Kidney in Systemic Disease

Lupus nephritis

Why it matters. Roughly half of patients with SLE develop clinically evident nephritis, a leading driver of SLE morbidity. Where immune complexes lodge in the glomerulus determines the lesion. Every SLE patient is screened with a urinalysis (hematuria, RBC casts) and a urine protein-to-creatinine ratio; biopsy assigns the ISN/RPS class, which guides therapy.

Class IV (diffuse proliferative). Subendothelial immune complexes on the blood side of the GBM recruit leukocytes and thicken capillary walls into rigid "wire loops," with diffuse endocapillary proliferation and, in severe cases, crescents. Immunofluorescence is "full house" (IgG, IgA, IgM, C3 and C1q). Patients are nephritic (hematuria, RBC casts, hypertension, rising creatinine), often with heavy proteinuria.

Class V (membranous). Subepithelial deposits provoke little inflammation, so the picture is nephrotic: proteinuria above 3.5 g/day, edema, hyperlipidemia and thrombotic risk, including renal vein thrombosis. Serology is often quieter and complement may be normal. Clues that membranous disease is lupus rather than primary: negative anti-PLA2R, added mesangial or subendothelial deposits, full-house staining and endothelial tubuloreticular inclusions.

Serology. Rising anti-dsDNA with falling C3 and C4 (classical-pathway consumption by immune complexes) heralds active nephritis. Anti-Smith is highly specific for SLE but does not track activity; anti-histone points to drug-induced lupus.

Treatment. Class III/IV (± V) induction is glucocorticoids plus mycophenolate mofetil or IV cyclophosphamide, then maintenance with mycophenolate or azathioprine; belimumab or voclosporin may be added. Hydroxychloroquine is given to all SLE patients, an ACE inhibitor or ARB lowers proteinuria, and plasma exchange has no routine role.

Mycophenolate spares ovarian function but is teratogenic (switch to azathioprine for pregnancy); cyclophosphamide risks gonadal failure and hemorrhagic cystitis from its metabolite acrolein, which mesna neutralizes.

Viral infections: HIV, hepatitis B and hepatitis C

HIV-associated nephropathy. The lesion is collapsing FSGS: capillary tufts collapse beneath hypertrophied, proliferating podocytes, tubules dilate into microcysts, and EM shows endothelial tubuloreticular inclusions. Typical patients are of African ancestry with uncontrolled HIV, and heavy proteinuria progresses rapidly to end-stage kidney disease. Unlike most CKD, in which kidneys shrink, HIVAN kidneys stay normal-sized or enlarged and highly echogenic. Treatment is antiretroviral therapy plus an ACE inhibitor or ARB.

APOL1. Two risk alleles (G1 and G2), common in West African ancestry, account for much of the excess risk of HIVAN and other FSGS. They spread because the variant protein protects against the trypanosomes of African sleeping sickness, a trade-off reminiscent of sickle trait and malaria.

Hepatitis B. Immune complexes cause membranous nephropathy, especially in children, and less often MPGN. HBV is also the classic trigger of polyarteritis nodosa, a necrotizing vasculitis of medium-sized arteries: renal microaneurysms, infarcts and renin-driven hypertension, often with mononeuritis multiplex, but glomeruli are spared (no GN, no RBC casts) and ANCA is negative. That separates PAN from the small-vessel vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis, IgA vasculitis), which cause GN.

Hepatitis C. HCV drives type II mixed cryoglobulinemia: a monoclonal IgM with rheumatoid factor activity binds polyclonal IgG, and the cold-precipitating complexes deposit in glomeruli. The result is MPGN with lobular tufts, "tram-track" GBM double contours and intracapillary cryoglobulin "thrombi." Clues are palpable purpura, arthralgia, neuropathy, positive RF and a markedly low C4 (classical-pathway consumption) with C3 normal or mildly low. Direct-acting antivirals treat the cause.

Sickle cell nephropathy

A medulla built to sickle. The inner medulla is hypoxic, hypertonic and acidic, and all three conditions polymerize HbS. Sickled cells occlude the vasa recta, destroying countercurrent exchange and infarcting papillae, in sickle cell disease and trait alike.

• Isosthenuria: urine fixed near plasma osmolality; the most common renal abnormality, even in trait. Nocturia, enuresis and dehydration follow, and dehydration promotes more sickling.
• Papillary necrosis: painless gross hematuria, sometimes with a sloughed papilla obstructing the ureter. Other causes: analgesic abuse (NSAIDs, historically phenacetin), diabetes, and severe acute pyelonephritis or obstruction.

Glomerular disease. In sickle cell disease, anemia raises renal plasma flow; children hyperfilter with enlarged glomeruli that later develop secondary FSGS with albuminuria and CKD, slowed by ACE inhibitors or ARBs. Creatinine runs deceptively low (hyperfiltration plus increased tubular secretion), so a "normal" value can hide lost function.

Renal medullary carcinoma. A rare, highly aggressive tumor of adolescents and young adults with sickle cell trait (or HbSC), more often right-sided, with loss of SMARCB1 (INI1). Hematuria, flank pain and metastases at diagnosis are typical; survival is often measured in months.

Plasma cell dyscrasias

Light-chain cast nephropathy. Filtered free light chains are normally reclaimed by proximal endocytosis (megalin–cubilin). When that capacity is overwhelmed, they reach the distal nephron and co-aggregate with uromodulin (Tamm-Horsfall protein, secreted by the thick ascending limb), forming dense, fractured casts in distal tubules and collecting ducts, ringed by multinucleated giant cells. The casts obstruct tubules and cause AKI; dehydration, hypercalcemia, NSAIDs, IV contrast and loop diuretics precipitate it.

The urine dipstick reads mainly albumin, so Bence Jones proteinuria may register as trace while a 24-hour collection holds grams; sulfosalicylic acid precipitation or urine immunofixation reveals the light chains.

AL amyloidosis. Light-chain fragments (λ more often than κ) form β-pleated fibrils in the mesangium, capillary walls and vessels, causing nephrotic-range proteinuria with normal-sized or enlarged kidneys. Congo red shows apple-green birefringence under polarized light; EM shows randomly arranged nonbranching fibrils about 10 nm wide. Light-chain deposition disease (usually κ) is Congo red–negative and forms nodules that mimic diabetes.

Fanconi syndrome and hypercalcemia. κ light chains can crystallize in proximal tubule cells, causing glycosuria with normal serum glucose, aminoaciduria, phosphaturia and proximal (type 2) RTA. Osteolytic hypercalcemia adds nephrogenic DI, afferent vasoconstriction, volume depletion and nephrocalcinosis.

Thrombotic microangiopathies

Shared picture. Endothelial injury seeds platelet microthrombi in arterioles and glomerular capillaries: microangiopathic hemolytic anemia (schistocytes, high LDH, low haptoglobin, negative Coombs test), thrombocytopenia and ischemic organ injury. PT, aPTT and fibrinogen stay normal because clotting factors are not consumed; prolonged times suggest DIC.

STEC-HUS. E. coli O157:H7 from undercooked beef, raw milk or petting zoos causes bloody diarrhea; absorbed Shiga toxin binds Gb3 on glomerular endothelium, and its A subunit depurinates 28S rRNA of the 60S subunit, halting protein synthesis (unlike diphtheria toxin on EF-2, cholera toxin on Gs or botulinum toxin on SNAREs). HUS is a leading cause of AKI in young children. Care is supportive (fluids, transfusion, dialysis); antibiotics and antimotility drugs are avoided.

Atypical HUS. Loss-of-function variants in factor H (most common), factor I or membrane cofactor protein (CD46), or anti-factor H antibodies, leave the alternative pathway unchecked on endothelium. There is no diarrheal prodrome, and relapses, ESKD and recurrence after transplant are common. The anti-C5 antibodies eculizumab and ravulizumab block membrane attack complex formation, so patients are vaccinated against Neisseria meningitidis first.

TTP. Autoantibodies (or congenital mutations, Upshaw–Schulman syndrome) abolish ADAMTS13, leaving ultra-large vWF multimers that string platelets into microthrombi. Neurologic signs dominate and renal injury is usually mild. ADAMTS13 activity below 10% confirms it; treatment is urgent plasma exchange with glucocorticoids, often plus caplacizumab and rituximab.

Scleroderma, sarcoidosis and preeclampsia

Scleroderma renal crisis. Early diffuse cutaneous systemic sclerosis, especially with anti-RNA polymerase III antibodies or high-dose glucocorticoids, can abruptly thicken interlobular arteries with concentric mucoid "onion-skin" intimal proliferation. Cortical ischemia drives massive renin release: malignant hypertension, rising creatinine, mild proteinuria and sometimes microangiopathic hemolysis. An ACE inhibitor (classically captopril, titrated rapidly) is lifesaving and is continued even if dialysis is needed, because function can recover over months.

Avoid high-dose glucocorticoids in diffuse scleroderma: prednisone above about 15 mg/day is a classic precipitant of renal crisis.

Sarcoidosis. Granuloma macrophages express 1α-hydroxylase free of PTH feedback, converting 25-hydroxyvitamin D to calcitriol. The result is hypercalciuria (more common than hypercalcemia) with suppressed PTH, nephrocalcinosis, calcium stones and nephrogenic DI; noncaseating granulomatous interstitial nephritis can also cause AKI. Glucocorticoids reverse both.

Preeclampsia. An ischemic placenta releases sFlt-1 (soluble fms-like tyrosine kinase-1, a decoy VEGF receptor) and soluble endoglin. Deprived of VEGF and placental growth factor, glomerular endothelial cells swell, vacuolate and occlude capillary lumens (glomerular endotheliosis) without immune deposits. The clinical result is new hypertension ≥140/90 mm Hg with proteinuria after 20 weeks, reversing after delivery.

Anti-VEGF drugs such as bevacizumab reproduce the lesion: hypertension, proteinuria and renal thrombotic microangiopathy.