Sindrom Nefrotik

01Pathophysiology

Nephrotic syndrome arises from damage to the glomerular filtration barrier, which consists of three layers: the fenestrated endothelium, the glomerular basement membrane (GBM), and the podocyte foot processes with their slit diaphragms. The podocyte layer is the final gatekeeper that prevents large proteins from crossing into the urine. When podocytes are injured, whether by immune complex deposition, metabolic damage, or cytokine-mediated effacement, the slit diaphragms lose their integrity and albumin freely passes into the filtrate.

The hallmark consequence is heavy proteinuria (>3.5 g/day), which directly drives the remaining features of the syndrome. As albumin is lost in the urine, serum albumin drops, reducing plasma oncotic pressure. This causes fluid to shift from the intravascular compartment into the interstitial space, producing edema. The liver responds to low oncotic pressure by ramping up protein synthesis broadly, which includes not only albumin but also lipoproteins, leading to hyperlipidemia. Since lipids are now elevated and filtered, they appear in the urine as lipiduria (oval fat bodies and fatty casts).

A critical and frequently tested consequence is hypercoagulability. The kidney loses antithrombin III in the urine (it is a relatively small protein that crosses the damaged barrier). Combined with elevated hepatic synthesis of clotting factors and hyperviscosity from hemoconcentration, patients are at high risk of venous thromboembolism, particularly renal vein thrombosis. Sudden-onset flank pain and hematuria in a nephrotic patient should immediately raise concern for this complication.

Another underappreciated consequence is increased susceptibility to infection. Loss of immunoglobulins (especially IgG) in the urine leaves patients vulnerable, particularly to encapsulated organisms such as Streptococcus pneumoniae. Spontaneous bacterial peritonitis is a well-recognized complication in nephrotic children with ascites. The Indonesian Pediatric Society (IDAI) consensus highlights that infection, cellulitis, and primary peritonitis are the leading infectious complications, with pneumonia and upper respiratory tract infections also frequently encountered.

02Classification and Clinical Manifestation

Nephrotic vs. Nephritic Syndrome

Nephrotic Syndrome Spectrum

A point that test-writers frequently exploit: minimal change disease presents with nephrotic syndrome but has a normal-appearing glomerulus on light microscopy. The diagnosis requires EM to reveal foot process effacement. If the vignette describes a child with sudden-onset nephrotic syndrome and a biopsy that "appears normal," this is the answer.

Key Clinical Definitions (IDAI Consensus)

These definitions are essential for pediatric nephrology questions, because the classification of nephrotic syndrome in children is based on clinical response to steroid therapy rather than histopathology:

The long-term prognosis of minimal change disease over 20 years of observation shows only 4-5% progress to end-stage renal disease. FSGS, by contrast, leads to end-stage renal disease in 25% within 5 years, with the majority experiencing progressive decline in renal function. This is why steroid response, rather than histology alone, is the stronger prognostic indicator in children.

03Diagnostic Workup

The best initial test when nephrotic syndrome is suspected is a urinalysis followed by quantification of proteinuria. The spot protein-to-creatinine ratio is increasingly favored over the 24-hour collection because it is faster and correlates well with the 24-hour value. A ratio exceeding 3.5 in adults (or >2 mg/mg in children) is diagnostic of nephrotic-range proteinuria.

Once nephrotic-range proteinuria is confirmed, the next step is to determine the cause. In children, the overwhelming likelihood is minimal change disease, and the standard approach is to start empiric corticosteroids without biopsy. A biopsy in a child is reserved for the following situations per the IDAI consensus: steroid-resistant cases; onset below age 1 or above age 16; persistent gross hematuria or persistent microscopic hematuria with low C3; sustained hypertension; declining renal function not attributable to hypovolemia; suspected secondary nephrotic syndrome; and before starting cyclosporine therapy.

In adults, a renal biopsy is almost always required because the differential is broader and treatment varies by subtype. Before performing the biopsy, a serologic workup should be sent to screen for secondary causes (SLE, hepatitis, HIV, diabetes, and malignancy screening in older adults with membranous nephropathy).

A classic exam trap involves lipiduria findings. Oval fat bodies are renal tubular epithelial cells that have absorbed filtered lipids. Under polarized light, the cholesterol esters within these cells produce the characteristic "Maltese cross" pattern, which is pathognomonic for nephrotic syndrome. If a vignette describes this finding on urinalysis, the diagnosis is essentially confirmed.

Before initiating steroid therapy in children, the IDAI consensus mandates a set of preliminary steps: measurement of weight and height, blood pressure check, physical examination for signs of systemic disease (SLE, Henoch-Schonlein purpura), screening for foci of infection (dental, ear, intestinal parasites), and a Mantoux test. If the Mantoux is positive, INH prophylaxis for 6 months must be given alongside steroids; if active tuberculosis is found, full anti-TB therapy is required before steroids begin. These steps often appear as "most appropriate next step" questions.

04Management and Treatment

General Measures

Diuretic Algorithm (Stepwise Escalation per IDAI)

Before giving diuretics, always rule out hypovolemia first. This is a common exam trap: a nephrotic patient can be hypovolemic despite appearing edematous, because the fluid is in the interstitial space rather than the intravascular compartment. Monitor electrolytes (potassium and sodium) if diuretics are used for more than 1-2 weeks.

• Step 1: Furosemide 1-3 mg/kg/day + spironolactone 2-4 mg/kg/day.

• If no response (no weight loss or diuresis within 48 hours), proceed to Step 2.

• Step 2: Double the furosemide dose (maximum 4-6 mg/kg/day).

• If no response, proceed to Step 3.

• Step 3: Add hydrochlorothiazide 1-2 mg/kg/day.

• If no response, proceed to Step 4.

• Step 4: IV furosemide bolus 1-3 mg/kg/dose, or continuous infusion at 0.1-1 mg/kg/hour.

• If no response, proceed to Step 5.

• Step 5: IV albumin 20% at 1 g/kg infused over 2-4 hours, followed immediately by IV furosemide 1-2 mg/kg.

The rationale for Step 5 is a critical exam pearl. Nephrotic patients may be diuretic-resistant because albumin is needed to transport furosemide to its site of action in the loop of Henle. In severe hypoalbuminemia ($\le \backslash leq$1 g/dL), co-administration of IV albumin with IV furosemide overcomes this resistance by restoring the drug's delivery mechanism. If albumin is not affordable (a real consideration in resource-limited settings), plasma at 20 mL/kg/day infused slowly (10 drops/minute) is an alternative, with care to prevent cardiac decompensation. Albumin infusions can be given on alternate days to allow fluid redistribution and prevent volume overload. If ascites is severe enough to impair respiration, repeated paracentesis may be necessary.

Immunization in Nephrotic Syndrome

Patients receiving corticosteroids at >2 mg/kg/day or a total of >20 mg/day for more than 14 days are considered immunocompromised. During this period and for 6 weeks after stopping the medication, only killed-virus vaccines (such as IPV) are permitted. After 6 weeks off prednisone, live-virus vaccines (oral polio, measles, MMR, varicella) can be given. All children with nephrotic syndrome are strongly recommended to receive vaccination against pneumococcal infection and varicella.

Corticosteroid Protocols

Initial Therapy (IDAI Protocol)

Prednisone dosing is calculated using ideal body weight (weight for height). If remission occurs within the first 4 weeks, the patient transitions to the alternating phase. If no remission occurs after 4 weeks of full-dose therapy, the patient is classified as steroid-resistant.

Relapse Therapy

Full-dose prednisone daily until remission (maximum 4 weeks), then alternating-dose prednisone at 40 mg/m${}^2^2$/day for 4 weeks.

A critical teaching point from the IDAI consensus: if proteinuria returns ($\ge \backslash geq$2+) without edema in a patient who was previously in remission, do not immediately treat as a relapse. First search for an infectious trigger (most commonly an upper respiratory tract infection). Give antibiotics for 5-7 days. If proteinuria resolves after treating the infection, no relapse therapy is needed. Only when proteinuria $\ge \backslash geq$2+ is accompanied by edema from the outset, or persists after treating the infection, should you initiate relapse-protocol steroids.

Frequent Relapse or Steroid-Dependent Disease

There are four escalating options:

• Option 1: Long-term low-dose steroid. After achieving remission with full-dose prednisone, continue alternating-dose at 1.5 mg/kg. Taper by 0.2 mg/kg every 2 weeks until the threshold dose is reached (the lowest alternating dose that does not trigger relapse, typically 0.1-0.5 mg/kg). Maintain this dose for 6-12 months, then attempt discontinuation. School-age children generally tolerate 0.5 mg/kg alternating; preschool children may tolerate up to 1 mg/kg alternating.

• Option 2: Levamisole. Given at 2.5 mg/kg as a single dose every other day for 4-12 months. It functions as a steroid-sparing agent. Side effects include nausea, vomiting, hepatotoxicity, vasculitic rash, and reversible neutropenia.

• Option 3: Cyclophosphamide (CPA). Oral CPA at 2-3 mg/kg/day as a single dose for 8-12 weeks. Alternatively, pulse IV CPA at 500-750 mg/m${}^2^2$ (dissolved in 250 mL normal saline, infused over 2 hours) given once monthly for 6 months (7 total doses). Monitoring of CBC (hemoglobin, WBC, platelets) every 1-2 weeks is mandatory. Hold the drug if WBC falls below 3,000/$\mu \backslash mu$L, Hb below 8 g/dL, or platelets below 100,000/$\mu \backslash mu$L; resume when WBC recovers above 5,000/$\mu \backslash mu$L. Cumulative gonadal toxicity and malignancy risk appear at total doses $\ge \backslash geq$200-300 mg/kg. A standard 3-month oral course delivers approximately 180 mg/kg, which is within the safe range.

• Option 4: Cyclosporine (CyA) or Mycophenolate Mofetil (MMF). CyA at 4-5 mg/kg/day (100-150 mg/m${}^2^2$), maintaining trough levels of 150-250 ng/mL. CyA can induce and maintain remission, allowing steroid reduction or discontinuation, but patients often become cyclosporine-dependent (relapse upon CyA cessation). CyA requires monitoring of drug levels, serum creatinine, and renal biopsy every 2 years due to nephrotoxicity (tubulointerstitial lesions). MMF at 800-1200 mg/m${}^2^2$ or 25-30 mg/kg/day, given alongside steroid taper for 12-24 months, is reserved for cases unresponsive to levamisole or cytostatic agents. MMF side effects include abdominal pain, diarrhea, and leukopenia.

Steroid Contraindication

When steroids are contraindicated (hypertension, elevated urea/creatinine, severe infection), proceed directly to CPA: either oral (2-3 mg/kg/day for 8 weeks) or pulse IV (500-750 mg/m${}^2^2$ monthly for 6 months).

Steroid-Resistant Nephrotic Syndrome (SRNS)

Before starting treatment, always perform a renal biopsy, because histopathology dictates prognosis.

CPA: Oral 2-3 mg/kg/day for 3-6 months with alternating-dose prednisone, followed by a 2-month taper (1 mg/kg/day for 1 month, then 0.5 mg/kg/day for 1 month). If CPA achieves remission but subsequent relapse occurs, try steroids again since previously resistant patients can become steroid-sensitive after CPA.

Cyclosporine: Reported to produce complete remission in 20% and partial remission in 13% of SRNS patients, but limited by cost in many settings.

Methylprednisolone Pulse (Mendoza Protocol):

CPA (2-2.5 mg/kg/day) or chlorambucil (0.18-0.22 mg/kg/day) for 8-12 weeks can be added if proteinuria persists after 10 weeks of methylprednisolone.

Management of Complications

Long-Term Steroid Side Effect Monitoring

Prolonged steroid use causes increased appetite, growth impairment, behavioral changes, increased infection risk, salt and water retention, hypertension, and bone demineralization. All nephrotic syndrome patients on steroids require monitoring for Cushingoid features, blood pressure measurement, weight and height every 6 months, and annual cataract evaluation.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common way students lose points on nephrotic syndrome questions is by confusing it with nephritic syndrome. Vignettes are deliberately written to blur the line. The key is to focus on two things: the degree of proteinuria and the urine sediment. If proteinuria exceeds 3.5 g/day with a bland sediment, it is nephrotic. If there are RBC casts and active sediment with moderate proteinuria, it is nephritic. If both features coexist, think MPGN or lupus nephritis (class IV progressing to class V).

Another frequent trap is the management of nephrotic syndrome in children versus adults. In a child with new-onset nephrotic syndrome, the answer is almost always "start corticosteroids" without biopsy, because minimal change disease is overwhelmingly likely (~80% of cases). In an adult, the answer is almost always "perform renal biopsy" because the differential is much broader. Getting this distinction wrong is a high-frequency error.

Test-writers also love to exploit complications. A nephrotic patient who suddenly develops flank pain and hematuria has renal vein thrombosis until proven otherwise. A nephrotic patient with acute dyspnea and pleuritic chest pain likely has a pulmonary embolism from the hypercoagulable state. A nephrotic child with fever and abdominal pain in the setting of ascites should raise concern for spontaneous bacterial peritonitis from immunoglobulin loss. Membranous nephropathy carries the highest thrombosis risk among the nephrotic subtypes, and prophylactic anticoagulation is considered when serum albumin falls below 2-2.5 g/dL.

A subtle but frequently tested point: proteinuria without edema in a previously remitted child does not automatically constitute a relapse. Per the IDAI protocol, you must first search for an infectious trigger (typically an upper respiratory infection), treat it, and reassess. Only if proteinuria persists with edema should relapse therapy be initiated. This "look before you leap" principle is a favorite exam question.

The "Maltese cross" under polarized light is pathognomonic for nephrotic syndrome and instantly confirms lipiduria. If a vignette mentions this finding, the diagnosis is locked in regardless of other confusing details in the stem.

Finally, be aware of the hypovolemia-edema paradox. Nephrotic patients can present with signs of intravascular volume depletion (hypotension, tachycardia, cold extremities, abdominal pain) even while appearing grossly edematous. Administering aggressive diuretics to a hypovolemic nephrotic patient is dangerous and can precipitate shock. Abdominal pain in a nephrotic child is a red flag for either peritonitis or hypovolemia, and the distinction must be made before choosing between antibiotics and volume resuscitation.