Nephrotic Syndrome in Adults: The Often-Missed Diagnosis

Dr Neeraj Manikath , claude.ai

Abstract

Nephrotic syndrome remains a diagnostic challenge in adult internal medicine, with delayed recognition contributing to significant morbidity. This review examines the pathophysiology, clinical presentations, diagnostic pitfalls, and management strategies, emphasizing the subtleties that lead to missed or delayed diagnoses. We highlight practical clinical pearls and evidence-based approaches to enhance diagnostic acuity in postgraduate medical education.

Introduction

Nephrotic syndrome, characterized by proteinuria exceeding 3.5 g/day, hypoalbuminemia, edema, and hyperlipidemia, affects approximately 3 per 100,000 adults annually. Despite its classic presentation, clinicians frequently miss this diagnosis in its early stages or atypical presentations, leading to progressive renal damage and complications including thromboembolism, infections, and cardiovascular disease.

The diagnostic delay stems from multiple factors: overlap with more common conditions, variable presentations across different etiologies, and insufficient clinical suspicion in high-risk populations. This review addresses these gaps, providing a framework for early recognition and appropriate management.

Pathophysiology: Beyond the Basics

The hallmark of nephrotic syndrome is podocyte injury leading to disruption of the glomerular filtration barrier. Unlike nephritic syndrome, which involves inflammatory glomerular injury, nephrotic syndrome primarily reflects non-inflammatory podocyte dysfunction. This distinction has profound clinical implications.

Pearl #1: The severity of proteinuria correlates inversely with serum albumin but does not always correlate with the degree of edema. Some patients with massive proteinuria maintain near-normal albumin through hepatic compensation, while others develop profound hypoalbuminemia with moderate proteinuria due to poor synthetic function.

The hypoalbuminemia triggers hepatic lipoprotein synthesis, explaining the characteristic hyperlipidemia. This is not merely a laboratory finding but contributes significantly to accelerated atherosclerosis. Urinary losses of immunoglobulins and complement factors predispose to infections, particularly encapsulated bacteria. Loss of antithrombin III, protein C, and protein S, combined with increased hepatic synthesis of procoagulant factors, creates a hypercoagulable state with venous thromboembolism risk as high as 25% in some series.

The Spectrum of Adult Nephrotic Syndrome

Primary Glomerular Diseases

Minimal Change Disease (MCD): Accounting for 10-15% of adult nephrotic syndrome, MCD is frequently overlooked beyond childhood. Adults present with abrupt-onset edema, often following respiratory infections or NSAID use.

Oyster #1: NSAIDs don't just cause MCD through direct toxicity; they unmask underlying podocyte vulnerability. Always inquire about recent NSAID use, including over-the-counter medications and topical preparations in elderly patients.

Focal Segmental Glomerulosclerosis (FSGS): The most common primary cause in adults, FSGS presents with variable proteinuria and progressive renal decline. The challenge lies in distinguishing primary from secondary forms.

Hack #1: Request adequate renal biopsy tissue. FSGS is often missed on inadequate samples because the lesions are focal. Insist on samples with at least 10-15 glomeruli when FSGS is suspected.

Membranous Nephropathy (MN): Responsible for 30-40% of adult nephrotic syndrome, MN classically presents insidiously in middle-aged patients. Primary MN involves anti-PLA2R antibodies in 70% of cases, revolutionizing diagnosis and management.

Pearl #2: Serum anti-PLA2R antibodies are 78% sensitive and 100% specific for primary MN. A positive test may obviate biopsy in classic presentations, while monitoring titers guides treatment decisions and predicts relapse.

Membranoproliferative Glomerulonephritis (MPGN): Now reclassified by immunofluorescence patterns, MPGN frequently presents with mixed nephrotic-nephritic features. Complement dysregulation, particularly in C3 glomerulopathy, requires specialized investigation.

Secondary Causes: The Great Mimics

Secondary nephrotic syndrome accounts for 40-50% of cases, yet these diagnoses are frequently delayed.

Diabetic Nephropathy: The most common secondary cause worldwide.

Oyster #2: Not all proteinuria in diabetics is diabetic nephropathy. Consider alternative diagnoses when: proteinuria precedes 5-10 years of diabetes duration, diabetic retinopathy is absent, active urinary sediment exists, or rapid decline in GFR occurs. These features warrant renal biopsy.

Amyloidosis: Missed in 40% of cases initially due to protean manifestations.

Hack #2: Think amyloidosis in nephrotic patients with: macroglossia, periorbital purpura, carpal tunnel syndrome, unexplained heart failure with preserved ejection fraction, or autonomic neuropathy. Fat pad or rectal biopsy (positive in 70-80%) is less invasive than renal biopsy for diagnosis.

Malignancy-Associated Nephropathy: Membranous nephropathy associates with solid tumors in 10-20% of elderly patients. Lung, colon, gastric, and breast cancers predominate.

Pearl #3: Age-adjusted cancer screening is mandatory in new-onset membranous nephropathy beyond age 60. Resolution of nephrotic syndrome may parallel tumor treatment response, serving as a disease marker.

Systemic Lupus Erythematosus: Class V lupus nephritis presents as pure nephrotic syndrome without systemic features in 20% of cases.

Oyster #3: Order ANA and complement levels in all nephrotic syndrome cases, even without systemic symptoms. Isolated lupus nephritis may be the presenting manifestation of SLE, particularly in younger women.

Infections: Hepatitis B and C, HIV, and syphilis all cause nephrotic syndrome through various mechanisms.

Hack #3: Screen for HIV, hepatitis B, hepatitis C, and syphilis in all new nephrotic syndrome diagnoses. Infection-associated glomerulonephritis may occur without known exposure history or typical risk factors.

Clinical Presentation: Recognizing the Atypical

While peripheral edema represents the classic presentation, nephrotic syndrome manifests variably:

Periorbital edema: Often dismissed as allergic reaction or sinusitis, morning periorbital swelling with progressive lower extremity edema throughout the day suggests nephrotic syndrome.

Isolated ascites or pleural effusions: Particularly in cirrhosis patients, new or worsening fluid accumulation may reflect concurrent nephrotic syndrome rather than purely hepatic decompensation.

Unexplained weight gain: Progressive weight gain of 5-10 kg over weeks, even without obvious edema, warrants urinalysis.

Dyspnea: Both pulmonary edema and pulmonary embolism occur. Acute dyspnea in nephrotic patients demands exclusion of thromboembolism.

Pearl #4: Measure spot urine protein-to-creatinine ratio in any patient with unexplained edema, even with normal serum creatinine. Waiting for renal impairment delays diagnosis by months to years.

Diagnostic Approach: What Not to Miss

Laboratory Evaluation

Beyond the classic tetrad, comprehensive evaluation includes:

Urinalysis: Lipiduria (oval fat bodies, Maltese crosses under polarized light) is pathognomonic. Red blood cells suggest concurrent glomerulonephritis.

24-hour urine vs. spot protein-to-creatinine ratio: While 24-hour collection remains gold standard, spot ratios correlate well (ratio >3-3.5 indicates nephrotic-range proteinuria) and improve compliance.

Hack #4: In hospitalized patients, calculate protein excretion from random urines: protein-to-creatinine ratio × 1000 approximates 24-hour protein in mg/day. A ratio of 4.0 suggests approximately 4,000 mg/day proteinuria.

Serum and urine electrophoresis: Essential for excluding monoclonal gammopathies and AL amyloidosis. Free light chain ratio abnormalities precede overt myeloma.

Complement levels: Low C3 and C4 suggest lupus, infection-related GN, or MPGN. Isolated low C3 with normal C4 indicates alternative pathway activation (C3 glomerulopathy).

Serologies: ANA, anti-dsDNA, ANCA, anti-GBM, hepatitis B and C, HIV, rapid plasma reagin, anti-PLA2R antibodies.

Pearl #5: Don't rely solely on serum albumin to gauge severity. Urinary albumin losses may be partially compensated hepatically. Assess volume status clinically and measure natriuretic peptides when heart failure is suspected.

Renal Biopsy: Timing and Interpretation

Biopsy remains the diagnostic standard but requires judicious timing.

Indications for urgent biopsy:

• Age >60 years (higher malignancy-associated disease risk)
• Hematuria or red cell casts
• Acute kidney injury
• Rapidly progressive symptoms
• Systemic features suggesting secondary disease
• Failure to respond to empiric corticosteroids in presumed MCD

Oyster #4: Partial treatment responses occur. A patient improving on corticosteroids for presumed MCD who plateaus at 1.5 g/day proteinuria may have FSGS. Don't assume MCD without biopsy confirmation if response is incomplete.

Complications: Prevention and Management

Thromboembolic Disease

Risk persists while nephrotic, with renal vein thrombosis occurring in 10-40% of membranous nephropathy patients.

Hack #5: Consider empiric anticoagulation for albumin <2.0 g/dL, particularly in membranous nephropathy. While controversial, emerging data suggest benefit outweighs bleeding risk in this subset.

Pearl #6: D-dimer is elevated at baseline in nephrotic syndrome and cannot reliably exclude thromboembolism. Maintain low threshold for imaging when pulmonary embolism or deep vein thrombosis is suspected.

Infections

Encapsulated bacterial infections predominate, with spontaneous bacterial peritonitis occurring in nephrotic ascites.

Oyster #5: Vaccinate nephrotic patients against pneumococcus, influenza, and COVID-19 early. Antibody responses diminish with worsening hypoalbuminemia and immunosuppression.

Acute Kidney Injury

Multifactorial AKI occurs from: hypovolemia (overzealous diuresis), acute tubular necrosis (hypoperfusion), interstitial edema, renal vein thrombosis, or drug nephrotoxicity.

Hack #6: Urine sodium is unreliable in nephrotic syndrome for assessing volume status due to proteinuria-induced natriuresis. Rely instead on clinical examination, fluid balance, and fractional excretion of urea (<35% suggests prerenal).

Treatment Strategies

Supportive Care

Diuretics: Loop diuretics combined with distal tubule agents (thiazides, amiloride) overcome resistance. Albumin infusions provide temporary benefit but risk fluid overload and offer no long-term advantages.

ACE inhibitors/ARBs: Reduce proteinuria by 30-40% independent of blood pressure effects. Continue unless contraindicated.

Lipid management: Statins reduce cardiovascular risk, though proteinuria may persist despite treatment. Aim for LDL <70 mg/dL given markedly increased atherosclerotic risk.

Pearl #7: Dietary protein restriction (0.8 g/kg/day) reduces proteinuria without compromising nutrition when combined with adequate caloric intake. Avoid severe restriction that worsens malnutrition.

Specific Therapies

Treatment depends on underlying etiology:

MCD: Prednisone 1 mg/kg/day achieves remission in >90% within 8-16 weeks. Steroid-dependent or frequently relapsing disease requires steroid-sparing agents (cyclophosphamide, cyclosporine, rituximab).

FSGS: Treat primary forms with prolonged corticosteroids (4-6 months) plus cyclophosphamide or calcineurin inhibitors. Secondary forms require addressing underlying causes.

Membranous nephropathy: Risk stratify using anti-PLA2R titers and proteinuria severity. Low-risk patients (proteinuria <4 g/day, normal renal function) receive conservative therapy. High-risk patients benefit from rituximab (now preferred) or cyclical cyclophosphamide-steroid regimens.

Oyster #6: Rituximab at 1,000 mg on days 1 and 15 achieves comparable remission rates to cyclophosphamide with superior safety in membranous nephropathy. Monitor anti-PLA2R titers to assess immunologic response before clinical remission.

Prognosis and Monitoring

Prognosis varies by etiology. MCD rarely progresses to ESRD; FSGS carries 50% ESRD risk at 10 years; membranous nephropathy demonstrates variable outcomes with spontaneous remissions in 30%.

Hack #7: Partial remission (proteinuria <3.5 g/day with ≥50% reduction) confers significant renal protection even without complete remission. Don't abandon therapy prematurely in partial responders.

Conclusion

Nephrotic syndrome in adults demands diagnostic vigilance given its varied presentations and etiologies. Early recognition, systematic evaluation for secondary causes, and etiology-specific therapy significantly improve outcomes. By maintaining clinical suspicion in atypical presentations, ordering appropriate initial testing, and knowing when to proceed with renal biopsy, clinicians can avoid the common pitfalls leading to delayed diagnosis. The integration of novel biomarkers like anti-PLA2R antibodies and evolving therapies such as rituximab has transformed nephrology practice, offering hope for improved patient outcomes when diagnosis occurs promptly.

Key References

1. Kodner C. Diagnosis and management of nephrotic syndrome in adults. Am Fam Physician. 2016;93(6):479-485.

2. Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017;91(3):566-574.

3. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502-517.

4. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.

5. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med. 2019;381(1):36-46.

6. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185-1189.

7. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.

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