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Adult Polycystic Kidney Disease - 9/19/2012

posted Sep 19, 2012, 10:22 AM by Rohit Das   [ updated Dec 27, 2012, 6:53 AM by Purnema Madahar ]

Going to spend a bit of time reviewing an important topic – Autosomal Dominant Adult Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of renal failure. It has a reported prevalence of around 1 in every 1,000, but a substantial amount of cases go undetected. There is no racial predilection. In the states, ADPKD is the etiology of end-stage renal disease in 5% of patients. Just some pathophysiology:

  • As an autosomal disorder, the child of an affected parent has a 50% chance of inheriting this disease, which has complete penetrance.
  • There are two genes that can be potentially affected – PKD1 and PKD2, both of which regulate proteins (polycystins) that are involved in tubular and vascular development in various organs throughout the body (kidney, liver, brain…explaining some of the extra-renal manifestations, which I’ll touch on). PKD1 mutations are present in 80-90% of cases of ADPKD.
  • Importantly, PKD1 patients have a much worse prognosis than patients with PKD2 mutations. The former present with renal failure at a much earlier age, and progress more rapidly. In a study cited in the attached review article, PDK1 patients had ESRD by age 50, whereas PKD2 patients had ESRD by age 70.

Diagnosis is often made in the presence of hypertension at a young age, the presence of hematuria (occurs in up to 50% of patients, often the presenting symptom), proteinuria (usually < 300mg/day) or renal failure found on routine labs. Acutely, ADPKD can present due to cyst related complications – cyst rupture can lead to hemorrhage, and cysts can also get infected (essentially acting like an abscess). Nephrolithiasis also occurs more frequently in ADPKD patients, occurring in up to 25% of patients. These issues can also lead to acute renal failure. On that note...ADPKD and CKD:

  • Kidney failure that ultimately requires renal replacement therapy occurs in about 50% of patients, though by the 4th to 5th decade of life, most patients will have some degree of renal insufficiency. Once GFR starts to decline, the average reduction, per year, is about 4-6 ml/min. 
  • Hypertension is the first marker of disease progression, and occurs in the majority of patients by the 4th decade of life. Importantly, though important to monitor, serum creatinine DOES NOT correlate well with disease progression, especially in younger patients. Compensatory hyperfiltration can maintain normal GFR for decades in patients with significant disease, and it is not until 50% of the parenchyma is destroyed before GFR starts to fall.
  • An interesting study in 2006 showed that kidney volume is a much better predictor, at any given age, of risk for and progression of renal insufficiency. Most patients with ADPKD have combined kidney volumes exceeding 1L (normal is 300-400mL), and a combined volume of > 1.5L is highly predictive of decreased GFR.

As mentioned above, since polycystin has a role in many different organ systems, ADPKD patients can have several other “extra” renal manifestations, including hepatic cysts, pancreatic cysts, and a higher incidence of MVP and AR. These manifestations are generally asymptomatic, and may be symptomatic due to similar cyst related complications as mentioned above. Let’s talk more about a particularly important extra-renal manifestation – cerebral aneurysms, the most serious complication of ADPKD:

·        Prevalence of this issue, in observational studies, is around 5% in young adults, and increases with age to about 20% in patients over 60 years old. This almost doubles in patients with a family history. Given that, screening via MR is recommended in any ADPKD with a positive family history.

·        Generally, rupture occurs with larger aneurysms, in younger patients, and usually in the context of poorly controlled hypertension. Of note, one half of patients with cerebral aneurysms had normal renal function, again reinforcing that GFR is not a good tool to gauge extent of disease.

 

There is no real treatment for ADPKD, or rather, none that are currently FDA approved. Very interestingly, Tolvaptan is currently being studied as a potential option for slowing progression of ADPKD. This is based on observations that intracellular cAMP levels are increased in ADPKD, and that this directly leads to increased cystogenesis. Tolvaptan decreases cAMP levels in renal epithelial cells.  Phase III studies are currently under way!! Some other things to touch on: 

  • Volume expansion has been shown to be the central issue in the development of HTN in ADPKD patients. For that reason, as well as some suggestive data from retrospective studies, ACE inhibitors are recommended as the first line agent for HTN treatment. The usual things, GFR and potassium, should be monitored closely – especially in those with preexisting renal failure and large combined kidney volume.
  • Ultimately, renal replacement therapy (usually hemodialysis, since PD is difficult in the context of very large kidneys) or transplantation may be needed in the long-term.

Quick thing about “uremia.” The patient presented at chief of service presented with uremic symptoms. During the conference, Dr. Folkert did reinforce that Urea/BUN is only a SURROGATE marker for uremia. If you or I were infused with urea, we would not develop uremic symptoms. Actually, we don’t have a clear idea of what molecules really cause uremia. Research has gone into this subject, and a very nice review is attached.

 

Okayyyy…that shall be it for this week as I’ll be away for interviews…use the opportunity to catch up on the NW Daily! Keep on reading!!!!

Autosomal Dominant Polycystic Kidney Disease
Torres et. al., Lancet 2007, Volume 369: 1287-301

Meyer et. al., NEJM 2007, Volume 357: 1316-1325
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