Inaccuracy of clinical phenotyping parameters for hypertensive nephrosclerosis

Background. Multiple studies suggest that hypertension-induced end-stage re nal disease (ESRD) is heritable. Identification of nephropathy susceptibili ty genes absolutely requires accurate phenotyping, but the clinical hyperte nsive nephrosclerosis (HN) phenotype is poorly characterized. We hypothesiz ed that many patients with HN as the indicated cause of ESRD on the Health Care Financing Administration (HCFA) 2728 form, fail to satisfy stringent H N phenotyping criteria. Methods. Since renal biopsy documentation of HN is uncommon, clinical param eters for HN phenotype were applied: family history of hypertension, left v entricular hypertrophy, proteinuria <0.5 g/day, and hypertension preceding renal dysfunction (Schlessinger et al., 1994) or urine protein:creatinine ( prot:creat) ratio <2.0 and no evidence of other renal diseases (AASK Trial Group, 1997). Results. ESRD patients (n = 607, 73% African American, 25% Caucasian) were enrolled in a study to identify HN susceptibility genes. HN was the most co mmon cause of ESRD according to HCFA 2728 forms (37% prevalence). Phenotypi ng of randomly selected patients with HN from the total cohort revealed tha t 4/100 subjects satisfied the Schlessinger criteria, and 28/91 African Ame ricans met AASK criteria for HN. From these figures, the adjusted prevalenc e of HN was only 1.5-13.5%. Of patients that could not be phenotyped for HN , 14 were misdiagnosed, 14 had urine prot:creat >2.0, and insufficient data were available in the remainder. Four patients underwent renal biopsy, but histology from only one was consistent with HN. If the HN phenotype defini tions are revised to exclude 'hypertension preceding renal dysfunction', or proteinuria limits, then 44/100 and 39/91 patients respectively satisfy cl inical phenotyping parameters for HN. Conclusions. (i) We provide the strongest evidence to date that HN is less frequent in an ESRD population than commonly assumed if strict clinical cri teria are used; many patients clinically diagnosed with HN may have undetec ted, treatable renal disease from other causes; (ii) relaxing HN phenotype criteria may erroneously include patients with glomerular diseases and seco ndary hypertension; (iii) reliance on HCFA 2728 diagnoses will confound ide ntification of HN susceptibility genes; (iv) to attain adequate statistical power for genotype analysis, rigorous HN phenotyping will require screenin g an extremely large number of patients, which can be reasonably accomplish ed only in a multi-centre trial design.