Approach
The goals of treatment are to prolong life, prolong time to development of kidney failure, and manage disease symptoms and complications.
Renoprotective strategies for all patients are healthy lifestyle choices (maintenance of optimal weight, regular cardiovascular exercise, avoidance of smoking) and early detection and rigorous treatment of hypertension.[1][4] A serum low-density lipoprotein (LDL)-cholesterol level ≤2.59 mmol/L (≤100 mg/dL) is recommended for optimised treatment of autosomal-dominant PKD (ADPKD).[35]
The disease-modifying agent tolvaptan is now widely available for use to slow kidney function decline and is indicated in adults at risk of rapidly progressing ADPKD.[69]
There is international variance in guidance for the assessment of the risk of ADPKD progression.[69][70] ADPKD has significant genetic and phenotypic heterogeneity, even within affected families.[70][71] Variability in the kidney phenotype ranges from mild chronic kidney disease at an old age to kidney failure at a young age.[69] Markers to predict progression include:[2][44][56][69][70]
Clinical factors: onset of hypertension before 35 years of age; first urological event (gross haematuria, flank pain, or cyst infection) before 35 years of age
Radiological factors: total kidney volume growth ≥5% per year; Mayo Clinic imaging class 1C to 1E
Genetic factors: truncating PKD1 mutation
Laboratory factors: confirmed estimated glomerular filtration rate (GFR) decline ≥5 mL/minute/1.73 m² within 1 year or average annual estimated GFR decline of ≥2.5 mL/minute/1.73 m² over a period of 5 years; albuminuria.
The Mayo Clinic imaging classification is a commonly used prognostic tool.[44] In patients with ADPKD with disease in Mayo Clinic imaging classes 1C to 1E, rapid disease progression is likely and treatment with tolvaptan is indicated.[35][70]
Tolvaptan, a selective vasopressin V2-receptor antagonist, lowers cyclic adenosine monophosphate (cAMP) concentrations in the distal nephron and collecting duct, the major site of cyst development in ADPKD, and inhibits the development of PKD.[72] In a large randomised trial, tolvaptan slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in individuals with early-stage ADPKD compared with placebo, but was associated with a higher discontinuation rate owing to adverse events.[73] Tolvaptan also resulted in a slower decline in estimated GFR than placebo in patients with later-stage ADPKD.[74]
Managing ADPKD symptoms and complications
Hypertension
Target blood pressure (BP) should be guided by the HALT polycystic kidney disease trials, which examined BP control in early and late ADPKD in 2 separate randomised controlled trials.[75][76]
One of the studies compared rigorous BP control (i.e., 95/60 mmHg to 110/75 mmHg) with standard BP control (i.e., 120/70 mmHg to 130/80 mmHg) using an ACE inhibitor and/or angiotensin-II receptor antagonist in patients with ADPKD aged 15 to 49 years who were at risk of progressing to end-stage renal disease. The study found that the annual percentage increase in total kidney volume was lower in the rigorous BP control group (i.e., 95/60 mmHg to 110/75 mmHg). The rate of change in estimated GFR was similar in both groups. Left-ventricular-mass index and urinary albumin excretion was reduced in the rigorous BP control group.[75] In a study of patients with more advanced chronic kidney disease (i.e., GFR 25-60 mL/minute), monotherapy with an ACE inhibitor is associated with good BP control in most patients.[76] Evidence does not support the use of dual angiotensin blockade in patients with ADPKD.[75][76]
First-line drug therapy should be with either an ACE inhibitor or an angiotensin-II receptor antagonist.[1] Use of these drug classes increases renal plasma flow in these patients and offers cardioprotective and renoprotective effects in early ADPKD.[77][78]
Choice of drug therapy should also be tailored to comorbidities.[31] Beta-blockers (useful in patients with hypertension and coronary artery disease, or in those with hypertension and cardiac arrhythmias), combined alpha- and beta-blockers (useful in patients with cardiac failure and ADPKD), and diuretics (useful in ADPKD patients with volume overload) are all good second-line options. Non-cardioselective beta-blockers with selective alpha-blocking properties (e.g., labetalol or carvedilol) are preferred over beta-blockers. Beta-blockers may be the first choice in the patient with an abdominal aortic aneurysm. In most cases diuretics are not needed to control hypertension in this patient group. Calcium-channel blockers are not considered antihypertensives of choice.
Urinary tract infections
Urinary tract infections have increased morbidity in patients with ADPKD; therefore, they should all be treated promptly according to cultures and current treatment guidelines. See our topics Urinary tract infection in women, Urinary tract infection in men, and Urinary tract infection in children.
If the infection relapses after completing antibiotic therapy, complications such as obstruction, cyst infection, or infected stone need to be excluded. When unavoidable, urinary tract instrumentation should be done under prophylactic antibiotic coverage before, and for 24 hours after, the procedure.
Infected renal cysts
Infected renal cysts should be treated with antibiotics first-line.[79] Fluoroquinolones accumulate in cysts and are considered the antibiotics of choice.[31][79] Fluoroquinolones have been associated with serious, disabling, and potentially irreversible adverse effects, including tendonitis, tendon rupture, arthralgia, neuropathies, and other musculoskeletal or nervous system effects.[80] Warnings have also been issued about the increased risk of aortic dissection, significant hypoglycaemia, and mental health adverse effects in patients taking fluoroquinolones.[81][82] Trimethoprim/sulfamethoxazole also has good cyst penetration and may be a second-line option.[31] A longer course of antibiotics may be needed to adequately treat these patients, for up to 6 weeks.
Percutaneous or surgical cyst drainage should be considered if there is no prompt response to treatment with antibiotics or presence of large cyst >5 cm where there is high index of suspicion of cyst infection.[83]
Severe infections that are resistant to drainage and/or antibiotic therapy may require nephrectomy.[1]
Renal pain
Abdominal discomfort and flank pain occur in up to 60% of patients and may have varying aetiology.[1] Cyst haemorrhage, renal infection, nephrolithiasis, and tumours are causes of renal pain and should be excluded before treatment is initiated. A stepwise approach to pain management is recommended in patients where no reversible cause can be found, such as cyst rupture or haemorrhage.
First-line therapy for all causes of pain is bed rest. Long-term administration of nephrotoxic drugs should be avoided. The second-line option is analgesic therapy including paracetamol or opioid analgesics for acute or severe pain. Despite the risk of nephrotoxicity, non-steroidal anti-inflammatory drugs may be used for short periods of time to treat acute pain in patients with good renal function. Adjuvant therapies including tricyclic antidepressants, gabapentin, or pregabalin may also be tried.
Pain related to cyst rupture tends to be localised. Surgery can be considered for the management of cyst complications when conservative measures fail. Cysts are aspirated under computed tomographic guidance, with sclerosing drugs used in some patients to prevent fluid reaccumulation. If there are multiple cysts, laparoscopic or surgical cyst fenestration or decortication may be used.[84] Despite a potential role in blood pressure management, cyst decortication has not been definitively shown to alleviate hypertension in patients with ADPKD. Renal function also does not appear to improve following surgery. Patients with compromised baseline renal function appear to be at an increased risk of further deterioration in renal function after cyst decortication. Improvement in pain symptoms appears to be transient, lasting only weeks to months. Therefore, repeat procedures or alternative approaches may be necessary.[85] Laparoscopic or thoracoscopic renal denervation is considered in some situations.[86]
Cyst haemorrhage is usually self-limiting and responds to conservative measures in an outpatient setting. Patients should be hospitalised if there is a serious episode of cyst haemorrhage from a renal or hepatic cyst. Haemoglobin should be monitored and, if haematocrit drops, transfusion, computed tomographic angiogram, or embolisation may be required.
Laparoscopic or retroperitoneoscopic unilateral or bilateral nephrectomy is used very rarely; it is an option reserved for patients with renal pain who have end-stage renal disease (ESRD) or in preparation for patients who meet criteria for renal transplant.
Gross haematuria is alarming to patients and they should be reassured. The patients should be advised to stay off work, drink large volumes of fluid, and avoid physical activity. If haematuria persists they should be medically evaluated. New onset of painless gross haematuria in older people may require additional evaluation to rule out other pathologies.
Nephrolithiasis
Stone type influences management, but potassium citrate is indicated for 3 types of stones seen in ADPKD: uric acid stones, hypocitraturic calcium oxalate nephrolithiasis, and distal acidification defects.[31][87]
Urology evaluation may be necessary for symptomatic stones. Extracorporeal shock wave lithotripsy (SWL) and percutaneous nephrolithotomy (PCNL) can often be performed without a greatly increased risk of complications.[1] The passage of stone fragments may be impaired in ADPKD patients following lithotripsy. Flexible ureteroscopy with laser fragmentation may also be considered.[1] The choice of intervention in patients with ADPKD depends on several factors, including location of the renal stone within the urinary tract, the clinical presentation (and its urgency), stone characteristics, and other complicating co-existing or intercurrent factors.[88][89] In one review, the postoperative complication and stone-free rates of SWL, PCNL, and ureteroscopy interventions were highly variable, in part due to the quality of the primary studies. As such, comparisons between patients with ADPKD and the general population are limited.[90]
Adequate fluid intake is recommended for prophylaxis of stones. See our topic Nephrolithiasis for further details.
Polycystic liver disease
Most patients will have liver cysts, but only a minority will be symptomatic.[37] Most cases do not require treatment. Patients should avoid oestrogens and compounds that lead to cAMP accumulation.
Symptomatic patients may need interventions to reduce cyst volume and liver size (e.g., cyst drainage, liver resection with cyst fenestration).[37] Choice of procedure is dictated by anatomy and cyst distribution. Antibiotics are required in patients with infected cysts (diagnosis of hepatic cyst infection may be aided by positron emission tomography scan).[1][57] Long-term suppression therapy may be required in selected patients. Patients with severe disease should be referred to a specialty centre for liver resection or transplant.
Intracranial aneurysm
Size, location, morphology, age of the patient, and their general health will determine management. Recommendation to intervene depends on size, site, and morphology; history of subarachnoid haemorrhage from other aneurysm; and feasibility to coil or clip.[91] Conservative management is usually recommended small aneurysms (<7 mm) identified in asymptomatic patients, especially if the location is the anterior circulation.
Ruptured cerebral aneurysms result in subarachnoid haemorrhage and require emergency treatment and early referral to the intensive care unit.[47][92] An urgent neurosurgical/interventional neuroradiologist referral should be made. See our topics Cerebral aneurysm and Subarachnoid haemorrhage for further management details.
Renal failure
Patients who reach chronic kidney disease stage 3 should be carefully monitored for hypertension with close attention focused on detection of early disease complications at each visit. Hypertension and hyperlipidaemia, if present, should be optimally controlled (i.e., BP <130/80 mmHg; LDL <2.59 mmol/L [<100 mg/dL]).
As patients reach chronic kidney disease stage 4 (estimated GFR <30 mL/minute/1.73 m²), they should be prepared for renal replacement therapy. Renal transplantation is the treatment of choice in patients with ADPKD.[31]
Living donor transplant is the preferred transplant option over cadaveric donor transplant. There is no difference in patient or graft survival between these patients with this disease and other disease cohorts in the ESRD population, and complications are no greater than in the general population.[93] It is not usually necessary to remove native polycystic kidneys before transplant. However, pre-transplant nephrectomy may be required for repeated cyst-related complications or frequent bleeding, and rarely for size reasons (permitting future allograft implants).[94] Post-transplant nephrectomy may be needed for similar reasons in some patients. Laparoscopic nephrectomy in patients with ADPKD and ESRD is an effective alternative to open nephrectomy. Benefits are decreased intraoperative blood loss, decreased postoperative pain, shorter hospital stay, and a more rapid convalescence.[95]
Dialysis is a second-line option. Patients should have a functioning permanent access at the time of dialysis therapy initiation, and vascular mapping should be completed in all patients before placement of vascular access. These patients tend to do better on dialysis than patients with ESRD due to other causes, which may be because patients with ADPKD typically have higher haematocrits at presentation than do patients with other causes of ESRD.[96] Haemodialysis is preferred over peritoneal dialysis in this patient group, as large kidney size will not permit adequate volumes of dialysis fluid instills, and risk of peritonitis and inguinal or umbilical hernias is increased. However, cyst infections can occur in haemodialysis patients as a result of haematogenous seeding.
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