Nephrology & Internal Medicine & Family Medicine
Nephrotic syndrome
Nephrotic syndrome (NS) is a clinico-biological syndrome defined by the association of massive proteinuria (≥ 3.5 g/24 h in adults + or urinary protein/creatinine ratio ≥ 300 mg/mmol) + hypoalbuminemia (serum albumin < 30 g/L) + peripheral declining edema + and hyperlipidemia (hypercholesterolemia + hypertriglyceridemia), resulting from damage to the glomerular filtration membrane - mainly at the level of podocytes (specialized visceral epithelial cells lining the outer surface of the glomerular basement membrane) - leading to massive protein loss in the urine, exceeding the capacity of compensatory hepatic synthesis. The cascade pathophysiology is as follows: podocyte injury (depending on the underlying cause) → increased glomerular protein permeability → massive proteinuria → hypoalbuminemia → reduced plasma oncotic pressure → hydrosodic leakage to the interstitial sector → edema + relative hypovolemia → activation of the renin-angiotensin-aldosterone system (RAAS) → hydrosodic retention → worsening of edema. Hepatic synthesis of lipoproteins is increased in response to hypo-oncotia (replacement lipoproteins) → hyperlipidemia. Urinary leakage of natural anticoagulant proteins (antithrombin III + protein C + protein S) + hyperlipidemia + hypovolemia → major prothrombotic state (renal venous thrombosis ++ + DVT + PE - risk of thrombosis particularly high in membranous glomerulonephritis). Positive diagnosis of SN is biological - simple and rapid - but the underlying cause requires in the vast majority of cases a renal biopsy to guide specific treatment.
Clinico-biological tetrad
- Massive proteinuria : ≥ 3.5 g/24 h or urine protein/creatinine ratio ≥ 300 mg/mmol on a urine sample + SN proteinuria is mainly selective (albumin ++ + in minimally lesioned forms) or non-selective (albumin + globulins in other glomerulonephritis)
- Hypoalbuminemia: serum albumin < 30 g/L + severe if < 20 g/L → hydrops + thrombotic + infectious + nutritional complications + hypoalbuminemia reduces the bound fraction of many drugs → increased drug toxicity (warfarin + phenytoin + furosemide)
- Edema : bilateral soft declivities + scooping + periorbital on awakening (characteristic of children) + ascites + pleural effusion + anasarca in severe forms
- Hyperlipidemia : hypercholesterolemia (high LDL + low HDL) + hypertriglyceridemia + total lipidemia may exceed 20-30 mmol/L + lipiduria (lipid cylinders + oval fatty bodies in urine sediment) + increased long-term cardiovascular risk
- Associated complications : prothrombotic state (renal venous thrombosis - particularly in GEM - DVT + pulmonary embolism) + bacterial infections (urinary loss of IgG + opsonins + hypoalbuminemia → relative immune deficiency → pneumococcus + encapsulated germ infections) + acute renal failure (hypovolemia + thrombi + nephrotoxics)
Main causes according to age and clinical picture
| Etiology | Epidemiology | Features | Specific treatment |
|---|---|---|---|
| Minimal glomerular lesions (LGM - Lipoid nephrosis) | Leading cause in children (90 % of childhood SN) + young adults + peak 2-6 years old | Pure SN + selective (albumin only) + normal light microscopy + electron microscopy: erasure of podocytic feet + rapid response to corticoids (94 %) + frequent recurrences (40-60 %) + no progression to CKD in general | Prednisone 60 mg/m² × 4-6 weeks + decrease + cortico-resistant forms: cyclosporine + tacrolimus + rituximab |
| Extra-membranous glomerulonephritis (EMG) | Leading cause of adult SN (20-40 + and > 60) + 80 % idiopathic (anti-PLA2R ++) + 20 % secondary (cancer + HBV + lupus + NSAIDs) | Non-selective SN + anti-PLA2R (phospholipase A2 receptor) antibodies positive in 70-80 % of idiopathic forms (pathognomonic) + biopsy: subepithelial deposits + basement membrane thickening + "spikes" on silver impregnation + high risk of renal venous thrombosis (up to 40 %) | Rule of thirds (1/3 spontaneous remission + 1/3 remission on treatment + 1/3 progressive CKD) → treatment if persistent proteinuria > 6 months or CKD: rituximab (375 mg/m² × 4 or 1 g × 2) + or cyclophosphamide + corticoids (Ponticelli protocol) + anti-PLA2R monitoring as biomarker of activity |
| Segmental and focal hyalinosis (GSFS) | Adult + African-American populations ++ + often secondary (obesity + nephron reduction + HIV + heroin) | Non-selective SN + focal and segmental glomerular sclerosis lesions on biopsy + often associated with hypertension + microscopic hematuria + frequent progression to CKD + cortico-resistant in 50-60 % of primary cases | Prednisone 1 mg/kg/d × 16 weeks (primary forms) + if resistant: cyclosporine + tacrolimus + mycophenolate + treatment of secondary factors (weight loss + HIV) |
| Diabetic nephropathy | World's leading cause of adult nephrotic syndrome in Western countries + type 1 and 2 diabetes + progressive albuminuria over 10-20 years | Progression from microalbuminuria (30-300 mg/d) to macroalbuminuria then SN + concomitant diabetic retinopathy in 90 % → if absent → biopsy recommended (other cause) + biopsy: basement membrane thickening + mesangial expansion + Kimmelstiel-Wilson nodules | ACE inhibitor or ARB II (renal protection ++ + proteinuria reduction) + SGLT2 (dapagliflozin + empagliflozin - proven nephroprotection) + GLP-1 + glycemic + lipid control + strict BP |
| Renal amyloidosis (AL and AA) | Elderly adults + multiple myeloma (AL) + chronic inflammatory diseases (AA) | SN severe + progressive + hepatomegaly + macroglossia (AL) + serum free light chain assay + immunofixation + fat or rectal biopsy (screening) + renal biopsy (confirmation) → amyloid deposits Congo red + bright green in polarized light | AL: chemotherapy + autograft if eligible (daratumumab + bortezomib) + AA: treatment of underlying inflammatory disease |
| Lupus nephropathy (classes III-IV-V) | Young woman + lupus + class V = pure membranous → SN + class III/IV = proliferative + hematuria + cylinders | Complementary C3 + C4 low + AAN positive + anti-native DNA high (lupus activity) + renal biopsy: ISN/RPS classification | Mycophenolate mofetil + corticoids (induction) + belimumab + voclosporin (class V + III/IV) → rituximab if refractory |
Renal biopsy - indications in SN
- Adult : systematic renal biopsy for any first presentation of NS in adults (unless type 2 diabetes with obvious diabetic retinopathy + progressive NS over years → sufficient probability of diabetic nephropathy not to biopsy straight away)
- Children aged 1 to 12 with no atypical signs: empirical treatment with prednisone (90 % of LGM + cortico-sensitive) + biopsy reserved for cortico-resistant + or frequent recurrent + or atypical forms (macroscopic hematuria + hypertension + CKD + age 12 years)
- Contraindications to biopsy : single kidney + uncorrected coagulation disorder + uncontrolled hypertension + active infection → correct before biopsy
ℙ️
Idiopathic extra-membranous glomerulonephritis (GEM) is the leading cause of SN in adults over 40, and is associated in 70-80 % of cases with anti-phospholipase A2 receptor antibodies (anti-PLA2R) - a discovery by Beck et al. (NEJM 2009) that has transformed management. Anti-PLA2R is pathognomonic of primary GEM + allows diagnosis without biopsy in some cases + and is a biomarker for monitoring activity and response to treatment (rituximab). A decrease in anti-PLA2R levels precedes clinical remission by several months.
Symptomatic treatment - common to all forms
- Sodium restriction: < 2 g sodium per day (strict low-salt diet) + avoid salt-rich processed foods + essential for controlling oedema
- Diuretics : furosemide (Lasix®) 40-120 mg/day po + or IV if refractory edema + monitor kalemia + creatinine + natremia + hypoalbuminemia reduces furosemide efficacy (less well transported to tubules) → IV albumin infusion before furosemide if albumin < 20 g/L + refractory edema
- ACEI or ARB II : reduction of proteinuria (30-50 %) + long-term renal protection + indicated in all causes of SN (even if no diabetes + even if normotensive) → combination ACEI + ARB II not recommended (hyperKalemia + ARF)
- Statins : atorvastatin or rosuvastatin for hyperlipidemia + reduced long-term cardiovascular risk (chronic SN)
- Prophylactic anticoagulation : if albumin < 20-25 g/L + or GEM (very high risk of renal vein thrombosis + PE) → low-molecular-weight heparin or warfarin depending on context + bleeding risk vs thrombotic risk to be assessed
- Vaccinations : pneumococcal vaccine (risk of pneumococcal infections ++) + varicella vaccine if naïve (immunosuppression) + HBV vaccine if IEC/rituximab
Medical consultation recommended
Seek prompt medical attention if progressive bilateral edema of the lower limbs + swollen eyelids on awakening + frothy urine (proteinuria) + or shortness of breath appear - a simple urine test (dipstick + urine protein/creatinine ratio) will confirm proteinuria and initiate investigation. Refer to the emergency department if signs of thrombosis (pain + swelling of a limb + dyspnea) + or acute renal failure (oliguria + very high creatinine) + or severe infection develop in the context of a known NS. For a complete nephrotic syndrome workup (24-hour proteinuria + albumin + lipids + creatinine + immunological workup) and referral to nephrology, Clinique Omicron offers consultations at its points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's specialized physicians and nurse practitioners (SPNs) diagnose nephrotic syndrome through an initial blood and urine test (proteinuria + albumin + creatinine + lipids + urine sediment), initiate symptomatic treatment (sodium restriction + furosemide + ACEI/ARB II + statins + prophylactic anticoagulation if indicated), refer to nephrology for renal biopsy and cause-specific treatment, and ensure longitudinal follow-up of proteinuria + renal function + complications. Consultations are available at several points of service in Quebec, and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a physician or nephrologist. Nephrotic syndrome requires renal biopsy in adults to identify the cause and guide specific treatment. Prophylactic anticoagulation should be discussed with the nephrologist according to the individual risk profile - it is particularly important in extra-membranous glomerulonephritis.
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