Nephrotic syndrome represents a significant clinical entity in both adult and pediatric nephrology, characterized by a constellation of findings that signal underlying kidney dysfunction. This syndrome is not a disease in itself, but rather a manifestation of glomerular injury, leading to a characteristic set of symptoms and laboratory abnormalities. First recognized in the 19th century, with early descriptions of “coagulable urine” preceding Richard Bright’s detailed work on albuminous urine, nephrotic syndrome continues to be a critical area of study and clinical attention in modern medicine.
Understanding the Diagnostic Criteria for Nephrotic Syndrome
The diagnosis of nephrotic syndrome hinges on the presence of several key clinical and laboratory findings, which are crucial for accurate identification and appropriate management. These criteria, summarized in Box 1, provide a framework for clinicians to recognize and diagnose this condition effectively.
Box 1: Core Diagnostic Criteria for Nephrotic Syndrome
- Significant Proteinuria: Defined as protein excretion greater than 3-3.5 grams per 24 hours, or a spot urine protein:creatinine ratio exceeding 300-350 mg/mmol. This is the hallmark of nephrotic syndrome, indicating excessive protein leakage into the urine.
- Hypoalbuminemia: A reduction in serum albumin levels. This occurs because of the substantial protein loss in the urine, exceeding the liver’s capacity to synthesize albumin.
- Peripheral Edema: Clinical evidence of swelling in the peripheral tissues, often manifesting as leg edema, but can also include periorbital edema and ascites. This is a direct consequence of reduced oncotic pressure due to hypoalbuminemia and sodium retention.
- Hyperlipidemia: Frequently observed as elevated serum cholesterol levels (often exceeding 10 mmol/l). This is a secondary effect, resulting from the liver’s increased protein synthesis, which also leads to overproduction of lipoproteins.
Alt Text: Diagnostic criteria for nephrotic syndrome outlined in a box, including proteinuria levels, serum albumin, peripheral edema, and hyperlipidemia.
Nephrotic syndrome, while clinically significant, is relatively uncommon compared to other manifestations of kidney disease. Incidence rates are estimated at approximately three new cases per 100,000 adults annually. It’s important to differentiate nephrotic syndrome from more common kidney issues like reduced kidney function or microalbuminuria, which are frequently seen as complications of systemic diseases such as diabetes mellitus and hypertension.
Why Accurate Diagnosis Matters
Prompt and accurate diagnosis of nephrotic syndrome is paramount due to its potential for serious complications and its indication of underlying kidney pathology. It should be a key consideration in the differential diagnosis for any patient presenting with new-onset edema. The syndrome can stem from a diverse range of primary (idiopathic) and secondary glomerular diseases, necessitating a thorough investigative approach to determine the root cause. Therefore, referral to a nephrologist is crucial for all patients suspected of having nephrotic syndrome, often requiring a renal biopsy to establish a definitive diagnosis and guide treatment strategies. Initial management focuses on identifying the underlying etiology, addressing complications, and alleviating the distressing symptoms associated with the disease.
Recognizing Nephrotic Syndrome: Clinical Presentation
Patients with nephrotic syndrome may present with a wide array of symptoms, reflecting both the primary kidney disease process and the systemic complications arising from the syndrome itself. While nephrotic syndrome is a common entity in nephrology practices, its relative rarity in primary and secondary care settings can lead to diagnostic delays or oversights. The symptoms can mimic those of other conditions, such as the peripheral edema seen in congestive heart failure, hypoalbuminemia associated with severe liver disease or malignancy, and periorbital edema observed in allergic reactions. This article focuses on nephrotic syndrome in adults, as its management differs significantly in the pediatric population.
Sources and Evidence Base
The information presented here is based on a comprehensive review of medical literature. Sources were identified through PubMed searches using terms like “nephrotic syndrome,” “epidemiology,” “glomerulonephritis, membranous,” “glomerulosclerosis, focal,” and “minimal change nephropathy.” The Cochrane Library was also consulted for systematic reviews, and the Oxford Textbook of Clinical Nephrology (3rd edition) served as a key reference for structuring and detailing the content. Due to the complex and varied nature of nephrotic syndrome, and a relative lack of robust randomized controlled trials and systematic reviews, some aspects of its investigation and management remain subject to expert consensus and best available evidence. This article aims to provide an updated overview of the causes, pathophysiology, diagnostic evaluations, complications, and therapeutic approaches for nephrotic syndrome in adults, grounded in the current understanding of this condition.
Etiology of Nephrotic Syndrome: Diverse Causes
Nephrotic syndrome can arise from a broad spectrum of underlying conditions, categorized as either primary glomerular diseases, where the kidney is the primary site of pathology, or secondary glomerular diseases, where the kidney involvement is a manifestation of a systemic illness.
Pathophysiology: The Mechanism of Nephrotic Syndrome
The fundamental pathological process in nephrotic syndrome, regardless of the underlying cause, is an increase in glomerular permeability. This heightened permeability allows large molecules, predominantly albumin but also other plasma proteins, to leak into the urine in excessive amounts. The resulting proteinuria leads to a decrease in serum albumin levels. If the liver’s compensatory albumin synthesis is insufficient to match the urinary protein losses, hypoalbuminemia ensues. This reduction in plasma oncotic pressure, along with potential primary sodium retention by the renal tubules, contributes to the formation of interstitial edema.
Primary (Idiopathic) Glomerular Diseases
Primary glomerular diseases are the most frequent cause of nephrotic syndrome. Historically, idiopathic membranous nephropathy was considered the most common primary cause three decades ago. However, the landscape has shifted, with focal segmental glomerulosclerosis showing an increased incidence, particularly with noted racial disparities. Membranous nephropathy remains the leading cause in white patients, while focal segmental glomerulosclerosis is predominant in black patients, accounting for 50-57% of cases.
Table: Primary Glomerular Diseases Causing Nephrotic Syndrome
| Disease | Frequency of disease (%) as a cause of nephrotic syndrome |
|---|---|
| 1960s and 1970s | |
| 1990s to the present | |
| Patients | |
| Patients >60 years | |
| Focal segmental glomerulosclerosis | 15 |
| Membranous glomerular disease | 40 |
| Minimal change glomerular disease | 20 |
| Membranoproliferative glomerular disease (IgA) | 7 |
| Other glomerular disease | 18 |
Alt Text: Table showing the frequency of primary glomerular diseases as causes of nephrotic syndrome across different time periods and age groups.
Secondary Glomerular Diseases
Secondary causes of nephrotic syndrome are extensive, encompassing a range of systemic diseases, medications, and infections. Diabetic nephropathy is a particularly prevalent cause, reflecting the global rise in diabetes incidence. Amyloidosis is another significant contributor, with immunoglobulin light chain amyloid nephropathy accounting for a notable proportion of cases.
Box 2: Secondary Causes of Nephrotic Syndrome
Systemic Diseases
- Diabetes mellitus
- Systemic lupus erythematosus (SLE)
- Amyloidosis
Malignancies
- Myeloma
- Lymphoma
Medications
- Gold compounds
- Antimicrobial agents
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Penicillamine
- Captopril
- Tamoxifen
- Lithium
Infections
- Human Immunodeficiency Virus (HIV)
- Hepatitis B and C
- Mycoplasma infections
- Syphilis
- Malaria
- Schistosomiasis
- Filariasis
- Toxoplasmosis
Congenital Conditions
- Alport’s syndrome
- Congenital nephrotic syndrome of the Finnish type
- Pierson’s syndrome
- Nail-patella syndrome
- Denys-Drash syndrome
Patient Assessment: Key Steps in Diagnosis
The primary objectives when assessing a patient suspected of having nephrotic syndrome are twofold: first, to evaluate the patient’s current clinical status, ensuring prompt identification and management of any complications; and second, to begin determining whether a primary or secondary cause underlies the syndrome, which is crucial for guiding further management and referral decisions. Referral to a nephrologist is generally indicated for comprehensive management. In pediatric cases, a pediatric nephrologist will oversee the diagnostic process and treatment plan.
History Taking: Uncovering Clues
A thorough patient history is pivotal in identifying the etiology of nephrotic syndrome. It’s important to document any features suggestive of systemic disease, medication history (especially new prescriptions or over-the-counter drugs), and any recent or chronic infections. Given the association between membranous nephropathy and certain cancers, particularly of the lung and colon, suspicion should be heightened, especially in older patients. A detailed family history is also valuable, as nephrotic syndrome has several congenital causes, such as Alport’s syndrome.
Clinical Signs: Recognizing the Manifestations
Nephrotic syndrome should be considered in the differential diagnosis of any patient presenting with new-onset edema. Edema associated with nephrotic syndrome often initially appears around the eyes (periorbital edema) and can progress to become severe, involving the lower legs, genitalia, and even leading to ascites, pleural effusions, and pericardial effusions.
Box 3: Clinical Signs of Nephrotic Syndrome
Edema
- Periorbital edema
- Lower limb edema
- Genital edema
- Ascites
Hypoalbuminemia Related Signs
- Fatigue and tiredness
- Leuconychia (white lines or spots on nails)
Respiratory Symptoms
- Breathlessness due to pleural effusion
- Fluid overload indicated by high jugular venous pressure
- Breathlessness with acute renal failure
Thromboembolic Risk
- Breathlessness accompanied by chest pain, suggesting thromboemboli
Dyslipidemia Signs
- Eruptive xanthomata (small, yellow-orange papules on skin)
- Xanthelasmata (yellowish plaques around eyelids)
Urinary Changes
- Frothy urine, due to increased protein content
Diagnostic Investigations: Confirming Nephrotic Syndrome
Currently, there are no formal guidelines dictating a specific sequence of investigations for nephrotic syndrome. However, Box 4 outlines a typical approach used to evaluate a patient’s clinical condition and identify the underlying cause. Assessing renal function is a crucial component, requiring measurement of serum urea and creatinine levels and calculation of the estimated glomerular filtration rate (eGFR). Urine dipstick testing is essential to detect hematuria (suggestive of glomerulonephritis) and proteinuria (3-4+ protein indicating nephrotic range). Quantifying protein loss is vital. Spot urine protein:creatinine or albumin:creatinine ratios, ideally from an early morning sample, are recommended due to their accuracy, faster results, and demonstrated equivalence to 24-hour urine collections in cross-sectional studies. A protein:creatinine ratio exceeding 300-350 mg/mmol confirms nephrotic-range proteinuria. Renal ultrasound is used to assess kidney size and morphology and may be urgently indicated if renal vein thrombosis is suspected, suggested by symptoms like flank pain, hematuria, and renal impairment. Doppler ultrasound of the renal veins can aid in diagnosing renal vein thrombosis.
Box 4: Sequence of Investigations for Nephrotic Syndrome
Confirm Proteinuria
- Urine dipstick test: positive (2/3/4+)
Check for Hematuria
- Urine dipstick test: positive for microscopic hematuria (1/2/3+)
Rule Out Urinary Tract Infection
- Midstream urine sample for microscopy, culture, and sensitivity
Quantify Proteinuria
- Early morning urine protein:creatinine ratio or albumin:creatinine ratio (mg/mmol)
- Typically >300-350 mg/mmol in nephrotic syndrome
Basic Blood Tests
- Full blood count and coagulation screen
- Renal function tests (plasma creatinine and eGFR)
- Liver function tests
- Bone profile including albumin-corrected plasma calcium
Investigations for Systemic Diseases and Causes
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
- Blood glucose
- Immunoglobulins and serum and urine electrophoresis
- Autoimmune screen (antinuclear antibody (ANA), anti-double stranded DNA antibody (dsDNA), complement levels C3 and C4) if autoimmune disease is suspected
- Hepatitis B and C and HIV testing (with informed consent)
Imaging Studies
- Chest X-ray and abdominal or renal ultrasound (especially if renal function is abnormal)
- To assess for pleural effusion or ascites
- To assess kidney size, shape, and rule out obstruction
Assess for Thromboembolic Complications
- Doppler ultrasound of leg veins for suspected deep vein thrombosis (DVT)
- Abdominal ultrasound, renal vein Doppler, venography of the inferior vena cava, CT or MRI of the abdomen for suspected renal vein thrombosis
- V/Q scan or CT pulmonary angiography for suspected pulmonary embolism (PE)
Investigate Underlying Renal and Systemic Causes
- Renal biopsy under ultrasound guidance
- Histological preparations for light microscopy, immunofluorescence/immunoperoxidase, and electron microscopy
Complications of Nephrotic Syndrome: Systemic Effects
Nephrotic syndrome has significant systemic consequences, largely stemming from alterations in the body’s protein environment due to increased hepatic protein production and urinary loss of low molecular weight proteins.
Box 5: Complications of Nephrotic Syndrome
Thromboembolism
- Deep vein thrombosis (DVT)
- Renal vein thrombosis (RVT), potentially leading to pulmonary embolism (PE)
- Arterial thrombosis (rare)
Infection
- Cellulitis
- Bacterial infections (pneumonia, peritonitis, cellulitis)
- Viral infections in immunocompromised patients
Other Complications
- Hyperlipidemia
- Vitamin D deficiency (due to loss of vitamin D binding protein), leading to bone disease
- Acute renal failure (acute kidney injury)
Thromboembolism Risk: A Major Concern
Patients with nephrotic syndrome are at a heightened risk of thromboembolic events. This increased risk is attributed to imbalances in prothrombotic and antithrombotic factors, along with impaired thrombolytic activity. Contributing factors include intravascular volume depletion, diuretic use, immobilization, and pre-existing procoagulant conditions like protein C and protein S deficiencies, or antiphospholipid antibodies. Deep vein thrombosis in the lower limbs is the most common site of thrombosis in adults. Renal vein thrombosis and pulmonary embolism are also significant risks. Arterial thrombosis is less frequent but can occur. Historical data indicated higher rates of thromboembolism, but more recent studies suggest lower, though still significant, risks. Membranous nephropathy is particularly associated with venous thrombosis, and the risk increases with lower serum albumin levels.
Prophylactic Anticoagulation: When is it Needed?
Currently, no randomized controlled trials provide definitive guidance on prophylactic anticoagulation in nephrotic syndrome. A Cochrane review protocol addressed this issue, but the limited trial data necessitated reliance on pooled meta-analysis and non-randomized evidence. Routine screening for thrombosis is not generally recommended to guide anticoagulation decisions. Factors such as immobility, edema severity, coexisting prothrombotic conditions, and prior thromboembolic history should be considered. While no specific proteinuria or hypoalbuminemia threshold definitively triggers anticoagulation, nephrologists often consider prophylactic anticoagulation with heparin followed by warfarin if serum albumin falls below 20 g/l and proteinuria is in the nephrotic range. Decisions regarding anticoagulation should be made in consultation with a nephrology team, especially considering contraindications such as the need for renal biopsy.
Infection Susceptibility: Increased Risk
Infection is a significant concern in nephrotic syndrome, reported in up to 20% of adult patients. Increased susceptibility is linked to decreased serum IgG levels, reduced complement activity, and impaired T cell function. Bacterial infections, particularly cellulitis, are common. The role of prophylactic antibiotics and vaccines remains debated, with no trials supporting prophylactic antibiotic use in adults. A Cochrane review found insufficient evidence to recommend any interventions for preventing infection.
Acute Renal Failure: A Serious, Though Rare, Complication
Acute renal failure (acute kidney injury) can occur as a rare spontaneous complication of nephrotic syndrome. It can also be precipitated by factors like excessive diuresis, interstitial nephritis from diuretics or NSAIDs, sepsis, or renal vein thrombosis. Chronic renal impairment may reflect underlying kidney damage from systemic or primary renal diseases. Older patients and those with more severe proteinuria appear to be at higher risk of acute renal failure, which may necessitate dialysis and prolonged recovery.
Treatment Strategies for Nephrotic Syndrome
Managing Edema: Fluid and Sodium Balance
There are no established guidelines or randomized trials specifically guiding edema management in nephrotic syndrome. The underlying mechanism is sodium retention, though the exact pathophysiology is complex and not fully understood. The cornerstone of treatment is achieving a negative sodium balance, often requiring dietary sodium restriction (<2-3 g/day).
Loop diuretics like furosemide are typically the first-line pharmacological treatment. However, edema of the gut wall can impair oral drug absorption, sometimes necessitating high doses of intravenous diuretics in refractory cases. Many diuretics are protein-bound, and their efficacy can be reduced by heavy proteinuria. Thiazide or potassium-sparing diuretics are often added to enhance sodium excretion, acting synergistically with loop diuretics. Intravenous albumin infusion has been used to improve diuresis, potentially by increasing diuretic delivery to the kidneys and expanding plasma volume. However, evidence supporting albumin use is limited and comes from small studies, with potential risks including anaphylaxis, hypertension, and pulmonary edema.
Addressing Proteinuria: Reducing Protein Excretion
Proteinuria is a major predictor of progression to end-stage renal disease in chronic kidney disease. Reducing or eliminating proteinuria is a primary treatment goal in nephrotic syndrome. In some cases, treating the underlying cause can achieve this, but additional measures are usually needed. Strategies to decrease protein excretion also indirectly help manage edema.
Angiotensin-converting enzyme inhibitors (ACEIs), used alone or in combination with angiotensin II receptor blockers (ARBs), are the mainstay of antiproteinuric therapy, supported by evidence from randomized controlled trials and meta-analyses. These agents can reduce proteinuria even without altering blood pressure, and combination therapy is more effective than monotherapy. Regular monitoring of plasma electrolytes is essential when using ACEIs and ARBs, and their full antiproteinuric effect may take several weeks to manifest. Older treatments like high-dose NSAIDs are rarely used now due to significant side effects. In rare cases of severe, intractable proteinuria with debilitating symptoms and complications like renal dysfunction or malnutrition, nephrectomy or renal embolization might be considered as a last resort.
Managing Dyslipidemia: Cardiovascular Risk Reduction
Hyperlipidemia in nephrotic syndrome is characterized by elevated LDL cholesterol and triglycerides, and altered HDL cholesterol levels. These lipid abnormalities may contribute to increased cardiovascular risk in nephrotic patients. While no prospective trials have definitively shown that lipid-lowering treatment improves survival in nephrotic syndrome, meta-analyses and subgroup analyses suggest that statins may have a modest protective effect on renal disease progression. Importantly, many patients experience spontaneous remission or remission with treatment of the underlying cause, which often improves or resolves dyslipidemia.
Dietary Considerations: Nutritional Support
Muscle wasting is a significant problem in severe nephrotic syndrome, and patients have increased albumin turnover. Optimal protein intake is not clearly defined due to limited evidence. Low protein diets are generally not recommended due to the risk of negative nitrogen balance and malnutrition.
Referral to Nephrology: Essential for Targeted Care
It is recommended that all new cases of nephrotic syndrome be discussed urgently with local nephrology specialists for prompt referral, investigation, and targeted treatment. Exceptions might include patients with established diabetic nephropathy where nephrotic-range proteinuria develops; in such cases, initial management may involve optimizing ACEI/ARB therapy.
Conclusion: Importance of Timely Management
Nephrotic syndrome presents with diverse clinical features across various healthcare settings and carries significant risks of complications. Investigation and management are complex, partly due to a limited evidence base, but expert consensus strategies guide initial care. Early discussion with nephrologists and prompt referral are crucial for all patients with suspected nephrotic syndrome. Further research, particularly large randomized trials focusing on nephrotic syndrome and glomerular diseases, is urgently needed to advance treatment and improve patient outcomes.
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