Pediatric Nephrotic & Nephritic Syndromes and HUS

Sorting the glomerular syndromes

Two patterns. In the nephrotic pattern the podocyte barrier fails and protein pours into the urine with a bland sediment. In the nephritic pattern the glomerulus is inflamed: red cells and casts appear, and salt and water retention cause hypertension and oliguria. Hemolytic uremic syndrome is a third process, a thrombotic microangiopathy.

Minimal change disease

Presentation. Minimal change disease causes roughly 80% of childhood nephrotic syndrome. It peaks at ages 2–6, favors boys, and often follows a URI or allergic trigger. Morning eyelid puffiness, often blamed on allergy, spreads to the legs, scrotum or labia, abdomen (ascites), and pleura. BP, creatinine, and complement are usually normal, and gross hematuria is absent.

Pathology. Light microscopy and immunofluorescence are normal; electron microscopy shows diffuse podocyte foot-process effacement with loss of the charge barrier, so the leak is selective, mostly albumin. Low oncotic pressure drives edema, and the liver increases lipoprotein synthesis, causing hypercholesterolemia and lipiduria (oval fat bodies forming Maltese crosses under polarized light).

Evaluation. Urinalysis (3–4+ protein, bland sediment), first-morning UPCR (≥2 mg/mg), serum albumin (<3 g/dL), lipids, electrolytes, creatinine, and C3. Normal C3 and BP support minimal change; a low C3 points to a nephritic or complement-driven disease.

When to biopsy. Steroid resistance; onset after about age 10 or before age 1 (under 3 months suggests congenital nephrotic syndrome, such as the NPHS1 form); gross hematuria, persistent hypertension, or low C3; AKI not explained by hypovolemia; or systemic features such as rash or arthritis.

Steroid-resistant disease. Biopsy usually shows FSGS, and some children carry podocyte gene variants (NPHS1 nephrin, NPHS2 podocin, WT1), which respond poorly to immunosuppression. Treatment is a calcineurin inhibitor (tacrolimus or cyclosporine) plus an ACE inhibitor; it can progress to ESKD, and FSGS may recur after transplant.

Edema control. A no-added-salt diet and cautious diuretics. Children can be intravascularly depleted despite anasarca: abdominal pain, tachycardia, oliguria, and a rising hematocrit signal hypovolemia. Severe symptomatic edema (respiratory compromise, tense scrotal edema) is treated with IV 25% albumin followed by furosemide.

Aggressive diuresis can precipitate hypovolemic shock, prerenal AKI, and venous thrombosis.

Nephrotic complications and relapses

Infection. Urinary loss of IgG and complement factor B impairs opsonization of encapsulated bacteria, and steroids add immunosuppression. Spontaneous bacterial peritonitis, most often from Streptococcus pneumoniae and next from E. coli, presents with fever and diffuse abdominal tenderness in a child with ascites: perform paracentesis and give IV ceftriaxone. Cellulitis and sepsis also occur. Complete pneumococcal vaccination per the ACIP risk-based schedule (PCV20, or PCV15 followed by PPSV23) plus yearly inactivated influenza vaccine, and defer live vaccines during high-dose steroids (≥2 mg/kg/day or ≥20 mg/day for 14 days or longer) and for at least 1 month after they stop.

Thrombosis. Antithrombin III is lost in the urine while the liver raises fibrinogen and factors V and VIII; diuretic hemoconcentration and immobility add risk. Renal vein thrombosis causes sudden flank pain, gross hematuria, an enlarged kidney, and AKI (Doppler ultrasound confirms). Cerebral venous sinus thrombosis and pulmonary embolism also occur.

Relapse. Up to ~80% of steroid-sensitive children relapse, often with a URI. A home first-morning dipstick of ≥3+ on 3 consecutive days defines relapse; prednisone is restarted daily until remission, then given on alternate days.

Steroid-sparing therapy. Frequent relapses (≥2 within 6 months of the first response, or ≥4 in any 12 months) or steroid dependence (2 consecutive relapses on steroids or within 14 days of stopping) call for cyclophosphamide, a calcineurin inhibitor, mycophenolate mofetil, rituximab, or levamisole, to limit steroid toxicity: slowed growth, obesity, hypertension, cataracts, bone loss, and behavior change.

Poststreptococcal glomerulonephritis

Timing. Nephritogenic group A Streptococcus triggers an immune-complex (type III) glomerulonephritis 1–2 weeks after pharyngitis or 3–6 weeks after impetigo, typically at ages 5–12.

Presentation. Cola-colored urine, periorbital edema, hypertension, and oliguria; severe cases develop pulmonary edema or hypertensive encephalopathy (headache, seizures).

Diagnosis. RBC casts, dysmorphic RBCs, and mild proteinuria. C3 is low with a normal C4 (alternative pathway) and normalizes within 6–8 weeks. ASO rises after pharyngitis but often stays low after impetigo because skin lipids inactivate streptolysin O; anti-DNase B is the best marker after skin infection. Biopsy only if C3 stays low beyond 8 weeks (C3 glomerulopathy, MPGN, lupus), renal failure progresses, or nephrotic proteinuria persists; it shows hypercellular glomeruli with neutrophils, "lumpy-bumpy" granular IgG and C3, and subepithelial humps on EM.

Management. Supportive: sodium and fluid restriction, furosemide for edema and hypertension, a calcium channel blocker if BP stays high, and dialysis only for refractory hyperkalemia or overload. Penicillin or amoxicillin eradicates the strain but does not alter the nephritis; glucocorticoids have no role. More than 95% of children recover; microscopic hematuria may persist 1–2 years.

Gross hematuria 1–2 days into a URI with a normal C3 is IgA nephropathy; low C3 plus low C4 suggests lupus nephritis.

IgA vasculitis (Henoch-Schönlein purpura)

Overview. The most common childhood vasculitis, usually at ages 3–10 and often after a URI. Galactose-deficient IgA1 immune complexes cause leukocytoclastic vasculitis of skin, gut, joints, and glomeruli: palpable purpura on the buttocks and legs, knee and ankle arthritis (sometimes preceding the rash), colicky abdominal pain with GI bleeding, and hematuria with or without proteinuria.

Diagnosis. Clinical. Normal platelets and coagulation studies separate it from ITP, leukemia, or a factor deficiency; skin biopsy (IgA deposits) is for atypical cases. Check urinalysis and BP at presentation.

Intussusception. Bowel-wall edema and hemorrhage create a lead point, usually ileoileal, unlike idiopathic ileocolic intussusception. Colicky pain, vomiting, or currant-jelly stool warrants ultrasound; small-bowel intussusception is often beyond reach of an air or contrast enema and may need surgery. Scrotal swelling can mimic torsion; Doppler ultrasound distinguishes them.

Treatment and surveillance. Hydration, rest, and acetaminophen, or NSAIDs if kidneys and gut are spared. Oral glucocorticoids ease severe abdominal pain or orchitis but do not prevent nephritis. Most nephritis appears within 4–6 weeks and nearly all within 6 months, so check urinalysis and BP for about 6 months; nephrotic-range proteinuria or a falling GFR prompts biopsy.

Hemolytic uremic syndrome

STEC-HUS. About 90% of pediatric HUS follows Shiga toxin–producing E. coli O157:H7 from undercooked beef, raw milk, or petting zoos (Shigella dysenteriae type 1 makes the same toxin). Bloody diarrhea, often with little fever, precedes HUS by about 5–10 days in up to 15% of infected children. The toxin binds Gb3 on glomerular endothelium and halts protein synthesis at the 60S ribosome; microthrombi consume platelets and shear red cells.

Laboratory picture. Schistocytes, high LDH, low haptoglobin, and a negative direct Coombs test; thrombocytopenia; AKI with hematuria. Normal PT/PTT separates HUS from DIC, and ADAMTS13 activity <10% would indicate TTP instead. Stool culture plus a Shiga toxin assay confirms the cause.

Management. Meticulous fluids and electrolytes (isotonic fluids during the diarrheal phase appear nephroprotective, with serial CBC and creatinine), RBC transfusion for Hb <7 g/dL, antihypertensives, and dialysis for oliguric AKI, hyperkalemia, or overload, needed by about half. Transfuse platelets only for bleeding or procedures. CNS involvement (seizures, stroke) is the main cause of death, and survivors need follow-up for hypertension and CKD.

Avoid antibiotics (may increase toxin release), antimotility agents, and NSAIDs in suspected STEC infection.

Atypical HUS. Uncontrolled alternative-complement activation from CFH (most common), CFI, CD46/MCP, or C3 variants, or anti–factor H antibodies, causes familial, relapsing HUS without a STEC prodrome, often with low C3; untreated, it frequently progresses to ESKD. Treat with the anti-C5 antibody eculizumab or ravulizumab after MenACWY and MenB vaccination, since C5 blockade leaves patients vulnerable to Neisseria.