumin are repelled by negatively chargedcapillary wall• Loss of charge but no overt structural injury can

cause→ albuminuria (minimal change disease)• Immunoglobulins are positively charged but toobig to get through unless structural injury

Urine Protein

• A normal person has 7200g(180Lx 40g/L albumin) passthrough the glomerulus every day(not filtered)• Normal excretion of < 20mg/day =fractional excretion of0.00028%!!!!!!!!!!!!!!!!!!!!!!!!!• Even a nephrotic patient excreting3g a day = 0.42%

Diagnosing Proteinuria

• Dipstick positive:– Likely > 150 – 300 mg/24h– Measure protein: creatinine ratio (PCR) 24h Urine Protein ≈PCR• Dipstick negative:– Cannot exclude proteinuria, especially in DMand HT– Send albumin : creatinine ratio (ACR) ifavailable (expensive)

Categories of nephrotic syndrome

• Primary renal:– Minimal change disease– Focal Segmental Glomerulosclerosis– Membranous• Secondary– Diabetes– Amyloid– HIV– Drug associated: NSAIDS, gold, pamidronate– Etc…

Diagnoses made clinically and onbiopsy

Age prevalences of nephroticsyndromes

Minimal change disease (MCD)

• 90% of nephrotic syndrome in children• 20% of nephrotic syndrome in adults• May not need biopsy• Trial of steroids is part of diagnosis• May be beginning of spectrum ranging to FSGSespecially in black children• Secondary forms may be associated withallergies, drugs (NSAIDS!!!), hematologicmalignancies, viral infections

Minimal Change Disease

• Light microscopy normal• Normal immunostaining• • Electron microscopy

shows fusion of podocyte foot processes

• There is loss of negative charge

Specific treatment of 1° MCD

• 90% respond to steroids with 4-6 weeks– Taper over 6 weeks– Proteinuria resolves before albumin improves• Implies not only decreased oncotic pressure driving

edema…• 25 % long term remission• 25-30% infrequent relapses• 20% chronically relapse – steroid dependent• 5% don’t respond – steroid resistant

Membranous Nephropathy

• Most common cause of 1°nephrotic syndrome inadults (25%)• Peak incidence in 4-5th decade (adult: child26:1)• 2-3:1 male predominance at ESRD• Affects all races• Differences in secondary causes may causegeographic differences in presentation

Membranous

• Thickening of capillarywall with “spikes”• Positiveimmunoflourescence• EM shows subepithelialdeposits within newly laidbasement membraneImmune complexesare far from bloodside – don’t inciteinflammation

Clinical features

• Usually presents as nephrotic syndrome but 10-20% have < 2g/d proteinuria• HT from 13-55%• Most have slightly decreased renal function• Usually progresses slowly → must investigateabrupt change in renal function– Crescents 1/3 have anti GBM, some have ANCA– Renal vein thrombosis (4-52%)– Drug-induced injury: NSAIDS, diuretics, antibiotics

Clinical features

• Microscopic haematuria in 30-50%• Impaired renal function at presentation <10%• C3 and C4 typically normal• Hyperfibrinogenaemia and decreasedantithrombin 3– Renal vein thrombosis in 5-63%– Deep vein thromboses 9-44%– Consider anticoagulation if albumin < 20g/L

Causes of Membranous Nephropathy

1° • Idiopathic2°• Malignancy (colon, lung, gastrointestinal)• Autoimmune diseases: SLE, rheumatoid arthritis,

autoimmune thryroiditis• Drugs: penicillamine, gold• Infections: Hep B virus, Syphilis (congenital and

secondary), Hep C, Hepatosplenic schistosomiasis• Chronic transplant rejection• Rarely sarcoid, captopril• Other Glomerulonephritides

Treatment of membranous

• Determine whether idiopathic or 2°• Decision should be based on anunderstanding of natural history:– Spontaneous remission in 5-30%– Partial remission (Proteinuria<2g/d) in 25-40%– Relapse rate 30-50% but only 5% → ESRD– Renal survival:• 86% at 5 years• 65% at 10 years

Treatment of membranous

• If poor prognositic factors or progressing– Hypertension– Male– Elevated creatinine• Steroids chlorambucil or otherimmunosuppression, ? Rituximab, ?mycophenolate

Nonimmunologic therapy of allnephrotic syndromes

• Treatment of hypertension esp. ACEI, ARB– Target < 120/75• Treatment of hypercholesterolemia– Target LDL < 2.0• Low sodium diet• Calcium and vit D to reduce bone loss if steroidtherapy is prolonged• Bactrim for PCP prophyllaxis if steroids• INH for TB prophyllaxis if immunosuppressed• Anticoagulate if high risk• Treat underlying cause if secondary

Nephritic syndrome

• e.g.. Post-infectious(streptococcal), lupus, IgA nephropathy

• Immune complexes and antibodies accumulate in subendothelial space → endothelial injury, recruitment of WBC →inflammation and injury. Serum complement = usually low

Nephritic Syndrome

• Hematuria – dysmorphic red blood cells, red blood cell casts

• Azotemia• Oliguria• Hypertension• Variable proteinuria

(usually < 3 g/day)

Nephrotic Nephritic

Onset Slowe r Ra p id

Edema + + + + a l l o v e r ++

BP Norma l/ low i n c r e a s e d

JVP Norma l/ low i n c r e a s e d

P r o t e i n u r i a > 3 g / d a y < 3 g / d a y

H e m a t u r i a May o c c u r +++

U r i n e s ediment Hya l i n e c a s t s, l i p i d droplets

R b c , wb c , r b c c a s t s , gr a n u l a r c a s t s

Albumin ↓ ↓ ↓ No rma l /mi l d ↓

Cre a t i n i n e Norma l / i n c r e a s e d Us u a l l y i n c r e a s e d

Ser u m sodium Ma y b e ↓ ↓ Ma y b e ≈ ↓

Work up summary

• History and physical exam– Including meds!!!• Quantitate urine protein• Electrolytes, creatinine, albumin, lipids• Urine dipstick + microscopy• If necessary:– C3, C4, SPEP, UPEP, Hep B, ANA, DS DNA,LFTs, echo etc…• Renal ultrasound• ? biopsy

Thanks