Polycystic Kidney Disease, Autosomal Dominant

Age-Specific Ultrasound Criteria

Age-specific ultrasound criteria in an individual with an affected first-degree relative [Pei et al 2009]:

• The presence of three or more (unilateral or bilateral) renal cysts in an individual age 15-39 years
• The presence of two or more cysts in each kidney in an individual age 40-59 years
• Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD

Note: (1) The positive predictive value of these criteria is described as 100%, regardless of (a) whether the disorder is PKD1- or PKD2-related ADPKD and (b) the age of the individual at the time of initial evaluation (see Table 1). Note that there are other genetic causes of renal cysts in addition to pathogenic variants in PKD1 or PKD2 (Table 3, Table 5). (2) The sensitivity is low (Table 1; 81.7%-95.5%), particularly in families with a pathogenic variant in PKD2 (69.5%-94.9%). A low sensitivity is likely true for families with a nontruncating PKD1 pathogenic variant (does not truncate or shorten the protein product, polycystin-1), and for pathogenic variants in GANAB or DNAJB11, which are typically associated with mild cystic disease (Table 3). In these situations, a significant number of affected individuals may not be diagnosed, which may pose a problem when exclusion of the diagnosis is critical (see Excluding the Diagnosis).

Age-specific MRI criteria are particularly useful when ultrasound results are equivocal [Pei et al 2015]. For individuals ages 16-40 years who are at 50% risk for ADPKD because they have an affected first-degree relative, the presence of more than ten cysts is sufficient for a diagnosis of ADPKD.

Note: These criteria may also be more appropriate to use when employing a modern, high-resolution ultrasound scanner that can detect cysts as small as 1-2 mm.

Excluding the Diagnosis

The absence of renal cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by a truncating PKD1 pathogenic variant, which predicts a truncated polycystin-1, in an at-risk person age 15-30 years (negative predictive value [NPV] = 99.1%) or older (NPV = 100%). However, absence of renal cysts does not exclude the diagnosis in persons younger than age 40 years who are at risk for ADPKD caused by incompletely penetrant, nontruncating PKD1 variants or pathogenic variants in other ADPKD-related genes associated with milder disease.

A normal renal ultrasound does not exclude ADPKD with certainty in an at-risk individual younger than age 30 years (see Table 2).

Ultrasound criteria used to exclude an at-risk relative as a potential living-related kidney donor are shown in Table 2.

MRI or contrast-enhanced CT examination, which has much higher sensitivity than ultrasound to detect cysts and is routinely performed in most transplantation centers to define the donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent (see Age-specific MRI criteria). When evaluating at-risk individuals in the same age group as living-related donors, fewer than five cysts is considered sufficient for exclusion of the disease.

When the family-specific pathogenic variant has not been identified:

• Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one renal cyst in an individual age 40 years or older has a negative predictive value of 100%.
• The family history of renal disease severity can be used as a rough guide to predict the severity of disease in other family members (see Genotype-Phenotype Correlations).

Molecular Genetic Testing

Testing approaches can include a multigene panel or concurrent gene testing.

Option 1 (recommended)

A multigene panel that includes PKD1, PKD2, GANAB, DNAJB11, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) Multigene panels using next-generation sequencing should be carefully designed to maximize identification of a PKD1 pathogenic variant, which is complicated by several highly homologous pseudogenes [Trujillano et al 2014, Eisenberger et al 2015]. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Concurrent gene testing. Sequence analysis and deletion/duplication analysis of PKD1 and PKD2 can be performed concurrently. Note: Sequence analysis should be designed to maximize identification of a PKD1 pathogenic variant, which is complicated by several highly homologous pseudogenes [Trujillano et al 2014, Eisenberger et al 2015].

Renal Manifestations

Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, there is substantial variability in severity of renal disease and other manifestations of the disease, even within the same family.

Poor prognostic factors include: diagnosis before age 30 years [Gabow 1996]; first episode of hematuria before age 30 years; onset of hypertension before age 35 years [Cornec-Le Gall et al 2016]; hyperlipidemia and high body mass index (BMI) [Nowak et al 2018]; high urine sodium excretion [Torres et al 2017a]; lower renal blood flow; lower serum HDL cholesterol [Torres et al 2011a]; large total kidney volume (TKV) [Chapman et al 2012, Irazabal et al 2015]; and the presence of a truncating PKD1 variant [Cornec-Le Gall et al 2013, Heyer et al 2016].

The lower incidence of end-stage renal disease (ESRD) in affected females compared to affected males suggests that ADPKD is a more severe disease in males. Analysis of a population of individuals with PKD1-related ADPKD from the French Genkyst cohort showed poorer renal survival in males than females (mean age at onset of ESRD was 58.1 years for males and 59.5 years for females) [Cornec-Le Gall et al 2013]. Heyer et al [2016] showed lower estimated glomerular filtration rate (eGFR) and larger height-adjusted TKV (htTKV) in males compared to females in the total HALT PKD study population and in individuals with PKD1-related ADPKD. Males with PKD2-related ADPKD also had lower eGFR. Males with truncating PKD1 variants, onset of hypertension before age 35 years, and/or a urologic event before age 35 years were the most severely affected [Cornec-Le Gall et al 2016].

Cyst development and growth. The renal manifestations of ADPKD include renal function abnormalities, hypertension, renal pain, and renal insufficiency. These manifestations are directly related to the development and enlargement of renal cysts. A study by the Consortium of Imaging Studies to Assess the Progression of Polycystic Kidney Disease (CRISP) of 241 non-azotemic affected individuals followed prospectively with annual MRI examinations showed that TKV and cyst volumes increased exponentially. At baseline, TKV was 1,060 ± 642 mL; the mean increase over three years was 204 mL, or 5.3% per year. The baseline TKV predicted the subsequent rate of increase in renal volume, meaning that the larger the kidney, the faster the rate of renal enlargement over time. Declining glomerular filtration rate (GFR) was observed in persons with baseline TKV above 1,500 mL [Grantham et al 2006].

Kidney size has been shown to be a strong predictor of subsequent decline in renal function with an htTKV of ≥600 mL/m showing a high predictive value for the individual to develop renal insufficiency within eight years [Chapman et al 2012]. Compartmentalizing age-adjusted htTKV into five classes based on htTKV/age has also shown that this strongly predicts decline in renal function and ESRD. A model including htTKV (that can be estimated using renal dimensions and the ellipsoid equation), age, and eGFR (available via an online app) has good predictive value in estimating future eGFR [Irazabal et al 2015].

Individuals with PKD1-related ADPKD often have significantly larger kidneys with more cysts than individuals with PKD2-related ADPKD. However, the rates of cystic growth are not different, indicating that PKD1-related ADPKD is more severe because more cysts develop earlier, not because they grow faster [Harris et al 2006].

Occasionally, enlarged and echogenic kidneys with or without renal cysts are detected prenatally in a fetus at risk for ADPKD [Zerres et al 1993]. The prognosis in these individuals is often more favorable than expected given the large kidney size with a decrease in volume and no decline in renal function commonly seen, at least during childhood. However, ESRD develops earlier than is typically seen in adult-onset disease [Fick et al 1993, Zerres et al 1993]. Biallelic PKD1 or PKD2 pathogenic variants have been reported in individuals with very early-onset ADPKD (see Genotype-Phenotype Correlations) [Cornec-Le Gall et al 2018].

Renal function abnormalities. Reduction in urinary concentrating capacity and excretion of ammonia occur early in individuals with ADPKD. The reduction of urinary excretion of ammonia in the presence of metabolic stresses (e.g., dietary indiscretions) may contribute to the development of uric acid and calcium oxalate stones, which, in association with low urine pH values and hypocitric aciduria, occur with increased frequency in individuals with ADPKD.

Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [Nagao et al 2006]. They may also contribute to the glomerular hyperfiltration seen in children and young adults, development of hypertension, and progression of chronic kidney disease [Torres 2005].

Plasma copeptin concentration (a marker of endogenous vasopressin levels) has been associated with various markers of disease severity (positively with TKV and albuminuria and negatively with GFR and effective renal blood flow) in a cross-sectional analysis of people with ADPKD [Meijer et al 2011]. Plasma copeptin concentration has also been associated with the change in TKV during follow up in the CRISP study [Boertien et al 2013].

A decline in renal function, detected as a rise in serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before ESRD. However, once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-6 mL/min/yr) [Klahr et al 1995]. The severity of the kidney disease may influence the timing and rate of decline.

Another early functional abnormality is a reduction in renal blood flow, which can be detected in young individuals (when systolic and diastolic blood pressures are still normal) and precedes the development of hypertension [Torres et al 2007b].

Hypertension usually develops before any decline in GFR. It is characterized by the following:

• An increase in renal vascular resistance and filtration fraction
• Normal or high peripheral plasma renin activity
• Resetting of the pressure-natriuresis relationship
• Salt sensitivity
• Normal or increased extracellular fluid volume, plasma volume, and cardiac output
• Partial correction of renal hemodynamics and sodium handling by converting enzyme inhibition

Hypertension is often diagnosed much later than when it first occurs in individuals with ADPKD. Twenty-four-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction [Seeman et al 2003]. Monitoring of blood pressure in children at risk for ADPKD is recommended [Massella et al 2018].

Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the main cause of death. Uncontrolled high blood pressure increases the risk for:

• Proteinuria, hematuria, and a faster decline of renal function;
• Morbidity and mortality from valvular heart disease and aneurysms;
• Fetal and maternal complications during pregnancy.

Renal pain. Pain is a common manifestation of ADPKD [Bajwa et al 2004]. Potential etiologies include: cyst hemorrhage, nephrolithiasis, cyst infection, and, rarely, tumor. Discomfort, ranging from a sensation of fullness to severe pain, can also result from renal enlargement and distortion by cysts. Gross hematuria can occur in association with complications such as cyst hemorrhage and nephrolithiasis or as an isolated event. Passage of clots can also be a source of pain. Cyst hemorrhage can be accompanied by fever, possibly caused by cyst infection. Most often, the pain is self-limited and resolves within two to seven days. Rarely, pain may be caused by retroperitoneal bleeding that may be severe and require transfusion.

Nephrolithiasis. The prevalence of renal stone disease in individuals with ADPKD is approximately 20% [Torres et al 1993]. The majority of stones are composed of uric acid and/or calcium oxalate. Urinary stasis thought to be secondary to distorted renal anatomy and metabolic factors plays a role in the pathogenesis [Torres et al 2007a]. Postulated factors predisposing to the development of renal stone disease in ADPKD include: decreased ammonia excretion, low urinary pH, and low urinary citrate concentration. However, these factors occur with the same frequency in individuals with ADPKD with and without a history of nephrolithiasis [Nishiura et al 2009].

Urinary tract infection and cyst infection. In the past, the incidence of urinary tract infection may have been overestimated in individuals with ADPKD because of the frequent occurrence of sterile pyuria. As in the general population, females experience urinary tract infections more frequently than males; the majority of infections are caused by E coli and other enterobacteriaceae. Retrograde infection from the bladder may lead to pyelonephritis or cyst infection. Renal cyst infections account for approximately 9% of hospitalizations in individuals with ADPKD [Sallée et al 2009].

Renal cell carcinoma (RCC) does not occur more frequently in individuals with ADPKD than in the general population. However, when RCC develops in individuals with ADPKD, it has a different biologic behavior, including: earlier age of presentation; frequent constitutional symptoms; and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. Males and females with ADPKD are equally likely to develop RCC. A solid mass on ultrasound; speckled calcifications on CT examination; and contrast enhancement, tumor thrombus, and regional lymphadenopathies on CT or MRI examination should raise suspicion for a carcinoma.

An increased risk for RCC in individuals with ADPKD who are on dialysis for ESRD can be explained by the increased incidence of RCC with advanced kidney disease [Hajj et al 2009, Nishimura et al 2009]. A retrospective study of 40,821 Medicare primary renal transplant recipients transplanted from January 1, 2000 to July 31, 2005 (excluding those with pre-transplant nephrectomy), demonstrated that acquired renal cystic disease pre-transplant, but not ADPKD, was associated with post-transplant RCC.

When age and other co-variants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD [Wetmore et al 2014].

Other. Massive renal enlargement can cause complications resulting from compression of local structures, such as inferior vena cava compression and gastric outlet obstruction (mainly caused by cysts of the right kidney).

Renal failure. Approximately 50% of individuals with ADPKD have ESRD by age 60 years. Mechanisms accounting for the decline in renal function include: compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells. The CRISP study [Grantham et al 2006] confirmed a strong relationship with renal enlargement and showed that kidney and cyst volumes are the strongest predictors of renal functional decline.

CRISP also found that renal blood flow (or vascular resistance) is an independent predictor of renal function decline [Torres et al 2007b]. This points to the importance of vascular remodeling in the progression of the disease and may account for reports in which the decline of renal function appears to be out of proportion to the severity of the cystic disease. Angiotensin II, transforming growth factor-β, and reactive oxygen species may contribute to the vascular lesions and interstitial fibrosis by stimulating the synthesis of chemokines, extracellular matrix, and metalloproteinase inhibitors.

Other factors including heavy use of analgesics may contribute to kidney disease progression in some individuals.

Extrarenal Manifestations

Polycystic liver disease (PLD) is the most common extrarenal manifestation of ADPKD.

Hepatic cysts are rare in children. The frequency of hepatic cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58% in participants age 15-24 years, 85% in those age 25-34 years, and 94% in those age 35-46 years [Bae et al 2006]. PLD develops at a younger age in women than men and is more severe in women who have had multiple pregnancies. After menopause, the size of liver cysts increased in women who received estrogen replacement therapy, suggesting that estrogens have an important effect on the progression of PLD [Everson & Taylor 2005]. Analysis of liver volumes and liver cyst volumes in 534 individuals with ADPKD in the HALT PKD study showed an increase in parenchymal volume and a correlation between the severity of PLD and biochemical and hematologic features, in addition to reduced quality of life [Hogan et al 2015]. Analysis of individuals with severe PLD, defined as a height-adjusted total liver volume of 1.8 liters, showed no difference in frequency among those with truncating PKD1 variants, nontruncating PKD1 variants, and PKD2 pathogenic variants, suggesting that other factors are primarily responsible for the severity of PLD [Chebib et al 2016]. This study also showed that severe PLD often regressed in females after menopause.

Liver cysts are usually asymptomatic and never cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava (IVC), hepatic veins, or bile ducts [Torres 2007].

The liver cyst epithelia produce and secrete carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of individuals with PLD and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume [Waanders et al 2009, Kanaan et al 2010].

Complications of PLD include cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Usually cyst infections are monomicrobial, are caused by enterobacteriaceae, and present with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. Elevations of CA19-9, however, can also be observed in other conditions causing abdominal pain and fever, such as acute cholangitis or diverticulitis. CT and MRI examination are helpful in the diagnosis of cyst infection but have low specificity. On CT examination, the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific but not always conclusive. ¹⁸F-fluorodeoxyglucose positron emission tomography examination is the most sensitive technique for diagnosis of infected cysts [Bleeker-Rovers et al 2003]. The rupture of a hepatic cyst can cause acute abdominal pain and ascites.

Other liver disease

• Dilatation of biliary ducts may be associated with episodes of cholangitis.
• Congenital hepatic fibrosis is rarely seen in individuals with ADPKD.
• Cholangiocarcinoma is infrequently associated with ADPKD.
• Adenomas of the ampulla of Vater have been rarely reported.

Pancreatic lesions

• Pancreatic cysts occur in approximately 8% of individuals with ADPKD. They are usually less prominent than those observed in von Hippel-Lindau syndrome (see Table 5). They are almost always asymptomatic, and rarely associated with recurrent pancreatitis [Başar et al 2006].
• Intraductal papillary mucinous tumors have been reported with increased frequency, but their prevalence and prognosis in ADPKD are uncertain [Naitoh et al 2005].
• An association between ADPKD and pancreatic carcinomas was reported [Sakurai et al 2001]; however, this may represent a chance association of two common disorders.

Cysts in other organs

• Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [Torra et al 2008].
• Arachnoid membrane cysts, present in 8% of affected individuals [Danaci et al 1998], are usually asymptomatic, but may increase the risk for subdural hematomas [Wijdicks et al 2000].
• Spinal meningeal diverticula may occur with increased frequency and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [Schievink & Torres 1997].
• Ovarian cysts are not associated with ADPKD [Stamm et al 1999, Heinonen et al 2002].

Vascular and cardiac manifestations. The most important non-cystic manifestations of ADPKD include: intracranial and other arterial aneurysms and, more rarely, dolichoectasias, dilatation of the aortic root, dissection of the thoracic aorta and cervicocephalic arteries, abnormalities of the cardiac valves, and, possibly, coronary artery aneurysms [Pirson et al 2002]. Evidence of familial clustering of thoracic aortic dissections in ADPKD also exists.

Intracranial aneurysms occur in approximately 10% of individuals with ADPKD [Pirson et al 2002]. The prevalence is higher in those individuals with a positive family history of intracranial or subarachnoid hemorrhage (22%) than in those without such a family history (6%). The majority of intracranial aneurysms are asymptomatic. Focal findings, such as cranial nerve palsy or seizure, may result from compression of local structures by an enlarging aneurysm.

The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years). The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site [International Study of Unruptured Intracranial Aneurysms Investigators 1998].

In the absence of a history of rupture from a different site, the risk for rupture is as follows:

• 0.05% per year for aneurysms <10 mm in diameter
• ~1% per year for aneurysms 10-24 mm
• 6% within one year for aneurysms ≥25 mm

In the presence of a history of rupture from a different site, the risk of rupture is 0.5%-1% per year regardless of size.

The risk of rupture of symptomatic aneurysms is higher – approximately 4% per year.

Intracranial aneurysm rupture confers a 35% to 55% risk for combined severe morbidity and mortality at three months [Inagawa 2001]. At the time of rupture of an aneurysm, most individuals have normal renal function; and up to 30% have normal blood pressure.

Follow-up studies of individuals with ADPKD with intracranial aneurysms found a moderate risk for the development of new aneurysms or enlargement of an existing one in previously symptomatic individuals and a low risk of enlargement of asymptomatic aneurysms detected by presymptomatic screening [Belz et al 2003, Gibbs et al 2004, Irazabal et al 2011].

Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography. They may also be at increased risk for central retinal arterial and venous occlusions, possibly as a result of enhanced vasoconstriction to adrenergic stimulation and arterial wall remodeling [Qian et al 2007b].

Mitral valve prolapse, the most common valvular abnormality in ADPKD, has been demonstrated by echocardiography in up to 25% of affected individuals.

Aortic insufficiency may occur in association with dilatation of the aortic root. Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination.

Several studies have shown increased left ventricular mass, left ventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise even in young normotensive individuals with ADPKD with well-preserved renal function. Even normotensive individuals with ADPKD may show significant biventricular diastolic dysfunction, suggesting cardiac involvement early in the course of the disease [Martinez-Vea et al 2004, Oflaz et al 2005]. The clinical significance of this finding remains to be determined. A study of 543 affected individuals with GFR >60 mL/min per 1.73 m², short duration of hypertension, and prior use of angiotensin-converting enzyme inhibitors / angiotensin receptor blockers who underwent cardiac MRI found a very low prevalence of left ventricular hypertrophy, possibly due to early blood pressure intervention [Perrone et al 2011].

Pericardial effusion occurs with an increased frequency in individuals with ADPKD, possibly because of increased compliance of the parietal pericardium. These effusions are generally well tolerated and clinically inconsequential. In the absence of known predisposing factors, extensive investigative and/or therapeutic interventions for silent pericardial effusion in persons with ADPKD are not indicated [Qian et al 2007a]. Recent studies have suggested that individuals with ADPKD may be predisposed to idiopathic dilated and hypertrophic obstructed cardiomyopathy, and left ventricular non-compaction [Paavola et al 2013, Chebib et al 2017].

Diverticular disease. Colonic diverticulosis and diverticulitis are more common in individuals with ESRD associated with ADPKD than in those with other renal diseases [Sharp et al 1999, Lederman et al 2000]. Whether this increased risk extends to persons with ADPKD prior to development of ESRD is uncertain.

Extracolonic diverticular disease may also occur with increased frequency and become clinically significant in a minority of affected individuals [Kumar et al 2006].

Mosaicism

Variable disease presentation in a family and apparent de novo disease can be due to mosaicism. Four families with ADPKD in which an individual has been found to have a somatic and/or germline PKD1 pathogenic variant have been described [Connor et al 2008, Consugar et al 2008, Reiterová et al 2013, Tan et al 2015]. The disease phenotype in these families is variable, ranging from similar to other non-mosaic affected family members, to much milder disease, presumably reflecting the level of the pathogenic variant in the kidneys. A recent study of individuals with ADPKD without a family history found germline mosaicism in two families and somatic mosaicism in one [Iliuta et al 2017].

Vasopressin V2 Receptor Antagonists

Studies have shown that modulation of cAMP levels by targeting the vasopressin V2 receptor can dramatically inhibit cyst development in animal models of nephronophthisis, ARPKD, and ADPKD [Gattone et al 2003, Torres et al 2004, Wang et al 2005, Wang et al 2008]. A Phase II open-label clinical trial [Higashihara et al 2011] and a Phase III global randomized double-blind placebo-controlled trial with a vasopressin V2 receptor antagonist (tolvaptan) have been completed [Torres 2008, Torres et al 2011b, Torres et al 2012]. The Phase III trial, which extended over three years, included 1,445 affected individuals with preserved renal function but large kidney volumes. The increase in kidney volume in the treated group was 2.8% per year compared to 5.5% in the untreated group. Use of tolvaptan was also associated with a slower decline in kidney function. There were fewer kidney-related adverse events in the treated group but more aquaresis, and reversible elevations in liver enzyme levels occurred in approximately 5% of individuals on tolvaptan. These elevations met Hy's law criteria denoting a 10% risk of liver failure.

Recently a one-year Phase III global randomized double-blind placebo-controlled trial of tolvaptan in 1,370 affected individuals with renal insufficiency has been completed [Torres et al 2017b]. Individuals were either 18-55 years with an eGFR of 25-65 mL/min/1.73 m² or 56-65 years with an eGFR of 25-44 mL/min/1.73 m². The change in eGFR was -2.34 mL/min/1.73 m² in the treated group compared to -3.61 mL/min/1.73 m² in the control group (p<0.001). As previously, elevations in liver enzymes were found in approximately 5% of treated subjects; elevations reversed on withdrawal from tolvaptan. No cases met Hy's law criteria likely because of more frequent monitoring of liver enzymes and earlier discontinuation of tolvaptan.

Tolvaptan has been approved for clinical use in persons with ADPKD in Japan, Canada, Europe, and the US. Various guidelines have been generated for guiding the administration of tolvaptan, focusing on selecting individuals with rapidly progressive disease that is likely to result in ESRD [Gansevoort et al 2016, Soroka et al 2017]. Factors considered for identifying rapidly progressive ADPKD are TKV/age, rate of change of TKV, eGFR/age, rate of decline of eGFR, genotype, and family history.

Hypertension

The antihypertensive agent(s) of choice in ADPKD have not been clearly established. However, because of the role of the renin angiotensin system in the pathogenesis of hypertension in ADPKD, ACE inhibitors and angiotensin II receptor antagonists may be superior to other agents in individuals with preserved renal function. ACE inhibitors and angiotensin II receptor blockers increase renal blood flow, have a low side-effect profile, and may reduce vascular smooth muscle proliferation and development of atherosclerosis:

• The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [Ecder & Schrier 2001].
• In a non-randomized study, the administration of ACE inhibitors without diuretics was found to result in a lower rate of decline in glomerular filtration rate (GFR) and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [Ecder & Schrier 2001]. However, another study found no renal protective effect of an ACE inhibitor over a β-blocker [van Dijk et al 2003]; another study found that although more rigorous blood pressure control did not preserve renal function, it did lead to a greater decrease in left ventricular mass [Schrier et al 2002].
• A long-term follow up of the Modification of Diet in Renal Disease (MDRD) Study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mmHg) experienced significantly less ESRD and combined ESRD/death than those randomized to the usual blood pressure target (MAP <107 mmHg) [Sarnak et al 2005].
• The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of renal function [Torres et al 2014]. However, in the same trial, a lower blood pressure target (95-110/60-75 mm Hg) compared to the standard target (120-130/70-80 mm Hg) in younger affected individuals with preserved renal function was associated with a slower increase in kidney volume but no overall change in the decline in renal function, as measured by eGFR [Schrier et al 2014].

Flank Pain

After excluding causes of flank pain that may require intervention, such as infection, stone, or tumor, an initial conservative approach to pain management is recommended:

• Nonopioid agents are preferred and care should be taken to avoid long-term administration of nephrotoxic agents such as combination analgesic and nonsteroidal anti-inflammatory drugs.
• Tricyclic antidepressants are helpful, as in all chronic pain syndromes, and are well tolerated.
• Narcotic analgesics should be reserved for the management of acute episodes, as chronic use can lead to physical and psychological dependence.
• Splanchnic nerve blockade with local anesthetics or steroids can result in pain relief beyond the duration of the local anesthetic.

When conservative measures fail, therapy can be directed toward cyst decompression with cyst aspiration and sclerosis:

• Cyst aspiration, under ultrasound or CT guidance, is a relatively simple procedure carried out routinely by interventional radiologists. Complications from aspiration of centrally located cysts are more common, and the morbidity of the procedure is proportional to the number of cysts treated. Cyst aspiration can help to establish causality between a cyst and the presence of pain, but seldom provides long-lasting relief because of fluid reaccumulation.
• Sclerosing agents, such as 95% ethanol or acidic solutions of minocycline, are commonly used to prevent the reaccumulation of cyst fluid. Good results have been obtained with 95% ethanol, achieving a success rate of 90% in benign renal cysts. Minor complications include: microhematuria, localized pain, transient fever, and systemic absorption of the alcohol. More serious complications such as pneumothorax, perirenal hematoma, arteriovenous fistula, urinoma, and infection are rare.

In individuals with many cysts contributing to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incision, renal denervation, and (in those who have reached ESRD) nephrectomy may be of benefit:

• Surgical decompression was effective in 80% to 90% of individuals for one year; 62% to 77% had sustained pain relief for longer than two years. Surgical intervention neither accelerates the decline in renal function nor preserves remaining renal function.
• Laparoscopic fenestration has been shown to be as effective as open surgical fenestration in short-term follow up for individuals with limited disease and has a shorter, less complicated recovery period than open surgery.
• Renal denervation via a thoracoscopic approach was successful in one affected individual [Chapuis et al 2004] and percutaneous transluminal catheter-based denervation was effective in a small number of individuals [Shetty et al 2013, Casteleijn et al 2014].
• Laparoscopic and retroperitonoscopic nephrectomy and arterial embolization have been used in individuals with ADPKD who have ESRD [Ubara et al 1999, Dunn et al 2000].
• Hand-assisted laparoscopic nephrectomy may be preferable to standard laparoscopic nephrectomy because of shorter operating time and lower morbidity [Lee & Clayman 2004].

Cyst Hemorrhage and Gross Hematuria

Cyst hemorrhage and gross hematuria are usually self limited and respond well to conservative management with bed rest, analgesics, and adequate hydration to prevent development of obstructing clots.

Rarely, episodes of bleeding are severe with extensive subcapsular or retroperitoneal hematoma, significant drop in hematocrit, and hemodynamic instability. These individuals require hospitalization, transfusion, and investigation by CT or angiography. In individuals with unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding. Some reports suggest a role for tranexamic acid in the treatment of life-threatening hematuria [Hulme & Wylie 2015].

Gross hematuria persisting more than one week or developing for the first time in an individual older than age 50 years requires thorough investigation.

Nephrolithiasis

Small uric acid stones can be missed on nephrotomography and are best detected by CT. CT should be obtained before and after the administration of contrast material to confirm the localization within the collecting system and to differentiate calculi from parenchymal calcifications. Dual absorption CT now facilitates the differentiation of uric acid stones from calcium-containing stones.

Excretory urography detects precaliceal tubular ectasia in 15% of individuals with ADPKD.

The treatment of nephrolithiasis in individuals with ADPKD is the same as that for individuals without ADPKD:

• High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects.
• Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol.
• Extracorporeal shock-wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [Umbreit et al 2010].

Cyst Infection

If cyst infection is suspected, diagnostic imaging should be undertaken to assist in the diagnosis:

• CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection.
• Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible.
• ¹⁸F-fluorodeoxyglucose positron emission tomography scanning is the most sensitive method to detect an infected cyst, but it is expensive, not readily available, and may not be reimbursed by insurance companies [Sallée et al 2009].

In the appropriate clinical setting of fever, flank pain, and suggestive diagnostic imaging, cyst aspiration under ultrasound or CT guidance should be undertaken to culture the organism and assist in selection of antimicrobial therapy, particularly if blood and urine cultures are negative [Torres et al 2007a].

Cyst infection is often difficult to treat. It has a high treatment failure rate despite prolonged therapy with an antibiotic to which the organism is susceptible. Treatment failure results from the inability of certain antibiotics to penetrate the cyst epithelium successfully and achieve therapeutic concentrations within the cyst. The epithelium that lines gradient cysts has functional and ultrastructural characteristics of the distal tubule epithelium. Penetration is via tight junctions, allowing only lipid-soluble agent access. Non-gradient cysts, which are more common, allow solute access via diffusion. However, kinetic studies indicate that water-soluble agents penetrate non-gradient cysts slowly and irregularly, resulting in unreliable drug concentrations within the cysts. Lipophilic agents have been shown to penetrate both gradient and non-gradient cysts equally and reliably and have a pKa that allows for favorable electrochemical gradients into acidic cyst fluids.

Therapeutic agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. Clindamycin, vancomycin, and metronidazole are also able to penetrate cysts well. Chloramphenicol has shown therapeutic efficacy in otherwise refractory disease.

If fever persists after one to two weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts should be undertaken. If fever recurs after discontinuation of antibiotics, complicating features such as obstruction, perinephric abscess, or stones should be considered and treated appropriately. If complicating features are not identified, the course of previously effective therapy should be extended; several months may be required to completely eradicate the infection.

End-Stage Renal Disease (ESRD)

Actuarial data indicate that individuals with ADPKD do better on dialysis than individuals with ESRD from other causes. Females appear to do better than males. The reason for this improved outcome is unclear but may relate to better-maintained hemoglobin levels through higher endogenous erythropoietin production. Rarely, hemodialysis can be complicated by intradialytic hypotension if the inferior vena cava is compressed by a medially located renal cyst. Despite renal size, peritoneal dialysis can usually be performed in individuals with ADPKD; although these individuals are at increased risk for inguinal and umbilical hernias, which require surgical repair.

Following transplantation, there is no difference in patient or graft survival between individuals with ADPKD and those with ESRD caused by other conditions, and complications are no greater than in the general population. Complications directly related to ADPKD are rare. One study has suggested an increased risk for thromboembolic complications [Jacquet et al 2011]. Whether individuals with ADPKD are at increased risk for new-onset diabetes mellitus after transplantation is questionable [Ruderman et al 2012].

Nephrectomy of the native kidneys is reserved for affected individuals with a history of infected cysts, frequent bleeding, severe hypertension, or massive renal enlargement. There is no consensus on the optimal timing of nephrectomy; whether nephrectomy is performed before, at, or following transplantation depends to some extent on the indication for the nephrectomy and other considerations [Lucas et al 2010, Kirkman et al 2011]. Hand-assisted laparoscopic nephrectomy is increasingly being used [Lee & Clayman 2004].

Polycystic Liver Disease (PLD)

Most individuals with PLD have no symptoms and require no treatment.

The treatment of symptomatic disease includes the avoidance of estrogens and caffeine and the use of H2 blockers or proton pump inhibitors for symptomatic relief.

Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. Any of these interventions should be tailored to the individual [Torres 2007, Drenth et al 2010].

• Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s).
• Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals; and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis.
• Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [Schnelldorfer et al 2009]. The surgery has good long-term results in individuals with severe PLD and is often preferable to liver transplantation, which is reserved for individuals for whom liver resection is not feasible or in whom liver function is impaired.
• Because individuals with severe PLD have mostly normal liver function, their MELD (model for end-stage liver disease) scores are low, placing them at a disadvantage for organ allocation. For highly selected individuals in this group, caval-sparing hepatectomy and subsequent living donor liver transplantation could provide a potential alternative [Mekeel et al 2008].
• Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [Takei et al 2007].

Intracranial Aneurysm

Ruptured or symptomatic. The mainstay of therapy is surgical clipping of the ruptured aneurysm at its neck.

Asymptomatic. Those aneurysms measuring ≤5.0 mm in diameter and diagnosed by presymptomatic screening can be observed and followed initially at yearly intervals. If the size increases, surgery is indicated.

The management of aneurysms 6.0-9.0 mm in size remains controversial.

Surgical intervention is usually indicated for aneurysms >10.0 mm in diameter.

For individuals with high surgical risk or with technically difficult-to-manage lesions, endovascular treatment with detachable platinum coils may be indicated. Endovascular treatment appears to be associated with fewer complications than clipping, but the long-term efficacy of this method is as yet unproven [Pirson et al 2002].

Aortic Dissection

When the aortic root diameter reaches 55-60 mm, replacement of the aorta is indicated. Guidelines for management of thoracic aortic disease have been published [Hiratzka et al 2010]. Management of aortic dissection requires coordinated input from a multidisciplinary team including a cardiologist and cardiothoracic and vascular surgeons.