Polycystic Kidney Disease & Hereditary Nephropathies

ADPKD: genetics and mechanism

Inheritance. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease (roughly 1 in 400–1,000 people) and causes about 5–10% of ESKD. About 80% of families carry a PKD1 mutation (chromosome 16, polycystin-1) and about 15% a PKD2 mutation (chromosome 4, polycystin-2, a calcium channel). PKD1 disease produces larger kidneys and reaches ESKD about two decades earlier, typically in the 50s versus the 70s.

How cysts form. Polycystins on the primary cilium convert urine flow into calcium signals. Their loss lowers intracellular calcium and raises cAMP, driving epithelial proliferation and CFTR-mediated fluid secretion into cysts. Vasopressin acting on V2 receptors adds cAMP, the rationale for tolvaptan and for liberal water intake. Cysts are focal because a somatic second hit must inactivate the normal allele.

ADPKD: presentation, diagnosis and renal complications

Presentation. Symptoms usually begin at 30–50 years. Hypertension precedes any fall in GFR in about 50–70%, because enlarging cysts compress intrarenal vessels and activate the renin–angiotensin system. Other features are flank or back pain, gross hematuria from cyst rupture, bilateral palpable kidneys, nocturia from an early concentrating defect, and stones in about 20–30% (uric acid and calcium oxalate). GFR is often preserved until the kidneys are massively enlarged.

Diagnosis. In a person with a family history, ultrasound is read against age-specific cyst counts, because simple cysts become common with aging. MRI is more sensitive and measures total kidney volume, the best predictor of progression. Genetic testing helps when imaging is equivocal, the family history is absent, or a young relative is a potential living donor.

Hypertension. ACE inhibitors or ARBs are first-line; in adults younger than 50 with preserved eGFR, a low target of about ≤110/75 mm Hg slows kidney growth.

Pain, bleeding and infection. Acute pain may reflect cyst hemorrhage, infection, a stone or, rarely, a tumor; CT or MRI sorts these out. Hematuria from a ruptured cyst usually stops within days with rest and fluids, and chronic NSAID use is avoided. Fever, focal flank tenderness and leukocytosis suggest an infected cyst even when the urine culture is negative, because many cysts do not drain into the collecting system. Lipid-soluble fluoroquinolones or TMP-SMX penetrate cyst walls and are given for about 4–6 weeks; β-lactams and aminoglycosides penetrate poorly. Large or nonresponding infected cysts are drained.

ADPKD: extrarenal disease and disease-modifying therapy

Liver. Hepatic cysts are the most common extrarenal lesion, present in most patients by age 40, usually with normal liver function. Massive polycystic liver disease favors women because estrogen (pregnancies, oral contraceptives, hormone therapy) stimulates cyst growth.

Intracranial aneurysms. Berry aneurysms occur in about 10% of patients and about 20% of those with a family history of aneurysm or subarachnoid hemorrhage. Screen with noncontrast MR angiography for that family history, a prior rupture, or a high-risk occupation such as pilot. A thunderclap headache needs emergent noncontrast head CT.

Other associations. Mitral valve prolapse (about 25%), colonic diverticula, abdominal wall and inguinal hernias, and pancreatic or seminal vesicle cysts.

Tolvaptan. This V2 antagonist slows kidney enlargement and eGFR decline in adults at risk of rapid progression (large height-adjusted kidney volume on MRI or fast eGFR loss). Aquaresis causes polyuria, nocturia and thirst. Idiosyncratic hepatotoxicity requires liver tests monthly for the first 18 months, then every 3 months, and the drug is avoided in liver disease and with strong CYP3A inhibitors. All patients should drink liberally to suppress vasopressin (unless CKD is advanced), restrict sodium and avoid nephrotoxins.

Alport syndrome and thin basement membrane disease

Alport syndrome. The GBM, cochlea and lens capsule share the α3-α4-α5 network of type IV collagen. About 80% of cases are X-linked (COL4A5); autosomal forms involve COL4A3 or COL4A4. Boys have microscopic hematuria from childhood, then proteinuria, hypertension and ESKD, often by early adulthood, with bilateral high-frequency sensorineural hearing loss, anterior lenticonus (essentially pathognomonic) and dot-and-fleck retinopathy. Female carriers usually have hematuria and may progress later.

Diagnosis and treatment. Electron microscopy shows irregular thickening, splitting and lamellation of the GBM, the basket-weave pattern; genetic testing now confirms most cases. An ACE inhibitor or ARB started once albuminuria appears delays ESKD. After transplant, about 3–5% develop anti-GBM nephritis because the recipient first meets normal collagen IV in the donor kidney.

Thin basement membrane disease. This benign familial hematuria usually reflects a heterozygous COL4A3 or COL4A4 variant. Persistent isolated microscopic hematuria runs in families with normal creatinine and no ear or eye disease; reassure and periodically check blood pressure, proteinuria and creatinine.

Fabry disease, sickle cell nephropathy and medullary sponge kidney

Fabry disease. X-linked α-galactosidase A (GLA) deficiency deposits globotriaosylceramide (Gb3) in endothelium, podocytes, heart and nerves. Boys develop burning acroparesthesias triggered by fever, heat or exercise, hypohidrosis, bathing-trunk angiokeratomas and corneal whorls; adults develop proteinuria and CKD, LVH and arrhythmias, and early stroke. Biopsy shows zebra bodies in podocytes. Low enzyme activity is diagnostic in men; women, who can be symptomatic from random X-inactivation, need GLA sequencing. Treat with enzyme replacement (agalsidase) or oral migalastat for amenable variants, plus an ACE inhibitor or ARB for proteinuria.

Sickle cell nephropathy. The hypoxic, acidic, hypertonic medulla promotes HbS polymerization in the vasa recta. Microinfarcts cause isosthenuria (urine fixed near specific gravity 1.010, with nocturia, enuresis and dehydration) and papillary necrosis with painless hematuria, usually from the left kidney, whose long renal vein is compressed between aorta and SMA. Both occur with trait as well as disease, and most bleeding settles with rest and hydration. Sickle cell disease adds hyperfiltration, albuminuria and FSGS, treated with ACE inhibitors or ARBs.

Renal medullary carcinoma, a rare and aggressive tumor of adolescents and young adults with sickle cell trait or HbSC, is usually metastatic at diagnosis. Gross hematuria in a young patient with trait needs CT urography, not reassurance.

Medullary sponge kidney. This usually sporadic ectasia of papillary collecting ducts appears as paintbrush striations on CT urography. Stasis, hypercalciuria and hypocitraturia cause medullary nephrocalcinosis, recurrent calcium stones, UTIs and hematuria, but GFR stays normal. Treat the stones: fluids, a thiazide for hypercalciuria and potassium citrate for hypocitraturia.

Contrast ARPKD (PKHD1; huge echogenic kidneys and congenital hepatic fibrosis in infancy) and ADTKD (UMOD or MUC1; small kidneys, bland sediment, early gout).