Berenice Reed

Presence of De Novo Mutations in Autosomal Dominant Polycystic Kidney Disease Patients Without Family History

BACKGROUND At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents. STUDY DESIGN Case series. SETTING & PARTICIPANTS 24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient. OUTCOME Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring. MEASUREMENTS Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found. RESULTS A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented. LIMITATIONS Size of patient group. No direct examination of RNA. CONCLUSION Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.

Variation in Age at ESRD in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Heterogeneity manifest as more severe disease in successive generations has been attributed to genetic anticipation in patients with autosomal dominant polycystic kidney disease (ADPKD). We evaluated variation in age at end-stage renal disease (ESRD) in ADPKD families for evidence of anticipation. STUDY DESIGN Retrospective. SETTING & PARTICIPANTS 413 families with ADPKD seen at our single center between 1985 and 2004 (including 95 families with documented polycystic disease type 1 [PKD1] and 213 ADPKD families with parents born before 1930). PREDICTOR Generational status. OUTCOME Age at ESRD onset. MEASUREMENTS Time to ESRD was evaluated by using survival analysis, Cox regression, and descriptive statistics. Unstable trinucleotide repeat expansion was evaluated by means of genotyping in 6 PKD1 families. RESULTS We analyzed 413 ADPKD families (1,391 parent-offspring pairs) with known age at ESRD or last known age without ESRD (informative pairs). There was no difference in age at ESRD between parents and offspring by means of Cox regression after adjusting for correlations among family members and sex (hazard ratio, 1.019; 95% confidence interval, 0.919 to 1.13; P = 0.7). Similar analysis of PKD1 informative pairs and those with parents born before 1930 showed no differences in age at ESRD. Male ADPKD patients were 42% more likely to reach ESRD (P < 0.001), and male patients with documented PKD1 were 41% more likely to reach ESRD (P = 0.01) than female patients. LIMITATIONS Hypertension treatment unknown. CONCLUSIONS We found no evidence for anticipation of ESRD in patients with ADPKD; thus, the observed variation in age at ESRD may result from other genetic, sex, or environmental causes.

Prevalence of cardiovascular events in patients with autosomal dominant polycystic kidney disease.

Background: This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients. Methods: We distributed surveys to 1,439 subjects from our ADPKD research database. In total, 426 subjects completed and returned surveys; 7 of these were from children and were excluded from the study. Results: The patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%). The mean age of the total group was 53.2 ± 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors, 86.6% were hypertensive with a mean age at diagnosis of 36.9 ± 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of the subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin-angiotensin inhibitors used by 75% of ADPKD patients. Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events. Conclusion: These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients which contribute to a greater mortality risk. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended.

Glomerular Hyperfiltration and Renal Progression in Children with Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ≥140 ml/min per 1.73 m(2). RESULTS Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (β: rate of change = +19.3 ± 10.8 cm(3)/year) over 5 years compared with those without GH at baseline (β = -4.3 ± 7.7 cm(3)/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (β = -5.0 ± 0.8 ml/min per 1.73 m(2) per year) compared with those without GH at baseline (β = +1.0 ± 0.4 ml/min per 1.73 m(2) per year), P < 0.0001. CONCLUSIONS This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.

Emergent early markers of renal progression in autosomal-dominant polycystic kidney disease patients: implications for prevention and treatment.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed.

Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease

BACKGROUND Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD). METHODS Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit. RESULTS Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6-8.9; P < 0.001) and 2.9 (1.6-5.3; P < 0.001)]. CONCLUSIONS Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.

Renal Ultrasonographic Evaluation in Children at Risk of Autosomal Dominant Polycystic Kidney Disease

BACKGROUND To date, there are no criteria for diagnosing autosomal dominant polycystic kidney disease (ADPKD) in at-risk children 15 years or younger. STUDY DESIGN Longitudinal (retrospective cohort study). SETTING & PARTICIPANTS 420 children (mean age, 8.3 +/- 4.2 years) with a family history of ADPKD were studied. MEASUREMENTS Renal ultrasonography was performed for cyst detection. Urine protein was measured using two 24-hour urine collections. Glomerular filtration rate was calculated using the Schwartz formula. Blood pressure measurements were performed in the arm with the highest blood pressure, using an appropriate cuff size. Standard 2-dimensional and Doppler echocardiography was performed for measuring left ventricular mass index. PREDICTORS None. OUTCOME Presence of renal cysts. RESULTS Renal cysts were detected in 193 children and no cysts were detected in 227 children. In children with renal cysts, 150 had bilateral and 43 had unilateral cysts. Children with bilateral cysts had larger kidneys and more hypertension than children with unilateral or no cysts. Follow-up in 77 children 15 years or younger showed bilateral cysts in 14 and unilateral cysts in 4 of the children who had no detectable renal cysts using ultrasonography at baseline. Similar follow-up of 26 children 15 years or younger with unilateral cysts detected at baseline showed bilateral cysts in 17 children using ultrasonography. By 15 years of age, 181 patients in the total group of 420 showed bilateral cysts. Overall, 193 of 304 children (63.4%) who had follow-up at any age developed bilateral cysts detected using ultrasonography. LIMITATIONS Follow-up unavailable for all participants. CONCLUSION The present results in 420 at-risk children with ADPKD 15 years or younger detected bilateral renal cysts using ultrasonography in 181 of the children who had a family history of this genetic disease.

Changing Referral Characteristics of Patients with Autosomal Dominant Polycystic Kidney Disease

OBJECTIVE Autosomal dominant polycystic kidney disease is the most frequent life-threatening hereditary disease. The study objective was to assess whether the clinical characteristics of patients with autosomal dominant polycystic kidney disease who are referred to a major autosomal dominant polycystic kidney disease center have changed over time. METHODS The clinical characteristics of patients with autosomal dominant polycystic kidney disease were compared between period A (1961-1990) and period B (1991-2011). The study took place at the Autosomal Dominant Polycystic Kidney Disease Center at the University of Colorado. A total of 837 patients referred with autosomal dominant polycystic kidney disease were included. Blood pressure control and renin-angiotensin-aldosterone system inhibition were instituted. Renal function, blood pressure, end-stage renal disease, and mortality were analyzed. RESULTS The results in period B compared with period A demonstrated an earlier age of autosomal dominant polycystic kidney disease diagnosis (29 vs 35 years, P < .001), lower mean blood pressure (129/82 vs 142/91 mm Hg, P < .001), better estimated glomerular filtration rate (63.6 vs 44.6 mL/min, P < .001), and more therapy with angiotensin-converting enzyme inhibition (42.5% vs 13.6%, P < .001). Time from birth to end-stage renal disease (52.8 ± 0.6 vs 49.1 ± 0.6 years, P < .001) and birth to death (63.5 ± 1.5 years vs 57.2 ± 1.0 years, P < .001) was longer in period B compared with period A when adjusted for age at diagnosis, sex, and estimated glomerular filtration rate. The study was retrospective, which is a limitation. CONCLUSIONS In period B, there was significantly better blood pressure control, more renin-angiotensin-aldosterone system inhibition, better preservation of renal function, and a longer period from birth to end-stage renal disease and death.

Angiogenic growth factors correlate with disease severity in young patients with autosomal dominant polycystic kidney disease

Renal cysts, pain, and hematuria are common presentations of autosomal dominant polycystic kidney disease (ADPKD) in children. Renal function, however, is typically preserved in these patients despite increased renal volume. Since angiogenesis has been implicated in promotion of renal cyst growth in ADPKD, we measured the serum level of various angiogenic factors and early renal structural changes and cardiovascular parameters in 71 patients with ADPKD, with a mean age of 16 years. Renal structure and left ventricular mass index were measured by magnetic resonance imaging or by echocardiogram. Renal function was assessed by creatinine clearance and urinary protein excretion. Serum growth factor levels were measured by enzyme-linked immunosorbent assay. Because of skewed distributions, the various parameters are reported as log(10). Serum log(10) vascular endothelial growth factor was positively correlated with renal and cardiac structure, but negatively with creatinine clearance. Serum angiopoietin 1 levels significantly correlated with structural change in both the kidney and the heart and with urinary protein. Thus, the correlation between angiogenic growth factors with both renal and cardiac disease severity is compatible with a possible role for angiogenesis in the early progression of disease in ADPKD.

The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease

BACKGROUND The epidemic of obesity and diabetes is increasing within the USA and worldwide. We have previously shown that body mass index has increased significantly in autosomal dominant polycystic kidney disease (ADPKD) subjects seen at our center in more recent years. However, the impact of Type II diabetes in ADPKD patients has not been well studied. METHODS This retrospective cohort study compared clinical characteristics in 44 pre-renal transplant patients with ADPKD and diabetes and 88 age- and sex-matched non-diabetic patients with ADPKD who were seen at the University of Colorado between 1977 and 2008. The primary outcomes in this study were renal volume determined by renal ultrasonography, renal function assessed by estimated glomerular filtration rate and time to onset of end-stage renal disease or death by Kaplan-Meier analyses. RESULTS Diabetic patients had significantly larger kidney volumes than those with ADPKD alone [geometric mean (95% confidence interval (CI)]: 2456 (1510-3992) versus 1358 (1186-1556) cm3, P=0.02. Among those whose age at hypertension diagnosis was known, the diabetic ADPKD patients had earlier median (95% CI) age at onset of hypertension compared to those with ADPKD alone: 32.5 (28-40) versus 38 (35-42) years, P=0.04. Diabetic ADPKD patients tended to have an earlier median age of death than those with ADPKD alone. CONCLUSIONS Patients with ADPKD and type II diabetes have larger renal volumes, earlier age at diagnosis of hypertension and may die at a younger age compared to those patients with ADPKD alone. This study emphasizes the importance of diabetes risk management in ADPKD.