Zarif L, Covic A, Iyengar S, Sehgal A R, Sedor J R, Schelling J R
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Nephrol Dial Transplant. 2000 Nov;15(11):1801-7. doi: 10.1093/ndt/15.11.1801.
Multiple studies suggest that hypertension-induced end-stage renal disease (ESRD) is heritable. Identification of nephropathy susceptibility genes absolutely requires accurate phenotyping, but the clinical hypertensive nephrosclerosis (HN) phenotype is poorly characterized. We hypothesized that many patients with HN as the indicated cause of ESRD on the Health Care Financing Administration (HCFA) 2728 form, fail to satisfy stringent HN phenotyping criteria.
Since renal biopsy documentation of HN is uncommon, clinical parameters for HN phenotype were applied: family history of hypertension, left ventricular 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).
ESRD patients (n=607, 73% African American, 25% Caucasian) were enrolled in a study to identify HN susceptibility genes. HN was the most common cause of ESRD according to HCFA 2728 forms (37% prevalence). Phenotyping of randomly selected patients with HN from the total cohort revealed that 4/100 subjects satisfied the Schlessinger criteria, and 28/91 African Americans met AASK criteria for HN. From these figures, the adjusted prevalence 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 definitions are revised to exclude 'hypertension preceding renal dysfunction', or proteinuria limits, then 44/100 and 39/91 patients respectively satisfy clinical phenotyping parameters for HN.
(i) We provide the strongest evidence to date that HN is less frequent in an ESRD population than commonly assumed if strict clinical criteria are used; many patients clinically diagnosed with HN may have undetected, treatable renal disease from other causes; (ii) relaxing HN phenotype criteria may erroneously include patients with glomerular diseases and secondary hypertension; (iii) reliance on HCFA 2728 diagnoses will confound identification of HN susceptibility genes; (iv) to attain adequate statistical power for genotype analysis, rigorous HN phenotyping will require screening an extremely large number of patients, which can be reasonably accomplished only in a multi-centre trial design.
多项研究表明，高血压所致终末期肾病（ESRD）具有遗传性。确定肾病易感基因绝对需要准确的表型分型，但临床高血压性肾硬化（HN）的表型特征尚不明确。我们推测，许多在医疗保健财务管理局（HCFA）2728表格上被列为ESRD病因的HN患者，并不符合严格的HN表型分型标准。
由于HN的肾活检记录并不常见，因此采用了HN表型的临床参数：高血压家族史、左心室肥厚、蛋白尿<0.5 g/天，以及肾功能不全之前出现高血压（施莱辛格等人，1994年）或尿蛋白：肌酐（prot:creat）比值<2.0且无其他肾脏疾病证据（非洲裔美国人肾脏疾病与高血压协作研究试验组，1997年）。
ESRD患者（n = 607，73%为非裔美国人，25%为白种人）被纳入一项旨在确定HN易感基因的研究。根据HCFA 2728表格，HN是ESRD最常见的病因（患病率37%）。从整个队列中随机选择的HN患者进行表型分型后发现，100名受试者中有4名符合施莱辛格标准，91名非裔美国人中有28名符合HN的非洲裔美国人肾脏疾病与高血压协作研究标准。根据这些数据，HN的校正患病率仅为1.5 - 13.5%。在无法进行HN表型分型的患者中，14名被误诊，14名尿prot:creat>2.0，其余患者数据不足。4名患者接受了肾活检，但只有1名患者的组织学检查结果与HN一致。如果修订HN表型定义以排除“肾功能不全之前出现高血压”或蛋白尿限制，那么分别有44/100和39/91的患者符合HN的临床表型参数。
（i）我们提供了迄今为止最有力的证据，表明如果使用严格的临床标准，ESRD人群中HN的发生率低于普遍假设；许多临床诊断为HN的患者可能患有其他原因未被发现、可治疗的肾脏疾病；（ii）放宽HN表型标准可能会错误地纳入患有肾小球疾病和继发性高血压的患者；（iii）依赖HCFA 2728诊断结果会混淆HN易感基因的鉴定；（iv）为了获得足够的统计学效力进行基因分型分析，严格的HN表型分型需要筛查大量患者，这只有在多中心试验设计中才能合理完成。
