Polycystic Kidney Disease (PKD)

1. Autosomal Dominant PKD (ADPKD)

Epidemiology

• Prevalence: 1 in 400 to 1 in 1000 - one of the most common hereditary diseases
• Accounts for ~5% of end-stage kidney disease (ESKD) in the US
• More progressive in men than women (gender ratio 1.2-1.3)
• ~30,000 patients have ESKD due to ADPKD in the United States

Genetics

• ~7% have no detectable mutation
• Two newer genes - GANAB and DNAJB11 - produce ADPKD-like phenotypes
• Homozygous mutations in either PKD1 or PKD2 are lethal in utero
• Patients heterozygous for both PKD1 and PKD2 mutations have more severe disease than those with one mutation alone

Pathogenesis

Pathology

• Kidneys become massively enlarged, studded with innumerable fluid-filled cysts of all sizes
• Cysts arise from any segment of the nephron (glomerulus to collecting duct) but most originate from the distal tubule and collecting duct
• Cyst fluid is usually amber-colored; may be hemorrhagic
• In end-stage disease, only scattered patches of normal parenchyma remain, with tubulointerstitial fibrosis and arteriolar sclerosis
• Liver cysts are present in up to 90% of adults - the most common extrarenal manifestation

Clinical Features

• Flank/abdominal pain (from the weight of enlarged kidneys, hemorrhage into a cyst, or infection)
• Gross or microscopic hematuria (can be severe)
• Renal colic (from clots or stones)
• Abdominal mass
• Symptoms of UTI/pyelonephritis
• Nausea, vomiting, weakness, headache when renal insufficiency develops

• Palpable, nodular kidneys (bilateral)
• Hypertension in 60-70% of patients (often presents before GFR declines - driven by intrarenal RAAS activation)
• Cardiac enlargement secondary to hypertension

Disease Progression

• A height-adjusted total kidney volume (htTKV) ≥600 mL/m at baseline most accurately predicts development of stage 3 CKD within 8 years (AUC 0.84)
• Baseline htTKV remained an independent predictor even at 13-year follow-up; OR 1.35 per 100 mL/m increment for reaching stage 5 CKD or ESRD
• Reduced renal blood flow (increased vascular resistance) is an independent predictor of GFR decline
• Notably, ADPKD patients have less anemia than other CKD patients because polycystic kidneys produce excess erythropoietin

Extrarenal Manifestations

Diagnosis

• Age 15-39 years: ≥3 renal cysts (unilateral or bilateral) - PPV 100%
• Age 40-59 years: ≥2 cysts in each kidney - PPV 100%
• Age ≥60 years: ≥4 cysts in each kidney

Management

• ACE inhibitors or ARBs are first-line (block the intrarenal RAAS)
• Target BP: The HALT-PKD trial showed aggressive BP control (95-110/60-75 mmHg) in younger patients slowed kidney volume growth and reduced left ventricular mass index

• Tolvaptan (vasopressin V2-receptor antagonist) - the first approved therapy to slow cyst growth and GFR decline in patients with rapidly progressive ADPKD (htTKV-based Mayo classification 1C-1E or PRO-PKD score >6). The TEMPO 3:4 and REPRISE trials demonstrated significant reduction in kidney volume growth and GFR decline. Hepatotoxicity is a risk - requires REMS enrollment and monitoring.
• mTOR inhibitors (sirolimus, everolimus) - showed reduction in kidney volume growth in trials but did not preserve GFR; not currently standard of care
• Statins, dietary protein restriction, and increased water intake (to suppress AVP) are often recommended but lack robust trial evidence

• Cyst infection: fluoroquinolones or TMP-SMX (penetrate into cyst fluid)
• Hematuria: conservative management; spontaneously resolves in most cases
• Nephrolithiasis: 20-36% prevalence; uric acid and calcium oxalate stones

• ADPKD patients on peritoneal dialysis (PD) have similar or better outcomes than other PD patients. Concern about large kidney volume causing inadequate dwell volume occasionally necessitates nephrectomy before initiating PD.
• Kidney transplantation: outcomes are excellent; bilateral native nephrectomy may be required for space

2. Autosomal Recessive PKD (ARPKD)

Epidemiology & Genetics

• Prevalence: 1 in 20,000; carrier frequency ~1 in 70
• Caused by mutations in PKHD1 (chromosome 6p21.1-p12) encoding fibrocystin (also called polyductin)
• PKHD1 is one of the largest human genes (~470 kb, 67 exons)
• Two truncating mutations = lethal neonatal phenotype; at least one non-truncating mutation = survival possible
• Biallelic mutations in DZLP1 or specific PMM2 mutations can produce ARPKD-like phenotypes

Pathology & Pathogenesis

• Fibrocystin is a large transmembrane protein localized to the primary cilium and basal body, particularly in collecting duct and thick ascending limb epithelium, and in the bile duct
• Cysts are characteristically fusiform dilations of the collecting ducts, creating a radially striated appearance on imaging
• Invariably associated with congenital hepatic fibrosis (CHF) - periportal fibrosis causing portal hypertension
• Non-obstructive intrahepatic bile duct dilatation (Caroli disease) is variably present

Clinical Features

• Presents at birth or in infancy with massive bilateral renal enlargement (can be detected on prenatal ultrasound)
• Severely affected neonates have Potter sequence (oligohydramnios, pulmonary hypoplasia, limb contractures, characteristic facies) - often die from respiratory failure
• Surviving infants/children develop progressive CKD
• Portal hypertension, esophageal varices, and cholangitis dominate in older patients who survive the neonatal period

Management

• No disease-specific therapy exists
• Supportive: antihypertensives, treatment of portal hypertension, management of CKD
• Combined kidney-liver transplantation may be required in severe cases

Summary Comparison