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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 . 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 . 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 (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 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 [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 and Transplantation Registry re- ports. In Utah, approximately 5% of all male patients with ESRD were considered to have hereditary nephritis [16]. . 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 , 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]. Although microspherophakia was the Although pyuria was thought to be a frequent manifestationlesion first described [331, later histologic examination showed in the large family with Alport's syndrome described by Perkoffthe disorder to be bilateral anterior lenticonus [35]. Anterior and colleagues [181, subsequent observations failed to confirmlenticonus predominates in males [15, 34] but occasionally this finding. It appears that in this series and in some otheroccurs in females as well [17]. It is always associated with series, leukocyturia did not accurately identify cases of thesensorineural hearing loss [171 but is less frequent than is the disease. In particular, unaffected females frequently were erro-hearing defect [15]. Anterior lenticonus usually is associated neously diagnosed as having hereditary nephritis. O'Neill,with gradual deterioration of vision with the development of Atkin, and Bloomer restudied the kindred originally investigat-axial myopia. Lens opacities have been observed in Alport's ed by Perkoff and concluded that affected persons typically did syndrome, but their specificity is uncertain. not have isolated pyuria (or, incidentally, isolated proteinuria) Recently attention has focused on the macular and perimacu- [16]. lar changes in Alport's syndrome [15, 36, 37]. The bright, The renal disease is progressive, leading to renal failure in atwhitish, dot-like lesions are located in the perimacular regions least some members of the affected kindreds. End-stage renal of both eyes, involving the more superficial layer of the retina. disease (ESRD) is uncommon before age 15. In the study byFluorescein angiography is normal; visual acuity is preserved, Gubler et al that I referred to before, 3 boys developed ESRD except in cases complicated by other ocular abnormalities [37]. Hereditary nephritis 85 — = Co C

Ca Fig. 2. Pedigree of Family 2. (See legend to Fig. 1.) Slash denotes family members no longer living; dia- mond denotes number of siblings of unknown sex; dot C within symbol denotes obligate asymptomatic carrier of Alport's syndrome.

In some children, disappearance of the foveolar reflex is the Table 1. Heredofamilial diseases with renal involvement in adults only abnormality that can be identified in the fundus [15]. The 1. Hereditary nephritis changes in macular structure and pigmentation were reported Progressive hereditary nephritis by Purriel et al in their large series [38], as well as by others in With nerve deafness (Alport's syndrome) isolated instances [37]. These changes frequently, but not Without hearing impairment always, accompany bilateral anterior lenticonus [371. Variants Familial benign hematuria Other extrarenal defects. Several other extrarenal abnormali- 2. Polycystic ties have been described in Alport's syndrome [15, 19]. Hyper- Adult type prolinemia and hyperaminoaciduria have been reported in a few Medullary cystic disease (or ) kindreds with hereditary or familial nephritis, including some 3. Hereditary metabolic disorders with nerve deafness [15, 19, 20]. In some of these families, Diabetes mellitus Fabry's disease urinary tract and neurologic abnormalities also were found. Lecithin cholesterol acyltransferase deficiency This association might be coincidental, because hyperproline- Primary hyperoxaluria mia is associated with several heterogeneous anomalies [151. Familial urate nephropathy In contrast, platelet disorders are significantly associated Wilson's disease Adult-type cystinosis with Alport's syndrome. The association of hereditary macro- Other identified or unidentified storage diseases thrombocytopathia, nephritis, and deafness was first reported Various complement defects by Epstein et al in 1972 [391, and other kindreds were subse- Genetic amyloidosis (including familial quently investigated. Thrombocytopenia and giant platelets Mediterranean fever and Muckle-Wells syndrome) Sickle-cell disease sometimes are accompanied by an in-vitro defect in platelet 4. Extrarenal defects (in the absence of detected function [15, 401. The May-Hegglin anomaly (megathrombocy- metabolic abnormalities) topenia and white blood cell cytoplasmic inclusions, termed Nail-patella syndrome Döhle bodies) has been found in one family with progressive Hereditary osteolysis nephritis without nerve deafness [401. Juvenile megaloblastic anemia (Imerslund- Gräsbeck syndrome) Serum antithyroid antibodies were detected in 2 Japanese Familial dysautonomia families with Alport's syndrome, both in subjects with renal AlstrOm' s syndrome disease as well as in some with normal urinalyses [411. In other Laurence-Moon-Bardet-Biedl syndrome series, the search for antithyroid antibodies has been negative 5. Unclassified [42; personal observations], except in one study [421 and in one of our patients, an adult female with hereditary nephritis, thrombocytopenia, and giant platelets, in whom we found a high titer of antithyroid antibodies. Her affected son had beenmal by light microscopy in young children. In older patients reported previously by Gubler et al [151. Simon et al reportedwith overt disease, the lesions were described as "mixed antithyroid antibodies and selective serum IgA deficiency in anephritis" [441, combining interstitial fibrosis, tubular atrophy, male patient with renal disease, neural hearing loss, and anteri-foam cells, and segmental proliferative glomerular changes. or lenticonus, without a positive family history [43]. TheImmunofluorescence study is generally negative, with the ex- significance of the platelet and antithyroid antibody abnormali-ception of scattered deposition of C3 in glomeruli or at their ties is uncertain. vascular poles in some cases [15]. Glomerular IgA [45] or IgG deposits may be detected in patients with heredofamilial nephri- Renal histopathologic changes tis with or without nerve deafness, but this finding is the For many years, renal pathologic lesions in Alport's syn- exception [46; personal data]. drome were considered nonspecific. The kidney appears nor- In 1972, three groups of pathologists independently drew 86 Nephrology Forum

Table 2.Distribution of GBM ultrastructural changes in the various when the immunofluorescent studies are negative [15, 17, 36, forms of hereditary nephritis 47, 55, 56]. Segmental areas of GBM splitting can be found in Hereditary other renal diseases, however [53]. These GBM changes also nephritis Benign have been observed in kindreds with progressive hereditary Alport's without familial nephritis (HN) without nerve deafness [16, 52, 57]. In other syndrome deafness hematuria families with the same clinical entity, a normal GBM was found Nerve deafnessa +b 0 0 by electron microscopy [17, 55]. We need further data to Renal failurea + + 0 estimate the relative frequency of normal and abnormal GBM in GBM this type of hereditary nephritis. The similarity in renal ultra- Normal +(rare) + ? Thick + + 0 structure between Alport's syndrome and hereditary nephritis Thin and thick d + 0 without nerve deafness underlines the nosologic conundrum Thin +(exceptional) + + referred to before. It is apparent that a more specific definition of these disorders is needed. Hereditary nephritis without nerve a In the propositus or the family. deafness is probably closely related to Alport's syndrome: both h+ denotes"presence." Common in adults. disorders have similar clinical findings, including greater sever- dCommonin children. ity in males than in females [8], both syndromes share a similar deficiency in affected sons in the offspring of affected males [19], and both show heterogeneity in ultrastructural findings. In attention to a definite ultrastructural lesion of the glomerularaddition, GBM thinning has long been considered characteristic basement membrane (GBM) in hereditary nephritis [47—49].of benign familial hematuria [13, 57, 58], the hereditary disorder The GBM is irregularly thickened, up to 4 or 5 times normalcharacterized by lack of progression to renal failure and lack of thickness. The lamina densa is distorted and split into ahearing impairment. As I noted previously, subsequent studies heterogeneous network of strands enclosing electron-lucenthave shown that thin GBM also can occur in Alport's syndrome areas. In some cases these areas contain small granulations[15, 53, 54, 57, 591, especially in children, in whom it represents approximately 50 nm in diameter. Some investigators found thethe prominent ultrastructural lesion [15]. Thus, the finding of tubular basement membranes to be normal or nonspecificallythin GBM in children should not be taken as conclusive involved [47, 501; others asserted that splitting of Bowman'sevidence that the patient has benign familial hematuria and that capsule and of the tubular basement membranes resembled, atthe prognosis will be good (Table 2). The best prognostic least in its early stages, the changes in the GBM [49]. With theinformation can be gleaned from the family history, but careful experience obtained from electron microscopy, pathologistsfollow-up is needed in all cases. In this regard, the classification also gained the ability to recognize thickening of the glomerularof some families as having hereditary nephritis without nerve capillary walls by light microscopy [36], thus confirming previ-deafness or benign familial hematuria is uncertain [11]. ous observations by Kaufman et al, who emphasized that GBM (3) Is electron microscopy reliable for classification and thickening was the earliest and most frequent change in heredo- diagnosis of persistent hematuria? Several investigators recent- familial nephritis [511. ly have claimed that the study of renal ultrastructure is useful in Subsequent studies revealed that the ultrastructural patternevaluating children with persistent microscopic hematuria. was more complex than initially conceived (Table 2). The GBMAmong 76 children investigated by Trachtman et al [60], 26 had lesions can be patchy, alternating with segments of normalGBM changes, including 9 with GBM thinning. Thickening of thickness. Reports of serial renal biopsies reveal that the lesionsthe GBM was the most prevalent lesion in the subgroup with may be absent on the first biopsy and appear subsequently [52],gross hematuria [60]. Similarly, Yum and Bergstein noted that or become more extensive [47]. In children, the most commonall patients with GBM thickening and splitting had episodes of ultrastructural picture is focal thickening and extreme thinninggross hematuria [61]. Gubler and coworkers have elaborated of the GBM [15, 53, 54]; thinning is prominent in youngermore precise data on the clinical relevance of electron micro- children, whereas thickening and splitting are more prevalent in scopic study (personal communication). Thirty of 50 children older patients. with persistent hematuria manifested normal glomeruli by light The GBM changes recently have attracted renewed interestmicroscopy, no igA deposits by immunofluorescence, and among nephrologists, and I will explore these alterations inextensive GBM changes by electron microscopy. These GBM some detail. Several questions have been raised with regard toalterations were characterized by an irregular sequence of thick the universality and specificity of the GBM changes in theand thin segments. Repeated clinical and familial investigation various forms of hereditary nephritis. revealed at least one criterion for Alport's syndrome or heredi- (I) Are GBM thickening and splitting found in all patients tary nephritis in 26 of these 30 children. Thus, one can conclude with Alport's syndrome? In our series, these lesions are presentthat persistent hematuria in children in the absence of IgA in 80% of patients [36]. However, among 60 cases of hereditarydeposits by immunofluorescence is a major indication for nephritis studied by electron microscopy [36], we have reportedelectron microscopic study of renal biopsy specimens. 10 fulfilling the clinical criteria of Alport's syndrome, with The clinical usefulness of ultrastructural study is exemplified either widespread thinning (15 cases) or even normal GBM (5in a 10-year-old girl, studied by Gubler et al (personal communi- cases). cation), who had ultrastructural changes of the GBM highly (2) Are the GBM changes characteristic of Alport's syn-suggestive of Alport's syndrome, but who had no extrarenal drome? Both GBM thickening and splitting are highly sugges-defects and no family history of renal disease or deafness. tive of Alport's syndrome when the changes are diffuse andEleven years later, she gave birth to a girl who developed Hereditary nephritis 87

Table 3. Anti-GBM antibody binding in patients with hereditary content of collagenous polypeptides and hydroxyproline of the nephritis GBM in 4 patients with Alport's syndrome [36]. Similar changes were found by DiBona [641. Others reported abnormalities in Alport's GBM Anti-GBM urinary excretion of various collagenous or noncollagenous n syndrome lesion binding GBM-related components [36, 67]. Using indirect immunofluo- McCoy et al (1976) 8 Yes + 0 (6M) rescence, Noel et al tested antibodies directed against collage- Wilson (1980) + (2F) nous and noncollagenous components of basement membranes. McCoy et al (1982) Identical fixation was found in normal kidneys and in kidneys Olson et al (1980) 7 ? + (6) 0 (5M, 2F) from patients with Alport's syndrome [68]. In another study, -(1)b Jenis et al (1981) 9 No + 0 (2M, 2F) the monoclonal antibody MBM4, known to be reactive with + (5F) type-IV , reacted with GBM of patients with hereditary Noel et al (1981) 6 Yes + + (4M) nephritis [69]. Similarities between GBM and anterior lens + (2F) capsule have been underscored [36]: for example, monoclonal Wilson, O'Neill ? ? ? + All but et al (1982) one antibodies against type-IV collagen react with anterior lens (unpublished data) capsule but not with posterior lens capsule, both of which are Jeraj et al (1983) 9 Yes (7) + (7) 0 (7M) basement membranes that contain type-IV collagen and + (2F) [66]. a Refersto presence of ultrastructural GBM lesion. Studies on the antigenicity of the GBM by indirect immuno- Refers to absence of ultrastructural GBM lesion. fluorescence are still inconsistent but raise the possibility that the biochemical changes result from a defective antigen con- trolled by one or more genes. Most studies revealed no binding hematuria at age 2. Two years later, the mother developed renalof human anti-GBM antibodies to glomeruli of male patients failure and hypertension. This example demonstrates the valuewith Alport's syndrome or hereditary nephritis without nerve of electron microscopic study in suggesting the diagnosis ofdeafness, whereas binding was detected in some affected fe- hereditary nephritis long before the family history becomesmales [69—7 1] (Table 3). In contrast, all patients studied reacted evident. The value of electron microscopy also is supported byas did normals with heterologous [69, 71, 72] and monoclonal Hinglais et al, who reported 2 patients with hearing and/or[69] anti-GBM antibodies. It was suggested that the lack of ocular defects and GBM changes but whose family historiesbinding reflected the absence of GBM antigen(s) and was were negative [47]. correlated with the severity of the GBM ultrastructural lesion (4) Are GBM changes homogeneous in affected families? In[70], but binding was also absent in one patient who had no most families, the GBM lesions are homogeneous. When pre-GBM thickening and splitting [73]. In contrast with the preced- sent, they were found in all affected subjects; when absent, theying results, Noel et al found glomerular binding of antihuman were absent in all [47, 62]. However, intrafamilial differences,GBM antibodies in all 6 renal specimens tested [68]. Similarly, although rare, were reported in 3 kindreds investigated byWilson, O'Neill et al detected antigens reactive with the panel Habib et al [36] and Yoshikawa et al [57], and in one family withof antihuman GBM antibodies in all but one of the Utah patients hereditary nephritis without nerve deafness studied by Beath-[71]. Therefore, only subsets of patients with hereditary nephri- ard and Granhoim [52]. The question therefore remains open astis lack an antigen in the GBM that is present in normal kidneys. to whether GBM thickening is characteristic of a particular typeIn addition, McCoy and Wilson et al performed more detailed of hereditary nephritis, or whether it indicates a progressiveimmunologic investigation [71, 72]. They showed that absorp- form of nephritis within a given family, as suggested bytion of human anti-GBM sera with GBM preparation from a Beathard and Granholm [52]. To assess the significance of thepatient with Alport's syndrome did not abolish binding proper- GBM lesion, we need adequate follow-up in the families withties, whereas absorption with normal GBM did. Binding also differences, as well as electron microscopic study in asymptom-was lacking along Bowman's capsule and tubular basement atic female carriers, to determine whether these individualsmembrane (TBM) when anti-GBM sera with additional anti- have the characteristic ultrastructural changes of the GBM. TBM reactivity were used [71]. Gubler et al have suggested that Pathogenesis of GBM lesions. It has been hypothesized thatthe abnormal persistence of neonatal (or fetal) GBM lacking altered composition and/or metabolism of GBM collagen isGBM antigen(s) is responsible for thin GBM with irregularities, present in Alport's syndrome. A similar defect might accountruptures, and repairs, leading finally to focal thickening [15]. for extrarenal changes, involving collagenous structures of theHowever, the lack of GBM antigen(s) in neonates and infants inner and lens capsule [63—651. A similar hypothesis hashas been challenged [65]. been put forward in other diseases, such as Alström's syndrome Further investigation of GBM antigenicity using large panels [29]. The results obtained by Martinez-Hernandez and Amentaof anti-GBM antibodies is needed in families with hereditary supported this hypothesis: they found that in Alport's syn-nephritis. From these preliminary results, some authors have drome, epidermal and vascular basement membranes in thesuggested that gene(s) controlling the defective antigen were skin had the same multilamellated appearance as did the GBM,localized on the [69, 70], some of the data being and that they also had an abnormal distribution of laminin andcompatible with an X-linked mode of transmission. According type-IV collagen antigens [66]. These authors also suggestedto this hypothesis, hemizygous males would lack the GBM that the epithelial and endothelial basement membranes failedantigen(s) completely. In heterozygous females, random inacti- to fuse in Alport's syndrome, resulting in the apparent splitting.vation of a lesser or greater proportion of X chromosomes could With P. Mahieu and J. -M. Foidart, we found a decrease in theresult in a wide range of antigen(s) defects and in a wide 88 Nephrology Forum

Table 4.Clinicaldata in females with hereditary nephritis Table 5.Renal ultrastructural changes in females with hereditary nephritis Patients with Patients without renal failure renal failure Patients Patients with renal without s35a 45a >30" 28yrs" failure renal failure Total number 9 5 14 8 45 >30h Alport's syndrome 7 5 7 7 Hereditary Thin GBM 3 nephritis Normal GBM without nerve Segmental deafness 2 0 7 thickening 1 3 Neural hearing Diffuse loss in the thickening 6 4 5 4 1 propositus a Gross hematuria 6 3 0 3 Ageat onset of renal failure. bPresentage. aAgeat renal failure. bPresentage.

excluding carriers with intermittent or no urinary abnormalities spectrum of clinical manifestations. However, male-to-male(GrUnfeld JP, Noel LH, Hafez S, unpublished data). These transmission (Fig. 2) is not compatible with an X-linked trait. patients were divided into 3 groups on the basis of renal In keeping with the hypothesis of "missing" GBM antigen(s),function and the age by which they had developed renal failure one might expect to observe anti-GBM antibodies and possibly (Table 4): (1) Nine females developed renal failure at 35 years of glomerulonephritis in some patients who received a renalage or less. In all but 2 the diagnosis of Alport's syndrome was transplant containing normal GBM antigens. Renal transplanta-made; 4 had neural hearing loss. (2) Five women developed tion has been performed in several hundred patients withrenal failure at 45 years of age or more; all 5 had nerve deafness. Alport's syndrome [74], and one group reported satisfactorily(3) The remaining 22 females, ranging from age 19 to 48 at last functioning transplants in 10 of 11 patients [74]. Four patients follow-up, so far have normal renal function. Four have neural with Alport's syndrome, however, developed linear IgGhearing loss. Fourteen are presently over 30 years of age. Seven glomerular deposits and crescentic proliferative glomerulone-belong to families with Alport's syndrome, and the other 7 have phritis after renal transplantation, and serum anti-GBM anti-hereditary nephritis without nerve deafness. In the kindred bodies were found in 2 of these patients [71, 74]. In one patient, studied by Alport [6] and further reported by Crawfurd and anti-GBM immunization recurred after a second transplant,Toghill [7], the renal course was quite heterogeneous among whereas it did not recur in another [74]. In two cases (includingaffected women: 2 females with nephritis died at ages 69 and 83; that studied by Wilson, O'Neill et al) [71], it was demonstratedthe first had nerve deafness. In contrast, 3 other affected by immunofluorescence that the native kidneys were lacking females died at ages 12, 22, and 24. the GBM antigen(s). Although unproved, the "missing" GBM We attempted to determine the factors that predict a poor antigen hypothesis remains attractive. renal prognosis by comparing female patients who developed early or late renal failure with those who are older than 30 and Prognosis who have normal renal function. Obviously, some of the latter Sex. The prognosis is poorest in affected males; they typically group may subsequently develop renal failure. From our data, develop ESRD between ages 15 and 40. As noted before,the following indicators of poor renal prognosis emerged: gross however, ESRD can develop later, after age 50 (Fig. 2). Chazan hematuria in childhood, neural hearing loss, Alport's syndrome et al reported a unique family with nonprogressive renal disease in the family (versus progressive hereditary nephritis without and nerve deafness. A 57-year-old deaf male had renal involve-nerve deafness), and presence of diffuse thickening and splitting ment and normal renal function, and no member of the familyof the GBM by electron microscopy (Table 5). Further follow- had developed progressive renal failure [75]. up is required to test the value of these indices. Additional It is well known that the renal prognosis is much less severeinformation is needed on the GBM ultrastructural changes in in affected females than in males. There is, however, a widewomen with late renal failure. Renal biopsy was performed in clinical spectrum of renal involvement in women, and theonly one of these 5 women and the GBM appeared normal prognosis may be difficult to predict in some affected females. (Table 5), whereas it was thickened and split in her affected son At one end of the spectrum are asymptomatic female carriers. who developed ESRD at age 17. In 3 of the other 4 women Numerous female carriers have intermittent or slight urinarybelonging to this group, the GBM was thickened and distorted abnormalities and never develop significant renal impairment. in at least one member of the family. Thus, GBM thickening and At the other end of the spectrum are females with progressive splitting is commonly found in females with early renal failure, nephritis that leads to ESRD when the women are between 15 but so far we cannot conclude whether females with late renal and 30 years of age, as in males. In some kindreds, severalfailure have abnormal GBM. female siblings all were affected by progressive nephritis (Fig. Heavy proteinuria and nephrotic syndrome. We have 1) [17, 76, 77]. stressed the poor renal prognosis of patients with heavy pro- The rate of progression of renal disease in females is eventeinuria or nephrotic syndrome in hereditary nephritis [171. The more heterogeneous. We recently reviewed 36 cases of heredi-incidence of the nephrotic syndrome is higher in patients who tary nephritis in women with persistent urinary abnormalities,progress to renal failure in childhood or in early adulthood than Hereditary nephritis 89

in those who develop renal functional impairment later (unpub- Genetic data. I will not review all the genetic observations lished data). and debates concerning the mode(s) of transmission of heredi- Hearing and ocular defects. Hearing loss augurs a poortary nephritis [36]. 1 will focus only on the information that is prognosis in males. Progression of hearing impairment in chil-useful for renal prognosis. Tishler and Rosner noted that ages at dren suggests a poor renal prognosis [151. However, males withdeath or "renal death" of affected males were most often highly normal hearing may progress to renal failure (Fig. 2), both inconcordant within affected families. From the data available, families with Alport's syndrome and in those with hereditarythey differentiated two groups of pedigrees. In most, age at nephritis without nerve deafness. Deaf males without renaldeath in males fell between 16 and 28 years; in contrast, in 10 involvement are claimed to transmit the deleterious gene tofamilies, age at death was distinctly higher, ranging from 33.5 to their offspring [14]. There is, however, no good evidence for52.5 years (Fig. 2) [801. These results may be relevant for such a transmission if the data available in the literature arepredicting outcome in affected males. The clinical course in carefully analyzed. Perkoff et al reported that deaf males withsome affected males in certain families has been highly atypical normal urinalysis had transmitted the disease [181. Indeed, a[80], however, and obviously these conclusions do not apply to few of these men's daughters were considered to be affected.affected females. The conclusions by Gubler vary with those of As noted earlier, however, leukocyturia in these reports wasTishler and Rosner. Gubler's group found that the rate of considered an indicator of renal disease, a concept rebutted byprogression to renal failure varied greatly not only among O'Neill et al, who studied the same kindred at a later time [16].families, but even within families between successive genera- Similarly, the data by Purriel et al are not convincing in thistions. The mean age at death was 17.4 years in the study regard [38]. Five males had isolated deafness, but no evidencepatients, whereas it was 33.1 years in their ascendants [15]. indicates that they had transmitted the renal disease. In anotherSuch a phenomenon of anticipation" was not found by Tishler family, one son had "intermittent proteinuria," a poor index ofand Rosner [8t]. It may be restricted to pediatric series, hereditary renal involvement [38]. Mulrow et a! reported a deafcomposed of children with the most severe courses, who male (111-12) with a normal urinalysis who had a 5-year-oldprogress to ESRD early. This phenomenon, however, may be daughter with renal disease [78]. Again, these authors consid-observed in other kindreds (Fig. 2). In addition, Gubler et al ered the children to be affected if they had more than 5 whiteunderlined the good concordance in the evolution of renal cells per high-power field. In our experience, we have not foundfailure among siblings (Figs. 1 and 2) [15]. a deaf male with a normal urinalysis who is an unequivocal Good evidence suggests genetic heterogeneity in Alport's carrier. This constellation of findings was not demonstrated in syndrome [36, 80], and this finding is consistent among patients the family of cases 7 and 8 we reported in 1972 [47], nor in thewith GBM thickening [36]. The kindreds presented in Figures 1 family reported by Gubler et al [15] (personal communication). and 2 illustrate this point well (Family 1 has already been The only possible example is in "Family 5" studied by Cassadyreported [17]). In the first kindred with familial nephritis (Fig. et al [791. 1), recessive autosomal inheritance is suggested; the disease The prognostic value of the hearing defect is not as clear inappeared after a consanguineous marriage, the parents were females as it is in males. Deaf female carriers with slight renalunaffected, and both affected women have renal and extrarenal impairment or normal renal function have been reported [6].features highly suggestive of Alport's syndrome. Family 2 (Fig. Deaf females may have a slow progression to renal failure. On2) represents an example of male-to-male transmission of the whole, deaf females have a worse renal prognosis than doAlport's syndrome, which previously has been observed, albeit thoe who are not deaf [19]. infrequently [17, 50, 55, 81], and which points to an autosomal I have indicated that the presence of anterior lenticonus [17]dominant trait. Lastly, it has been proposed that in many and perimacular changes [37] correlates with poor renal progno-kindreds the transmission of hereditary nephritis is compatible sis. However, both lesions predominate in males and arewith an X-linked trait [16, 81, 82]. strongly associated with deafness. The association of deafness Genetic theory, as well as genetic counseling, must take into and anterior lenticonus in males or in females is indicative ofaccount the greater severity of Alport's syndrome in males than poor renal prognosis (Fig. 1). No instance of a carrier with anin females, and the anomalous proportions of normal and isolated ocular defect and a normal urinalysis has been reportedaffected offspring, most particularly, the significant excess of so far. unaffected sons in the offspring of affected males. In addition, Thickening and splitting of the GBM. I suggested that thewe found that in affected males inheritance from the mother is presence of this ultrastructural GBM lesion in a family indicatedassociated with a worse prognosis than is inheritance from the a more progressive nephritis, compared with families in whomfather [17]. such a lesion was not detected [17]. Mean age at death was Some confusion regarding genetic conclusions may originate approximately 27 years in families with, versus 37 years infrom the lack of adequate markers of various types of heredi- those without, these GBM lesions. I should point out, however,tary nephritis. Clinical identification of affected subjects must that the former mainly had Alport's syndrome, whereas therest on appropriate criteria, particularly the results of a careful- latter kindreds all had hereditary nephritis without nerve deaf-ly performed urinalysis. A proper diagnosis is most critical and ness [17]. Our recent data on females also suggest that somedifficult to make in some females. Relying on the reports of prognostic value may be ascribed to the GBM lesion. As I havelarge families with many severely affected subjects may intro- emphasized, male sex, deafness, anterior lenticonus, perimacu-duce bias in genetic analysis and counseling. There is a substan- lar changes, and GBM thickening indicate a poor prognosis.tial prevalence of hearing abnormalities in the general popula- However, female sex and the absence of deafness, oculartion, so that hearing loss alone is not a good clinical marker. defects, and GBM lesions do not preclude the progression ofThe identification of the ultrastructural lesions of the GBM is nephritis to renal failure [37]. clinically helpful, but the results of electron microscopic study 90 NephrologyForum

have not yet clarified the classification of the various forms ofyou give? Should it be different for affected males and females? hereditary nephritis. Yet to be developed are adequate bio- DR. GRUNFELD: Genetic counseling is not easy. The first step chemical markers that identify the individual with a defectiveis collecting adequate clinical information to determine the gene. mode of transmission in a given family. As I discussed earlier, this mode can differ from one family to another. The second Questions and answers step is adapting genetic counseling according to the type of DR. KASSIRER: I am struck by the remarkable differences ininheritance, if this can be determined. In addition, it should be the renal manifestations of patients with hereditary nephritis.recalled that affected males have a low risk of transmission to Some patients have insignificant proteinuria, even by quantita-sons, but they have a substantial risk of transmission to tive techniques, and others have overt nephrotic syndrome. Isdaughters whose renal disease is often, but not always, benign. there a correlation between these clinical findings and theIn contrast, affected female patients, or even carriers, can histopathology? transmit the disease to sons who often are severely affected. DR. GRUNFELD: As you know, it is difficult to perform DR. RENÉE HABIB (Directeur de Recherche, INSERM, Unite quantitative studies on electron microscopy data. We attempted192, Hôpital des Enfants Malades, Paris): I wonder whether we to quantify the lesions, but it is a difficult task. Perhaps Dr.have an adequate definition of what is and what is not Alport's Gubler would like to comment on this point. syndrome. Would you be comfortable diagnosing Alport's DR. MARIE-CLAIRE GUBLER (Maître de Recherche, INSERM syndrome in a family in whom ultrastructural studies show no Unite 192, Hôpital des Enfants Malades, Paris): Most of ourGBM changes? Wouldn't you question the diagnosis of Alport's observations have been made in children aged 2 to 16. In youngsyndrome if you found no changes in the GBM? Perhaps the children with only hematuria, extensive thinning of the glomer-characteristic diffuse changes of the GBM should be considered ular basement membrane is present. In older children withdiagnostic of Alport's syndrome whether the patient is deaf or abundant proteinuria, the GBM tends to be thickened. Thusnot, whether there is hematuria or not, and even if no other there is some correlation, but I did not perform quantitativesigns of the disease are present. measurements of the GBM. DR. GRUNFELD: This issue is a difficult one. Several years DR. EBERHARD RITZ (Chief, Division of Nephrology, Univer-ago we reported a few patients with Alport's syndrome who did sity of Heidelberg, Heidelberg, Federal Republic of Germany):not have the characteristic GBM changes [361. It is possible that You pointed out that the frequency of familial nephritis as athe GBM changes are characteristic of a certain type of cause of renal disease is underestimated, sometimes for person-hereditary nephritis. We need additional histologic data in al reasons. In an analysis of our patient population, Dr.families with hereditary nephritis without nerve deafness. Waldherr and I found that 13% of all patients with glomerularEventually we may be able to better define varieties of heredi- nephritis in our unit had a positive familial history, but only 50%tary nephritis with or without GBM changes. Such studies may of these had classic Alport's syndrome [5]. These observationsdisclose a new entity, independent of deafness. confirm your assertion that the magnitude of the problem is DR. HABIB: Unfortunately, we find many forms of hereditary underestimated. nephritis. I think we should use the terms "Alport's syn- I also might comment on the occurrence of patients whodrome," perhaps "with" and "without deafness." Maybe there appear to have Alport's syndrome but who have a negativeare variants of Alport's syndrome, but I think that the term family history of renal disease. In the report of the transplanta-"hereditary nephritis" is too broad. tion teams in Munich and Copenhagen, at least 10% of the DR. GUBLER: I have some experience with the GBM changes individuals reported to be the father cannot possibly be the truein hereditary nephritis without deafness [83]. In biopsy speci- father on genetic grounds. So I think this introduces a largemens from 6 children, the GBM was thin in all. But, Yo- margin of error and underlines the Roman proverb, "Certa,shikawa, Cameron, and White observed either thin or thick semper incertus." GBM in patients with hereditary nephritis without deafness [56, DR. GRUNFELD: Je répondrai en Francais que les épouses57]. So the status of the GBM in this disorder awaits further francaises sont au-dessus de tout soupcon. clarification. DR. DAVID MCCARRON (Division of Nephrology and Hyper- DR. JACQUES CHANARD (Chief, Division of Nephrology, tension, Department of Medicine, Oregon Health SciencesHôpital Maison Blanche, Reims, France): We have been look- University, Portland, Oregon): When this type of inheritance ising for biochemical abnormalities in the urine of patients with encountered, we should suspect that environmental factorsAlport's disease. We measured the urinary excretion of 3- and might be playing a role in these families. In other words, a4-hydroxyproline. Glomerular basement membrane could appear to be familial in transmission but actuallycontains on average 8 to 12 residues of 3-hydroxyproline per might be caused by familial exposure to a common environmen- 1000 residues. In 5 male patients with progressive hereditary tal pathogen that results in glomerulonephritis and interstitialnephritis, we have found normal urinary excretion, contrary to disease. Do we know anything about the effects of environmen-our observations in patients with polycystic renal disease [84]. tal conditions? DR. GRUNFELD: Your results are interesting. With Philippe DR. GRUNFELD: Environmental factors can affect the rate ofMahieu and Jean-Michel Foidart we found a decrease in the progression, but transmission in several successive genera-hydroxyproline content of the GBM in Alport's syndrome [36]. tions, as in the family studied by Alport [6], strongly indicates a DR. CLAUDE BARBANEL (Chief, Division of Nephrology, genetic disease. Hopital de Meaux, Meaux, France): Have you observed fam- DR. ALBERT FOURNIER (Chief, Division of Nephrology,ilies with platelet abnormalities? Hôpital d'Amiens, Amiens, France): What genetic advice do DR. GRUNFELD: As I recall, you described a family with the Hereditary nephritis 91

May-Hegglin abnormality including megathrombocytopenia 17. GRUNFELD J-P, BoIs EP, HINGLAIS N: Progressive and nonpro- and leukocyte inclusions [40]. Although we have not encoun- gressive hereditary chronic nephritis. Kidney mt 4:216—228, 1973 18.PERKOFFGT, NUGENT CA,DoLowITzDA, STEPHENS FE, CAR- tered a similar family, Michel Broyer, Marie-Claire Gubler, and NES WH, TYLER FH: A follow-up study of hereditary chronic Renée Habib found one family with a platelet defect [15]. The nephritis. Arch Intern Med 102:733—746,1958 mother had both a platelet defect and high titers of antithyroid 19.GRUNFELD J-P, HINGLAIS N: Néphropathie héréditaire avec sur- antibodies. These findings appear to be isolated instances and dité, in Nephrologie(2nd ed),edited by HAMBURGERJ,RICHETG, do not seem to provide specific insights. CROSNIER J, FUNCK-BRENTANO JL, ANTOINE B, DUCROTH, MERY J-P, DEMONTERA H, Paris, Flammarion, 1974, pp 1107—11 15f DR. KASSIRER: Can we prevent progression of renal insuffi- 20. DUBACH UC, MINDER FC, ANTENER I: Familial nephropathy and ciency in such patients after renal function begins to decline? Is deafness: first observation of a family and close relatives in transplantation or dialysis the only hope for a patient with this Switzerland. HelvMed Acta 1:36—43,1966 disease? 21.MCDONALD TJ,ZINCKE H, ANDERSON CF, OTTNT: Reversalof DR. GRUNFELD: I hope that the future will bring us some way deafness after renal transplantation in Alport's syndrome. Laryngo- scope 88:38—42,1978 of slowing the rate of progression of renal failure. Hypertension 22. MITSCHKEH,SCHMIDTP,ZAZGORNIKJ,KOPSA H, PILSP:Effect must be controlled as in other patients. Brenner has suggested of renal transplantation on uremic deafness: a long-term study. that the propensity for young males with hereditary nephritis to Audiology16:530—534, 1977 develop progressive renal disease might be due in part to the 23. MYERSGJ, TYLERHR:The etiology of deafness in Alport's syndrome. Arch Otolaryngol96:333—340, 1972 renotrophic effects of androgenic hormones, and he also has 24.JOHNSSON LG, ARENBERG1K:Cochlear abnormalities in Alport's proposed that low protein intake might reduce the rate of syndrome. Arch Otolaryngol107:340—349,1981 progression of chronic renal failure [85, 86]. 25.HERRMANNC JR, AGUILAR MJ, SACKS OW: Hereditary photomyo- clonus associated with diabetes mellitus, deafness, nephropathy Reprint requests to Dr. J.-P. Grunfeld, Département de Nephrologie, and cerebral dysfunction. Neurology (Minneap) 14:212—221, 1964 Hôpital Necker, 161, rue de Sèvres, 75743 Paris, Cedex 15, France 26.GOYERRA, REYNOLDS J JR, BURKE J, BURKHOLDERP:Hereditary renal disease with neurosensory hearing loss, prolinuria and ichth- Acknowledgments yosis. AmJMed Sci 256:166—179, 1968 27.ROSENBERGAL, BERGSTROM L, TRoosT BT, BARTHOLOMEW BA: The author thanks Drs. M.-C. Gubler, L. H. Noel, and N. Hinglais Hyperuricemia and neurologic deficits. NEngi J Med 282:992—997, for fruitful discussion, and Mrs. M. A. Monod and D. Broneer for 1970 excellent secretarial assistance. 28.HAMET P, KUCHEL 0, NOWACZYNSKI W, ROJO-ORTEGA JM, SASAKKI 0, GENE5T J: Hypertension with adrenal, genital, renal References defects and deafness. Arch Intern Med 13 1:563—569, 1973 1. GUTENBERGER J, TRYGSTAD CW, STIEHM ER, OPITz JM, 29. GOLDSTEIN JL, FIALKOW PJ: The AlstrOm syndrome. Medicine TATCHER LG, BL000w0ETH JM, SETZKORN J: Familial thrombo- (Baltimore) 52:53—71, 1973 cytopenia, elevated serum IgA levels and renal disease. Am J Med 30. BARAKAT AY,D'ALBORAJB, MARTIN MM, JOSE PA:Familial 49:729—741, 1970 nephrosis, nerve deafness and hypoparathyroidism. J Pediatr 2. THOMSEN M, LADEFOGED J: A hereditary renal disease with 91:61—64, 1977 clinical and histological picture as in chronic glornerulonephritis. 31. 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YUM M, BERGSTEIN JM: Basement membrane nephropathy: a new pathies and with polycystic renal disease. C/in Nephrol 17:64—69, classification for Alport's syndrome and asymptomatic hematuria 1982 based on ultrastructural findings. Hum PaIhol 14:996-1003, 1983 85.BRENNER BM: The progressive nature of renal disease, in Sémin- 62. SHERMAN RL, CHURG J, YUDIS M: Hereditary nephritis with a airesd'Uro-Néphrologie, edited by Küss R, Legrain M, Masson, characteristic renal lesion. Am J Med56:44—51,1974 Paris,1984, p 67 63. SPEAR GS: Alport's syndrome: a consideration of pathogenesis. 86. BRENNER BM: Nephrobogy Forum: Hemodynamically mediated Clin Nephrol 6:336—337,1973 glomerular injury and the progressive nature of kidney disease. 64.DIBONA GF: Alport's syndrome: a genetic defect in biochemical KidneyInt 23:647—655, 1983