Familial glomerular disease with asymptomatic proteinuria and nephrotic syndrome: A new clinical entity BEVERLY J. MATInS, DO KENNETH E. CALABRESE, DO GARY L. SLICK, DO Seventy-three members of a nerve deafness. The hereditary protein­ 100-member kindred with asymptomatic uria and nephrotic syndrome described proteinuria, nephrotic syndrome, and in this kindred represents another facet progressive renal failure were studied. Of in the spectrum of hereditary renal dis­ those studied, 11 members had progressed ease. to end-stage renal disease and seven had (Key words: Familial nephrotic syn­ significant proteinuria (> 1 g/24 hours) drome, hereditary renal disease, familial with normal renal function. The genetic glomerulopathy) mode of inheritance was autosomal domi­ nant with variable penetrance and expres­ The existence of familial renal disease such sivity. Histopathologic changes were as benign familial hematuria,1 familial p-eph­ variable but included focal segmental rotic syndrome,2 and chronic hereditary nephri­ glomerulosclerosis and diffuse glomer­ tis with hearing loss3 is well known. Wald­ ulosclerosis. Renal failure usually oc­ herr,4 who reviewed the familial renal diseases curred in the fifth decade of life. The most with p'rominent glomerular involvement, consistent clinical finding was proteinuria found lesions consistent with familial glom­ without microscopic hematuria or other erular disease in 7% of adults with glomeru­ significant urinary sediment elements. lar lesions on renal biopsy specimens and in This disease differed from Alport's heredi­ 13% of patients with end-stage renal failure tary nephritis and congenital nephrotic secondary to glomerulonephritis. syndrome in age of onset, urinary find­ Chronic hereditary nephritis has been de­ ings, and associated conditions, that is, scribed extensively among varying kindreds throughout the literature since Alport's origi­ 5 13 From Tulsa Regional Medical Center and Okla homa nal description in 1927. - The most promi­ State University College of Osteopathic Medicine, Tulsa, nent manifestations are as follows: hematuria, Okla mrs Mathis and Calabrese), and from the Chicago with or without proteinuria; progressive renal College of Osteopathic Medicine, Chicago, III (Dr Slick ). This work was partially supported by an intramural failure before the second decade; and neurosen­ grant from the Oklahoma State University College of sory hearing loss. In this report, a unique kin­ Osteopathic Medici ne. dred with quite different features is presented, Repring requests to Gary L. Slick, professor and chair­ with the purpose of describing the clinical man, Department ofinternal Medicine, Chicago College of Osteopathic Medicine, 5200 S Ellis Ave, Chicago, IL course, the genetic mode of transmission, and 60615. the histopathologic features. Origina l co ntribut ion · Mathis et al JAOA • Vol 92 • No 7 • July 1992 • 875 Methods ("Bright's disease") at ages 12 and 35 years, The family members studied more extensively lived respectively. Four had died of other causes; two primarily in northeastern Oklahoma, with addi­ of these had had diabetes mellitus. Of the re­ tional scattered members along the West Coast, maining three second -generation subjects, two who were studied by means of their medical re­ were evaluated clinically. One had normal re­ cords. The descendants were identified and were nal function but significant proteinuria (1.8 sent a medical history questionnaire with specific g/24 h) and hypertension. The other had a his­ questions regarding kidney disease, proteinuria, he­ tory of hypertension. The remaining member, maturia, urinary tract infection, diabetes mellitus, not evaluated, had a history of diabetes melli­ and hypertension. Of the 89 questionnaires sent, 73 were returned. Fifty-seven family members tus. were seen and evaluated in our clinic. Because In the third generation, 49 were identified, blood sampling was included in the study, children 26 of whom were evaluated clinically and 8 younger than 12 years were excluded with the ex­ who were evaluated by medical records. Nine ception of a 3-year-old girl with the nephrotic syn­ members of the third generation were identi­ drome. fied as having end-stage renal disease. Of the Clinical evaluation included a history and physi­ nine, three underwent renal biopsy within 6 cal examination, careful urinalysis performed by years of end-stage renal failure. Two renal bi­ one ofthe authors, blood urea nitrogen (BUN) and opsies revealed focal segmental glomeruloscle­ serum creatinine determination, and complete rosis, and one revealed diffuse glomeruloscle­ blood cell count. Those patients with qualitative rosis. Three members had minimal proteinuria 1 + or greater protein determination by dipstick but normal renal function, and one member were requested to collect a 24-hour urine sample for creatinine clearance and quantitative protein had significant proteinuria. determination. In addition, those members with In the fourth generation, 52 members were trace proteinuria and a dilute urine by specific grav­ identified, but records of the family were in­ ity « 1.010) also collected a 24-hour urine sample. complete or the members were younger than Significant proteinuria was defined as a total urine 12 years of age. Thirty-three were evaluated; protein excretion greater than 1.0 g/24 h; minimal out of those, 2 members had end-stage renal proteinuria, greater than 150 mg but less than 1.0 disease, 4 had significant proteinuria, and 6, g/24 h. The adequacy ofthe 24-hour collection was minimal proteinuria. One had a previous re­ determined by total creatinine excretion (20 to 25 nal biopsy, but the slides were unavailable for mg/kg/day). Those who were already identified as review. The dictated report suggested mem­ having end-stage renal disease and being on main­ branous glomerulopathy, but electron micros­ tenance dialysis were interviewed, and data from copy and immunofluorescence were not per­ previous medical records were collected. When pre­ vious renal biopsies had been performed, the his­ formed. The Table summarizes the status of topathologic material was reviewed, when avail­ those family members from whom 24-hour able, to confirm the preexisting dictated reports. urine collections for protein were obtained. To examine the genetic transmission of this dis­ Urinalysis performed on the kindred mem­ ease entity, segregation analysis was done on the bers (N = 60) revealed no consistent signifi­ family members by identifying the presence of pro­ cant urinary sediment abnormalities « 2-3 teinuria or renal failure in the progeny of affected WBCs, < 2-3 RBCs, and no significant casts). parents. Oval fat bodies were seen in five specimens irrespective of significant proteinuria. Results Eight members out of the total 100 were de­ From the member interviews and medical termined to have diabetes mellitus, but none records obtained, four generations were identi­ of these had a history of renal disease or dem­ fied (Figure 1). No direct information was onstrated significant proteinuria during exami­ available from the first generation except for nation. Nineteen patients, excluding those a family history of a maternal uncle who died with end-stage renal disease, were hy­ of kidney disease. In the second generation, pertensive, but only three of these demon­ two family members had died of renal failure strated any proteinuria (> 150 mg/24 h). (co ntinued on page 878) 876 • JAOA • Vol 92 • No 7 • July 1992 Original contribution' Mathis et al II III IV II III IV o Male , no disease o Female , no disease • ESRD IllD > 1 g prolein/24 h !3 > 160 mg and < 1 g prolein/24 h 0' Deceased Figure 1. Pedigree of kindred reported in this article. Numerals I through IV indicate the generations within the family. ESRD = end-stage renal disease. Of those members affected by clinical renal The age of onset of renal failure in this kin­ disease, the sex distribution was predomi­ dred (most often fifth decade of life, Figure 2 ) nantly male, with 9 (64%) of 14 of the mem­ was generally later than previously reported bers having end-stage renal disease and 8 in hereditary renal disease.1 1 The time from (75%) of 12, proteinuria. However, the pres­ onset of proteinuria to the onset of renal fail­ ence of male-to-male transmission eliminated ure exceeded 10 years (mean, 9 years) in four the possibility of X-linked transmission of the patients but could not be documented in the gene. others. The inheritance was autosomal dominant Focal segmental glomerulosclerosis was with variable penetrance and expressivity (Fig­ found in two of four reviewed renal biopsy speci­ ure 1). In general, there was a higher incidence mens. One of these (generation III No. 14) had of disease severity in those families that were some thickening of the basement membrane more severely affected. on electron microscopy but no lamination as Only one member (generation IV No. 10) seen in Alport's syndrome. Immune complexes had nerve deafness. No ocular abnormalities were not found in either specimen. The remain­ were detected on any clinical examinations. ing biopsy specimens unfortunately were not 878 • JAOA • Vo l 92 • No 7 • July 1992 Original co ntribution • Mathis et al Table Status of Family Members Thsting Positive on Protein Dipstick Determination Total Member Age, protein, Generation No. yr g/24 h Associated problems II 6 68 1.80 Mild hypertension III 1 48 1.50 ESRD,* diffuse glomerulo- sclerosis on biopsy, erythrocytosis, no his- tory of diabetes mellitus III 4 42 0.17 . III 12 44 10.00 ESRD, focal segmental glom- erulosclerosis on biopsy, erythrocytosis III 14 38 16.2 ESRD, focal segmental glomerulosclerosis and membranous thickening on biopsy III 16 33 1.20 ... III 18 41 2.50 ESRD, biopsy inadequate III 22 36 3.80 ... III 24 48 5.20 Hypertension, proteinuria (20 years) IV 2 23 1.40 .. IV 10 21 3.00 ESRD, membranous neph- ropathy on biopsy (creatinine, 3.0 mg/dL at biopsy) IV 17 20 0.98 . IV 18 24 0.17 ... IV 37 19 0.27 Recurrent urinary tract in- fections IV 38 18 0.22 .