Editor’s note: This article summarizes a presentation that Dr. Perrone is scheduled to give at the National Kidney Foundation’s 2016 Spring Clinical Meetings in Boston. The presentation will be part of the Updates in PKD program, April 28, 10:00–11:30 a.m. 

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, affecting 1–2/1000 individuals in the general population. Growth and expansion of multiple kidney cysts results in increased volume of both kidneys, complications such as gross hematuria, cyst infection, nephrolithiasis, and pain, and the development of end-stage renal disease (ESRD) in half of affected individuals by the time they are in their mid-to-late 50s.  Advances in the diagnosis and management of ADPKD are readily translatable to everyday clinical practice.

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ADPKD Diagnosis

Diagnosis of ADPKD is readily accomplished by the detection of multiple kidney cysts throughout the parenchyma using available imaging technologies, including ultrasound, computerized tomography, and magnetic resonance imaging (MRI).  Refinements in the cyst number required to make a specific diagnosis by ultrasound or MRI in younger individuals with small numbers of cysts will be reviewed. In the common situation of an ADPKD family where the genotype is not known, the presence of 3 or more kidney cysts (unilateral or bilateral) is sufficient for establishing the diagnosis in individuals aged 15–39 years.1  For individuals aged 40 years or older, having no cysts or 1 cyst is sufficient to exclude the diagnosis of ADPKD. In individuals under age 30 years with a family history of ADPKD, a new study reports that the presence of more than 10 cysts as demonstrated by MRI confers a diagnostic sensitivity and specificity of 100%.2 Quantitative criteria for individuals without a family history of ADPKD remain to be developed.

ADPKD Management

The completion of the HALT PKD study provides important insights to the management of hypertension in ADPKD.  Intensive blood pressure (BP) control (95/60– 110/75 mm Hg) versus standard BP control (120/70 to 130/80 mm Hg) in HALT Study A (ages 15–49 years; estimated glomerular filtration rate [eGFR] greater than 60 mL/min/1.73 m2) using treatment based on use of the angiotensin-converting enzyme inhibitor (ACEI) lisinopril with or without the angiotensin receptor blocker (ARB) telmisartan slowed the annual rate of total kidney volume (TKV) growth by 14.2% over the 5-year study period.3 The chronic eGFR slope, after accounting for the acute drop in eGFR in the intensive BP group, was marginally reduced (P = 0.05).  The HALT Study A (early PKD) and HALT Study B (advanced PKD: eGFR 25–60 mL/min/1.73 m2; ages 18–64 years)4 showed neither benefit nor increased incidence of adverse events (AKI and hyperkalemia) of combined ACEI/ARB use. These findings indicate that intensive BP control in closely monitored younger individuals with preserved eGFR is safe, reduces the rate of TKV growth, and might have a beneficial effect on eGFR. In practice, the option of more intensive BP control should only be offered to compliant individuals matching the HALT Study A entry criteria who are willing to undergo frequent home BP assessment and possibly increased frequency of laboratory assessment of eGFR and serum potassium.

The vasopressin receptor blocker tolvaptan was found to slow the enlargement of TKV by 50% and the rate of eGFR loss by 30%.5  Tolvaptan has not been approved by FDA for use in ADPKD. The drug cannot be used for ADPKD in the United States. There is a 30-day limitation on its use due to concerns about hepatotoxicity.  Tolvaptan is available for clinical use in Europe, Japan, and Canada after approval by the respective regulatory agencies. A global trial of tolvaptan in more advanced ADPKD (late stage 2 to early stage 4 CKD) is underway (REPRISE; NCT02160145).

Vasopressin blockade or elimination slows progression in cystic kidney disease in animal models.6  Provision of increased water intake (2.5–3 L/day) to individuals with an eGFR greater than 30 mL/min/1.73 m2 to suppress vasopressin is a reasonable strategy in clinical practice.7  Serum sodium should be monitored, and those with risk factors for hyponatremia (preexisting hyponatremia, reduced eGFR, use of diuretics) should not have high water intake. Reduction of sodium intake to 2–3 grams per day will reduce the amount of water required to lower urine osmolarity and suppress vasopressin.

TKV, genetics, and prognosis in ADPKD

An abundance of evidence demonstrates that a TKV greater than about 1100 cc (height-corrected TKV of 600 cc/m) predicts a high likelihood of future GFR decline.8  Evidence from the PKD Outcomes Consortium has been used to qualify TKV as a biomarker for the selection of participants for clinical studies evaluating progression of ADPKD.  Large TKV in younger individuals with preserved eGFR have an increased likelihood of the development of a 30% decline in eGFR and ESRD. 

Measurements of TKV are not routinely available in the clinical setting. However, an image classification system developed by investigators at the Mayo Clinic allows the relatively simple estimation of TKV and prediction of future GFR decline using measurements of kidney length, width and depth readily available from CT or MR images of polycystic kidneys (http://www.mayo.edu/research/documents/pkd-center-adpkd-classification/doc-20094754).9 This classification system is applicable only to cystic kidneys with diffuse symmetrical distribution of cysts throughout the kidneys (class 1) but not those with solitary kidneys, severe atrophy, asymmetric or lopsided cyst distribution, or unilateral cystic disease (class 2).  Entering kidney size measurements into the classification web form along with age, gender, and eGFR, yields an estimate of height-corrected TKV and a rough estimate of future GFR decline.  Although designed for selection of patients into clinical trials, nephrologists and patients could use such a system for estimating time to ESRD, recognizing inter-patient variability and unforeseen clinical events that could alter the accuracy of the prediction.

Recent studies have clarified genetic factors impacting prognosis. It is well known that PKD1 mutations result in progression to ESRD at a younger age, and larger TKV at any given age as compared to PKD2.  Further classification of PKD1 mutations into truncating (which markedly reduce the amount of polycystin 1) and non-truncating (with lesser impact on the amount of functional polycystin 1) demonstrates that patients with non-truncating PKD1 mutations have a slower course, intermediate between that of PKD1 and PKD2 patients.10,11  The Genkyst investigators have incorporated mutation type (PKD1 truncating, PKD1 non-truncating, or PKD2) along with markers of ADPKD severity, including onset of hypertension before age 35, or first urological complication (e.g., gross hematuria) before age 35, to develop a risk assessment tool designated the PROPKD score.12  An individual with a PKD1 truncating mutation, and hypertension and first urological complication before the age of 35 would have the highest risk of ESRD at a younger age. An individual with a PKD2 mutation and absence of hypertension or first urological complication before age 35 would have the lowest risk of ESRD at a younger age.

At present, assessment of risk for progression is most germane to recruitment of participants into clinical trials, although some patients would like to know what the future may hold. TKV, in concert with age and eGFR, can be used to assess likelihood of future decline in GFR. Genotyping is not widely available because of expense and because knowing the specific mutation does not currently impact clinical care. Caution must be exercised in applying risk projections to individual patients because of wide confidence bands for such projections and the likelihood of making erroneous predictions that potentially impact life planning and other important decisions. Nonetheless, discussions of level of risk for progression may provide a useful framework to guide management and to employ more intensive treatments (rigorous BP control, high water intake, low sodium diet) in those patients predicted to have a worse outcome.

Ronald D. Perrone, MD, FASN, FNKF, is associate chief of the division of nephrology and medical director of kidney transplantation at Tufts Medical Center and professor of medicine at Tufts University School of Medicine in Boston.


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