Familial Glomerular Disease with Asymptomatic Proteinuria and Nephrotic Syndrome: a New Clinical Entity

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 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 glomerulosclerosis on biopsy, erythrocytosis, no history of diabetes mellitus III 4 42 0.17 . . . III 12 44 10.00 ESRD, focal segmental glomerulosclerosis 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 nephropathy 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 . . . IV 42 24 1.20 . . . IV 32 24 1.18 . ..

*ESRD = end'stage renal disease. studied by immunofluorescence or electron mi with the classic histologic findings associated croscopy. One biopsy specimen (generation III, with Alport's syndrome. No. 1) was consistent with early diffuse glom erulosclerosis seen in diabetes mellitus; how Discussion ever, this member had never demonstrated bio This family represents another hereditary re chemical or clinical evidence of diabetes up to nal disease not previously described, with pro 12 years postbiopsy. The remaining biopsy re teinuria being the most prominent feature. In port indicated membranous glomerulopathy the patients evaluated in this study, the aver (generation IV No. 10), but the slides were not age onset of renal failure occurred fairly late, available for review and electron microscopy usually in the fifth decade of life, and hema and immunofluorescence were not performed. turia was not detected in any of them. The ques This member also has two sisters with protein tion whether this family demonstrates diabetic uria, and his mother has end-stage renal dis nephropathy was explored. None of the pa ease. One sister had undergone biopsy but she tients with end-stage renal disease or protein could not be located. The limited biopsy find uria had a history of glucose intolerance or any ings are not conclusive but are not consistent of the clinical manifestations of diabetic mi-

Original contribution' Mathis et al JAOA • Vol 92 • No 7 • July 1992 • 879 croangiopathy, such as retinopathy or neuropa 1 ~------' thy. None of the examined family members n u 6 ~------~~~~----~ with clinical diabetes had proteinuria. The rela m b tively high incidence of hypertension was an e II ~------ independent variable that was unrelated to the r o 4~------, presence of proteinuria or nephrotic syndrome. f

Erythrocytosis with an increase in red cell P 3 ~------mass without secondary cause of the erythro 8 1 2 f------." cytosis was documented in two members with II end-stage renal disease, one with biopsy n, e proved focal sclerosis and the other with dif 0 '------= fuse glomerulosclerosis. Erthrocytosis has -20 20-30 30-40 40-50 '110 been reported previously in association with age focal sclerosis and represents a rare manifes 14 Figure 2. Age distribution of 11 family members in tation of the di$ease. ,15 Sonneborn and whom progressive renal failure developed. Shaded bars coauthors15 propose that the cause is related indicate age of onset of renal failure. to differential ischemia of the juxtaglomeru lar apparatus and that erythrocytosis may rep Finnish forms of familial nephrotic syn resent a local compensation mechanism in re drome.1,4,23-26 The familial nephrotic syndrome sponse to focal renal disease and ischemia.15 appears chiefly in siblings, with only one well The familial incidence of renal disease with documented case in which more than one gen the nephrotic syndrome has been reported as eration was involved. 1 Of the 14 or 15 previ between 3% and 6%.16,17 Familial nephrotic syn ously reported series of non-Finnish congeni drome was first reported by Fanconi and tal nephrotic syndrome, most have their onset coauthors18 in 1951. Benign familial hema after 12 months and younger than 5 years,1 turia,19 chronic hereditary nephritis with hear a clearly distinct difference from our adult ing impairment and ocular defects, 20 the Finn onset disease. The histopathologic conditions ish type of congenital nephrotic syndrome,21 in these previous reports varied considerably and the recently reported, less frequent, cases from optically normal-appearing glomeruli to of familial focal segmental glomerulosclerosis mesangial hypercellularity to focal segmental are examples of other familial renal diseases. 22 glomerulosclerosis.24-26 The clinical features, histologic characteristics, In the previously reported series, environ and genetic transmission of our kindred show mental factors may have been involved in caus some similarities to previously reported series ing the familial nephrotic syndrome because offamilial glomerular disease but none to oth the inheritance has been polygenic and rarely ers. We will contrast this family with other appears in multiple generations. 21,25 However, reported diseases to determine if this is a White and coworkers' survey1 showed one well newly reported entity. documented case in which more than one gen Congenital nephrotic syndrome ofthe Finn eration was involved. More recently, Sanchez ish type21 has an autosomal recessive pattern Tomero and colleagues26 reported seven biopsy of inheritance and invariably becomes clini proved cases offocal segmental glomeruloscle cally evident by 6 months of age, usually rosis in adults from three generations of a fam within the first few days or weeks of life. The ily in which there appeared to be a high inci renal disease in our report is in sharp contrast dence of proteinuria, microhematuria, and re to congenital nephrotic syndrome in that this nal insufficiency. Their cases demonstrate a family manifested the nephrotic syndrome dur lot of similarity to our family except that none ing adulthood and did not demonstrate an of our members had hematuria. autosomal recessive pattern. Several other reports offamilially occurring The age at onset and the renal histopatholo focal segmental glomerulosclerosis have ap gic findings have varied widely in the non- peared in the literature.23,24 Tejani and asso (continued on page 883)

880 • JAOA • Vol 92 • No 7 • July 1992 Original contribution • Mathis et al ciates24 reviewed 22 reported cases through Benign familial nephropathy is a third he 1983 including eight of their own. McCurdy reditary renal disease that is characterized by and colleagues23 identified 14 additional cases thin glomerular basement membranes on elec including 3 of their own, so that the current tron microscopy, hematuria, absence of nerve number of reported cases in the medical lit deafness, and renal disease without renal fail erature is 36. Most of these cases were in chil ure. In both forms of chronic progressive heredi dren who initially appeared with steroid-re tary nephritis, the following clinical features sistant nephrotic syndrome and whose condi are consistent: microscopic hematuria in al tion usually progressed rapidly to renal fail most all patients; proteinuria only when he ure. Tejani and coauthors24 and McCurdy and maturia is present; and erythrocyte casts in associates23 reported a high incidence of HLA a high percentage of patients with hema DRw8 in their cases of familial focal segmen turia.!1 O'Neil and coauthors1 emphasize that tal glomerulosclerosis, although the signifi hematuria is the most precise urinary crite cance of this particular HLA type remained rion for diagnosing hereditary nephritis, and unclear. Glicklich and coworkers22 found a ge that proteinuria does not occur in persons with netic predisposition to focal segmental glom this disorder. Nephrotic syndrome in heredi erulosclerosis with a significant increase in tary nephritis may develop in 30% to 40% of HLA-DR4 antigen in two different adult eth patients but, when it does, it occurs at a young nic groups. age (between the ages of 14 and 20 years).20 Most of the patients in our series did not Because of the clinical features we have de have renal biopsies, but diffuse or focal seg scribed, the conditions of the family reported mental glomerulosclerosis was demonstrated here would not be consistent with anyone of in three of the five patients who had under the three varieties of hereditary glomerular gone biopsy. In the other two patients, the bi disease. There was no history of hearing loss opsy material was inadequate for a diagnosis (except one isolated case) and neither a his in one and the information was unobtainable tory of hematuria nor microscopic hematuria in the other. At the present time, HLA typing in any of the observed urinalyses. None of the is not available in any of our patients. It would members with isolated proteinuria had con be interesting to speculate that the family re comitant hematuria. Hematuria was not pre ported here had the lesion of focal segmental sent in any ofthe nephrotic members in whom glomerulosclerosis, but insufficient histologic the nephrotic syndrome usually developed dur material is available to make that conclusion. ing adulthood, with only one instance devel Although microscopic hematuria is frequently oping at a young age. seen in patients with focal and segmental The specific ultrastructural lesion of chronic glomerulosclerosis, it was not seen in our fam hereditary nephritis is in the glomerular cap ily members. illary basement membranes, which are split The varied manifestations of chronic heredi longitudinally into many thin layers separated tary nephritis has recently been reviewed by by lucent spaces that often contain small dense Grunfeld.2o Al port's syndrome (chronic heredi particles that look like lipid droplets.27 This tary nephritis with nerve deafness) was once histologic pattern has been termed lamination believed to be a uniform chronic hereditary re of the basement membrane or the "basket nal disease. It is now generally recognized that weave" pattern.!9 None of the biopsy speci chronic progressive hereditary nephritis con mens reviewed from our kindred displayed sists of two major forms of disease: (1) progres these characteristic findings. sive hereditary nephritis with nerve deafness (Alport's syndrome); and (2) progressive heredi Comment tary nephritis without nerve deafness. Both This large kindred appears to represent a fa conditions are closely related and have simi milial glomerular renal disease with clinical lar clinical findings including greater sever manifestations and clinical course not previ ity in male than in female patients. ously reported. The family members with this

Original contribution • Mathis et al JAOA • Vol 92 • No 7 • July 1992 • 883 disease are first seen with asymptomatic pro dreds and review of the literature. Hum Pathol 1979;10:655- .668. teinuria that appears to progress to nephrotic 13. Pashayan H, Fraser FC, Goldbloom RB : A family showing syndrome and renal failure without any evi hereditary nephropathy. Am J Hum Genet 1971;23:555-567. dence of microscopic or gross hematuria. This 14. Myers DI, CuifTo AA, Cooke CR: Focal glomerulosclerosis family adds another facet to the array of here and erythrocytosis. Johns Hopkins Med J 1979;145:192-195. 15. Sonneborn R, Perez GO, Epstein M, et al: Erythrocytosis dofamilial renal diseases. associated with the nephrotic syndrome. Arch Intern Med 1977;137:1068-1072. 16. White RHR: The familial nephrotic syndrome: I. A Euro pean survey. Clin NephroI1973;1(4 ):215-219. References 17. Bader PI, Grove J, Trygstad CW, et al: Familial nephrotic 1. McConville JM, West CD, McAdams AJ: Familial and non syndrome. Am J Med 1974;56:34-43. familial benign hematuria. J Pediatr 1966;69:207-214. 18. Fanconi G, Kousmine C, Frischknecht W: Die konstitu 2. Vernier RL, Brunson J , Good RA: Studies on familial neph tionelle Bereitschaft zum Nephrosesyndrom (Constitional fac rosis: I. Clinical and pathologic study of four cases in a single tors in the pathogenesis of the nephrotic syndrome) Helu Pae family. Am J Dis Child 1957;93:469-485. diatr Acta 1951 ;6:199-218. 3. Alport AC: Hereditary familial congenital haemorrhagic ne 19. Yoshikawa N, White RHR, Cameron AH: Familial hema phritic. Br Med J 1927;1:504-506. turia: Clinico-pathological correlations. Clin N ephrol 4. Waldherr R: Familial glomerular disease. Contrib Nephrol 1982;17:172-182. 1982;33:104-121. 20. Grunfeld JP: The clinical spectrum of hereditary nephritis. 5. Knepshield JH, Roberts PL, Davis CJ, et al: Hereditary Kidney Int 1985;27:83-92. chronic nephritis complicated by nephrotic syndrome. Arch In 21. Norio R: Heredity in the congenital nephrotic syndrome: tern Med 1968;122:156-158. A genetic study of 57 Finnish families with a review of reported 6. Dockhorn RJ: Hereditary nephropathy without deafness. Am cases. Ann Paediatr Fenn 1966;12(Suppl 27):1-94. J Dis Child 1967;114:135-138. 22. Glicklich D, Haskell L, Senitzer D, et al: Possible genetic 7. Goldman R, Haberfelde CC: Hereditary nephritis: Report of predisposition to idiopathic focal segmental glomerulosclerosis. a kindred. N Engl J Med 1959;261:734-738. Am J Kidney Dis 1988;12:26-30. 8. Chazan JA, Zacks J , Cohen JJ, et al: Hereditary nephritis: 23. McCurdy FA, Butera PJ, Wilson R: The familial occurrence Clinical spectrum and mode of inheritance in five new kindreds. of focal segmental glomerular sclerosis. Am J Kidney Dis Am J Med 1971;50:764-771. 1987;10:467-469. 9. Gaboardi F, Edefonti A, Imbasciata E, et al: Alport's syn 24. Tejani A, Nicastri A, Phadke K, et al: Familial focal seg drome (progressive hereditary nephritis). Clin N ephrol mental glomerulosclerosis. Int J Pediatr NephroI1983;4:231-234. 1974;2:143-156. 25. Chandra M, Mouradian J , Hoyer JR, et al: Familial neph 10. Gubler M, Levy M, Broyer M, et al: Alport's syndrome: A rotic syndrome and focal segmental glomerulosclerosis. J Pe report of 58 cases and a review of the literature. Am J Med diatr 1981;98:556-560. 1981;70:493-505. 26. Sanchez Tomero JA, Arrieta J , Alguacil A, et al: Focal seg 11. O'Neill WM Jr, Atkin CL, Bloomer HA: Hereditary nephri mental glomerular sclerosis in three generations of a single tis: A re-examination of its clinical and genetic features. Ann family. Int J Pediatr Nephrol 1985;6:199-204. Intern Med 1978;88:176-182. 27. Beathard GA, Granholm NA: Development of the charac 12. Farboody GH, Valenzuela R, McCormack W , et al: Chronic teristic ultrastructural lesion of hereditary nephritis during the hereditary nephritis: A clinicopathologic study of 23 new kin- course of the disease. Am J Med 1977;62:751-756.

884 • JAOA • Vol 92 • No 7 • July 1992 Original contribution • Mathis et al