The Rogosin Institute

Preliminary Data – Rogosin ADPKD Repository

The Rogosin Institute Polycystic Kidney Disease Center Data Repository was established in December 2002 to provide a centralized database of clinical, genetic, biochemical and imaging information obtained longitudinally on a large population of patients with autosomal dominant polycystic kidney disease (ADPKD). This project is conducted at RU CCTS, the WMC MRI facility, and WMC Echocardiography Laboratory in the Division of Cardiology.

Enrollment:
From January 2003 to September 2007, 139 subjects with ADPKD were enrolled in this study. Seven patients were excluded after the initial evaluation because of uncertainty regarding the diagnosis of ADPKD. An interim analysis of 132 subjects is available for presentation. The sole inclusion criterion is a diagnosis of PKD, based upon a family history and a renal imaging study (e.g., renal ultrasonography). Enrollment was initially focused on subjects with chronic kidney disease (CKD) of varying stages of severity (NKF CKD Stages 1-6), including those with end-stage renal disease (ESRD, including subjects treated with dialysis or transplantation [CKD Stage 6]).
   

Demographics:
Of the 132 evaluable ADPKD subjects, 56.1% are women, 88.6% white, and 5.3% Hispanic. The mean age at enrollment was 46.9±14 years and age of ADPKD diagnosis 35.4±14 years. A family history of ADPKD was known in 75.8% of subjects, with 11 families providing 25 patients.
   

PKD Genotype: (See Table)

Athena Diagnostics, Inc performed PKD genotyping for this study until December 2006. Since then, all PKD genotyping has been conducted at the Molecular Diagnostic Laboratory at WMC. The WMC laboratory methods enable more extensive analysis of intronic regions not accessible by the techniques employed by Athena. In addition, the WMC method is more efficient, enabling more rapid reporting of results at lower cost.
   
PKD genotype data were analyzed, thus far, for 115 subjects (Table 1). Either a known disease associated mutation, or unknown probable mutation in either PKD1 or PKD2 gene was identified by mutation analysis in 53.9% of these subjects. Of those, known positive disease associated mutations (KPDAM) or the unknown probable disease associated mutations (UPDAM), 74.2% were PKD1 and 25.6% were PKD2 mutations.

                   

The KPDAM and UPDAM were comprised by truncation mutations. Of these truncation mutations, stop codons were identified in 46.8%, frameshift mutations in 38.7%, and splice site mutations in 14.5% (Table 1). Missense mutations causing amino acid changes were identified in 46.1% of all subjects. The pathogenic potential of the vast majority of PKD gene missense mutations is not well defined. At the present time, we are intensively investigating this issue.
   
The relatively small sample size, particularly of those with the PKD2 genotype, mitigates stratification of phenotype variables by PKD genotype. However, this is ultimately one of the goals of this study.
   

Renal manifestations:
At enrollment, mean serum creatinine 1.9±1.5 mg/dl, BUN 28±19 mg/dl. Azotemia, (i.e., MDRD-estimated glomerular filtration rate [GFR]<60 ml/minute/1.73 m2) was present in 60.3%, with 7% of all subjects reaching ESRD. Of the 9 ESRD subjects, 3 have a functioning renal transplant and 6 require maintenance hemodialysis.

Compared with non-azotemic subjects (median GFR = 76.2 ml/min/1.73 m2), those with azotemia (GFR 32.7 ml/min/1.73 m2) were significantly older (52.6 vs 37.5 yrs; p<0.0001), with borderline higher mean systolic BP (126 vs 120 mm Hg; p<0.05), larger mean renal volume by MRI (933 vs 436 ml; p<0.0001), and higher mean serum uric acid level (6.5 vs 4.9 mg/dl; p<0.0001). There was a significant, inverse correlation between renal volume and estimated glomerular filtration rate (R2= 0.22; p=0.0003). In a multivariate regression model, serum uric acid (Beta= -78; p = .02), urine protein (Beta = -12; p<0.05), and age (Beta = -.39; p<.05) were independent predictors of estimated GFR. In this multiple regression analysis, the association of renal volume and estimated GFR was significant, suggesting mild confounding from the other independent variables. This may reflect insufficient power to detect the assocoation and this will be reevaluated as additional subjects are included.
   
A history of hypertension was found in 69.7% of all subjects in the repository. Of these, 59.8% were treated with an antihypertensive drug, with 26.5% requiring at least two drugs. At the time of enrollment, 75% of those with a history of hypertension had their BP controlled (i.e., systolic BP<140 and diastolic BP <90 mm Hg). The mean blood pressure levels in the hypertensive and non-hypertensive groups were as follows: systolic 126 vs 117 mmHg (p<0.001) and diastolic 81 vs 78 mm Hg (p<0.05). Urine volume was significantly higher in hypertensive than normotensive subjects (2200 vs 1798 ml/24 hr), although 24-hour urine sodium excretion was comparable (146 vs 147 mmol/24h; p = .94). However, those with hypertension also had more severely impaired renal function (42.7 vs 70.6 ml/min/1.73 m2; p<0.0001), which confounded the association between hypertension and the presence of a urinary concentrating defect.
   
Azotemic subjects were also more likely to be hypertensive (odd ratio 14.8 [95%CI 5.4 to 40]; p<0.0005) and have a significantly higher mean plasma renin activity level (mean 4.5 vs. 2.6 ng/ml/h; p<0.05). However, azotemic patients were also more likely to be treated concurrently with drugs that stimulate renin secretion and either interrupt angiotensin II production or its receptor binding (e.g., ACE inhibitors, angiotensin II receptor blockers; OR 3.3 [95%CI 1.5 TO 7.4]; P<0.01). Therefore, a relationship between renin activity and azotemia could not be established at this point in the study because of possible confounding by concurrent drug treatment.
       
Other renal manifestations included a history of hematuria (gross 33.3%, microscopic 27.1%), symptomatic renal stone (19.4.7%), nocturia (50%), and urinary tract infections (40.9%).
   

Extrarenal manifestations:
Liver cysts were found in 75.8% of patients. Intracranial aneurysm screening occurred in 47.3% of subjects prior to enrollment; an aneurysm was first detected during the onset of intracranial hemorrhage in both patients with an aneurysm history. Other relatively common manifestations included hernia (umbilical 9.1%, inguinal 5.7%), and pain (flank 38%, back 31.8%, abdominal 23.3%).
   
Echocardiographic abnormalities are reportedly prevalent in ADPKD.  To date, echocardiograms have been analyzed in 44 subjects. The prevalence of the following abnormalities was identified: mitral valve prolapse 6.8%, mitral regurgitation 30.6%, left ventricular hypertrophy (LVH) 4.2%. In hypertensive subjects, the prevalence of left ventricular hypertrophy is 16.1%, reflecting the effect of elevated blood pressure on cardiac remodeling.
   

Summary:
This interim analysis demonstrates the ability to steadily recruit a significant number of ADPKD patients within a relatively short period and to collect, store and analyze a broad array of data including patient history, biochemistry, echocardiography, MRI, and PKD genotype. This relatively small sample confirmed some of the established ADPKD phenotype characteristics. As the sample size increases, additional analysis of the potential associations between PKD1 and PKD2 genotypes and their phenotypes is planned. Our collaboration with the WMC Molecular Diagnostics Laboratory has broadened the scope of PKD gene analysis that is available to the ADPKD Repository.