Polycystic Kidney Disease (ADPKD)

There are two major clinical forms

• Autosomal Dominant Polycystic Kidney Disease (ADPKD): This is the more prevalent form and typically manifests in adulthood. It is marked by progressive bilateral renal cyst formation and enlargement, often leading to end-stage renal disease (ESRD). ADPKD is also associated with extrarenal features including liver and pancreatic cysts, intracranial aneurysms, aortic root dilatation, mitral valve prolapse, and abdominal wall hernias.
• Autosomal Recessive Polycystic Kidney Disease (ARPKD): A rarer and typically more severe form that presents in infancy or childhood. It is associated with collecting duct dilatation and congenital hepatic fibrosis. In contrast to ADPKD, the kidneys in ARPKD may shrink over time due to fibrosis.

ADPKD is caused by mutations in several genes

• PKD1 (chromosome 16p13.3), encoding polycystin-1 – responsible for the majority of cases (~78%)
• PKD2 (chromosome 4q21), encoding polycystin-2 – found in ~15% of cases
• Rarely, mutations in genes such as GANAB, DNAJB11, ALG9, and others

 Genetic Basis and Major Causative Genes

• PKD1 and PKD2 are the principal genes implicated in ADPKD:
  • PKD1, located on chromosome 16p13.3, is responsible for approximately 78–85% of cases. It encodes polycystin-1 (PC1), a large membrane-bound glycoprotein involved in cell–cell and cell–matrix interactions and intracellular calcium regulation.
  • PKD2, located on chromosome 4q21–q22, accounts for 10–15% of cases. It encodes polycystin-2 (PC2), a member of the TRP (transient receptor potential) family of calcium-permeable ion channels.
• Polycystin-1 and Polycystin-2 interact to form a functional complex, predominantly localised to the primary cilium of renal epithelial cells. These proteins play a mechanosensory role, converting fluid shear stress from luminal flow into intracellular calcium signalling. Disruption of this pathway results in abnormal cell proliferation and fluid secretion, promoting cystogenesis.

Minor and Atypical Genetic Loci

• GANAB: Encodes the α-subunit of glucosidase II. Though accounting for only ~0.3% of cases, mutations may present with milder phenotypes (non-enlarged cystic kidneys with eventual atrophy). These cases may contribute to the pool of genetically unexplained ADPKD.
• DNAJB11: A rare cause (~0.1%) of atypical ADPKD, it encodes a co-chaperone involved in endoplasmic reticulum protein homeostasis. Associated phenotypes include normal-sized cystic kidneys and progressive interstitial fibrosis.
• ALG9, LRP5, HNF1B and others: These genes have been implicated in cases with atypical or blended phenotypes. For instance, dual mutations in PKD1 and HNF1B may present as an ADPKD-like syndrome with unique characteristics.

Genotype–Phenotype Correlation

• PKD1 truncating mutations are associated with earlier onset and more severe disease progression than non-truncating variants.
• Patients with PKD1 mutations typically require kidney replacement therapy (KRT) around the age of 53 years, whereas those with PKD2 mutations tend to progress more slowly, with KRT needed at a mean age of 74 years.
• Despite this, both genotypes may show wide inter- and intrafamilial phenotypic variability, influenced by modifier genes and possibly environmental or epigenetic factors.

Sporadic and Unresolved Cases

• A positive family history is absent in 10–25% of patients. This may result from:
  • Undocumented or misdiagnosed parental disease
  • Hypomorphic PKD1 variants leading to subclinical or late-onset disease
  • Early parental death before disease manifestation
  • De novo mutations or somatic/germline mosaicism
• Despite comprehensive gene panel sequencing, 10–15% of clinically suspected cases yield no detectable mutations in PKD1 or PKD2. These individuals may benefit from re-evaluation for rare or novel mutations, such as those in GANAB, or targeted testing for mosaicism.

Molecular Mechanisms

• Functional loss of PC1 or PC2 disrupts mechanosensory ciliary signalling, leading to decreased intracellular calcium and elevated cyclic AMP (cAMP) levels, which in turn stimulates abnormal epithelial proliferation and fluid secretion.
• The “two-hit hypothesis” applies, wherein a germline mutation in one allele is followed by a somatic mutation or loss of heterozygosity in a renal tubular epithelial cell, initiating cyst formation.

Cyst Initiation: The ‘Second Hit’ Hypothesis

• Individuals with ADPKD carry a germline mutation in either the PKD1 or PKD2 gene. However, cysts form only when a somatic mutation inactivates the wild-type allele in a subset of renal epithelial cells.
• This second somatic event triggers unregulated cell division and cyst formation, despite all nephron cells being genetically predisposed.
• The frequency and distribution of these somatic events correlate with disease severity.

Cystogenesis and Growth

• The initial cyst forms as an outpouching of the tubule wall, retaining communication with the tubular lumen. With progressive growth, most cysts lose this connection and continue to expand autonomously.
• Cyst fluid is derived from transepithelial secretion rather than glomerular filtration. This process is fuelled by:
  • Increased activity of chloride channels
  • Active sodium transport
  • Water influx via aquaporins
• Elevated cyclic adenosine monophosphate (cAMP) levels stimulate both epithelial proliferation and fluid secretion. Vasopressin plays a key role by promoting cAMP-mediated signalling pathways.

Renal Structural Changes and Progressive Dysfunction

• Cyst expansion compresses neighbouring nephrons and the intrarenal vasculature, causing:
  • Tubular atrophy
  • Formation of atubular glomeruli
  • Interstitial fibrosis
  • Progressive nephron loss
• Progressive cyst growth leads to markedly enlarged kidneys, loss of functional parenchyma, and eventual decline in glomerular filtration rate (GFR). The average annual GFR decline is estimated at 4.4 to 5.9 mL/min.

Polycystin Dysfunction and Ciliary Signalling

• PKD1 and PKD2 encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively—transmembrane proteins co-localised to the primary cilium of renal epithelial cells.
• This cilium functions as a mechanosensor. Bending from luminal fluid flow activates PC1, which interacts with PC2 to initiate a calcium influx.
• Disruption of this mechanosensory complex impairs intracellular calcium signalling, altering pathways that govern cell cycle regulation, apoptosis, and epithelial architecture.

Early Manifestations and Systemic Pathophysiology

• A decrease in urinary concentrating ability is one of the earliest clinical findings. It is accompanied by elevated vasopressin levels, which may further contribute to cystogenesis.
• Bleeding within cysts may occur due to abnormal angiogenesis. Fragile vessels lining cyst walls rupture easily with trauma or spontaneously, leading to cyst haemorrhage, pain, and potential rupture into the collecting system or retroperitoneum.
• Fibrosis within the renal interstitium develops early, accompanied by neovascularisation, macrophage infiltration, and thickening of tubular basement membranes.

Genotype–Phenotype Correlation and Disease Progression

• Mutations in PKD1 are associated with:
  • More numerous cysts
  • Larger kidneys
  • Earlier onset of end-stage renal disease (ESRD) (mean age ~55 years)
• In contrast, PKD2 mutations generally present with:
  • Fewer cysts
  • Later progression to ESRD (mean age ~79 years)
• Although the rate of kidney growth is similar between genotypes, individuals with PKD1 have more severe disease.

Comparative Notes on ARPKD

• Though not the focus of this topic, it is worth noting that autosomal recessive polycystic kidney disease (ARPKD) arises from cysts in the collecting ducts and is often accompanied by congenital hepatic fibrosis.
• In contrast to the progressive enlargement seen in ADPKD, ARPKD kidneys often shrink due to increasing fibrosis over time.

 Prevalence and Incidence

• ADPKD affects an estimated 4 to 7 million individuals worldwide.
• In North America and Europe, it accounts for 6–10% of individuals on kidney replacement therapy (KRT).
• The estimated carrier frequency ranges from 1 in 800 to 1,000 individuals.
• In the United States, average annual prevalence is estimated at 2.34 per 10,000, with an incidence of 3.06 per 100,000 person-years in some population studies.
• European reports show variation by region:
  • 3.96 per 10,000 in multi-country registries
  • 4.76 per 10,000 in Modena, Italy
  • 5.73 per 10,000 in parts of Germany by age 60
• In Japan, ADPKD-related end-stage kidney disease (ESKD) is less common, with rates of 5.6 per million males and 4.0 per million females.

Genetic and Clinical Distribution

• Approximately 85–90% of affected individuals have mutations in the PKD1 gene; most of the remaining cases are attributed to PKD2 mutations.
• While the disease can be detected early through imaging, symptoms typically present in the third to fourth decade of life.

Sex Differences and Age of Diagnosis

• Males generally experience a more aggressive disease course and earlier onset of ESKD.
• Females are more likely to be diagnosed in early adulthood, often due to incidental imaging findings during pregnancy.
• Cyst development may be observed in childhood, although progression to advanced renal dysfunction is rare before adulthood.

Disease Contribution to Kidney Failure

• ADPKD is the fourth leading cause of ESKD in the United States, after diabetes, hypertension, and glomerulonephritis.
• It accounts for approximately 7–15% of patients receiving dialysis or kidney transplantation.
• By the age of 70, around 50–75% of individuals with ADPKD will require KRT.

Geographical and Familial Variability

• Regional clustering due to founder effects can influence local prevalence.
• The disease burden may be underrecognised in areas lacking genetic testing or imaging infrastructure.
• Genetic testing and family-based screening have improved detection, particularly in asymptomatic relatives.

Sex-Based Extrarenal Manifestations

• Renal disease is more severe in males.
• Polycystic liver disease, an extrarenal manifestation, is more prominent in females and linked to hormonal influences such as oestrogen exposure.

Ethnic Disparities

• ESKD due to ADPKD is reportedly less common in African American populations compared to White populations, which may reflect underdiagnosis or differences in disease expression.

Improved Detection and Prognosis

• Earlier diagnosis through family screening and imaging has led to delayed onset of ESKD and reduced mortality.
• Blood pressure control and targeted therapy have further contributed to slowing disease progression.

 Pain-Related Symptoms

• Flank, abdominal, or back pain is the most frequent presenting symptom.
  • Pain may stem from cyst enlargement, haemorrhage, infection, nephrolithiasis, or less commonly, malignancy.
  • Dull aching is often associated with hepatomegaly due to polycystic liver disease.
  • Rarely, pain arises from cyst rupture or retroperitoneal haemorrhage, often accompanied by nausea or severe discomfort.

Haematuria

• Macroscopic (gross) haematuria may be the first symptom.
  • Commonly caused by cyst haemorrhage, especially when cysts communicate with the collecting system.
  • Episodes are usually self-limiting but may recur and lead to anxiety or anaemia.
  • Mild trauma can precipitate significant intrarenal bleeding or retroperitoneal extension.

Urinary Tract Infections (UTIs)

• UTIs are common and may involve the bladder, renal parenchyma, or cysts.
  • Typical symptoms include dysuria, fever, and suprapubic or flank pain.
  • Recurrent infections suggest underlying cyst involvement.
  • Common pathogens include E. coli, Klebsiella, and Proteus species.

Nephrolithiasis

• Renal stone disease occurs in 20–25% of patients.
  • Stones are usually composed of uric acid or calcium oxalate.
  • Contributing factors include low urinary volumes, stasis, hypocitraturia, and reduced urinary magnesium.
  • Diagnosis may be difficult due to cyst wall calcifications; unenhanced CT is preferred.

Hypertension

• Often the earliest and most consistent clinical sign, sometimes predating renal dysfunction by years.
  • Typically presents between ages 30–34.
  • Associated with microalbuminuria, proteinuria, and increased risk of cardiovascular morbidity and mortality.
  • A history of early-onset hypertension may be the only early indicator in some families.

Renal Dysfunction

• Glomerular filtration rate (GFR) may decline rapidly once impairment begins, with average annual loss of 4–5 mL/min.
  • Predictive factors include male sex, early-onset hypertension, PKD1 genotype, proteinuria, and increased total kidney volume.

Extrarenal Manifestations

• Liver cysts are highly prevalent and increase with age; most individuals over 35 years have some degree of hepatic involvement.
  • Symptoms may include fullness, discomfort, early satiety, or pain if cysts become infected or rupture.
  • Polycystic liver disease is more common and severe in women, especially those with multiple pregnancies or oestrogen exposure.
• Pancreatic cysts occur in 7–36% of cases, more often with PKD2 mutations.
• Cardiovascular manifestations:
  • Include mitral valve prolapse, aortic regurgitation, coronary aneurysms, and congenital anomalies.
  • Intracranial aneurysms occur in up to 6% of patients without, and 16% with, a family history of aneurysms or subarachnoid haemorrhage.
  • A history of unexplained or atypical headaches should prompt further investigation.
• Gastrointestinal issues:
  • Colonic diverticulosis is frequent, particularly in end-stage kidney disease.
  • Symptomatic diverticulitis is more common in this population.
• Hernias:
  • Inguinal, umbilical, and incisional hernias are often reported, sometimes preceding the diagnosis of renal disease.

Constitutional and Non-Specific Symptoms

• Fatigue, breathlessness, generalised malaise, and weakness may occur even in early disease stages.
  • These symptoms often reflect the cumulative burden of hypertension, anaemia, and early renal dysfunction.

Family History

• A positive family history is a key diagnostic criterion.
  • Absence does not exclude the diagnosis due to the possibility of de novo mutations (occurring in 10–15% of cases), incomplete penetrance, unrecognised disease in a parent, or early parental death.
• Family history of cerebrovascular events, especially subarachnoid haemorrhage, may indicate a higher risk of intracranial aneurysms.

Screening Triggers from History

• Early-onset hypertension, especially in individuals with a family history of ADPKD or ESRD.
• History of gross haematuria, recurrent flank pain, or renal calculi.
• Positive family history of intracranial aneurysms or sudden death.
• Recurrent UTIs or antibiotic-resistant cyst infections.

 Cardiovascular Examination

• Hypertension is often the earliest and most consistent clinical finding, sometimes present even before renal impairment is evident.
  • Detected in 50–75% of patients at initial presentation.
  • Typically presents with elevated diastolic blood pressure.
  • Often more severe early in the disease course, diminishing as renal insufficiency progresses.
  • Associated with increased risk of left ventricular hypertrophy and cardiovascular morbidity.
• Cardiac murmurs may indicate:
  • Mitral valve prolapse or mitral/aortic regurgitation.
  • Aortic root dilation is also a recognised feature.
  • These findings are common and should prompt echocardiographic evaluation.

Abdominal Examination

• Palpable kidneys are a hallmark in advanced ADPKD.
  • Kidneys are typically bilaterally enlarged, nodular, and may occupy a significant portion of the abdominal cavity.
  • Palpation may elicit discomfort or pain.
• Abdominal mass may be present due to:
  • Massive polycystic kidneys
  • Hepatomegaly from polycystic liver disease
• Hepatomegaly occurs particularly in patients with extensive hepatic cysts.
  • Liver enlargement may be nodular and asymmetrical.
  • More common and more voluminous in women, particularly those with multiple pregnancies or prior oestrogen use.
• Abdominal wall hernias such as:
  • Inguinal
  • Umbilical
  • Incisional hernias
  • These are common due to increased intra-abdominal pressure from massively enlarged kidneys or liver.

Urinary and Systemic Signs

• Fever in the presence of flank tenderness may suggest cyst infection or pyelonephritis.
  • UTIs are common and often present with suprapubic tenderness or costovertebral angle tenderness on percussion.
• Signs of advanced chronic kidney disease (CKD), though uncommon at initial presentation, may include:
  • Pallor
  • Dry, sallow skin
  • Peripheral oedema
  • Uraemic fetor

Neurological Signs

• Headache should raise suspicion of underlying intracranial aneurysm, particularly if:
  • New in onset
  • Atypical in character
  • Accompanied by neurological symptoms
• These patients may require neuroimaging depending on risk stratification (e.g., family history of aneurysm or previous subarachnoid haemorrhage).

Additional Observations in Specific Subgroups

• Children with ADPKD may exhibit:
  • Mild hypertension detectable on routine examination
  • Proteinuria if urine is tested
  • Palpable kidneys in some cases

Imaging as a Complementary Diagnostic Tool

• Although not part of the physical exam per se, imaging findings often correlate with examination signs:
  • Renal ultrasound may reveal multiple bilateral cysts
  • CT or MRI may be necessary for further characterisation, especially in cases with atypical features or negative family history

Initial Clinical Evaluation

• Diagnosis is often suspected based on clinical context—positive family history, hypertension, or early-onset renal insufficiency in the presence of multiple bilateral renal cysts.
• A thorough history should screen for complications like intracranial aneurysm, subarachnoid haemorrhage, end-stage renal disease (ESRD), and polycystic liver disease.
• Physical examination may reveal palpable kidneys or hepatomegaly and detect signs of hypertension or cardiac murmurs from valvular anomalies.

Imaging Modalities

Ultrasonography

• Primary diagnostic modality, particularly in at-risk individuals due to its availability, safety, and cost-effectiveness.
• Sensitivity for detecting PKD1-related disease in adults is high, but lower for PKD2.

Original Ravine criteria

• Age 15–29: ≥2 cysts (unilateral or bilateral)
• Age 30–59: ≥2 cysts in each kidney
• Age ≥60: ≥4 cysts in each kidney

Modified Pei criteria 

• More inclusive of PKD2 variants
• Age 15–39: ≥3 cysts total (unilateral or bilateral)
• Age 40–59: ≥2 cysts in each kidney
• Age ≥60: ≥4 cysts in each kidney
• Presence of fewer than 2 cysts in individuals >40 years has a negative predictive value of 100%

CT and MRI

• More sensitive than ultrasound and useful in selected situations
• CT detects cysts as small as 0.5 cm; ideal for complex cysts, nephrolithiasis, or suspected renal malignancy
• MRI is superior for assessing total kidney volume (TKV), which guides prognostication and therapy planning (e.g. tolvaptan initiation)
• eTKV (ellipsoid method) is a rapid MRI-based estimate of TKV and suitable for monitoring progression

Magnetic Resonance Angiography (MRA)

• Preferred method for detecting intracranial aneurysms
• Especially used in high-risk individuals:
  • Family history of aneurysm or stroke
  • Prior to major surgery
  • High-risk occupations
  • Unexplained headaches

Laboratory Investigations

Standard blood tests

• Serum creatinine and estimated glomerular filtration rate (eGFR)
• Electrolytes: potassium, calcium, phosphorus
• Uric acid, intact parathyroid hormone, and vitamin D
• Lipid profile—elevated lipids may be associated with disease progression
• Complete blood count—elevated haematocrit can result from ectopic erythropoietin production

Urinalysis

• Microalbuminuria occurs in ~35% of patients, often with hypertension
• Nephrotic-range proteinuria is rare
• Haematuria and leukocyturia may be present
• Sterile pyuria can occur due to non-communicating cyst infections
• Urine cultures should be obtained in symptomatic cases

C-reactive protein

• May support diagnosis of cyst infection in febrile patients with abdominal or flank pain

24-hour urine collections

• For recurrent nephrolithiasis
• Assesses urine pH, citrate, oxalate, sodium, calcium, phosphate, uric acid, and volume
• Low urine citrate and acidic urine are key risk factors for stone formation

Genetic Testing

Indications include

• Young individuals with negative imaging but positive family history, especially in context of living kidney donation or family planning
• Absence of family history with a phenotype suggestive of ADPKD
• Clinical discordance (e.g. unusually early or mild disease)
• Differential diagnosis includes other cystic diseases

Additional genetic notes

• Sequencing of PKD1 and PKD2 identifies pathogenic variants in ~85–90% of affected individuals
• Broader panels may include GANAB, DNAJB11, ALG9, and others in atypical cases
• Whole-exome sequencing is emerging, especially where pseudogene interference complicates PKD1 analysis
• All mutation data are curated in the publicly accessible ADPKD Variant Database

Screening for Extrarenal Manifestations

Intracranial aneurysms

• MRI or CT angiography indicated based on family history or neurological symptoms

Cardiac anomalies

• Echocardiography or cardiac MRI evaluates mitral valve prolapse, aortic root dilatation, and congenital defects

Hepatic and pancreatic cysts

• Detected on ultrasound or MRI
• Liver cysts are near-universal in patients >35 years
• Pancreatic cysts are generally asymptomatic but can rarely be associated with malignancy

Nephrolithiasis

• Seen in ~20% of patients
• Stones are typically uric acid or calcium oxalate
• Dual-energy CT helps differentiate stone composition

Approach in Asymptomatic At-Risk Children

• Routine ultrasonography and genetic testing are generally deferred until adolescence unless early diagnosis is required for psychological, clinical, or reproductive reasons
• Blood pressure monitoring should begin by age 2 and continue biennially

Diagnostic Strategy

• Confirm diagnosis via imaging, supported by clinical features and family history
• Stratify risk using kidney volume measurements and genotype (PKD1-associated disease tends to progress faster than PKD2)
• Use laboratory studies to assess renal function, identify early complications, and guide monitoring
• Reserve genetic testing for situations where imaging is inconclusive or family history is absent

Inherited Disorders

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

• Presents in neonates or early childhood.
• Features include enlarged echogenic kidneys, congenital hepatic fibrosis, and portal hypertension.
• Progresses to renal failure in childhood or adolescence.
• Family history typically negative due to recessive inheritance.

 Tuberous Sclerosis Complex (TSC)

• Multisystem disorder with characteristic dermatological findings: facial angiofibromas, shagreen patches, hypomelanotic macules, and subungual fibromas.
• Renal findings include cysts, angiomyolipomas, and renal cell carcinoma.
• Neurological involvement (e.g. cortical tubers, subependymal nodules, and astrocytomas) is common.
• Genetic testing for TSC1 or TSC2 mutations confirms diagnosis.

Von Hippel–Lindau Syndrome (VHL)

• Autosomal dominant disorder characterised by:
  • CNS and retinal haemangioblastomas
  • Renal cell carcinoma
  • Pancreatic and epididymal cysts
  • Phaeochromocytomas
• VHL gene mutation testing is diagnostic.

HNF1B-Related Disorders (e.g., MODY5)

• Heterogeneous renal phenotypes including cysts, hypoplastic kidneys, and maturity-onset diabetes of the young (MODY).
• Associated with genital tract malformations, pancreatic hypoplasia, early-onset gout, and abnormal liver enzymes.
• HNF1B mutation testing is diagnostic.

Medullary Cystic Kidney Disease / Uromodulin-Associated Kidney Disease

• Autosomal dominant tubulointerstitial nephropathy.
• Small kidneys with corticomedullary cysts.
• Gout and progressive renal failure common.
• UMOD or MUC1 gene mutation analysis may confirm diagnosis.

Bardet-Biedl Syndrome

• Rare ciliopathy involving:
  • Retinal dystrophy
  • Obesity
  • Polydactyly
  • Cognitive impairment
  • Hypogonadism
  • Renal abnormalities including cysts
• Renal disease is variable and not pathognomonic.

Orofaciodigital Syndrome Type I (OFD1)

• X-linked dominant disorder, often lethal in males.
• Facial anomalies, oral clefts, and digital malformations.
• PKD occurs in <50% of cases.
• OFD1 gene mutation testing confirms diagnosis.

HANAC Syndrome (Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps)

• Due to COL4A1 mutations.
• Features include cerebral aneurysms, haematuria, renal cysts, and muscle cramps.
• MRI may show leukoencephalopathy.

Developmental and Acquired Cystic Diseases

Medullary Sponge Kidney

• Congenital disorder with tubular ectasia confined to medullary pyramids.
• Strongly associated with nephrocalcinosis, nephrolithiasis, and urinary tract infections.
• CT shows sparing of the renal cortex.

 Acquired Cystic Kidney Disease (ACKD)

• Occurs in patients with chronic kidney disease or dialysis.
• Small, shrunken kidneys with numerous cysts.
• Higher risk of renal cell carcinoma.
• No family history; cysts develop over time.

Localised Cystic Disease of the Kidney

• Unilateral, non-genetic cystic disease affecting a segment of one kidney.
• Asymptomatic, benign, and non-progressive.
• Family history absent; no risk of renal failure.

Simple Renal Cysts

• Extremely common with advancing age.
• Usually asymptomatic, non-progressive.
• Characterised on ultrasound by smooth margins, anechoic centre, and posterior acoustic enhancement.
• Bosniak classification helps stratify complex cysts.

Parapelvic Cysts

• Located in the renal sinus, can mimic hydronephrosis.
• Usually solitary and do not involve the renal cortex.
• Distinguishable on imaging.

Therapeutic Goals and General Principle

• The overarching aim of ADPKD management is to delay kidney function decline, prolong survival, and address disease-related complications.
• All patients are advised to adopt renoprotective lifestyle practices, including maintaining optimal weight, engaging in regular cardiovascular exercise, avoiding smoking, and achieving early, aggressive blood pressure control.
• Lipid control with target LDL cholesterol ≤2.59 mmol/L is recommended to reduce cardiovascular risk.
• Monitoring disease progression uses imaging, renal function decline, and genetic markers, as phenotypic expression varies significantly across patients.

Prognostic Tools and Criteria for Progression

• Mayo Clinic imaging classification (classes 1A–1E) helps stratify patients by total kidney volume (TKV). Classes 1C–1E are considered high-risk.
• Indicators of rapid progression:
  • Early-onset hypertension (<35 years)
  • First urological event (e.g., haematuria, cyst infection) before age 35
  • Annual TKV growth ≥5%
  • Truncating PKD1 mutations
  • Estimated GFR decline ≥5 mL/min/1.73 m² in 1 year or ≥2.5 mL/min/1.73 m² per year over 5 years
  • Presence of albuminuria

Disease-Modifying Therapy: Tolvaptan

• Tolvaptan, a vasopressin V2-receptor antagonist, lowers cyclic AMP in renal collecting ducts, slowing cyst growth and kidney enlargement.
• It is indicated for adults with rapidly progressing ADPKD and has been shown to reduce the rate of kidney volume increase and GFR decline (e.g., TEMPO 3:4, REPRISE trials).
• Monitoring for hepatotoxicity is mandatory. Liver enzymes must be checked at baseline, then biweekly during the first month, monthly up to 18 months, and quarterly thereafter.
• Adverse effects include polyuria, thirst, nocturia, and elevated liver enzymes. It is contraindicated with CYP3A4 inhibitors.

Hypertension Management

• First-line therapy: ACE inhibitors or angiotensin II receptor blockers (ARBs), offering both reno- and cardioprotective benefits.
• HALT-PKD trials demonstrated that intensive BP control (95/60 to 110/75 mmHg) slows kidney volume expansion.
• Additional options tailored to comorbidities:
  • Beta-blockers for coronary artery disease or arrhythmias
  • Combined alpha-/beta-blockers for heart failure
  • Diuretics in fluid overload
  • Avoid routine use of calcium-channel blockers

Treatment of Complications

Urinary Tract Infections (UTIs)

• Prompt treatment is critical
• Recurrent or complicated infections warrant imaging and possibly prophylactic antibiotics during instrumentation

Infected Cysts

• Preferred agents: fluoroquinolones or trimethoprim-sulfamethoxazole (good cyst penetration)
• Drainage required for large (>5 cm) or refractory cysts
• Nephrectomy in severe, unresponsive cases

Renal Pain

• Bed rest and avoidance of nephrotoxic drugs
• Paracetamol or opioids for acute pain; NSAIDs short-term only if renal function preserved
• For persistent pain: cyst aspiration, laparoscopic fenestration, or renal denervation

Cyst Haemorrhage

• Usually self-limiting; severe cases may require transfusion or embolisation

Gross Haematuria

• Conservative management includes increased fluid intake and rest
• Persistent haematuria necessitates exclusion of other pathology

Nephrolithiasis

• ADPKD predisposes to uric acid and calcium oxalate stones
• Preventative strategies
  • High fluid intake
  • Potassium citrate supplementation
  • Urinary alkalinisation
• Interventions
  • Shock wave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy depending on stone type and location

Polycystic Liver Disease

• Liver cysts are common but usually asymptomatic
• Symptomatic cases may benefit from cyst drainage or surgical fenestration
• Infected cysts require antibiotics; severe cases may need resection or liver transplantation

Intracranial Aneurysms

• Risk-based screening: consider in patients with a family history of aneurysms, or prior rupture
• Small anterior circulation aneurysms (<7 mm) can be monitored; larger or symptomatic aneurysms require neurosurgical intervention

Renal Failure and Replacement Therapies

• Close monitoring from CKD stage 3 onwards, with optimal management of hypertension and hyperlipidaemia
• When GFR <30 mL/min/1.73 m² (CKD stage 4), preparation for renal replacement therapy begins
• Renal transplantation is the preferred treatment for end-stage renal disease (ESRD) in ADPKD; living donor grafts are ideal

Dialysis

• Haemodialysis preferred over peritoneal dialysis due to large kidney size and risk of complications
• Patients often maintain better haematocrit levels compared to other causes of ESRD

Emerging and Investigational Therapies

• Metformin: Early trials show safety and a trend towards slower GFR decline
• Somatostatin analogues (e.g., octreotide): May reduce liver volume but have minimal impact on renal function
• CFTR inhibitors: Being explored as potential anti-cystic agents in preclinical studies
• Glucosylceramide synthase inhibitors: Reduce cystogenesis in animal models
• Curcumin: May reduce inflammation and cell proliferation; under investigation

 Renal Function Decline and Survival Estimates

• The decline in glomerular filtration rate (GFR) generally begins after significant renal enlargement, with kidneys often appearing grossly distorted and devoid of normal parenchyma on imaging.
• The average GFR decline is estimated at 4.4 to 5.9 mL/min per year once progression begins.
• By age 50, approximately 77% of individuals maintain preserved renal function; this declines to about 52% by age 73.
• Males are more likely to experience faster progression to ESKD and require RRT earlier than females.

Risk Factors for Disease Progression

• Genotype: PKD1 mutations, particularly truncating variants, are associated with more aggressive disease than PKD2 mutations.
• Kidney size: Larger total kidney volume strongly predicts faster progression.
• Early onset clinical markers:
  • Hypertension before age 35
  • First episode of gross haematuria, flank pain, or urinary tract infection before age 35
• Infection: Frequent or severe kidney infections increase the risk.
• Demographics: Male sex, multiple pregnancies, and individuals of Black racial background are associated with a worse prognosis.

Genotype-Phenotype Correlation

• PKD1 mutations: Median age of ESKD onset is around 56 years.
• PKD2 mutations: Median age of ESKD onset is later, at approximately 68 years.
• Although PKD2 is milder, it still shortens overall life expectancy.

Mortality and Morbidity

• The leading causes of death in patients undergoing dialysis or post-transplant are cardiovascular disease and infection, accounting for approximately 90% of mortality.
• A rarer but serious cause of death is subarachnoid haemorrhage due to rupture of intracranial aneurysms.

Prognostic Tools

• Mayo Imaging Classification: Categorises patients (Classes 1A to 1E) based on total kidney volume and age; classes 1C to 1E predict more rapid progression and are used to guide tolvaptan eligibility.
• PROPKD Score: A predictive model integrating genotype and early clinical events:
  • Male sex: 1 point
  • Hypertension before 35 years: 2 points
  • First urological event before 35 years: 2 points
  • Non-truncating PKD1 mutation: 2 points
  • Truncating PKD1 mutation: 4 points
  • PKD2 mutation: 0 points
• Score Interpretation:
  • 0–3 points: Low risk (median RRT age ~70.6 years)
  • 4–6 points: Intermediate risk (~56.9 years)
  • 7–9 points: High risk (~49 years)
• A score ≤3 is associated with an 81.4% negative predictive value for progression to ESKD before age 60, while a score >6 has a 90.9% positive predictive value for progression before that age.

Life Expectancy

• Average life expectancy ranges between 53 and 70 years.
• Studies show ESKD onset in 25% of patients by age 47, 50% by age 59, and up to 75% by age 70.
• For individuals with stage IV chronic kidney disease, the best outcomes are associated with early planning and pre-emptive kidney transplantation from a living donor.

 Renal Complications

Progressive Kidney Failure

•  The most common complication of ADPKD, with many patients developing ESKD requiring dialysis or renal transplantation, typically between the fourth and sixth decades of life.

Nephrolithiasis

•  Kidney stone formation is seen in 20–25% of patients. Uric acid and calcium oxalate are the most frequent types. 
• Stone formation is facilitated by low urinary citrate, acidic pH, and urinary stasis due to distorted renal anatomy.

Infected Renal Cysts

•  Present with fever, flank pain, and elevated inflammatory markers. Diagnosis may require cross-sectional imaging, and cyst aspiration is performed where feasible. 
• Fluoroquinolones are often used due to superior cyst penetration.

Cyst Haemorrhage

•  Can lead to gross haematuria and perinephric haematomas. 
• Most episodes are self-limiting, but serious bleeding may require hospitalisation, imaging, embolisation, or rarely nephrectomy.

Hypertension

•  Early onset and often the first clinical sign of disease. Contributes to cardiovascular morbidity and accelerates renal deterioration.

Cardiovascular Complications

Left Ventricular Hypertrophy (LVH)

•  Present in up to half of hypertensive ADPKD patients before reaching ESKD. Increases the risk of major cardiovascular events.

Valvular Abnormalities

• Commonly include mitral valve prolapse, mitral and aortic regurgitation, and tricuspid valve abnormalities.
• These typically do not require surgical intervention but may be detected on auscultation.

Aortic Root Dilation and Pericardial Effusion

•  These structural abnormalities are more frequent in ADPKD than in the general population. 
• Echocardiography is reserved for symptomatic patients or those with audible murmurs.

Primary Cause of Mortality

•  Cardiovascular disease remains the leading cause of death in this patient population, underscoring the importance of early blood pressure management and cardiovascular risk reduction.

Neurological Complications

Intracranial Aneurysms (ICAs)

•  Occur in approximately 6–10% of patients and are four times more prevalent than in the general population. 
• The risk is further increased in those with a personal or family history of cerebral aneurysm or subarachnoid haemorrhage (SAH), female sex, and advancing age.

Subarachnoid Haemorrhage

•  A life-threatening event that may occur if an ICA ruptures. Screening is indicated in high-risk individuals. 
• Sentinel headaches or new, severe headaches should always prompt investigation.

Hepatic and Gastrointestinal Complications

Polycystic Liver Disease

•  Seen in over 50% of patients over 60 years. Often asymptomatic but may cause hepatomegaly, abdominal discomfort, or complications from cyst haemorrhage or infection. 
• Liver function usually remains preserved.

Gastro-Oesophageal Reflux Disease (GORD)

•  May result from liver enlargement and abdominal mass effect. Symptomatic treatment includes proton pump inhibitors or H2 antagonists.

Diverticular Disease

•  There is a recognised association between ADPKD and colonic diverticulosis. 
• Patients, particularly those on dialysis, are at higher risk of complications such as diverticulitis or perforation.

Infectious Complications

Sepsis

•  May occur from cyst infection. If a bacteraemic patient has negative urine cultures, an infected renal or hepatic cyst should be suspected. Imaging and cyst aspiration guide diagnosis and treatment.

Pregnancy-Related Complications

Hypertensive Disorders of Pregnancy

•  Gestational hypertension, pre-eclampsia, and oedema are more common in pregnant women with ADPKD.

Foetal and Maternal Outcomes

•  Women with elevated pre-pregnancy serum creatinine (≥106 µmol/L or ≥1.2 mg/dL) are at increased risk. 
• Approximately 16% of women with ADPKD develop new-onset hypertension during pregnancy, and up to 25% experience hypertensive complications.

Chronic Hypertension

•  Pregnancy can unmask or exacerbate chronic hypertension, increasing long-term cardiovascular and renal risks. 

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