Approach

The goals of treatment are to prolong life, prolong time to development of renal failure, and manage disease complications.

Many manifestations of the disease are directly related to cyst growth and enlargement. Kidney and cyst volumes increase exponentially over time. Mean total kidney volume increases 5.3% per year, and baseline kidney volume predicts the subsequent rate of increase in kidney volume and is associated with declining GFR in patients with total kidney volume >1500 mL.

Mutated gene PKD1 versus PKD2, position of the PKD1 mutation, and modifier genes determine clinical course. Other unfavorable clinical factors are gross hematuria, onset before 30 years of age, onset of hypertension before 35 years of age, hyperlipidemia, black race, low HDL, male sex, and sickle cell trait.

Hypertension

Target BP should be guided by the HALT polycystic kidney disease trials, which examined BP control in early and late autosomal-dominant PKD (ADPKD) in 2 separate randomized controlled trials. [71] [72]

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 ages 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. [71]

Combination therapy with an ACE inhibitor and angiotensin-II receptor antagonist did not show benefit in regard to change in total kidney volume or estimated GFR in this study. Therefore, first-line drug therapy should be with either an ACE inhibitor or an angiotensin-II receptor antagonist. [ Cochrane Clinical Answers logo ] Use of these drug classes increases renal plasma flow in these patients [73] [74] and offers cardioprotective and renoprotective effects in early ADPKD. The safety of both dual blockade and rigorous BP control is considered to be excellent. [71] In 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. The addition of an angiotensin-II receptor antagonist did not alter the decline in estimated GFR. [72]

Choice of drug therapy should also be tailored to comorbidities. Beta-blockers (useful in patients with hypertension and coronary artery disease, or in those with hypertension and cardiac arrythmias), 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. Noncardioselective 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.

UTIs

UTIs have increased morbidity in patients with ADPKD; therefore, they should all be treated promptly according to cultures and current treatment guidelines. If the infection relapses after completing antibiotics, complications such as obstruction, cyst infection, or infected stone need to be excluded. If none is found, several months of continued antibiotic treatment may be needed to eradicate the infection. 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. Quinolones accumulate in cysts and are considered the antibiotics of choice. Trimethoprim/sulfamethoxazole also has good cyst penetration and may be a second-line option. Chloramphenicol is reserved for special cases. Treatment can fail because of poor antibiotic penetration into cysts. 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. [75] A longer course of antibiotics may be needed to adequately treat these patients, for up to 6 weeks. Persistent or recurrent cyst infections are an indication for pretransplant removal of polycystic kidneys.

Renal pain

Abdominal discomfort and flank pain occur in up to 60% of patients and may have varying etiology. [8] Cyst hemorrhage, renal infection, nephrolithiasis, and tumors 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 hemorrhage.

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 acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioid analgesics for acute or severe pain. Despite the risk of nephrotoxicity, NSAIDs 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, nerve blockade with local anesthesia, or splanchnic nerve blockade may also be tried.

Pain related to cyst rupture tends to be localized. Surgery can be considered for the management of cyst complications when conservative measures fail. Cysts are aspirated under CT 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. [76] 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. [77] Laparoscopic or thorascopic renal denervation is considered in rare situations, especially in patients with polycystic kidneys without large cysts; however, only a few cases have been reported. [78] [79] [80] [81]

Cyst hemorrhage is usually self-limiting and responds to conservative measures in an outpatient setting. Patients should be hospitalized if there is a serious episode of cyst hemorrhage from a renal or hepatic cyst. Hemoglobin should be monitored and, if hematocrit drops, transfusion, CT angiogram, or embolization 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 ESRD or in preparation for patients who meet criteria for renal transplant.

Gross hematuria 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 hematuria persists they should be medically evaluated. New onset of painless gross hematuria 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. [82] Urology evaluation may be necessary for symptomatic stones. Extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy can often be performed without a greatly increased risk of complications. The passage of stone fragments may be impaired in ADPKD patients following lithotripsy. Retrograde endoscopy or manipulation may also be considered. Adequate fluid intake is recommended for prophylaxis of stones.

Polycystic liver disease

Most patients will have liver cysts, but only a minority will be symptomatic. Most cases do not require treatment. Patients should avoid estrogens 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). 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 PET scan [63] ); long-term suppression therapy may be required in selected patients. Patients with severe disease should be referred to a specialty center 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 hemorrhage from other aneurysm; and feasibility to coil or clip. [83] Conservative management is usually recommended for small aneurysms (<7 mm) identified in asymptomatic patients, especially if the location is the anterior circulation.

Ruptured cerebral aneurysms result in subarachnoid hemorrhage (SAH) and requires emergency treatment and early referral to the intensive care unit (ICU). [84] [85] An urgent neurosurgical/interventional neuroradiologist referral should be made. Oral nimodipine reduces risk of poor outcome and secondary ischemia after aneurysmal SAH from vasospasm and should be started on admission. [86]

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 hyperlipidemia, if present, should be optimally controlled (i.e., BP <130/80 mmHg; LDL <100 mg/dL).

As patients reach chronic kidney disease stage 4 (estimated GFR <30 mL/min/1.73 m^2), they should be prepared for renal replacement therapy. Renal transplantation is the treatment of choice in patients with ADPKD.

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. [87] It is not usually necessary to remove native polycystic kidneys before transplant. However, pretransplant nephrectomy may be required for repeated cyst-related complications or frequent bleeding, and rarely for size reasons (permitting future allograft implants). [88] 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. [89]

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, [90] which may be because patients with ADPKD typically have higher hematocrits at presentation than do patients with other causes of ESRD. Hemodialysis 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 hemodialysis patients as a result of hematogenous seeding.

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