ADPKD Recent Australian Article

I was granted permission by my specialist Dr Nankivell, and his co-author Dr Rangan, to edit and publish this article on morethanpkd.com. It was originally written for the General Practitioner readership of Medecine Today but I have adapted it to make it more relevant to PKD patients.

 

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Adapted, with permission, from the article by the same name, authored by:

Dr Gopala Rangan1,2 PhD (Syd), FRACP, MB BS (UNSW), Senior Staff Specialist;

Dr. Brian J. Nankivell1,2, PhD (Syd), FRACP, MRCP, MPharm, MB BS, MD, Senior Staff Specialist

 

Institution:

1Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District; 2Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney.

 

Published in Medecine Today Journal 2014 

 

 Abstract

ADPKD is a genetic condition characterized by the formation of multiple fluid-filled renal cysts, together with kidney enlargement.  ADPKD leads to end-stage kidney failure, and is associated with early-onset high blood pressure and kidney stones as well as other potential complications such as brain aneurysm and polycystic liver disease. Your GP should play an important role in all aspects of your ADPKD management, including referring you to a nephrologist, genetic counselling, prevention and management of high blood pressure, preventing kidney function decline, and screening for complications.

 

How common is ADPKD?

ADPKD affects about one in every 500-1000 people and occurs in all races. In Australia, it is the fourth most common cause of end-stage renal failure (ESRF). Currently approximately 1200 Australians with ESRF due to ADPKD receive dialysis or have a transplant.

 

What are the characteristics of ADPKD?

The hallmark of ADPKD is the presence of multiple cysts in the kidney together with kidney enlargement, typically detected by renal ultrasound in an adult patient. The cysts form early in life (possible in utero or in early childhood) when they are microscopic and not visible by radiological imaging. Over time, the renal cysts grow by 10-20% per year and when they are about 1 cm in diameter, they first become detectable by ultrasound.  When the disease is established in mid-adult life, the kidney has a markedly abnormal appearance, containing thousands of cysts that vary in size from 1 to several centimetres in diameter, resulting in large (sometimes weighing up to 3-5kg) and irregularly shaped kidneys. Kidney failure occurs in later life when a critical number of cysts have collectively reached a sufficient size to crowd out the healthy kidney tissue and destroy normal kidney function.

Other important systemic characteristics include:

  • hypertension (high blood pressure)
  • frequent need to urinate
  • pain due to kidney size or if cysts bleed or become infected
  • an increased risk of developing kidney stones
  • cysts in other organs (liver, pancreas, lungs)
  • brain or heart aneurysm
  • Other: diverticulosis (out-pouchings in the intestinal wall which can trap food and lead to infection), hernias, heart valve abnormalities, enlargement of lung airways, and male infertility (rarely).

 

What causes ADPKD?

ADPKD is a dominant single gene disorder with complete penetrance which means that only one copy of the mutated gene is required for a person to have the disease. Therefore, if a parent has ADPKD, each child will have a 50% chance of also having it. In the majority (85% of cases) ADPKD is due to mutations in the Polycystic Kidney Disease 1 (PKD1) gene. In the remainder (15%) ADPKD is due to mutations in the PKD2 gene.

 

How do the renal cysts form in the first place and why do they keep growing?

The PKD1 and PKD2 genes encode the proteins, polycystin-1 and polycstin-2 respectively, which are vital for maintaining the normal structure of the kidney. Being a systemic disease, all cells in the body of a person with ADPKD actually carry the mutated gene, but only some cells start to proliferate (either in utero or during early life), leading to the formation of protrusions in the kidneys and other organs. With continued growth, the diameter of these protusions, in the kidneys, increases over time and eventually they lose their connection with the organ walls and form independent “encapsulated cysts”. The cysts continue to slowly grow and expand over many decades, but at different rates, ultimately leading to the haphazard and grossly abnormal appearance of the late-stage ADPKD. It is currently unknown why protrusions only form in some organs and why the kidneys are the prime location of cyst formation.

 

How do patients with ADPKD typically present?

ADPKD symptoms typically do not appear until after early-middle adulthood. Rarely, it may present in utero or in early childhood. About 50% of all patients have no symptoms that they are generally aware of and therefore diagnosis is usually a result of: (i) detection on radiological imaging (ultrasound, CT or MRI) which has been performed either for screening of at-risk individuals who have a positive family history, or for other reasons (such as to detect the cause of sudden pain or blood in the urine); (ii) detection of high blood pressure in a young individual (<40 yrs of age); and/or (iii) blood or urine test results suggesting a reduction in kidney function.

 

How is the diagnosis of ADPKD made?

Making the diagnosis requires a positive family history of ADPKD, along with the presence of multiple cysts, in both kidneys, as viewed on an ultrasound. In about 5% of patients, no family history is found (even after screening of both parents) and this is most likely due to the development of a spontaneous mutation in the affected person’s genes. There is currently no known cause of these ‘one off’ mutations.

 

What is the role of DNA genetic testing?

DNA genetic testing is available to determine the type of mutation (PKD1 or PKD2) but the successful detection rate with these techniques varies between 65-85%. Since general ADPKD diagnosis can be made easily by ultrasound, and confirmation of mutation type does not alter medical management, genetic testing is not required or performed in routine clinical practice (genetic testing is also very expensive).

 

Screening of family members of affected patients to exclude the diagnosis

Counselling and screening of at-risk first degree family members should include a discussion of the risks and benefits of making the diagnosis. The benefits of making the diagnosis are the early detection and treatment of complications (particularly high blood pressure and the prevention of kidney function decline) and possible assistance with future family planning. However, the emotional impact of making the diagnosis of ADPKD on the individual, and future issues for life insurance applications and employment, need to be taken into account. The screening methods employed include measurement of blood pressure and renal ultrasound. A normal ultrasound does not exclude the diagnosis of ADPKD until the age of 40 years of age.

 

Management of ADPKD

(i)                 Counselling regarding the risk of End Stage Renal (Kidney) Failure (ESRF): The possibility of ESRF can cause significant anxiety in patients affected by ADPKD. However, it is important to highlight that the life-time risk of developing ESRF varies significantly from one person to another (even within the same family), and the diagnosis of ADPKD does not necessarily imply a future risk of developing ESRF. Individuals with PKD1 mutations tend to have larger kidneys, a greater number of cysts and almost all experience ESRF by 70 years of age. In contrast, patients with PKD2 mutations have milder disease and more than 50% can have adequate renal function at age 70. ADPKD patients also have a long period of stable or mildly abnormal kidney function until the fourth to sixth decade of life.

(ii)               Dietary and lifestyle treatments to slow the progression of ADPKD: There are no dietary guidelines specifically for patients with ADPKD. However, generic interventions recommended to reduce cardiovascular risk are likely to be beneficial (i.e. regular exercise, no smoking, avoiding alcohol, maintenance of a healthy weight range, dietary salt restriction). A low protein diet has not been shown to slow the rate of decline in renal (kidney) function in ADPKD. Patients with ADPKD are at increased risk of kidney stones and should maintain adequate fluid intake. Caffeine stimulates cyst growth in cultured cells, and patients are advised to limit their intake to less than 2 caffeinated drinks per day (coffee, tea, energy drinks etc).

(iii)             Hypertension (high blood pressure): Hypertension occurs in 60% of patients prior to the loss of kidney function and is almost universal in late-stage ADPKD. The average age of onset of hypertension is between 30-35 years. Over the last 20 years, the appropriate treatment of hypertension in ADPKD patients has significantly reduced the incidence of cardiovascular disease.

(iv)             Generic treatments to slow the progression of ADPKD: Generic interventions that are recommended to slow the progression of all types of CKD (Chronic Kidney Disease) should not be ignored in ADPKD, as they may also slow cyst growth. There are a number of human drug trials underway testing these CKD treatments for their effect on APKD. Finally, as in CKD, acute kidney injury (AKI) and exposure to kidney toxins should be avoided where possible. Kidney toxins include Non-Steroidal Anti-inflammatory medications (NSAIDS) such as Nurofen and Voltaren, radiocontrast agents and aminoglycoside antibiotics.

(v)               Disease-modifying drugs currently under investigation: There are currently no approved therapies in ADPKD to stop kidney cysts from forming in early life or in slowing the rate of cyst growth during adulthood. However, several randomized controlled trials are currently in progress and specific disease-modifying treatments could be available within the next decade. For example, the pituitary hormone, vasopressin, is known to promote cyst growth and a recent randomized controlled trial showed that 3-years of treatment with a vasopressin blocker (Tolvaptan) reduced cyst growth by almost 50% in early-stage ADPKD. These results are encouraging but further clinical trial data has been requested by the United States Food and Drug Administration and, at least in Australia and the United States, the use of Tolvaptan for the treatment of ADPKD is experimental and remains in the clinical trial setting. Interestingly, adequate fluid intake also regulates vasopressin but a recent non-randomised clinical trial in ADPKD patients showed inconclusive results, and further studies are needed to evaluate this.

 

Management of ADPKD with Stage 4-5 CKD

Late-stage ADPKD requires careful monitoring of kidney function and evaluation of CKD-related complications, pre-dialysis counseling, timely creation of chronic dialysis access and consideration for pre-emptive kidney transplantation by living kidney donation.

Other renal complications:

(i)                 Impaired urinary concentrating ability: This means ‘needing to urinate often’ and is a common symptom which occurs even in the early stages ADPKD

(ii)               Chronic renal pain: Mild discomfort in the side and/or abdomen, that is present on most days, is reported in 60% of patients who have large kidneys, relative to the size of their abdominal cavity. Typically, the discomfort is mild in severity and does not require pain killers. Occasionally chronic pain can be severe and disabling and requires appropriate chronic pain management and occasionally surgical interventions, such as draining of large cysts and nerve deadening procedures.

(iii)             Acute renal pain: The sudden onset of acute pain requires careful evaluation with history, physical examination and renal imaging (CT scan). The following causes should be considered in the diagnosis:

  • Cyst Haemorrhage (Bleed): This may present with a sudden abdominal pain and/or with blood in the urine, and will occur in up to 50% of patients, at some stage. It may relate to trauma to the kidney (particularly when playing contact sports) or can be spontaneous. Management of cyst bleeds typically entails bed rest, increased fluid intake and simple pain killers. The episodes are typically resolve within 2-7 days. If symptoms last longer than 1 week or if the initial episode occurs after the age of 50 years, further investigations should be considered.
  • Urinary tract and cyst infection: Pain due to an infected cyst may present with fever, chills and joint stiffness. Cyst infections are difficult to diagnose, but if a cyst infection is suspected, treatment with antibiotics should be used. Occasionally, draining an infected cyst may be required if the infection does not respond to treatment with antibiotics.
  • Kidney Stones: Kidney stones occur in 30% of ADPKD patients (compared to 8-10% of the population). Symptoms may include pain, blood in the urine, chills and fever and an urgent need to urinate.

 

Important systemic complications:

(i)                 Intracranial cerebral (brain) aneurysms (ICAs) and counselling regarding screening for ICAs: The prevalence of ICAs in patients with ADPKD is approximately 5-10% compared to 1% in the general population. Ruptured ICAs account for 5% of deaths in the ADPKD population and occur at an earlier age (39 years vs 51 years in the general population). Screening for ICAs is indicated in patients with a family history of ICA but other reasons for screening include previous ICA or rupture, preparation prior to major elective surgery or at the request of the patient. In counselling patients regarding the latter, the risk and benefit of screening for ICAs should be discussed. In general, routine screening for ICAs  is not undertaken as it mostly reveals small aneurysms with a low risk of rupture. Cerebral CT with low-dose contrast or cerebral MRA are suitable screening tests for ICAs.

(ii)               Liver cysts: Liver cysts can occur in up to 80% of ADPKD sufferers. Generally, they do not cause any symptoms and liver function tests remain normal. Rarely, people develop severe polycystic liver disease (PLD). Severe PLD more commonly occurs in females. Risk factors predisposing to severe PLD include multiple pregnancies, exposure to oral contraceptives and hormone replacement therapy, suggesting that female sex hormones promote the growth of liver cysts.

 

What clinical, laboratory and imaging investigations are useful for monitoring ADPKD?

Clinical and laboratory investigations: ADPKD is a form of CKD, and the frequency of clinical monitoring and type of laboratory testing should follow the 2012 Kidney Health Australia CKD guidelines and be tailored according to the stage of kidney function decline. In ADPKD, clinical monitoring should include periodic review of symptoms (e.g. pain), cardiovascular risk assessment, blood and urine tests, kidney ultrasound, and blood pressure measurement. Routine blood and urine tests should measure urea (the waste produced by the body after metabolizing protein), creatinine (a chemical waste product that’s produced by your muscle metabolism), eGFR (estimated Glomerular Filtration Rate – describes the flow rate of filtered fluid through the kidney), electrolytes (minerals in the blood), FBC (full blood count) and proteinuria (protein in the urine).

 

Will care be shared between a specialist and the GP?

The GP has a vital role in long-term management, as the majority of patients with ADPKD will be relatively healthy and without troublesome symptoms.  Patients should be referred to a Nephrologist (kidney specialist) for initial evaluation when the diagnosis is known or suspected. The Nephrologist will provide further detail about the condition, assess disease severity and presence of symptoms/complications, provide advice on management of CKD-related complications including the timely preparation for dialysis and/or transplant and discuss screening of family members. In early-stage or mild disease, the visits to a Nephrologist usually occur infrequently (1-3 year intervals) but in late-stage or severe disease, (stage 3-5), visits may be more frequent.

 

Conclusion

ADPKD is an important genetic cause of CKD. The risk of End Stage Renal Failure (ESRF) is highly variable, and generic treatments that slow the progression of CKD are also likely to be useful in ADPKD. For those ADPKD patients that have a high risk of developing ESRF, rapid progress in the field is being made, and it is likely that the first generation of disease-modifying drugs and other interventions will become available to slow disease progression in the near future. The development of more sophisticated tools for predicting an individual’s future risk of ESRF using genetic tests and biomarkers will also allow the introduction of these interventions in early adult-hood.

 

Further reading

  1. Thomas MC. Autosomal Dominant polycystic kidney disease. Nephrology 12: S52-S56, 2007
  2. Hughes PD, Becker GJ. Screening for intracranial aneurysms in autosomal dominant polycystic kidney disease. Nephrology 8: 163-70, 2003
  3. Barlow-Stewart K, Emery J, Metcalfe S. Genetics in Family Medicine: The Australian Handbook for General Practitioners. Accessed online at http://www.gpgenetics.edu.au
  4. Torres VE, Chapman AB, Devuyst O, Ganesvoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS. Tolvaptan in patient with autosomal dominant polycystic kidney disease. N Engl J Med 367: 2407-18, 2012.
  5. Higashihara E, Nutahara K, Tanbo M, Hara H, Miyazaki I, Koboyashi K, Nitatori T. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease? Nephrol Dial Transplant (epress), 2014
  6. Cadnapapphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, Schrier RW. Effect of pravastatin on total kidney volume, left ventricular mass index and microalbuminuria in pediatric ADPKD. Clin J Am Soc Nephrol (epress, doi: 10.2215/CJN.08350813), 2014

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