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Background and Objectives: Disease-specific treatment options for autosomal dominant polycystic kidney disease are limited. Clinical intervention early in life is likely to have the greatest effect. In a 3-year randomized double-blind placebo-controlled phase 3 clinical trial, the authors recently showed that pravastatin decreased height-corrected total kidney volume (HtTKV) progression of structural kidney disease over a 3-year period. However, the underlying mechanisms have not been elucidated., Design, Setting, Participants, & Measurements: Participants were recruited nationally from July 2007 through October 2009. Plasma and urine samples collected at baseline, 18 months, and 36 months from 91 pediatric patients enrolled in the above-mentioned clinical trial were subjected to mass spectrometry-based biomarker analysis. Changes in biomarkers over 3 years were compared between placebo and pravastatin-treated groups. Linear regression was used to evaluate the changes in biomarkers with the percent change in HtTKV over 3 years., Results: Changes in plasma concentrations of proinflammatory and oxidative stress markers (9- hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, and 15-hydroxyeicosatetraenoic acid [HETE]) over 3 years were significantly different between the placebo and pravastatin-treated groups, with the pravastatin group showing a lower rate of biomarker increase. Urinary 8-HETE, 9-HETE, and 11-HETE were positively associated with the changes in HtTKV in the pravastatin group., Conclusions: Pravastatin therapy diminished the increase of cyclooxygenase- and lipoxygenase-derived plasma lipid mediators. The identified biomarkers and related molecular pathways of inflammation and endothelial dysfunction may present potential targets for monitoring of disease severity and therapeutic intervention of autosomal dominant polycystic kidney disease., (Copyright © 2015 by the American Society of Nephrology.)

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression., (Copyright © 2014 the American Physiological Society.)

Inflammatory activity is evident in patients with chronic kidney disease with limited data available in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inflammation is an upstream event in the pathogenesis of ADPKD and may be a contributing factor in the disease severity and progression. Serum samples from 61 HALT study A group patients were compared with samples from 49 patients from HALT study B group with moderately advanced disease. Targeted MS analysis of bioactive lipid mediators as markers of inflammation was performed and correlated with eGFR and total kidney volume (TKV) normalized to the body surface area (BSAR) to assess if these markers are predictive of ADPKD severity. ADPKD patients with eGFR >60 ml/min/1.73 m(2) showed higher levels of 5- and 12/15-lipoxygenase (LOX) and cyclooxygenase, and generated higher levels of hydroxy-octadecadienoic acids 9-HODE and 13-HODE and HETEs 8-HETE, 11-HETE, 12-HETE, and 15-HETE as compared with healthy subjects. Linear regression of 9-HODE and 13-HODE revealed a significant relationship with eGFR and TKV, while 15-HETE significantly correlated with TKV/BSAR. Production of 20-HETE, a P450-produced metabolite of arachidonic acid, was higher in ADPKD patients as compared with healthy subjects and significantly correlated with eGFR and TKV/BSAR. Perturbation in fatty acid metabolism is evident early in ADPKD patients, even in those with preserved kidney function. The identified LOX pathways may be potential therapeutic targets for slowing down ADPKD progression., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background and Objectives: In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD., Designs, Setting, Participants, & Measurements: There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a ≥ 20% change in HtTKV, LVMI, or UAE over the study period., Results: Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23% ± 3% versus 31% ± 3%; P=0.02)., Conclusions: Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

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.

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.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8-22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and has important clinical manifestations in childhood. Numerous studies have documented the superiority of magnetic resonance imaging (MRI) for serial monitoring of kidney and cyst volume in this condition in adults. However, no studies have examined the utility of MRI for serial assessment of kidney and cyst volume in children with ADPKD., Design, Setting, Participants, & Measurements: Subjects 4 to 21 years of age with ADPKD underwent abdominal MRI on an annual basis for 5 years. Subjects were grouped according to BP as hypertensive (HBP; BP≥95th percentile for age, height, and gender) or as normotensive (NBP; BP<95th percentile). Total kidney volume (TKV), cyst volume, and cyst number were assessed by stereology., Results: MRI studies (n=302) were obtained in 77 children with ADPKD. TKV and cyst volume were significantly increased in HBP versus NBP subjects. HBP subjects demonstrated a greater increase in fractional cyst volume over time versus NBP subjects. Cyst number increased more rapidly in HBP ADPKD children., Conclusions: This is the first large-scale clinical study examining the utility of MRI for serial assessment of TKV, cyst volume, and cyst number in children with ADPKD. These results demonstrate that MRI is an acceptable means to follow these parameters in children with ADPKD. Because of the embryonic occurrence of cysts, interventional trials are needed in ADPKD children and MRI may be the preferred renal imaging approach.

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.

Background and Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive hereditary disorder affecting children and young adults. Early intervention may be necessary to significantly affect the long-term consequences of this disease., Design, Setting, Participants, & Measurements: The authors conducted a 5-yr randomized clinical trial to assess the effect of BP control with angiotensin-converting enzyme inhibition (ACEI) on disease progression in 85 children and young adults with ADPKD. Study groups were determined by subject BP, including hypertension (BP >or= 95th percentile), borderline hypertension (BP 75 to 95th percentile), and severe ADPKD (BP 10 renal cysts). The primary outcome variable was renal volume by ultrasound, with secondary outcome variables including left ventricular mass index (LVMI) and microalbuminuria. In secondary analysis, the authors compared results between hypertensive and normotensive groups., Results: The authors were not able to demonstrate a significant effect of ACEI on renal growth in young subjects with ADPKD. Hypertensive children were at particular risk for increases in renal volume and LVMI and decreased renal function as compared with the other study groups, and borderline hypertensive children were at high risk to develop hypertension over time. However, ACEI treatment was associated with stable renal function and LVMI in this group of children., Conclusions: Close monitoring of cardiovascular and renal status is indicated in ADPKD children with hypertension or borderline hypertension. In contrast to effects in hypertensive ADPKD children, ACEI treatment in normotensive or borderline hypertensive ADPKD children may prevent the development of increased LVMI and deterioration in renal function.

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.

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary condition that may be diagnosed in utero. Our goal was to evaluate symptoms of ADPKD in children, including left ventricular mass index (LVMI), renal volume, renal function and microalbuminuria in relation to systolic and diastolic blood pressure. Eighty-five children were stratified by blood pressure into three cohorts: hypertensive (95th percentile and over), borderline hypertensive (75-95th percentile) and normotensive (75th percentile and below). There were no differences in gender, age, height, renal function, or microalbuminuria between the groups. Both the hypertensive and borderline hypertensive children had a significantly higher LVMI than normotensive children, with no significant difference between hypertensive and borderline hypertensive groups. There was a significant correlation between renal volume and both systolic and diastolic blood pressures in all subjects. Renal volume in hypertensive children was significantly larger than in the borderline hypertensive group, with no significant difference between normotensive and borderline hypertensive groups. These findings show that an increase in LVMI may be detected earlier than an increase in renal volume in children with ADPKD and borderline hypertension, suggesting that close monitoring of cardiac status is indicated in these children.

Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst-lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including IL-8, epithelial neutrophil-activating peptide (ENA-78), growth-related oncogene-alpha (GRO-alpha), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e., cholangiocytes). In polarized pkd2(WS25/-) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating that they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP, and NF-kappaB were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between -272 and -1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth.

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.

Aim: The goal of this study was to compare the clinical features of patients with isolated polycystic liver disease (PCLD) with those of patients with polycystic liver and autosomal dominant polycystic kidney disease (ADPKD)., Methods: Cases were identified from clinical records at the University of Colorado Hospital in Denver (USA) and at the Radboud University Hospital in Nijmegen (the Netherlands) by ICD-10 codes. To be included in this analysis, patients had to have an initial diagnosis of PCLD within six years of presentation to our clinics. Medical records were reviewed for demographic information, medical history, physical examination, symptoms, complications, laboratory and imaging results, therapy and outcomes., Results: Out of a total of 94, 53 patients met our criteria for entering this study, 19 with PCLD and 34 with ADPKD. The mean time interval from diagnosis of PCLD to presentation in our clinics was 1.21 years for PCLD and 2.76 years for ADPKD (P=NS). PCLD was associated with female gender in both PCLD and ADPKD. Patients with PCLD had greater numbers (P=0.031), and larger sizes of liver cysts (P=0.0051), but had less associated morbidities than patients with ADPKD. Liver cyst decompressions were performed more frequently in PCLD patients (57.9 vs. 23.5%, P=0.012). However, serious hepatic complications, sufficient to require consideration of liver transplantation, were more frequent in patients with ADPKD (0/19 vs. 6/34, P<0.0001)., Conclusions: Although PCLD in patients with PCLD is characterized by larger and greater number of hepatic cysts, the clinical course is relatively benign compared with ADPKD.

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) often develop hypertension before any abnormalities in renal function are detected clinically. Therefore, standard screening (serum creatinine and urinalysis) of young individuals with unexplained hypertension to exclude renal parenchymal disease would rarely detect ADPKD., Methods: Data from 516 subjects with ADPKD (217 male and 299 female), aged newbornto 55 years with a normal serum creatinine and no proteinuria based on urine dipstick, studied between 1985 and 2000, were compared with data from similar subjects from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES IV (1999-2000) data, by gender., Results: There was a highly significant occurrence of hypertension in young patients with ADPKD when compared to patients aged 20 to 34 years in the U.S. population. The hypertension in patients with ADPKD occurred in the absence of abnormal renal function or abnormal urinalysis., Conclusions: These data indicate that renal ultrasound screening of young hypertensive individuals (aged 20 to 34 years) should be considered when searching for causes of secondary hypertension. Identifying affected ADPKD individuals early in their disease will permit aggressive blood pressure treatment and early inhibition of the renin-angiotensin-aldosterone system, which has been shown to reverse left ventricular hypertrophy, an important cardiovascular risk factor. In the present era of renal replacement therapy, cardiovascular complications are the main cause of death in patients with ADPKD.

Background: Hypertension in autosomal-dominant polycystic kidney disease (ADPKD) patients is associated with more rapid progression of renal disease and a high incidence of left ventricular hypertrophy (LVH). The present study was undertaken to examine the role of parental hypertension in the occurrence of hypertension in 475 ADPKD offspring., Methods: Adult subjects participating in an ongoing study of the natural history of ADPKD were included in the analysis if they were diagnosed with ADPKD, had a known affected parent, and knew the hypertensive status of both parents., Results: When the affected parent was hypertensive, the ADPKD male (82% versus 62%, P < 0.05) and female (61% versus 37%, P < 0.005) offspring had a significantly higher frequency of hypertension than when the ADPKD-affected parent was normotensive. The median age of diagnosis of hypertension was also significantly earlier in both male (33 years versus 40 years, P < 0.05) and female (38 years versus 50 years, P < 0.05) ADPKD patients when their affected parents were hypertensive as compared with normotensive. These effects of hypertension in the affected parent on hypertension in the ADPKD offspring were independent of age, renal volume, and renal function in the offspring. Hypertension in unaffected parents also increased the frequency of hypertension in the ADPKD female (69% versus 53%, P < 0.01), but not male (89% versus 77%, NS) subjects., Conclusion: The results indicate that parental hypertension influences the frequency of hypertension in ADPKD patients.

Background: The natural history of intracranial aneurysms (ICAs) in individuals with autosomal-dominant polycystic kidney disease (ADPKD) is poorly defined., Methods: We followed twenty ADPKD subjects, eleven with ruptured and nine with intact ICA, for 15.2 +/- 8.1 years (range, 6.0 to 33.2 years). Initial diagnosis was by four-vessel cerebral angiography in eighteen subjects. Follow-up examinations were four-vessel cerebral angiography in fourteen and magnetic resonance angiography (MRA) in six subjects. We examined the occurrence of new ICAs, an increase in size of existing ICAs, recurrent rupture or surgical intervention, and death., Results: Age at initial diagnosis of ICA was 37.7 +/- 10.4 years (range, 20.2 to 53.1 years). Seventeen subjects (85%) had an anterior and three (15%) had a posterior ICA at initial diagnosis. On restudy, five subjects (25%) had a significant change, consisting of new ICAs in a different location in all five and an increase in size of an existing ICA in two of the five. All subjects with ruptured ICA and one subject with intact ICA had undergone surgery at the time of initial diagnosis. Ten subjects (50%) underwent further surgery 8.1 +/- 6.1 years later (1.3 to 17 years). No subject died during follow-up and one subject experienced a recurrent RICA (RICA). We were unable to identify risk factors associated with development of a new ICA or increase in size of an existing ICA., Conclusion: Individuals with ADPKD and ICA appear to be at moderate risk for new ICAs and increase in size of existing ICAs; mortality and risk of recurrent rupture, however, appear to be low.

In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal study from 1985 to 2001. Sequential ultrasound examinations were performed at a mean interval of 7.8 +/- 3.1 years (range, 2.6 to 15.1 years). Renal volume was calculated using a standard formula for a modified ellipsoid. The Modified Diet in Renal Disease equation was used to calculate glomerular filtration rate (GFR). The mean annual increase in renal volume was 46 +/- 55 cm3, and mean annual decline in GFR was 2.4 +/- 2.8 mL/min/1.73 m2. Men had faster renal growth, more severe hypertension, and a faster decline in GFR than women of similar ages. Multiple linear regression showed a significant relationship between rate of change in GFR and renal volume growth rate, initial renal volume, proteinuria, and age at entry. Correlational analysis showed a significant correlation between GFR and renal volume over time (R = -0.53) and between follow-up renal volume and follow-up GFR (R = -0.50) for both men and women. We conclude that renal volume and rate of renal volume growth may be useful markers for disease progression in early stages of ADPKD when GFR is preserved., (Copyright 2002 by the National Kidney Foundation, Inc.)