Why Men Experience More Severe Autosomal Dominant Polycystic Kidney Disease (ADPKD) Than Women

Understanding the Gender Disparity in ADPKD Progression

Research consistently shows that men with autosomal dominant polycystic kidney disease (ADPKD) tend to experience faster cyst growth, earlier onset of hypertension, and more rapid decline in kidney function compared to women. This gender-based difference isn't coincidental—it's strongly linked to hormonal influences, particularly testosterone's role in accelerating cyst expansion and tubular epithelial cell proliferation.

Hormonal Mechanisms Driving Worse Outcomes in Men

Testosterone acts as a biological accelerator in ADPKD pathogenesis. Preclinical and clinical evidence indicates that androgens stimulate cAMP signaling pathways—key drivers of cyst-lining cell proliferation and fluid secretion. In contrast, estrogen appears to exert protective effects by modulating renal blood flow, reducing oxidative stress, and suppressing pro-fibrotic cytokines. This hormonal "double advantage" helps explain why women often retain preserved kidney function 5–10 years longer than men with similar genetic mutations.

Genetic & Clinical Characteristics of ADPKD

ADPKD is the most common inherited kidney disorder, affecting approximately 1 in 400–1,000 people worldwide. It's caused primarily by mutations in PKD1 (85% of cases) or PKD2 genes, leading to progressive cyst formation in both kidneys. Symptoms typically emerge between ages 30–50 and include flank pain, microscopic or gross hematuria, recurrent urinary tract infections, nephrolithiasis, and palpable abdominal masses. Hypertension develops early—even before significant loss of glomerular filtration rate—and serves as both a marker and contributor to disease progression.

Strategic Blood Pressure & Proteinuria Management

Aggressive blood pressure control remains one of the most evidence-backed interventions to slow ADPKD progression. Current guidelines recommend:

For patients with proteinuria ≥1 g/24 hours: Target BP ≤125/75 mmHg using renin-angiotensin-aldosterone system (RAAS) inhibitors as first-line therapy.
For patients with proteinuria <1 g/24 hours: Target BP ≤130/80 mmHg, prioritizing RAAS blockade and lifestyle modifications (e.g., sodium restriction <2 g/day, regular aerobic activity).

Consistent control not only preserves kidney function but also reduces left ventricular hypertrophy risk and cardiovascular mortality—both significantly elevated in ADPKD populations.

When Chronic Kidney Disease Advances to End-Stage Renal Disease

Without intervention, ADPKD progresses inexorably toward end-stage renal disease (ESRD), typically by age 55–65 in PKD1 carriers and later in PKD2 cases. ESRD triggers a cascade of life-threatening complications collectively known as uremic syndrome—including:

Gastrointestinal: Nausea, vomiting, anorexia, occult or overt GI bleeding
Cardiopulmonary: Dyspnea, orthopnea, pulmonary edema, congestive heart failure
Neurological: Cognitive fog, confusion, hallucinations, seizures, or coma
Metabolic: Severe metabolic acidosis (bicarbonate <15 mmol/L)
Hematologic: Normocytic, normochromic anemia resistant to iron or erythropoietin therapy
Dermatologic: Pruritus due to calcium-phosphate crystal deposition and histamine dysregulation
Skeletal: Renal osteodystrophy—manifesting as bone pain, spontaneous fractures, and radiographic osteopenia

Comprehensive Uremia Management Requires Multidisciplinary Care

Once uremic symptoms become refractory to medical therapy, timely initiation of kidney replacement therapy (KRT) is essential. Options include hemodialysis (HD), peritoneal dialysis (PD), and preemptive kidney transplantation—the gold standard for eligible candidates. Importantly, KRT must be paired with proactive management of comorbidities: phosphate binders and vitamin D analogs for mineral bone disorder; intravenous iron and ESA dosing for anemia; nutritional support to combat protein-energy wasting; and infection surveillance given heightened susceptibility to bacterial and fungal pathogens.

Emerging Hope: Disease-Modifying Therapies on the Horizon

While no cure exists yet, breakthrough therapies like tolvaptan—a selective vasopressin V2-receptor antagonist—have demonstrated proven efficacy in slowing TKV growth and eGFR decline in adults with rapidly progressing ADPKD. Ongoing clinical trials are evaluating novel agents targeting CFTR, mTOR, Src kinase, and inflammation pathways—offering renewed optimism for personalized, precision-based ADPKD care in the near future.