View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 27 (1985), pp. 83—92 NEPHROLOGY FORUM The clinical spectrum of hereditary nephritis Principal discussant: JEAN-PIERRE GRUNFELD Hôpital Necker, Paris, France sion (180/130 mm Hg) and chronic renal failure (serum creatinine 3.1 Editors mgldl). Protein excretion, 3 g/day, was associated with microscopic JORDANJ.COHEN hematuria. Audiometric testing was normal, and ophthalmic examina- tion did not reveal lenticonus or perimacular changes. JOHN 1.HARRINGION The patient belongs to a kindred with Alport's syndrome (Fig. 2). His JEROME P.KASSIRER father, who is 63 years of age, has undergone hemodialysis for 10 years. NIcoiAos E.MADIAS He has severe perceptive deafness. Three males and one female in the kindred died from renal failure. One cousin (IV 1, Fig. 2) had a renal Managing Editor transplant in 1972 at age 39 and has stable renal function at present. Renal biopsy in another affected cousin (IV 2, Fig. 2) disclosed CHERYL J.ZUSMAN characteristic ultrastructural changes of Alport's syndrome in the glomerular basement membrane. Now, one year later, the patient's blood pressure is well controlled MichaelReese Hospital and Medical Center with 200 mg of metoprolol per day, and serum creatinine is 4.5 mgldl. Universityof Chicago Pritzker Sc/iou! of Medicine and Discussion New England Medical Center Tufts University School of Medicine DR. JEAN-PIERRE GRUNFELD (Département de Néphro/ogie, Hôpital Necker, Paris, France): Various heredofamilial dis- eases involve the kidney (Table 1). The first two groups in Table 1 consist of disorders in which the renal disease is the predomi- Case presentations nant feature of the illness. Groups 3 and 4 are more heteroge- Patient 1. A 30-year-old woman had been referred to the Department neous diseases that affect several organs, including the kidneys. of Nephrology of Hôpital Necker at age 19 for evaluation of proteinuria Group 5 comprises isolated and poorly classified cases of and microscopic hematuria. At that time, blood pressure was 110/60 mm Hg and urinary protein excretion ranged from 2.7 to 5.7 g/24 hr. hereditary renal diseases [1—4]. In my experience, the frequen- Urine erythrocyte count was 500,000/mm. Serum protein and albumin cy of hereditary renal disease is often underestimated: many levels were 5.7 and 3.1 g/dl, respectively. Creatinine clearance was 95 cases are undetected or unreported because they lack either mI/mm and serum creatinine 0.9 mg/dl. Percutaneous renal biopsy specific extrarenal defects or renal pathologic changes. Indeed, showed mild interstitial fibrosis associated with ischemic glomerular Waldherr, who focused attention on familial diseases with changes, but no foam cells or glomerular segmental lesions were found. Electron microscopy revealed a thickened glomerular basement mem- prominent glomerular involvement, found lesions compatible brane with splitting and splintering of the lamina densa. with familial glomerular disease in 7% of adults with glomerular A diagnosis of hereditary nephritis was made, based on the following lesions on renal biopsy specimens and in 13% of patients with data. (1) The 20-year-old sister of the patient had end-stage renal failure end-stage renal failure secondary to glomerulonephritis [51. necessitating regular hemodialysis, and she subsequently received a Thelist in Table I is not all-inclusive. I have omitted renal cadaveric renal transplant. (2) Both the patient and her sister had bilateral perceptive deafness, bilateral anterior lenticonus, and retinal diseases in which familial aggregation can occur, such as IgA perimacular changes. No other member of the kindred was affected mesangial glomerulopathy (Berger's disease), lupus nephritis, (Fig. 1). The parents were first-degree cousins. and vesicoureteral reflux complicated by renal scarring. The At age 21, the patient became pregnant. The nephrotic syndrome discussion today will concern itself with the first group in Table worsened and renal failure developed during the pregnancy; serum creatinine increased from 1.0 to 2.3 mg/dl. Blood pressure did not1, that is, hereditary nephritis, and most particularly, progres- increase. She delivered a 2.7 kg boy at 41 weeks gestation. Subsequent- sive hereditary nephritis. Both case presentations illustrate ly her renal function decreased progressively. At age 26, regular many features of these syndromes. hemodialysis was initiated, and at age 29 she received a cadaveric renal The existence of hereditary or familial renal diseases was transplant. One year later, creatinine clearance was 87 ml/min; norecognized at the end of the 19th century. In 1927, Alport proteinuria was found. The patient's child is now 8 years old and has no extended the study of a family that first had been investigated urinary symptoms. Patient 2. A 35-year-old man was referred for evaluation of hyperten- by others in 1902. His report drew attention to the syndrome of hereditary nephritis and perceptive deafness that now bears his name [6]. In 1968 the original family was retraced, but no new Presentation of the Forum is made possible by grants from Smith Kline cases had appeared since Alport's report [7]. As stated by & French Laboratories, CIBA Pharmaceutical Company, and GEIGY Crawfurd and Toghill, "Alport's original family has rid itself of Pharmaceuticals. Alport's disease" [7]! © 1985 by the International Society of Nephrology The following definitions have evolved and will be useful in 83 84 Nephrology Forum before age 9, and 5 other boys developed ESRD between ages 9 and 16 [15]. In adults, ESRD develops between ages 20 and 40 [17, 19] but can appear even after age 50. I will discuss later the various rates of progression to ESRD. Alport's syndrome represents approximately 3% of the causes of ESRD in the periodic European Dialysis and Transplantation Registry re- ports. In Utah, approximately 5% of all male patients with ESRD were considered to have hereditary nephritis [16]. Hearing loss. Nerve deafness is one of the hallmarks of Alport's syndrome. The neurogenic hearing impairment is bilateral and may lead either to clinically evident deafness or to Fig. 1. Pedigree of Family 1. Symbols are: Li consanguineous marriage; / propositus;affected female; affected male; • neural a mild defect predominating in the middle or high tone range. hearing loss; () age at death or "renal death." Because subclinical hearing impairment may exist, audiometric testing is required to detect all affected individuals. Audiometry rarely has been performed in all members of affected kindreds, discussing these heredofamilial disorders. (1) Alport's syn-and for this reason the true incidence of neural hearing loss is drome is characterized by renal disease that progresses to renalnot known. We do know, however, that hearing loss varies failure and by neural hearing loss in the patient or other familyfrom one kindred to another. members. (2) Hereditary nephritis without nerve deafness is The hearing defect often can be detected before age 10 [15]. characterized only by progressive renal disease in the patient orIts frequency is high, at least in boys. In the pediatric series of other family members [8]; diagnosis of this disease is difficult inGubler et al [15], 34 of 42 boys had hearing defects, whereas the absence of a strong family history. (3) Familial benignonly 3 of 16 girls had hearing loss. In children, serial audiome- hematuria is characterized by renal disease without renal fail-tric tests may show progressive hearing loss, necessitating a ure; nerve deafness is absent in the patient and other familyhearing aid [15, 201. In contrast, hearing impairment generally members. Only a few kindreds with this disorder have beendoes not progress in adults. Although hearing improvement has reported [9—13]. As I will discuss later, the specificity andbeen described after successful renal transplantation [21], this independence of these syndromes are not totally established,change may be nonspecific because deafness attributable to but these definitions provide a convenient clinical classificationuremia also may improve after renal transplantation [22]. for analyzing these conditions. The pathologic lesions responsible for the hearing defect are not well delineated. Although some investigators have identi- Clinical presentation of A/port's syndrome fied a variety of lesions [23], others have not found any Renal symptoms. As noted even in the first description of thissignificant changes. Johnsson and Arenberg detected abnormal- disease, hematuria is the most frequent initial symptom inities of the temporal bones, strial atrophy, vacuolation of the children [6, 14]. Hematuria is either microscopic or gross,spiral ligament, and a predominance of sensory cell degenera- recurrent or not. It can appear at birth or within the first fewtion [24]. These abnormalities are not specific, however. It months of life [151. Of 58 affected children reported by Gubler etshould be noted that strial atrophy is commonly associated with al, manifestations appeared during the first year of life in 8, 32sensorineural degeneration, such as that occurring in various children had gross hematuria, and in 25 the first episodeforms of hereditary deafness and in noise exposure. In addition, occurred before the age of 5. Gross hematuria recurred in 26 butearly childhood deafness is a common feature in a great variety usually disappeared after age 15 [15]. Gross hematuria is quiteof hereditary syndromes, only some of which include renal infrequent in adults, but microscopic hematuria persists and redinvolvement [25—32]. blood cell casts are frequent [16]. Proteinuria is usually absent Ocular defects. Ocular disorders, first described by Sohar in or minimal in young children but it increases with age. The1956 [33], mainly involve the lens. Bilateral anterior lenticonus nephrotic syndrome develops in 30% to 40% of the patients [15,has been considered the most specific eye abnormality in 17]; its incidence peaks between ages 14 and 20. Alport' s syndrome [34].