INTRODUCTION — Polycystic kidney disease (PKD) includes inherited diseases that cause an irreversible decline in kidney function. PKD is most commonly encountered as an autosomal dominant disease, while the rare autosomal recessive form represents a different entity. The autosomal dominant form (autosomal dominant PKD [ADPKD]) is the most common genetic cause of chronic kidney disease (CKD) [1,2]. The majority of individuals with PKD eventually require kidney replacement therapy .
The course and disease-modifying treatment of ADPKD in adults are discussed here. The epidemiology, clinical presentation, diagnosis, genetics, pathogenesis, kidney complications, and extrarenal manifestations of ADPKD, and autosomal recessive PKD in children, are discussed elsewhere:
IDENTIFICATION OF HIGH-RISK PATIENTS — The identification of individuals who are at high risk for progression of chronic kidney disease (CKD) is important for prognostic reasons and to identify patients who may benefit from specific therapies, such as tolvaptan.
Preferred method — Our preferred method for identifying high-risk patients with ADPKD is the Mayo classification system, which categorizes patients into five prognostic classes from the lowest to the highest risk for disease progression (classes 1A, 1B, 1C, 1D, and 1E) . Classes 1C, 1D, and 1E are defined as high risk for progression to end-stage kidney disease (ESKD).
The major advantage of this method is the ability to predict an individual patient's estimated glomerular filtration rate (eGFR) at any point in the future using a single total kidney volume (TKV) measurement at any given age [4,5].
The Mayo classification requires demographic data such as the patient's age, height, and TKV. The TKV can be calculated using a TKV calculator available online using a single representative coronal image . The calculator requires coronal and sagittal length and width and depth measurements of both kidneys to be entered using images obtained by computed tomography (CT) without contrast or magnetic resonance imaging (MRI) without gadolinium ; ultrasound is less accurate . The calculator is based on the formula for an ellipsoid. Nephrologists can work with radiologists at their practice or institution to make these measurements a routine part of the imaging report in patients with ADPKD.
The Mayo classification provides an age-adjusted assessment of progression risk for those with typical ADPKD (ie, diffuse distribution of cysts throughout the kidney parenchyma). This classification system categorizes patients into five prognostic classes from the lowest to the highest risk for disease progression (1A, 1B, 1C, 1D, and 1E) . The frequency of ESKD at 10 years increases serially from subclass 1A to 1E; as examples:
●In the older Mayo cohort, the rate of ESKD at 10 years was 2.4 and 66.9 percent among patients categorized as 1A and 1E, respectively.
●In the younger Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort, the rate of ESKD at 10 years was 2.2 and 22.3 percent among patients categorized as 1C and 1E, respectively.
An important caveat of the Mayo classification is that it does not apply to patients with atypical ADPKD, constituting 5 percent of patients, who have unilateral, asymmetrical, or segmental cyst burden. Such patients are at lower risk for progression because the spared kidney helps preserve the GFR .
Alternate criteria — Alternate criteria aside from the Mayo classification that may identify patients at high risk for progression are [3-5,8-11]:
●Adults aged ≤55 years who have an eGFR <65 mL/min/1.73 m2); this was one eligibility criterion for the Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) study.
●Average kidney length (by ultrasound, MRI, or CT) >16.5 cm in a patient aged <50 years predicts the development of CKD stage 3 [3,4,12].
●PROPKD score >6 in patients who have genetic data available . The score varies from 0 to 9 and includes the following parameters: sex, presence of hypertension before 35 years of age, occurrence of the first urologic event before 35 years of age, PKD1 versus PKD2 mutation, and truncating versus nontruncating PKD1 mutation. The PROPKD score categorizes patients into low risk (0 to 3 points), intermediate risk (4 to 6 points), and high risk (7 to 9 points) for progression to ESKD, with corresponding median ages for ESKD onset of 70.6, 56.9, and 49 years. Genetic testing is unavailable in the vast majority of patients, limiting the utility of this tool .
INITIAL MANAGEMENT FOR ALL PATIENTS
Management of blood pressure — In young, healthy individuals aged 18 to 50 years with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2, we generally use an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) to target a blood pressure of <110/75 mmHg using home blood pressure measurements or daytime ambulatory blood pressure monitoring. In such patients, intensive blood pressure lowering may reduce the rate of kidney growth and, in high-risk patients (Mayo class ID and IE), may slow the rate of decline in eGFR . In other patients, we treat with an ACE inhibitor or ARB to target the same blood pressure as that for patients with chronic kidney disease who do not have ADPKD. These issues are presented in detail separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of hypertension".)
Dietary sodium restriction — We advise all PKD patients to restrict dietary sodium, with a goal of 2 grams intake per day or less (approximately 5 grams of salt). In order to ensure adherence, the authors measure a 24-hour urine sodium and obtain a nutrition consult at least once during the course of the management.
In the Halt Progression of Polycystic Kidney Disease (HALT PKD) trial, all participants were instructed to limit dietary sodium to <2400 mg per day . Adherence to dietary sodium restriction, as reflected by degree of reduction in urinary sodium, was moderate and variable among participants. Higher sodium excretion was associated with an increased risk of kidney growth and eGFR decline .
This relationship between higher sodium excretion and eGFR decline was also observed in the Developing Interventions to Halt Progression of ADPKD (DIPAK) cohorts . However, the association of sodium with eGFR was thought to be mediated by vasopressin release rather than by kidney growth in these cohorts [17,18].
In addition to beneficial effects on eGFR, reduction in sodium intake will help to improve blood pressure control among patients with ADPKD. (See "Salt intake, salt restriction, and primary (essential) hypertension" and "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of hypertension".)
Increased fluid intake — We advise patients with ADPKD to drink >3 L of fluid per day, unless the eGFR is <30 mL/min/1.73 m2 or the patient is at risk for hyponatremia (eg, taking a thiazide diuretic). We monitor fluid intake periodically by collecting a 24-hour urine, typically at the time of initial evaluation, and subsequently when there is a clinical change or decline. An accurate history of estimated or measured fluid intake can also be helpful. A higher fluid intake helps mitigate the increased risk of nephrolithiasis in patients with ADPKD and also may inhibit cyst growth by suppressing plasma vasopressin levels.
Increasing fluid intake to suppress plasma vasopressin levels has been postulated as a possible therapeutic mechanism to inhibit cyst growth in ADPKD and, in a small proof-of-concept study, water intake of at least 3 L/day increased urine volume and decreased urine osmolality to mean values of 3.1 L/day and 270 mosmol/kg in 13 patients with ADPKD [19,20].
Although this study suggests that an increase in fluid intake to 3 L/day can suppress urine osmolality (and can partially suppress plasma vasopressin levels), a water intake of this magnitude may be difficult to attain. As an example, in a trial of 184 patients with ADPKD who were randomly assigned to a prescribed high water intake (calculated to suppress the urine osmolality to <270 mosmol/kg) or ad lib water intake, fewer than half of patients prescribed a high water intake attained a mean urine output >3 L/day, and only 52 percent achieved a mean urine osmolality <270 mosmol/kg . There was no difference in the change in total kidney volume or eGFR between the groups at three years.
ADDITIONAL MANAGEMENT FOR HIGH-RISK PATIENTS — Patients at high risk for progression may be identified based upon criteria described above. The major clinical challenge is to define the patients at risk for rapid progression who are the most likely to derive benefit from tolvaptan . (See 'Identification of high-risk patients' above.)
Tolvaptan — Tolvaptan is a vasopressin V2-receptor (V2R) antagonist with proven beneficial results in ADPKD.
Mechanism of action — In animal models, vasopressin activates the V2R, triggering a cascade of intracellular events that result in cellular proliferation and fluid secretion, thereby leading to cystogenesis . Conversely, sustained suppression of vasopressin production, release, or action results in lower cyst burden, preserved kidney function, and prolonged survival of the animal. Tolvaptan, a short-acting competitive inhibitor of V2R, completely blocks vasopressin action on cyst production.
Candidates for treatment — Unless contraindications are present or cost is prohibitive, we prescribe tolvaptan to adult patients with ADPKD who have an estimated glomerular filtration rate (eGFR) ≥25 mL/min1.73 m2 and who are at risk of rapid progression, defined by at least one of the following [24-26] (see 'Identification of high-risk patients' above and 'Contraindications' below):
●Age ≤55 years and an eGFR <65 mL/min/1.73 m2 (see 'Alternate criteria' above)
●Kidney length (by ultrasound, magnetic resonance imaging [MRI], or computed tomography [CT]) >16.5 cm in a patient aged <50 years (see 'Alternate criteria' above)
There are limited data on safety and efficacy of tolvaptan in patients >55 years of age, and prescription drug coverage may not pay for it in such patients. However, if feasible, we generally offer tolvaptan to patients >55 years who have an eGFR ≥25 mL/min1.73 m2 and who are high risk for developing ESKD if they have few comorbidities that would limit their life expectancy.
Tolvaptan is not approved for use in patients with ADPKD who are <18 years of age, and we do not prescribe it for such patients.
Based on the evidence from those animal studies, two randomized controlled trials of tolvaptan were conducted in a select population of ADPKD patients.
●In the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial that included 1157 patients with estimated creatinine clearance >60 mL/min and total kidney volume (TKV) >750 mL, the annual increase in TKV was smaller among patients who received tolvaptan compared with placebo (2.8 versus 5.5 percent, respectively) [24,25]. The annual decline in eGFR was slower among patients who received tolvaptan compared with placebo (-2.72 versus -3.70 mL/min/1.73 m2 per year). Tolvaptan also reduced the rate of decline in kidney function at three years (hazard ratio [HR] 0.39, 95% CI 0.26-0.57), and the rate of clinically significant kidney pain (HR 0.64, 95% CI 0.47-0.89). In addition, tolvaptan led to a modest decline in systolic and diastolic blood pressure at three years (mean absolute change -3/-1.4 versus +1/+0.2 mmHg) .
●The REPRISE (Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD) multicenter, randomized trial examined the effect of tolvaptan in patients with ADPKD who had reduced eGFR; such patients were generally not included in the TEMPO trial . Patients aged 18 to 55 years with eGFRs of 25 to 65 mL/min/1.73 m2, and those ages 56 to 65 years with eGFRs 25 to 44 mL/min/1.73 m2, with evidence of declining eGFR of at least 2 mL/min/1.73 m2 constituted the study population. REPRISE included an eight-week prerandomization period, during which patients were sequentially administered placebo and tolvaptan to assess their ability to tolerate tolvaptan. Patients who did not tolerate tolvaptan at a dose of 60 mg in the morning and 30 mg in the evening were not randomized, leaving a final sample size of 1370 patients. At 12 months, the change from baseline eGFR was lower among those assigned tolvaptan compared with placebo (-2.34 versus -3.61 mL/min/1.73 m2); the group difference was 1.27 mL/min/1.73 m2 (95% CI 0.86-1.68).
These data show that, among patients who can tolerate the drug, tolvaptan slows the decline in kidney function, even if the baseline eGFR is significantly reduced. Although long-term risks and benefits of tolvaptan were not assessed in the scope of these clinical trials, extrapolations of the REPRISE trial and TEMPO trial data suggested that tolvaptan may extend the time until stage 5 chronic kidney disease (CKD; ie, eGFR <15 mL/min/1.73 m2) from six to nine years among patients who start tolvaptan with an eGFR <60 mL/min/1.73 m2 and even longer among those who start tolvaptan earlier [26,28-31].
The decision to give tolvaptan to individual ADPKD patients should be made after careful assessment of risks (liver toxicity, polyuria, polydipsia), benefits, and affordability, on an individual basis.
Contraindications — Tolvaptan should not be used in patients with liver impairment or injury (except for uncomplicated polycystic liver disease).
We generally do not treat patients with acute hepatitis from any cause. In addition, we do not treat patients with chronic elevations of liver enzymes (that exceed three times the upper limit of normal [ULN]) unless, after an exhaustive evaluation, the cause of liver disease is determined to be uncomplicated polycystic liver disease.
The use of tolvaptan is also contraindicated in patients taking strong inhibitors of the CYP3A4 (table 1), who were excluded in the TEMPO and REPRISE trials. Alternatively, patients may be taken off of these agents (CYP3A4 inducers, inhibitors, or substrates) before initiating tolvaptan.
Other important contraindications include abnormal serum sodium (particularly hypernatremia), inability to sense or respond to thirst, hypovolemia, concomitant use of diuretics, or uncorrected urinary outflow obstruction.
Dosing and titration — The preferred starting dose is 45 mg in the morning and 15 mg eight hours later and before 4 PM to diminish the risk of severe nocturia. We typically increase the dose every one to four weeks, as tolerated, to a maximum of 90 mg in the morning and 30 mg in the afternoon . (See 'Monitoring' below.)
The degree of reduction in urinary osmolality achieved with tolvaptan is associated with the rate of reduction in cyst growth. However, this reduction in urinary osmolality is diminished among patients with impaired kidney function. Thus, continued uptitration of the dose is necessary to achieve a continued reduction in urinary osmolality.
The dose titration should be stopped if the patient develops excessive (or intolerable) polyuria/polydipsia, hypernatremia, or hepatic transaminitis or if the serum creatinine rises by 30 percent.
Tolvaptan that is packaged under another name (ie, SAMSCA, Jinarc) cannot be prescribed for treatment of ADPKD in the United States (different tablet sizes, frequency of dosing, limitation of 30-day duration of treatment, and required monitoring).
Cost considerations — The cost and affordability of tolvaptan for ADPKD (brand name Jynarque) depends upon individual prescription drug policies. The wholesale acquisition cost of the drug is approximately USD $13,000 for a 28-day supply, but monthly copayments as low as USD $10 are available for eligible patients. Also, other patient assistance programs are available through the manufacturer for uninsured or underinsured patients.
●Thirst – 4 to 55 percent
●Polyuria – 5 to 38 percent
●Nocturia – 5 to 29 percent
●Polydipsia – 2 to 10 percent
●Hypernatremia – 1 to 4 percent
●Increased liver enzymes – 1 to 6 percent
The overall rate of side effects in the TEMPO trial was similar between groups, but the discontinuation rate was higher in the tolvaptan compared with placebo group (23 versus 14 percent, respectively) . Patients who received tolvaptan had a higher frequency of adverse events due to increased aquaresis (polyuria, polydipsia, nocturia, and urinary frequency) but a lower frequency of adverse events related to ADPKD (kidney pain, hematuria, urinary tract infection, and back pain). Serious adverse events occurring in at least 0.5 percent of the patients included increased liver enzymes (0.9 percent in tolvaptan versus 0.4 percent in the placebo group), chest pain (0.8 percent in tolvaptan versus 0.4 percent in the placebo group), and headache (0.5 percent in tolvaptan versus 0 percent in placebo group). A greater than 2.5-fold increase in serum alanine transaminase levels occurred more often among patients who received tolvaptan compared with placebo (4.9 versus 1.2 percent, respectively). In all cases, these abnormalities either resolved spontaneously or after withdrawal of tolvaptan. Treatment with tolvaptan also resulted in an increase in the mean serum sodium level of less than 2.5 mmol per liter by the end of the dose-escalation period. A serum sodium concentration of ≥150 mEq/L occurred in 4 and 1.4 percent of the tolvaptan and placebo groups. Hyperuricemia and/or gout occurred in 2.9 and 1.4 percent of tolvaptan and placebo groups.
The safety profile of tolvaptan in the REPRISE trial appeared similar to that in TEMPO . However, adverse effects were generally less frequent than in TEMPO, possibly because of a shorter duration of follow-up and exclusion of patients during the run-in, who were intolerant of tolvaptan. Tolvaptan was discontinued in 101 patients (6.8 percent) during the run-in period (68 for aquaretic reasons, such as polyuria, nocturia, thirst, polydipsia). A greater than threefold increase in serum alanine transaminase levels occurred more often among patients who received tolvaptan compared with placebo (5.6 versus 1.2 percent, respectively). Increases in the aminotransferase concentration were reversible after stopping tolvaptan, and there were no severe cases meetings Hy's law criteria, probably due to the monthly monitoring.
Monitoring — To ensure the safety of patients taking tolvaptan, the JYNARQUE Risk Evaluation and Mitigation Strategy (JYNARQUE REMS; https://www.jynarquerems.com/#Main) was created as a restricted drug distribution program . It is a condition of the JYNARQUE REMS program to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin before initiating treatment, at two and four weeks after initiation, then monthly for 18 months (20 liver function tests during the first 18 months), and then quarterly while on the medication, for it to be dispensed.
The utility of the REMS protocol to detect early liver injury and prevent severe liver injury was supported by the results of a retrospective safety study that analyzed data from the TEMPO and REPRISE trials (and their long-term trial extensions) and included over 2900 tolvaptan-treated patients, 2300 of whom had 18 months or more of tolvaptan exposure . ALT elevations associated with tolvaptan therapy (>3 times the upper limit of normal in approximately 5 percent of patients) most often occurred within 18 months after tolvaptan initiation and normalized after treatment interruption or discontinuation.
Providers need to be registered on the JYNARQUE REMS program website before prescribing the drug. The drug is directly mailed to patients from a specialty pharmacy on a monthly basis.
At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to >2 times the ULN, tolvaptan should be immediately discontinued and repeat tests obtained within 48 to 72 hours. If laboratory abnormalities stabilize or resolve, tolvaptan may be reinitiated with increased frequency of monitoring.
Tolvaptan may be continued as long as ALT and AST levels remain <3 times the ULN. Tolvaptan should not be restarted in patients with signs or symptoms consistent with hepatic injury or whose ALT or AST >3 times the ULN during treatment with tolvaptan, unless there is another explanation for liver injury and the injury has resolved.
In patients with a stable, low baseline AST or ALT, an increase above twice the baseline level, even if <2 times the ULN, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) reevaluation of liver test trends prior to reinitiating therapy (with more frequent monitoring).
More information about the JYNARQUE REMS program, as well as the registration process to prescribe the drug, can be found at the JYNARQUE REMS website (https://www.jynarquerems.com/#Main) or by calling the JYNARQUE REMS Program Coordinating Center at 1-866-244-9446.
In addition to monitoring liver enzymes, patients should be monitored for possible interactions between tolvaptan and commonly used drugs (eg, diuretics and calcium channel blockers).
Patients on tolvaptan should temporarily discontinue the medication during situations in which water intake may be inadequate (eg, severe illness, gastroenteritis, general anesthesia, other reason for lack of access to water, etc). Tolvaptan should not be restarted until fluid intake has returned to normal. In cases of elective surgery, we stop tolvaptan 24 hours prior to general anesthesia, and, in all cases, tolvaptan should be resumed only after fluid intake has returned to normal.
Approaches we do not use — We do not prescribe other potentially disease-modifying agents (other than tolvaptan), because they lack demonstrable benefit and because their interactions have not been evaluated.
Somatostatin and somatostatin analogs — Somatostatin, long-acting somatostatin (octreotide), somatostatin analogs (lanreotide), and pansomatostatin analogs (pasireotide) may reduce kidney and liver cyst fluid accumulation among patients with PKD [35-42]. However, these agents have not been shown to slow the progression of kidney function decline and they produce a variety of prohibitive adverse effects (eg, hepatic cyst infection with lanreotide, hyperglycemia and diabetes with pasireotide). Based on the available evidence, we do not recommend these agents for routine clinical use, although they may be used in some countries.
The best data come from the Developing Interventions to Halt Progression of ADPKD 1 (DIPAK 1) trial, in which 309 patients with PKD and eGFR between 30 and 60 mL/min/1.73 m2 were randomly assigned to lanreotide, 120 mg subcutaneously once every four weeks for 2.5 years or to usual care . Although lanreotide reduced the annual increase in TKV (4.1 versus 5.6 percent per year), it failed to slow the loss of eGFR (3.6 versus 3.5 mL/min/1.73 m2 annual decline), did not reduce the incidence of a 30 percent decrease in eGFR (14 versus 19 percent), and did not prevent the development of ESKD (2 versus 1 percent). The drug also led to more serious adverse events, including hepatic cyst infection (5 versus 0 percent), as well as other adverse events.
Another long-term study with 75 patients compared the one- and three-year effects of octreotide versus placebo on the change in total kidney and cyst volume and on GFR and failed to show significant differences between the two groups .
Mammalian target of rapamycin — The mammalian (mechanistic) target of rapamycin (mTOR) signaling pathway may modulate disease progression in ADPKD, although there is absence of evidence in clinical trials to recommend these for routine clinical use [43-45]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)
A proof-of-concept randomized, crossover study (SIRENA) suggested that rapamycin stabilized cyst growth at six months . However, larger randomized trials showed no benefit on kidney function, despite a slowing of cyst growth [47,48]. As an example, in a two-year, double-blind trial of 431 patients with ADPKD (mean baseline eGFR of approximately 55 mL/min/1.73 m), patients received either the mTOR inhibitor (everolimus) or placebo . The increase in TKV, as measured by MRI, was smaller in the everolimus group, compared with placebo, at one (102 versus 157 mL) and two (230 versus 301 mL) years. However, there was no difference in the mean decrease in eGFR; the mean protein-to-creatinine ratio remained stable in the placebo group but increased in the everolimus group. Side effects associated with everolimus, including leukopenia, thrombocytopenia, and hyperlipidemia, were common and resulted in a high rate of discontinuation (approximately 35 percent).
A variety of medical therapies, including methylprednisolone, urinary alkalinization, paclitaxel, lovastatin, epidermal growth factor receptor tyrosine kinase inhibitors, peroxisome proliferator-activated receptor agonists, cyclin-dependent kinase inhibitors, bardoxolone methyl, and mitogen-activated protein kinase (MAPK) inhibitors, are being studied in animal models of ADPKD and in Phase II and III clinical trials [1,52-66].
A phase II study has examined the safety and efficacy of bosutinib, an oral tyrosine kinase inhibitor . Among patients with eGFR ≥60 mL/min/1.73 m2, and TKV 750 mL, compared with placebo, bosutinib reduced the rate of kidney growth but had no effect on the annualized eGFR decline.
SPECIFIC MANAGEMENT OF END-STAGE KIDNEY DISEASE — Patients with ADPKD who progress to end-stage kidney disease (ESKD) require kidney replacement therapy. Peritoneal dialysis is less commonly performed than hemodialysis because it is perceived to be difficult for the patients to accommodate large volumes of peritoneal dialysate fluid in the setting of massively enlarged kidneys.
Patients with ADPKD and ESKD are therefore most commonly treated with hemodialysis or undergo kidney transplantation. In general, such patients have equivalent, or perhaps better, overall outcomes with any kidney replacement therapy compared with non-ADPKD patients [68-72]. It is important to note that therapy for other manifestations of ADPKD should continue in patients who reach ESKD. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations", section on 'Summary and recommendations'.)
Kidney transplantation — The evaluation for kidney transplantation in patients with ADPKD is largely the same as for other patients with ESKD. In addition, we screen all transplant candidates with ADPKD for intracranial aneurysm , although some experts use a more selective screening approach pretransplant. These issues are discussed elsewhere. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient" and "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations", section on 'Screening'.)
Considerations for nephrectomy at the time of transplantation are discussed elsewhere. (See 'Nephrectomy in selected cases' below.)
Data suggest that survival of patients with ADPKD after transplant is either similar or better compared with other causes of ESKD [69,74]. In one study of 271 patients with ADPKD matched by sex and age at transplantation to 542 controls (half with diabetic nephropathy), the median survival of patients with ADPKD was approximately five to seven years longer than that of patients with ESKD due to other causes . Patients with ADPKD had lower rates of left ventricular hypertrophy, diastolic dysfunction, and impaired left ventricular ejection fraction at time of transplantation; it is possible these findings contributed to the survival difference.
The rate of complications following kidney transplant is similar to that in patients without ADPKD . However, a few specific complications may be more frequent or unique to this patient population; these include new-onset diabetes mellitus, posttransplant erythrocytosis, symptomatic aneurysms, urinary tract infections, diverticulitis, and gastrointestinal disorders requiring surgery [69,76-79]:
●One study compared the posttransplant outcomes and manifestations of 114 patients with ADPKD with a matched control population . Clinical characteristics more frequently observed or unique to patients with ADPKD included elevated hematocrit levels, the requirement for nephrectomy (19 before and 7 after transplantation), diverticulitis (four patients, two with perforation), and symptomatic aortic aneurysms (death in two patients).
●A second series of 1417 kidney transplant recipients, 145 of whom had ADPKD, found that gastrointestinal surgery was required twice as often in patients with polycystic disease (12 versus 6 percent for those without ADPKD) . A perforated colon was the most common abnormality in the ADPKD group, a possible reflection of the high frequency of colonic diverticulosis in patients with ADPKD who progress to ESKD. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)
Hemodialysis — Survival of patients with ADPKD receiving hemodialysis may be better (by 10 to 15 percent at five years) compared with that of patients receiving hemodialysis for ESKD due to other causes [68,70,71]. In one large survey using data from the United States Renal Data System, the relative risk (RR) of death was lower among patients with ADPKD compared with nondiabetic control dialysis patients (RR 0.57, 95% CI 0.53-0.61) .
This difference in survival is primarily due to a lower incidence of coronary artery disease in these generally healthier patients with ADPKD. Clinical problems more frequently observed in patients with ADPKD include kidney pain (36 versus 2 percent for non-ADPKD patients), gross hematuria (36 versus 16 percent), and kidney infection (16 versus 2 percent) .
Peritoneal dialysis — Survival among patients with ADPKD receiving peritoneal dialysis is better than among peritoneal dialysis patients with other causes of ESKD. In addition, limited evidence suggests that patients with ADPKD may have superior survival rates with peritoneal dialysis than with hemodialysis . However, there may be an increased risk of peritonitis secondary to cyst infections or complications of diverticular disease . Nevertheless, some centers have found that peritoneal dialysis is well tolerated and results in no specific difficulties in the patient with ADPKD requiring kidney replacement therapy .
NEPHRECTOMY IN SELECTED CASES — Indications for transplant-specific considerations surrounding and technical issues of nephrectomy are discussed below.
Indications — Nephrectomy is avoided whenever possible in ADPKD because of potential complications and the adverse effects of removing a partially functioning kidney. However, it may be a reasonable therapeutic option in certain circumstances:
●Debilitating abdominal discomfort and/or marked limitation of daily activities due to massively enlarged kidneys, or chronic kidney pain refractory to treatment. In such cases, all other treatable causes of discomfort, limited activity, and pain should be ruled out before nephrectomy takes place for these indications. (See "Autosomal dominant polycystic kidney disease (ADPKD): Pain syndromes", section on 'Surgical management'.)
●Marked anorexia, particularly in the presence of signs of malnutrition, attributed to mass effect of enlarged kidneys on the stomach.
●Suspected renal cell carcinoma.
●Uncontrollable kidney hemorrhage among patients who have a contraindication to or failure of intra-arterial embolization.
●Development of ventral hernia due to massive renomegaly.
●Kidney infection with a gas-forming organism that does not respond to other measures (eg, percutaneous drainage).
●Staghorn calculus in a relatively nonfunctioning kidney causing recurrent urinary tract infection.
The management of complicated urinary tract infection in patients with ADPKD is discussed in detail elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections", section on 'Management'.)
Considerations in patients undergoing transplant — Indications for nephrectomy specific to transplantation for patients with ADPKD are discussed below.
●No need for preemptive nephrectomy – Absent other indications, preemptive nephrectomy is not performed routinely in most patients with ADPKD who undergo kidney transplantation. A major reason for not pursuing preemptive nephrectomy is that native polycystic kidneys tend to regress in volume in the posttransplant period. A report of 78 patients quantified the regression in mean total kidney volume (TKV) as 20.2, 28.6, 38.3, and 45.8 percent after 0.5 to 1 (mean 0.7), 1 to 3 (mean 1.8), 3 to 10 (mean 5.7), and >10 (mean 12.6) years of transplantation, respectively .
●Potential indications – General indications for nephrectomy in patients with ADPKD are discussed elsewhere (see 'Indications' above). Additionally, there may be other reasons for nephrectomy specific to patients undergoing transplant:
•Rarely, the native polycystic kidney extends into the potential surgical site of the kidney allograft. These patients may require a nephrectomy to accommodate the transplanted kidney.
•Additionally, nephrectomy may be appropriate for patients who have had recurrent or refractory urinary tract infections . In this setting, nephrectomy will minimize the risk of posttransplant infection when immunosuppressive agents are administered to prevent rejection.
Technical issues — Nephrectomy can be performed by an open procedure or, if possible, laparoscopically, which shortens the recovery time . Bilateral nephrectomies are rarely performed and are mostly indicated for patients who have a severe limitation of daily activities due to massive renomegaly, severe kidney pain refractory to pharmacologic management, recurrent bilateral infections, or malnutrition.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Polycystic kidney disease (The Basics)")
●Beyond the Basics topic (see "Patient education: Polycystic kidney disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Course of autosomal dominant polycystic kidney disease – Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD). The majority of individuals with ADPKD eventually require kidney replacement therapy. (See 'Introduction' above.)
●Identification of high-risk patients – The identification of individuals who are at high risk for progression of CKD is important for prognostic reasons and to identify patients who may benefit from specific therapies, such as tolvaptan (see 'Identification of high-risk patients' above):
•Our preferred method for identifying high-risk patients is the Mayo classification system. Classes 1C, 1D, and 1E are defined as high risk for progression to end-stage kidney disease (ESKD). The Mayo classification requires demographic data, such as the patient's age, height, and total kidney volume (TKV). The TKV can be calculated using a TKV calculator available online using a single representative coronal image obtained by computed tomography (CT) without contrast or magnetic resonance imaging (MRI) without gadolinium. (See 'Preferred method' above.)
•Alternate criteria can be used to identify patients at high risk for progression if TKV cannot be calculated. (See 'Alternate criteria' above.)
●Blood pressure management – In hypertensive patients with ADPKD, we suggest using an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) rather than another antihypertensive drug (Grade 2C). In young, healthy individuals aged 18 to 50 years with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2, we generally use an ACE inhibitor or ARB to target a blood pressure of <110/75 mmHg using home blood pressure measurements or daytime ambulatory blood pressure monitoring. In other patients, we treat with an ACE inhibitor or ARB to target the same blood pressure as that for patients with chronic kidney disease who do not have ADPKD. These issues are discussed in detail elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of hypertension", section on 'Treatment'.)
●Dietary recommendations – We advise all ADPKD patients to restrict dietary sodium, with a goal of 2 grams intake per day or less. In addition, we advise patients with ADPKD to drink >3 L of fluid per day, unless the eGFR is <30 mL/min/1.73 m2 or the patient is at risk for hyponatremia (eg, taking a thiazide diuretic). (See 'Dietary sodium restriction' above and 'Increased fluid intake' above.)
●Treatment with tolvaptan – In adult patients with ADPKD who have an eGFR ≥25 mL/min1.73m2 and who are at high risk of CKD progression (defined above), we suggest treatment with tolvaptan (Grade 2C). Tolvaptan has the most benefit on the rate of eGFR decline compared with other treatments, but it is costly and produces a high rate of adverse effects. Tolvaptan should not be used in patients with liver impairment or injury (except for uncomplicated polycystic liver disease). (See 'Identification of high-risk patients' above and 'Candidates for treatment' above.)
•Tolvaptan administration – Dosing, cost considerations, and side effects of tolvaptan are presented above. (See 'Dosing and titration' above and 'Cost considerations' above and 'Side effects' above.)
•Required monitoring – To ensure the safety of patients taking tolvaptan, the JYNARQUE Risk Evaluation and Mitigation Strategy (JYNARQUE REMS; https://www.jynarquerems.com/#Main) was created as a restricted drug distribution program. Providers need to be registered on the REMS program website before prescribing the drug. The drug is directly mailed to patients from a specialty pharmacy on a monthly basis. (See 'Monitoring' above.)
●End-stage kidney disease – Patients with ADPKD who progress to ESKD require kidney replacement therapy. Peritoneal dialysis is less commonly performed than hemodialysis because it is perceived to be difficult for the patients to accommodate large volumes of peritoneal dialysate fluid in the setting of massively enlarged kidneys. Patients with ADPKD and ESKD are therefore most commonly treated with hemodialysis or undergo kidney transplantation. In general, such patients have equivalent, or perhaps better, overall outcomes with any kidney replacement therapy compared with non-ADPKD patients. (See 'Specific management of End-Stage Kidney Disease' above.)
●Nephrectomy – Nephrectomy is generally avoided in ADPKD because of potential complications and the adverse effects of removing a partially functioning kidney. However, nephrectomy may be an option in patients with disabling symptoms due to massively enlarged kidneys, development of ventral (abdominal wall) hernias, or suspected renal cell carcinoma. Among those who are undergoing kidney transplantation, potential indications include recurrent urinary tract infection or extension of the native polycystic kidney into the potential graft site. (See 'Nephrectomy in selected cases' above.)
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