Polycystic Kidney Disease: Genetics, Extrarenal Disease and Tolvaptan

Last updated 17 August 2026.

Key points

Autosomal dominant PKD (ADPKD): the commonest inherited kidney disease, affecting around 1 in 1,000 people, in which progressive bilateral cyst formation destroys renal parenchyma over decades.
Two genes: PKD1 on chromosome 16 (around 85% of cases, encoding polycystin-1) causes earlier renal failure - median around 55 years. PKD2 on chromosome 4 is milder, with failure around 70.
Presentation: hypertension in a young adult, loin or abdominal pain, haematuria, recurrent urinary infection, palpable kidneys, or an incidental finding while screening a family member.
Extrarenal disease is the key exam material: hepatic cysts (commonest), intracranial berry aneurysms with risk of subarachnoid haemorrhage, mitral valve prolapse, colonic diverticula and abdominal wall hernias.
Diagnosis: ultrasound with age-adjusted cyst criteria in a patient with a positive family history; genetic testing where imaging is equivocal or for reproductive planning.
Disease-modifying treatment: tolvaptan, a vasopressin V2 receptor antagonist, slows cyst growth and eGFR decline in rapidly progressing disease. It causes marked thirst, polyuria and hepatotoxicity needing LFT monitoring.
Supportive management: rigorous blood pressure control with an ACE inhibitor or ARB, high fluid intake, low sodium diet, and prompt treatment of infection and stones.
ARPKD: autosomal recessive PKD presents in infancy with enlarged echogenic kidneys, Potter sequence and pulmonary hypoplasia, plus congenital hepatic fibrosis - a distinct and far more severe disease.

Introduction

Polycystic kidney disease is a group of inherited disorders characterised by the development of multiple fluid-filled cysts that progressively replace functioning renal parenchyma. Autosomal dominant polycystic kidney disease (ADPKD) is by far the commoner form, affecting around 1 in 1,000 people, making it the commonest inherited kidney disease and the fourth commonest cause of end-stage renal disease in the UK.¹

It is fundamentally a systemic disorder rather than a purely renal one. The polycystin proteins are expressed in epithelial cilia throughout the body, which is why cysts also form in the liver and pancreas, and why the vasculature and connective tissues are affected - producing the intracranial aneurysms, valvular disease and hernias that make up much of the clinically important burden.

ADPKD compared with ARPKD.
Feature	ADPKD	ARPKD
Inheritance	Autosomal dominant - 50% risk to each offspring; there is usually a family history, though around 10% arise de novo	Autosomal recessive - 25% risk with two carrier parents; parents are unaffected
Gene	PKD1 (chromosome 16, ~85%) or PKD2 (chromosome 4, ~15%)	PKHD1 (chromosome 6), encoding fibrocystin
Age at presentation	Adulthood, typically third to fifth decade	Neonatal or antenatal
Kidneys	Progressively enlarging cysts of varying size, massively enlarged in advanced disease	Bilaterally enlarged, diffusely echogenic kidneys with microcysts
Liver	Hepatic cysts (very common, rarely cause dysfunction)	Congenital hepatic fibrosis with portal hypertension
Prognosis	End-stage renal disease typically in the fifth to seventh decade	High perinatal mortality from pulmonary hypoplasia; survivors usually reach ESRD in childhood or adolescence

Genetics and pathophysiology

The two ADPKD genotypes.
Gene	Chromosome	Protein	Proportion	Severity
PKD1	16	Polycystin-1	~85%	More severe - larger kidneys, earlier hypertension, median age at end-stage renal disease around 55 years
PKD2	4	Polycystin-2	~15%	Milder - later presentation, median age at end-stage renal disease around 70 years, and some never reach it

Polycystin-1 and polycystin-2 form a complex in the primary cilium of renal tubular epithelial cells, where they act as a mechanosensor detecting urinary flow and regulating intracellular calcium. Loss of function reduces intracellular calcium and raises cyclic AMP, which drives epithelial cell proliferation and fluid secretion into the tubular lumen. Segments of tubule progressively balloon into fluid-filled cysts that detach from the nephron and continue to enlarge.

Cysts arise from only a small proportion of nephrons, but their relentless expansion compresses and destroys the surrounding normal parenchyma, causing interstitial fibrosis - which is why renal function declines even though most nephrons are not cystic
Vasopressin drives the process by raising cyclic AMP through the V2 receptor. This is the mechanistic basis both for advising a high fluid intake (suppressing endogenous vasopressin) and for treating with tolvaptan (a V2 receptor antagonist).
GFR is preserved for decades by compensatory hyperfiltration of surviving nephrons, so a normal creatinine in a young adult with ADPKD is entirely expected and does not indicate mild disease. Total kidney volume rises long before eGFR falls, and is the better early marker of progression.
Hypertension develops early, often before any fall in eGFR, because cyst expansion causes local ischaemia and activates the renin-angiotensin-aldosterone system - and it then accelerates the decline in function

Clinical features

Renal manifestations

Hypertension - present in the majority by early adulthood and frequently the first sign; ADPKD should be considered in any young person with unexplained hypertension and a relevant family history
Loin, flank or abdominal pain - either chronic and dragging, from the mass effect of enlarging kidneys, or acute, from cyst haemorrhage, cyst infection or an obstructing stone
Haematuria - visible or non-visible, commonly from cyst haemorrhage, which is usually self-limiting
Recurrent urinary tract infection and cyst infection - cysts are poorly perfused and antibiotic penetration is limited
Renal calculi - in around 20%, from urinary stasis, hypocitraturia and low urine pH
Palpable, ballotable kidneys - often bilateral and, in advanced disease, filling the flanks and causing early satiety and abdominal distension
Nocturia and polyuria - from an early loss of urinary concentrating ability
Progressive chronic kidney disease leading to end-stage renal disease, with the associated anaemia, bone disease and uraemic features
Asymptomatic presentation - increasingly common, found on screening a relative or incidentally on imaging performed for another reason⁵

Axial abdominal CT scan showing both kidneys grossly enlarged and replaced by numerous rounded fluid-filled cysts of varying size, with cysts also visible in the liver. — Abdominal CT in **autosomal dominant polycystic kidney disease**. Both kidneys are massively enlarged and almost entirely replaced by innumerable cysts of varying size. **Hepatic cysts** are also present - the commonest extrarenal manifestation. The bilateral, symmetrical pattern distinguishes this from simple renal cysts.Steven Fruitsmaak, CC BY-SA 3.0, via Wikimedia Commons

Extrarenal manifestations

These are frequently examined, because they explain how a renal genetic disease can present to neurosurgery, cardiology or general surgery.

Extrarenal features of ADPKD.
System	Manifestation	Significance
Liver	Hepatic cysts - the commonest extrarenal feature, present in the majority by middle age and more numerous in women (oestrogen-dependent)	Usually asymptomatic with preserved liver function; occasionally cause pain, mass effect or infection. Massive polycystic liver disease may rarely need intervention.
Cerebral vasculature	Intracranial ('berry') aneurysms in around 5 to 10%, with a risk of subarachnoid haemorrhage	The most serious extrarenal complication. Risk is higher with a family history of aneurysm or haemorrhage, smoking, hypertension and female sex.
Heart	Mitral valve prolapse (the commonest valve lesion), mitral and aortic regurgitation; also left ventricular hypertrophy from hypertension	Usually mild; may cause a murmur. Also increased risk of thoracic aortic dissection.
Gastrointestinal	Colonic diverticula (and an increased risk of diverticulitis), and pancreatic and splenic cysts	Pancreatic cysts are almost always asymptomatic
Abdominal wall	Inguinal and umbilical hernias, from a connective tissue abnormality compounded by raised intra-abdominal pressure	Common, and a recognised complication of peritoneal dialysis in these patients
Other	Seminal vesicle cysts (a cause of male subfertility), arachnoid cysts, bronchiectasis	Less commonly relevant

Berry aneurysms and screening for them

Subarachnoid haemorrhage is the extrarenal complication most likely to kill a patient with ADPKD, and the questions about who to screen and how are commonly examined.

A sudden, severe 'thunderclap' headache in a patient with ADPKD must be treated as subarachnoid haemorrhage until excluded, with urgent CT head and, if negative and within the appropriate window, lumbar puncture for xanthochromia
Routine screening of all patients is NOT recommended, because most small aneurysms will never rupture and intervention carries its own risk
Screen selected higher-risk patients with MR or CT angiography: those with a family history of intracranial aneurysm or subarachnoid haemorrhage, those in high-risk occupations (e.g. pilots), those about to undergo major elective surgery, and those who specifically request it after counselling
Optimise modifiable risk in everyone - rigorous blood pressure control and smoking cessation reduce rupture risk and are effective for the whole population rather than just the screened few

Investigations

Imaging

Renal ultrasound is the first-line investigation, being cheap, safe and sufficient in most cases. Because cyst number increases with age, the diagnostic thresholds are age-adjusted in patients with a positive family history (the Ravine or unified criteria):²

Ultrasound diagnostic criteria in a patient with a positive family history of ADPKD.
Age	Diagnostic criterion
15 to 39 years	At least 3 cysts in total (unilateral or bilateral)
40 to 59 years	At least 2 cysts in each kidney
60 years or over	At least 4 cysts in each kidney

In the absence of a family history, more cysts are required, and the presence of bilateral renal enlargement with numerous cysts plus hepatic cysts strongly supports the diagnosis
MRI is more sensitive than ultrasound for small cysts and is used to measure total kidney volume, which is the best predictor of future eGFR decline and is used to select patients for tolvaptan
CT demonstrates cysts well and is often how the diagnosis is made incidentally, though it involves radiation
A normal ultrasound in a person aged over 40 with a positive family history effectively excludes the diagnosis; in a younger person it does not, and genetic testing or repeat imaging may be needed

Genetic testing

Not routinely required when imaging and family history are clear
Indicated where imaging is equivocal (particularly in a young person), for potential living kidney donors from an affected family, for reproductive planning including pre-implantation genetic diagnosis, and in atypical presentations
Requires genetic counselling, because a diagnosis has implications for insurance, employment, relatives and reproductive decisions - and because testing a child raises significant ethical issues, as there is no intervention in childhood

Other investigations

U&Es and eGFR, monitored serially to establish the rate of decline
Urine ACR - proteinuria is usually modest, and heavy proteinuria should prompt consideration of another diagnosis
Urine dipstick and culture - for haematuria and infection
Blood pressure monitoring, including ambulatory measurement, as hypertension is early and prognostically important
Full blood count - note that these patients may have a relatively high haemoglobin for their eGFR, because cyst epithelium continues to produce erythropoietin
Family screening - offer counselling and, where appropriate, ultrasound to first-degree relatives, with blood pressure checks for all
MR or CT angiography for selected patients, as discussed above

Management

Slowing progression

Interventions to slow decline in renal function.
Intervention	Detail
Blood pressure control	The cornerstone of management. An ACE inhibitor or ARB is first line, given the central role of the renin-angiotensin system. Rigorous control (targets around or below 130/80 mmHg, and lower in younger patients with preserved function) slows eGFR decline, reduces left ventricular hypertrophy and reduces aneurysm rupture risk.
High fluid intake	Around 2.5 to 3 litres daily, to suppress endogenous vasopressin and therefore cyst growth - the same mechanism that tolvaptan exploits pharmacologically. Also reduces stone formation.
Low sodium diet	Improves blood pressure control and reduces vasopressin drive
Tolvaptan	See below - the only licensed disease-modifying drug
Avoid nephrotoxins	Particularly NSAIDs, which are often reached for because of the chronic pain - a genuine clinical tension requiring alternative analgesia
Avoid caffeine in excess and stop smoking	Caffeine raises cyclic AMP in vitro; smoking accelerates renal decline and increases aneurysm risk
Weight management and exercise	Standard cardiovascular and renal benefit

Tolvaptan

Tolvaptan is a selective vasopressin V2 receptor antagonist and the first drug shown to modify the natural history of ADPKD. By blocking vasopressin-driven cyclic AMP generation it slows cyst growth and the rate of eGFR decline.³

NICE recommends it for adults with ADPKD who have CKD stage 2 or 3 at the start of treatment with evidence of rapidly progressing disease, within a specialist service
Predictable and troublesome adverse effects: it produces an aquaretic effect, so marked polyuria, nocturia and thirst are near-universal and are the commonest reason for discontinuation. Patients must have free access to water - it is hazardous in anyone who cannot respond to thirst.
Hepatotoxicity is the serious risk - idiosyncratic and potentially severe liver injury occurs, so liver function must be monitored monthly for the first 18 months and regularly thereafter, and the drug stopped promptly if transaminases rise
It does not cure the disease - it slows progression, delaying rather than preventing end-stage renal disease, and this needs to be explained clearly when weighing it against the symptom burden

Managing complications

Management of specific complications.
Complication	Management
Cyst haemorrhage	Usually self-limiting: bed rest, analgesia and increased fluid intake to prevent clot colic. Investigate if prolonged, and consider malignancy if atypical.
Cyst infection	Presents with fever, localised loin pain and tenderness, often with negative urine cultures because the cyst does not communicate with the collecting system.⁴ Requires lipophilic antibiotics that penetrate cysts - ciprofloxacin or co-trimoxazole - given for a prolonged course. Drainage may be needed for a large or refractory infected cyst.
Urinary tract infection	Treat promptly and consider imaging for stones or an infected cyst if recurrent
Renal calculi	High fluid intake, treat as per standard stone management; potassium citrate may help given the low urine pH and hypocitraturia
Chronic pain	A significant quality-of-life problem. Simple analgesia and neuropathic agents; avoid NSAIDs and be cautious with long-term opioids. Cyst aspiration or sclerosis, laparoscopic cyst decortication, renal denervation or (rarely) nephrectomy are options in refractory cases.
Hypertension	As above - ACE inhibitor or ARB first line
Progressive CKD	Managed as for CKD generally - anaemia, bone disease, acidosis and cardiovascular risk; note anaemia is often less severe than expected for the eGFR
End-stage renal disease	Transplantation is the treatment of choice. Native nephrectomy is sometimes required before or at transplantation if the kidneys are massive, leaving no room for the graft, or if there is recurrent infection, bleeding or intractable pain. Peritoneal dialysis is often less suitable because of the space occupied by enlarged kidneys and the increased hernia risk.

Genetic counselling and family screening

Explain the 50% inheritance risk to each child and offer referral for genetic counselling
Offer screening to first-degree relatives - though this must be a genuine choice, since a diagnosis in an asymptomatic young person has implications for insurance and employment as well as for health
Check blood pressure in all at-risk relatives, regardless of whether they choose imaging - this is a low-cost, high-value intervention
Discuss reproductive options including pre-implantation genetic diagnosis and prenatal testing
Screening children is generally avoided because there is no beneficial intervention in childhood, though blood pressure monitoring is appropriate

Complications

Progressive chronic kidney disease and end-stage renal disease
Hypertension and its consequences - left ventricular hypertrophy, heart failure and stroke
Subarachnoid haemorrhage from a ruptured berry aneurysm - the most feared complication
Cyst haemorrhage and haematuria
Cyst infection, pyelonephritis and recurrent urinary tract infection
Renal calculi
Chronic pain, with the attendant risks of long-term analgesic use
Hepatic cyst complications - infection, haemorrhage, mass effect and, rarely, portal hypertension
Diverticulitis
Hernias, which also complicate peritoneal dialysis
Cardiac valve disease and thoracic aortic dissection
Anaemia and renal bone disease as CKD advances (anaemia being milder than expected because of continued erythropoietin production)
Complications of pregnancy - increased risk of pre-eclampsia and hypertensive complications, so pre-pregnancy counselling and close monitoring are needed
Psychological burden - a hereditary progressive condition affecting multiple family members carries a substantial and under-addressed emotional impact

Red flags

Act on these

Sudden severe 'thunderclap' headache - assume subarachnoid haemorrhage from a ruptured berry aneurysm; urgent CT head and neurosurgical input
Fever with localised loin pain and tenderness, with or without a positive urine culture - suspect cyst infection; culture-negative infection is characteristic, and treatment needs a cyst-penetrating antibiotic such as ciprofloxacin for a prolonged course
Severe loin pain with haematuria - cyst haemorrhage or an obstructing stone; usually self-limiting but requires assessment and analgesia
Rapidly worsening renal function - look for obstruction, infection, a nephrotoxic drug (especially NSAIDs) or superimposed AKI
Heavy proteinuria - not typical of ADPKD; consider a coexisting glomerular disease
Uncontrolled hypertension in a young adult with a family history of kidney disease - consider ADPKD, and control the blood pressure rigorously to protect both kidney and aneurysm
Rising transaminases in a patient on tolvaptan - stop the drug; hepatotoxicity can be severe
Confusion or collapse in a patient on tolvaptan without free access to water - risk of severe dehydration and hypernatraemia from the obligatory aquaresis
A new focal neurological deficit or cranial nerve palsy - consider an expanding unruptured aneurysm
Planning peritoneal dialysis in a patient with massive kidneys or hernias - often unsuitable; discuss modality carefully

Prognosis

ADPKD is a slowly progressive disease with a course measured in decades, and the genotype is the strongest single determinant. Patients with PKD1 mutations reach end-stage renal disease at a median age of around 55 years, whereas those with PKD2 mutations do so around 70 years, and a proportion of PKD2 patients live a normal lifespan without ever needing renal replacement therapy.¹

Because compensatory hyperfiltration preserves eGFR for so long, creatinine is a poor early marker and typically only begins to fall in the fourth or fifth decade, by which time substantial parenchymal destruction has occurred. Total kidney volume measured on MRI rises much earlier and is the best predictor of future decline, which is why it is used to identify rapidly progressing patients who stand to benefit most from tolvaptan.

Features associated with faster progression include a PKD1 truncating mutation, hypertension developing before age 35, large total kidney volume for age, episodes of visible haematuria, male sex, and multiple pregnancies. Recognising these matters practically, since they select patients for disease-modifying therapy and closer surveillance.

Overall survival has improved considerably, and cardiovascular disease - not renal failure - is now the commonest cause of death, reflecting the early and sustained hypertension. Outcomes on renal replacement therapy are relatively good compared with other causes of end-stage renal disease, largely because these patients tend to be younger and have less diabetes and vascular disease; transplant outcomes are correspondingly favourable. With tolvaptan, rigorous blood pressure control and modern transplantation, the prognosis for a young person diagnosed today is considerably better than the historical figures suggest.

References

Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. The Lancet. Available here
Pei Y, Obaji J, Dupuis A et al. Unified criteria for ultrasonographic diagnosis of ADPKD. Journal of the American Society of Nephrology. 2009. Available here
NICE TA358. Tolvaptan for treating autosomal dominant polycystic kidney disease. 2015. Available here
UK Kidney Association. Clinical practice guidelines - autosomal dominant polycystic kidney disease. Available here
NICE Clinical Knowledge Summaries. Autosomal dominant polycystic kidney disease. Available here
Steven Fruitsmaak, CC BY-SA 3.0, via Wikimedia Commons. Available here

This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.