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Clinical Review

Autosomal dominant polycystic kidney disease

BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i679 (Published 11 February 2016) Cite this as: BMJ 2016;352:i679
  1. Roslyn J Simms, NIHR clinical lecturer in nephrology
  1. University of Sheffield, Academic Nephrology Unit, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield Medical School, Sheffield, S10 2JF, UK
  1. Correspondence to: r.simms{at}sheffield.ac.uk

What you need to know

  • Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease with a variable spectrum of severity and extent of extrarenal complications

  • For adults with a family history of ADPKD, criteria for diagnostic screening with ultrasound exist, although repeat screening may be required for younger adults if they had an initially negative scan

  • Hypertension is the earliest manifestation of ADPKD and is preferentially managed with ACE inhibitors or angiotensin receptor antagonists

  • For at-risk individuals and affected patients, the 50% risk of inheriting ADPKD or passing it on to offspring is associated with uncertainty and a psychosocial burden

  • A new therapy (tolvaptan) to delay disease progression is available for use in selected patients in some countries after specialist assessment

What is polycystic kidney disease?

Polycystic kidney disease (PKD) is an inherited condition defined by the pathological development of fluid-filled cysts throughout the kidneys leading to organ enlargement (fig 1⇓) and chronic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited kidney disease1 and is the fourth commonest cause of kidney failure worldwide.2 Autosomal recessive PKD is a rare disease usually identified antenatally or during the neonatal period by enlarged echogenic kidneys on ultrasound.3 This review will focus on ADPKD.

Figure1

Fig 1 Anatomical illustration of a polycystic kidney (right) compared with a normal kidney (left)

Sources and selection criteria

I searched PubMed, Clinical Evidence, and the Cochrane Library for primary and review articles available in English until October 2015. Articles included systematic reviews, randomised clinical trials, and observational studies. The following search terms were used in isolation and combination: “ADPKD,” “polycystic kidney disease,” “progression,” “treatment,” “humans,” “complications,” “mutations.” I identified additional references from my personal archive. Where evidence based medicine was not available, published expert opinion was referenced.

Who gets ADPKD?

ADPKD presents to a variety of doctors and is more prevalent than the combination of Huntington’s disease, cystic fibrosis, Down’s syndrome, sickle cell disease, haemophilia, and myotonic dystrophy.4 A recent review found the incidence of ADPKD varies markedly across different continents, ranging from 3.9 to 15.3 cases per million population per year.2 Prevalence rates vary according to geographic location: in Denmark (1 in 10005), in France (1 in 11116), in Wales (1 in 24597), and in Japan (1 in 40338). In the United Kingdom the number of patients per full time general practitioner varies considerably in different areas, but if the average number of patients per GP is 1800, each GP could have one or two patients with ADPKD.

Affected individuals have a 50% risk of passing the condition on to offspring (autosomal dominant inheritance). Family history is not always positive, and 6-8% of all cases of ADPKD are as a result of a de novo mutation.2

What causes ADPKD?

ADPKD is caused by a heterozygous mutation in one of two genes (PKD1 on chromosome 16,9 in 80-85% of cases,10 or PKD2 on chromosome 411). The mutation leads to dysfunction of the corresponding protein products (polycystin 1 and 2), resulting in aberrant cellular signalling pathways with increased or disorganised cell growth and fluid secretion12 that results in fluid accumulation and cyst formation. The timing of onset and severity of disease is thought to relate to the reduction of polycystin function below a critical threshold.13 Evidence from case-control studies and expert opinion 1 suggests the condition is more severe in patients with PKD1 mutations, who experience earlier onset of clinical problems 14 and reduced survival.15

How does ADPKD manifest clinically?

Patients may present with a symptom, after screening because of a known family history, or incidentally after abdominal imaging.16Table 1⇓ lists the renal and extra-renal manifestations. The clinical course of the disease is variable (particularly the age of onset of end stage renal failure) and is influenced by the causal mutation.14 Severity can also vary within a family with the same genetic mutation, which suggests modifier genes or environmental factors may play a role.48

Table 1

Clinical manifestations of ADPKD

View this table:

Physicians should be aware of the psychological impact of ADPKD and its adverse influence on quality of life, particularly as the condition progresses as reported in cross sectional studies.49 50 Expert opinion describes a high prevalence (>60%) of anxiety and depression among patients.1 A recent meta-analysis highlighted five areas of concern from the perspective of patients: “unvalidated” pain, uncertainty, guilt, parenthood, and disclosure to children.51

How is ADPKD diagnosed?

People with a family history of ADPKD

ADPKD is most commonly diagnosed by abdominal ultrasound. Age related diagnostic criteria exist for at-risk individuals (those with a family history of ADPKD) (table 2⇓). These criteria were derived from analysis of a large cohort of patients with a confirmed genetic diagnosis of ADPKD.52

Table 2

Imaging criteria diagnostic of ADPKD in at-risk individuals*

View this table:

Expert opinion is that conventional ultrasound is suboptimal to exclude ADPKD in individuals with a family history who are younger than 40 years old,1 a population who may be potential living related kidney donors. In this age group, genetic testing is recommended for disease exclusion.54 However, expert opinion also supports the use of magnetic resonance imaging in individuals aged 16-40 years, with a total kidney cyst count of less than five, to exclude a diagnosis of ADPKD.1 53

Screening asymptomatic at-risk adults with a family history of ADPKD by ultrasound is considered by expert opinion to be beneficial enabling earlier treatment of complications and to outweigh the risks.1 It is important to note that the diagnostic criteria are age related, so that a negative ultrasound scan in a young adult may not exclude the condition before 40 years of age.52 55

The implications of a positive diagnosis should be discussed before the test,1 and the individual supported to make an informed decision on how to proceed. Some young at-risk adults may prefer not to know. Screening recommendations may change in different countries as new treatments become available. Diagnostic screening of asymptomatic children is not recommended. However, expert opinion advises screening for hypertension from 5 years of age in at-risk children,1 to identify and treat hypertension and prevent later cardiovascular complications.56

Figure2

Ultrasound of a kidney showing numerous fluid-filled cysts (dark areas)

SPL

People without a family history

Some 10-15% of patients diagnosed with ADPKD will report no family history. This can be due to a new mutation, lack of parental medical record, inability to test parents, or mild (subclinical) disease. Symptoms, signs, and radiological investigations should be considered carefully, and alternative diagnoses to ADPKD should be considered (table 3⇓). Bilateral renal enlargement with cysts and the presence of liver and pancreatic cysts is diagnostic of ADPKD.1 If ADPKD is highly likely, after incidental detection of numerous cysts (>10 in each kidney)55 on imaging, a careful family history is needed (to facilitate diagnosis and identify other at-risk family members).

Table 3

Differential diagnosis of ADPKD

View this table:

Genetic testing (see box 1) is only performed for specific clinical indications.2

Box 1: Genetic testing for ADPKD

Expert opinion1 advises genetic testing may be required to diagnose ADPKD in the following circumstances:

  • Equivocal or atypical renal imaging including potential living related kidney donors

  • Discordant disease within a family; prenatal or preimplantation diagnosis sought

  • Severe early onset disease; because of the risk of recurrence in future pregnancies.

The cost of genetic testing currently limits its routine availability, and appropriate genetic counselling with a geneticist is advised if testing is planned2

How is progression monitored?

Some risk factors for progression have been identified in cohort studies (see box 2) Progression of ADPKD is ultimately defined by the onset of end stage renal failure. A key challenge is to identify factors predictive of rapid progression in order to assess risk and select patients who may benefit from new treatments.2 Expert advice is that estimated glomerular filtration rate (eGFR) typically remains within normal range for many years despite a significant burden of cystic kidney disease because of compensatory hyperfiltration.1 When renal function does begin to decline, the mean rate of deterioration observed in placebo group patients in clinical trials is 2.3-3.7 mL/min/1.73 m3 per year.67 68 69 The CRISP (Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease) studies support the use of total kidney volume (measured on magnetic resonance imaging) as a biomarker of disease progression in ADPKD.70 A rate of increase in total kidney volume of ≥5% per year is a predictor of rapid disease progression.68 70 An imaging classification of ADPKD using total kidney volume to identify patients at risk of rapid disease progression (Mayo Classification) may be useful in selecting patients for treatment or clinical trials.71

Figure3

Expert opinion supports treatment of hypertension with medication to block the renin angiotensin aldosterone system (RAAS)

BSIP / ALAMY

Box 2: Risk factors for progression of ADPKD

  • Genotype15; a truncating PKD1 mutation is predictive of an earlier age at onset of end stage renal failure14

  • Age of end stage renal failure in a relative is predictive of the familial genotype66

  • Male

  • Hypertension21

  • Urinary tract manifestation before age 35 years22

Can progression be slowed?

A systematic Cochrane review of interventions to prevent progression of ADPKD concluded there was minimal evidence of improved patient outcome from various potential treatments,72 because the reviewers deemed single clinical trials to be inconclusive and there was insufficient evidence of a benefit in surrogate outcomes.

Tolvaptan

A pivotal clinical trial showed that, over three years, tolvaptan treatment resulted in a 50% reduction in the annual rate of kidney growth (increase in total kidney volume 2.8% per year, versus 5.5% per year in the placebo group (P<0.001)) and a 33% reduction in the rate of decline in kidney function (reciprocal creatinine level −2.61 (mg/mL)−1 per year v −3.81 (mg/mL)−1 per year with placebo (P<0.001)).68 On the basis of these results, tolvaptan has been approved for use as the first specific treatment to slow progression in ADPKD.

Tolvaptan, a selective vasopressin receptor 2 antagonist, is approved for use in Japan, Canada, the European Union, and the UK. Recommendations for use and patient eligibility varies between countries and health care systems. Within Europe, excluding England and Wales, tolvaptan is recommended for patients with “rapidly progressive disease” at chronic kidney disease stages 1-3 (only stages 2-3 in England and Wales). There is no established definition of “rapidly progressive disease.” However working groups within the UK Renal Association (box 3) and the European Renal Association have produced evidence based recommendations which will be imminently available and facilitate delivery of this treatment for eligible patients.

Box 3: Tolvaptan UK Renal Association Working Group recommendations (www.renal.org)

These recommendations are based on interpretation of the NICE guideline for patients in England and Wales. In most healthcare systems a nephrology specialist will initiate tolvaptan therapy and supervise monitoring of patients.

Eligible patients must fulfil all of the following criteria:

  • ≥18 years old with an established diagnosis of ADPKD, and have an initial assessment by a nephrologist

  • An eGFR (calculated using the CKD-EPI equation73) of 30-89 mL/min confirmed on two blood tests (72 hours apart with no intercurrent illness)

  • Evidence of “rapidly progressive disease,” defined as:

    • Continuous fall in eGFR of >2.5 mL/min per year (evident over 5 years) or

    • Continuous fall in eGFR of >5 mL/min in one year (confirmed on two blood tests (72 hours apart with no intercurrent illness) and with measurements taken at least 6 months apart) or

    • Increase in total kidney volume* >5% per year (measured on at least three scans, 6 months apart).

In all patients who start treatment with tolvaptan, monthly monitoring of liver function tests is compulsory for the first 18 months and at least every three months thereafter. Patients must be informed about the side effects (increased urine volume and thirst) and the essential need to keep themselves well hydrated.

Additional recommendations of how to assess risk of “rapidly progressive disease” in patients without the above information will be available. For patients who are not currently eligible for treatment, further evaluation at least every 3-5 years is recommended.

  • *Measured on computed tomography or magnetic resonance imaging

Other treatments

Other available evidence based treatments are not disease-specific. Expert opinion1 supports treatment of hypertension with medication to block the renin angiotensin aldosterone system (RAAS). The HALT-PKD clinical trial74 found that patients (aged 15-49 years) with early ADPKD (eGFR >60 mL/min) treated with an ACE inhibitor who achieved the lower blood pressure target (≤110/75 mm Hg) benefited from a reduction in the annual rate of increase in total kidney volume (5.6% v 6.6%, P=0.006), greater reduction in left ventricular mass index (−1.17 g/m2/year v −0.57 g/m2/year, P<0.001), and reduction in urinary albumin excretion (decrease of 3.77% v increase of 2.43%, P<0.001) compared with those with higher blood pressure targets (120/70-130/80 mm Hg).74

In children, a single randomised clinical trial of treatment with pravastatin over three years slowed disease progression, as defined by a smaller increase in total kidney volume over the three years (23% v 31% with placebo).75 However, this benefit was not confirmed in adults.

Somatostatin analogues are another novel therapy currently being evaluated in clinical trials and would target both kidney and liver cysts.

Management in primary care and when to refer to nephrology

In 2015 the first KDIGO (Kidney Disease: Improving Global Outcomes) consensus of recommendations for ADPKD was published after recognition of the need to standardise care.1 Expert opinion recommends ADPKD care is best delivered by nephrologists.2

All patients with a new diagnosis of ADPKD or uncertainty of the nature of their cystic kidney disease should be referred to a nephrologist for assessment. This will enable evaluation for complications (intracranial aneurysm, polycystic liver disease) of ADPKD and facilitate discussion about risk to the extended family (including children), which may require multidisciplinary input. Furthermore, in view of the recent availability of tolvaptan, patients should undergo specialist review to enable individual assessment of their risk of rapid disease progression.

A patient’s perspective of being diagnosed with ADPKD

My diagnosis came as a real shock, which is probably quite unusual due to the heritability of the disease. In my early teens I was screened and given the all clear at this stage and therefore believed I did not have it. I tried for quite a number of years to conceive my two children, which I had 16 months apart, so when I went for my postnatal check-up I was not particularly concerned to find my GP suspected a hernia, as I knew the two pregnancies would have had a toll on me physically. I was referred for a scan, which I went off to quite happily on my own, thinking they would just diagnose a hernia. During the scan I knew there was something unusual as the sonographer was taking a long time and kept leaving the room to consult with a doctor. She told me I had a number of large cysts on my liver and kidneys and asked about family conditions. It suddenly dawned on me that I had PKD, the same as my mother and grandfather had.

The diagnosis came at a really difficult time for me as I was struggling with all the usual adjustments to having two young children and I was really looking forward to getting my body back and feeling healthy again. The diagnosis was like a cloud forming over me. Knowing how it had affected my mother and grandfather—the infections, the limits on what you can eat, dialysis, struggling for energy, hospital visits—I already felt that I had had enough of hospitals, procedures, being scanned, manipulated, and asked questions; and getting the diagnosis was like being signed up for a lifetime of it. It was especially hard knowing that I may have passed it on to my children without knowing that was a risk when they were conceived. I also worried about their future; watching their mother struggle, getting ill, and worrying about me as I have done with my mother.

I am now a year on from my initial diagnosis, and I have begun to accept it. I can see that, at the moment, it is more “life challenging” than “life threatening.” I have also been encouraged by the advances in research, and I am hopeful that, at least if there is nothing that can be developed for my lifetime, then there will be something for my children. I have come to realise that there are some positive things about being diagnosed with PKD as it has given me more motivation to look after myself physically and it has given me a different kind of focus in life, pushing me to get on with doing things while I am well and able.

I also appreciate the support and information I have received from my kidney doctors, although on my first few visits I did feel a bit like a grumpy teenager who wanted to escape as soon as possible. It’s not nearly as painful to go there now. I feel that having more knowledge about the disease has helped me adjust, but I also look at my mother and what she is going through with a mix of feeling sadness for her now and for me in the future, which will always be difficult to live with.

Questions for future research

The ADPKD KDIGO conference1 published a detailed clinical research agenda devised from acknowledged gaps in knowledge. This list summarises the research themes:

  • How to monitor kidney disease progression. For example, When does eGFR start to fall? What is the prognostic value of serum or urine biomarkers? What are appropriate measures of quality of life and patient reported outcomes?

  • Management of renal manifestations, including: When and how frequently to screen for hypertension in children? Do statins slow disease progression in adults? What is the pathogenesis of chronic pain, and how should it be managed? What is the optimal method to investigate and manage cyst infections? Is there a role for tranexamic acid to treat cyst haemorrhage?

  • Management of extra-renal complications: How to investigate and manage liver cysts, including optimal antibiotic duration?

  • Integrated patient support: What is the effect of dietary changes? How to evaluate the psychological effect of diagnosis and impact of age? What is the impact on career and financial status?

Some clinical trials to further evaluate therapeutic agents are currently ongoing, such as the effect of somatostatin analogues on disease progression in ADPKD (DIPAK1 (Developing Interventions to Halt Progression of ADPKD) and LIPS (Lanreotide in Polycystic Kidney Disease Study)) in patients with an eGFR 30-90 mL/min and in polycystic liver disease associated with ADPKD (Pasireotide LAR in Severe Polycystic Liver Disease)

Additional educational resources

Information resources for patients

Approved sources of valid and free information for patients and their personal contacts include:

Resources for healthcare professionals

Tips for non-specialists

  • 10-15% of patients will have no family history of ADPKD and require careful exclusion of alternative diagnoses

  • A diagnosis of ADPKD cannot be excluded in patients younger than 40 years old by means of an ultrasound scan

  • Kidney function (eGFR) can remain within normal range for years despite disease progression (increasing kidney cyst development and growth) that can cause patients symptoms of pain and distress

  • Currently there are no analgesics that have superior therapeutic effect for managing pain from kidney or liver cysts, but avoiding non-steroidal anti-inflammatory drugs is advised

How patients were involved in creating this article

A local patient group voluntarily expressed interest in acting as an advisory panel and being involved in research related to ADPKD. A patient from this group contributed directly to this article, providing a patient perspective and reviewing the article content. Her feedback was positive, and she did not make any recommendations for change to the content.

Footnotes

  • I thank our patients, and particularly the text contributed by a patient about their personal experience. I thank Professor Albert Ong for his mentorship, advice, and comments on the manuscript. Information from the commentary created by members of the Renal Association Working Group (www.renal.org) on tolvaptan in ADPKD contributed to the information box on tolvaptan. I acknowledge Dr Jiehan Chong for early discussions about the review.

  • Competing interests: I have read and understood the BMJ Group policy on declaration of interests and I have nothing to declare.

  • Funding: I am supported through a clinical lectureship from the National Institute for Health Research (NIHR) UK.

  • Provenance and peer review: Commissioned; externally peer reviewed.

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