Inherited Diseases of the Glomerular Basement Membrane

CLINICAL CONFERENCE

Inherited Diseases of the Glomerular Basement Membrane Kenneth A. Bodziak, MD, William S. Hammond, MD, and Bruce A. Molitoris, MD • The inherited diseases of the glomerular basement membrane include Alport's syndrome (AS), nail-patella syndrome, and thin basement membrane nephropathy. Classical AS is inherited in an X-linked manner and accounts for approximately 85% of the cases. Its manifestations include hematuria, sensorineural hearing loss, ocular defects, and a progression to renal failure. A defect(s) in the 005 (IV) chain of type IV collagen is believed to be the etiology of classic AS, and alterations in its encoding gene localized to the X-chromosome have been elucidated. Although isolated cases of anti-glomerular basement membrane glomerulonephritis have been reported following renal transplantation in patients with AS, it is considered an effective form of renal replacement therapy. Less is known regarding the genetic basis of the autosomal-dominant form of AS, which apparently accounts for the remaining 15% of the cases. Nail-patella syndrome is characterized by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. It is inherited in an autosomal-dominant fashion with the gene locus assigned to the long arm of chromosome 9. Possible linkage between the COL5A 1 gene and the gene for nail-patella syndrome has been suggested. Approximately 30% of the patients progress to end-stage renal failure. Renal transplantation has been successful in treating patients who progress to end-stage renal failure. Thin basement membrane nephropathy is an autosomal dominant trait that accounts for approximately 30% of the cases presenting as persistent, asymptomatic hematuria. The cause of thin basement membrane nephropathy is unknown at present. No decline in renal function is associated with thin basement membrane nephropathy. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Alport's syndrome; nail-patella syndrome; thin basement membrane nephropathy; glomerular basement membrane; Goodpasture antigen.

CASE REPORTS

Case No. 1 A 19-year-old woman was admitted to the Hopital Necker for evaluation of microscopic hematuria and nephrotic-range proteinuria.' She and her 20-year-old sister both suffered from bilateral anterior lenticonus, retinal perimacular changes, and perceptive deafness. The sister had already reached end-stage renal failure and was on dialysis. Other family members were unaffected. A percutaneous renal biopsy was performed and revealed mild interstitial fibrosis with associated ischemic glomerular changes. Electron microscopic findings were significant for thickened glomerular basement membranes (GBMs) with splitting and splintering of the lamina densa. At 21 years of age, the patient became pregnant, her serum creatinine increased from 0.9 mg/dL to 2.3 mg/dL, and she delivered a healthy 2.7-kg boy. However, by the age of 26 years she required dialysis. Three years later she received a cadaveric renal transplant, and I year posttransplant she was faring well with no evidence of proteinuria and a creatinine clearance of 87 mL/min.

Case No. 2 A 31-year-old man was admitted to the University of Minnesota for malignant hypertension. 2 He had been treated at that institution from early childhood for multiple skeletal deformities (talipes equinovarus, hypoplastic patellae and thumbnails, and "iliac horns" seen on x-ray film) and proteinuria(2.85 gj24 hr at 4.5 years of age). At time of admission his serum creatinine and urinary protein excretion were 3.0 mgjdL and 15.1 gj24 hr, respectively. Intravenous pyelography and audiography were both normal. At 33 years of age, the

patient was started on chronic hemodialysis. Within several months of this time, he received a renal homograft from his mother. At I year posttransplant, the patient's serum creatinine was 2.2 mg/dL and his urinary protein excretion was less than 100 mgj24 hr.

Case No.3 An 18-year-old man presented to the US Army Institute of Surgical Research (Fort Sam Houston, TX) for evaluation of asymptomatic microscopic hematuria. 3 His past medical history and that of his family were otherwise negative for renal disease, deafness, and skeletal deformities. His physical examination was totally unremarkable. Extensive work-up, including serologies, complete urologic evaluation, audiometry, and urinary testing, was unrevealing. On renal biopsy the glomeruli appeared normal by light microscopy except for the presence of red blood cells within Bowman's space. Immunofluorescence microscopy was negative for immunoglobulin, complement components, and fibrinogen. The sole abnormal finding on electron microscopy was thinning of the basement From the Renal Division, University of Colorado Health Sciences Center, Denver, CO; and the Department of Pathology, Department of Veteran Affairs Medical Center, Denver, CO. Received June 28, 1993; accepted in revised form October 18, 1993. Address reprint requests to Kenneth A. Bodziak, MD, Indiana University School ofMedicine, Indianapolis University Medical Center, Fesler Hall108, 1120 South Dr, Indianapolis, IN 46202-5116. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2304-0019$3.00;0

American Journal of Kidney Diseases, Vol 23, No 4 (April), 1994: pp 605-618

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BODZIAK, HAMMOND, AND MOLITOR IS

Fig 1. Electron micrographs featuring GBMs representative of (A) normal kidney, (B) thin basement membrane disease, (C) Alport's syndrome, and (0) nail-patella syndrome. Each bar is 0.5 Itm in length for respective photographs. Arrows in 0 depict collagen fibrils within the GBM. (Figure 10 reprinted with permission. 102)

membrane as assessed by latex particles of known diameter for comparison. These three cases illustrate the diversity of the clinical presentations and sequelae of the inherited GBM diseases that will be discussed here: Alport's syndrome (AS) in case no. 1, nail-patella syndrome (NPS) in case no. 2, and thin basement membrane nephropathy (TBMN) in case no. 3.

THE GLOMERULAR BASEMENT MEMBRANE

The primary function of the GBM is to serve as a filtration barrier, acting to select out molecules based both on size and charge. Heparin sulfate proteoglycans possessing polyanionic side chains of chondroitin sulfate and dermatan sulfate present an electrostatic barrier to negatively charged particles and prevent them from traversing the GBM. These side chains also permit the proteoglycans to bind to type IV collagen. 4 The GBM has been described as appearing as a trilaminar structure in transmission electron microscopy, consisting of an electron-dense centrallayer (the lamina densa, which is now considered an artefact) that is flanked on either side by two electron-lucent layers (the laminae rarae)

(see Fig 1).4 The latter lie apposed to the endothelial and the visceral epithelial cells of the glomerulus (the laminae rarae intema and the laminae rarae extema, respectively), and are composed of laminin, fibronectin, and proteoglycans. The lamina densa is a highly woven meshwork of type IV collagen. 5 The overall width of the GBM increases from childhood to adulthood, measuring approximately 100 nm at birth to approximately 310 nm in women and 375 nm in men. The thickness of the GBM is taken as the distance between the epithelial and endothelial cytoplasmic membranes averaged from numerous (eg, 10) measurements per capillary loop magnified on a grid. The major component of the GBM is type IV collagen, which accounts for approximately 50% of the dry weight. Unlike the fibrillar collagen types, type IV collagen has frequent interruptions in the characteristic amino acid triplet repeat of Gly-Xaa-Yaa. This modification provides type IV collagen with more flexibility than its fibrillar counterparts. The protein molecule of type IV

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collagen is primarily composed of two a 1 (IV) chains and one a2 (IV) chain. In addition, the novel chains a3 (IV), a4 (IV), and a5 (IV) have been identified over the past several years and have been shown to be present within type IV collagen at the carboxyl termini (Table 1). The a 1 (IV) and a2 (IV) chains form a centralized triple helix with a highly conserved globular noncollagenous domain (NC 1) of approximately 230 amino acid residues at the C-terminal end, and a small (30 nm) triple helical domain (7S) at the N-terminus. The NCI domains of two type IV collagen molecules interact, and four molecules of type IV collagen associate to form tetramers at the 7S domains, joined by disulfide bonds. The end result is a highly flexible collagenous meshwork that provides mechanical stability to theGBM. Other constituents present in the GBM are collagen types I and VI and entactin, which bind directly or indirectly to the other components, including laminin, nidogen, fibronectin, amyloid P component, and collagen type IV. THE GOODPASTURE ANTIGEN

Located within the globular NCI domain of the GBM type IV collagen is the Goodpasture (GP) antigen, the binding site for auto-antibodies present in GP syndrome. The relevance of this antigen to AS will be further addressed below. In general, the GP antigen tends to be absent in AS, but present in NPS and TBMN. Evidence that the GP antigen resides in the noncollagenous domain of type IV collagen first came in 1973 when Marquardt et al showed that anti-GBM antiserum taken from patients with GP syndrome still binds to human GBM following collagenase digestion. 6 Wieslander et allater purified the collagenase digests of human GBM through gel and affinity chromatography, and found a protein with an apparent molecular weight of 26 kd to be the GP antigen. 7 ,s These investigators also reported that the antigenicity

was lost on breakage of intrachain disulfide bonds within the GP antigen. 9 This latter finding is relevant to AS patients, as discussed below. In 1985, Butkowski et al resolved three monomeric fractions (MI, M2*, and M3) from collagen-digested bovine kidneys with 6 M guanidine HCl extraction and SDS-PAGE. 1O The monomer M2* was found to be reactive with sera from GP syndrome patients, comprised 2.5% of the mass of type IV collagen, and had an apparent molecular weight of 28.3 kd. The same group subsequently ascertained that Ml comprises two polypeptides that correspond to the non collagenous domains of the a 1 and a2 chains of type IV collagen, and that M2* and M3 were found to be unique among known collagens. II Hence the naming of the novel collagen chains q3 (IV) and a4 (IV), which correspond to the monomers M2* and M3, respectively. In 1990, Hostikka et al identified the last known type IV collagen chain, a5 (IV), through cDNA cloning. 12 Indirect immunofluorescence revealed that antiserum raised against an a5 (IV) synthetic peptide was restricted to the GBM. In addition, the gene for a5 (COL4A5) was localized to the Xq 22-26 region through in situ hybridization. 12 In summary, it appears that the GP epitope may reside within the noncollagenous domains of several chains. However, the binding of GP antiserum has given the greatest reactivity with a3 (IV), and the location of a3 (IV) correlates with the sites of greatest tissue damage in GP syndrome (ie, the kidney and lung). ALPORT'S SYNDROME

Attlee first called attention to the familial idiopathic recurrent hematuria occurring in three cases from one family in 1901Y One year later, Gutherie drew comparisons between those cases and 12 persons from three generations of a single family whom he had followed for idiopathic hematuria. 14 Gutherie's diagnosis of idiopathic hematuria was made on the basis of "personal and

Table 1. Characteristics of Type IV Collagen Chains Type IV Chain

Gene-Encoding Location

Normal GBM Distribution

a1 (IV) and a2 (IV) a3 (IV) and a4 (IV)

Chromosome 13 Chromosome 2 X-chromosome

Confined to the subendothelial region of the GBM (and to the mesangium) Associated with the lamina densa of the GBM Awaiting detailed information on the distribution within the GBM

a5(IV)

608

family history, on the occurrence of febrile exacerbations in which hematuria far exceeds that of acute nephritis; on the absence of oedema, dropsy, and cardiovascular changes; and, finally, on the absence of any of the well-known causes of hematuria." He observed that inheritance appeared to be from the mother and that the hematuria was likely congenital. This latter observation led Gutherie to suppose there must be some inherent weakness of the renal vessels or perhaps an abnormality of the renal vasomotor system. In 1927, Alport published his classic paper describing the association of nerve deafness with congenital nephritis he had observed among a later generation of the same family that Gutherie first described. 15 He also mentioned that males tended to die of renal failure early in life, whereas females lived to an old age. Definition In recognition of the apparent confusion in distinguishing AS from other types of inherited nephritides (eg, familial benign hematuria), Flinter et al adopted four main criteria, of which three are required to be present, for fulfilling the diagnosis of classical AS in patients with hematuria, chronic renal failure, or both: positive family history of hematuria/chronic renal failure, electron microscopic evidence on renal biopsy of AS, hightone sensorineural deafness that is progressive, and characteristic eye signs. 16 As discussed below, other investigators have proposed the existence of different variants of AS based on clinical, pathologic, and genetic heterogeneity and rely solely upon the electron microscopic findings to make the diagnosis. Epidemiology Classic AS has been cited to have a disease frequency of approximately one in 5,000 individuals. Among family members of patients with documented glomerulonephritis, Rambausek et al classified 51 of 101 cases they evaluated as classic AS.17 Furthermore, Milliner reported a prevalence rate of 2.3% of AS cases among patients who had undergone renal transplantation from 1963 to October 1980 at the Mayo Clinic (Rochester, MN).18 Genetics The mode of inheritance of AS has remained controversial. As alluded to earlier, many believe

BODZIAK, HAMMOND, AND MOLITORIS

this disorder to be heterogenous and it may consist of several different genetic variants. Classic AS appeared to take the form of X-linked inheritance based on pedigrees. Initial confusion over whether AS is inherited in an autosomal-dominant manner arose over the report of Perkoff et al, who described two affected sons of affected fathers hailing from a single family.19 However, when the family was later reinvestigated and hematuria was used as an essential diagnostic criterion in place of pyuria and proteinuria, these two cases were dismissed. As a result, the ratio of affected females to males in that family became 2: 1. Furthermore, in a report of 23 kindreds (including the one reported by Perkoff et al), Hasstedt et al stated that no father-son affected pairs were observed. 20. In addition, they reported that 84% of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected, compatible with X-linked inheritance. However, other investigators have reported several cases of documented father-to-son transmission, implicating an autosomal dominant mode. 2l ,22 Nonetheless, Atkin et al proposed six phenotypes of AS based on kindreds reported in the literature23 : Type I: Classic juvenile AS with deafness; onset of end-stage renal disease (ESRD) at younger than 31 years of age. Type II: X-linked juvenile AS with deafness; onset of ESRD at younger than 31 years of age. Type III: X-linked adult AS with deafness; onset on ESRD at older than 31 years of age. Type IV: X-linked adult AS without deafness or other defect; onset of ESRD at older than 31 years of age. Type V: Autosomal AS with deafness and thrombocytopathia. Type VI: Autosomal juvenile AS with deafness; onset of ESRD at younger than 31 years of age. In studying families who presented with classic AS, Brunner et al and Flinter et al independently localized the gene for AS to the middle of the long arm of the X chromosome in the region of Xq21.3-q22 through DNA probing and genetic linkage. 24 ,25 This agrees with the findings of Szpiro-Tapia et ai, who reported the gene to be in the q21.3-q22 region, as did Atkin et al, using different DNA probeS. 26 ,27 In the autosomal

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forms of AS, identification of the defective gene(s) is still lacking, but C0L4A3 or COL4A4 are candidates. 28 Clinical Presentation

Hematuria is the most frequent presenting symptom in AS.I It may be either microscopic or gross, the latter occurring more often after an upper respiratory tract infection and usually disappearing after the age of 10 to 15 years. In Gubler et aI's report of 58 children followed for 20 years, 45 had persistent microscopic hematuria. 29 Proteinuria has been reported to be usually absent or minimal in early age, but tends to progress with patient age. I,30,31 Gubler et al reported that 33 of 42 boys and two of six girls in this same study later developed nephrotic syndrome. 29 The overall prevalence of nephrotic syndrome has been reported to be between 30% and 40%, and usually heralds a poor prognosis. 22,29 Pyuria, described earlier by Perkoff et al to be a frequent finding in patients with AS, has since been reported not to occur as an isolated finding. 32 Bilateral neurogenic hearing impairment is one of the diagnostic criterion used by Flinter et al for AS. 16 Although not reported to be congenital, a hearing deficit can often be detected before the age of 10 years. 29 It is much more prevalent in boys than in girls (81 % v 19%, respectively) and is often in the high-frequency range. For some unknown reason, the hearing impairment does not appear to progress during adulthood. In spite of this latter observation, Gubler et al reported that 10 of their 58 patients followed required permanent hearing aids. 29 Sohar is accredited as being the first to associate ocular defects with familial nephritis. 33 Although incorrectly reported as microspherophakia, later histologic studies revealed that these patients suffered from anterior lenticonus. 34 The latter is defined as a conical anterior protrusion of the crystalline substance of the lens and may appear as an oil droplet during the red reflex of the eye. Bilateral anterior lenticonus is now cited as the most specific eye abnormality in AS.35 It is predominantly found in male patients and is always associated with sensorineural hearing loss. Other ocular findings in AS include macular and perimacular lesions. 36 Gubler et al reported that 13 of their 58 patients had whitish or yellowish dotlike lesions surrounding the foveal area, while

Habib et al found similar lesions in 29 of 79 patients. 29 ,31 Other extrarenal anomalies have been associated with AS. Peterson et al described a family (named Fechtner) comprising four generations with nephritis, deafness, cataracts, macrothrombocytopenia, and leukocyte inclusions resembling Dohle bodies. 37 A similar association of macrothrombocytopenia with nephritis and deafness had been described previously by Epstein et al in 1972. 38 Platelet function in the patients may be altered, resulting in increased in bleeding time. Garcia-Torres and Guamer associated AS with esophageal, tracheobronchial, and genital leiomyomatosis in 1983 39 (Table 2). Histopathology

Kaufman et al first reported in 1970 that GBM thickening was the earliest and most common anomaly found histologically on biopsy (or autopsy) specimens taken from 23 patients with hereditary nephritis. 30 In addition, centrilobular and epithelial cell proliferation were common and occurred more often with disease progression. Blood vessels reportedly were spared, whereas tubular atrophy and interstitial inflammation were seen in over 50% of cases. Lipid-laden foam cells were not observed often, nor were they deemed pathognomonic when they were seen since they probably reflected only the degree of associated proteinuria. Churg and Sherman later addressed the electron microscopy findings and declared a glomerular lesion typifying AS as one in which focal or diffuse splitting of the capillary basement membrane into several layers, separated by dense particles, was observed. 40 They further added that when seen in one family member, the lesion was subsequently present in all examined members (see Fig 1). A more recent review of the morphology of the GBM in patients with AS was published by Rumpelt. 41 As others before him had described, Rumpelt observed the presence of fetal-like glomeruli in eight of 70 biopsy specimens. These glomeruli were small in size and were accompanied by a reduced number of capillaries. Furthermore, two ultrastructural lesions were seen to co-exist side by side in the same glomerulus: one was the split GBM as described by Kaufman et al,30 and the other was GBM thinning due to a reduction in the width of the lamina densa by

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Table 2. Clinical Characteristics of the Inherited Glomerular Basement Membrane Diseases AS

Inheritance

Clihical findings

Histologyt

Clinical course

85% X-linked; -15% autosomal dominant; autosomal recessive (rare) Hematuria (100%)'; proteinuria (70%); sensorineural hearing loss (81% male; 19% female); anterior lenticonus, perimacular flecks (15% to 40%); thrombocytopathia (rare); leiomyomatosis (rare) Thickened GBM with splitting of lamina densa Males: all progress to ESRD; females: usually do not progress to ESRD

NPS

TBMN

Autosomal dominant

Autosomal dominant

Hematuria (33%)*; proteinuria (42%); nail hypoplasia (98%); patellar aplasia/hypoplasia (90%); "iliac horns" (80%); elbow deformities (90%); Lester's sign (50%)

Hematuria (100%); proteinuria (60% to 71%); hypertension (not documented)

Thickened GBM with fibrillar collagen deposition

Thin GBM with attenuation of the lamina densa Rarely progresses to ESRD

28% reach ESRD by age 33 yr

* Prevalence of clinical finding.

t See Fig 1.

20% to 75% of values for age-matched controls. Split GBM segments were always found to be more prevalent than thin segments, leading Rumpelt to conclude that splitting increases with time, while the number of thin segments decreases. 41 Thus, it is the thin GBM that is the basic lesion in AS, supplanted later by the split, thickened GBM. Rumpelt further conjectured that the lamina densa widens from the addition of new layers being synthesized. 41 As for the dense particles within the lamina densa described previously by Churg and Sherman,40 Rumpelt suggested that these may be detached cytoplasmic projections from podocytes. Immunofluorescence studies have failed to show any immunoglobulin present within the glomeruli along with scant or no components of complement. However, McCoy et al reported that while anti-GBM sera (taken from patients with GP syndrome) localized on 20 control kidneys, the same sera failed to localize on the GBMs of six patients with AS.42 A nonspecific rabbit antihuman GBM sera did localize on both control kidneys and on kidneys from patients with AS. This led to the conclusion that the nephritogenic antigen observed in GP syndrome must be absent in AS. However, this has not been a universal finding as other investigators have reported that the GBMs of certain male AS patients have retained their antigenic reactivity to anti-GBM antiserum. 42,43

Pathogenesis The possible genetic causes leading to the disruption ofthe GBM in AS are numerous. Initial investigators concentrated on the absence of the GP epitope in the noncollagenous domain of type IV collagen (NC 1). In 1987, Kleppel et al reported that the 28-kd monomer that corresponds to the a3 (IV) chain was absent in the GBMs of kidneys explanted from three unrelated males with AS at the time oftransplantation. 44 Other investigators, including Savage et al,45 suggested that the 26-kd band that corresponds to the alpha 1 (IV) chain is absent.45 This latter finding was interesting at the time because the gene encoding for a 1 (IV) had been localized previously to chromosome 13,46 and the majority of AS cases (approximately 85%) are inherited via an X-linked mode. 2o However, Savige later showed through polymerase chain reaction amplification of DNA extracted from peripheral blood neutrophils taken from six patients with AS that the gene encoding for a3 (IV) is apparently intact. 47 This did not rule out the possibility for an abnormality in the transcription or translation of the gene, nor did it exclude a possible posttranslational alteration in the a3 (IV) protein itself. More recently, a plethora of findings has been reported on abnormalities in the gene encoding for the a5 (IV) chain, C0L4A5. Barker et al first reported, in 1990, finding three different muta-

INHERITED DISEASES OF THE GBM

tions in the COL4A5 gene in three kindreds with AS, all occurring at the 3' end of the gene. 48 Through DNA sequencing, Zhou et al were able to demonstrate that one mutation resulted in the changing of the TGT codon for cysteine to the TCT codon for serine. 49 As mentioned earlier, disulfide bonds play an important role in the intrachain binding at the NCI domains. Thus, the loss of cysteine could affect the formation of crosslinks between two type IV molecules at their NCI domains. In addition, such a substitution could potentially disrupt the conformation of the NC 1 domain as well and, in turn, interfere with helix formation. 50 Additionally, Renieri et al reported finding a deletion at the 5' end of the COL4A5 gene in one patient with AS. 51 Antignac et al also implicated a deletion at the 5' end of the COL4A5 gene in three AS patients who also presented with diffuse leiomyomatosis. 52 Although the a5 (IV) chain protein itself has yet to be characterized, the entire primary structure of the chain has been discerned from overlapping cDNA clones. 28 It appears that the a5 (IV) and al (IV) chains are quite homologous and that polyclonal antibodies made against individual chains may cross-react. This might explain why the GP antigen was earlier assigned to the a 1 (IV) chain.

Course and Therapy As Alport originally pointed out in his classic paper in 1927, males tend to progress to ESRD and females usually are spared renal failure in spite of suffering intermittent hematuria. 15 Exceptions to this generalization have been cited in the literature. For example, Kaufman et al noted three of 11 females developing ESRD over 11 years of follow-up, while only one of 13 males had a decreased creatinine clearance. 3o Of 36 female subjects, Griinfeld et al reported nine who developed ESRD before the age of 35 years and five with ESRD who developed ESRD after the age of 45 years. I However, in their review of 58 children who were followed for 20 years, Gubler et al reported that 18 of the 42 boys and only two of the 16 girls developed ESRD. This disparity in clinical course appears to parallel the renal pathology seen in specimens from male and female patients. 29 Rumpelt reported that male patients had more splitting of the GBMs seen at

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biopsy than female patients. 41 In addition, the degree of splitting correlated with the amount of proteinuria. Several investigators have pointed to proteinuria as a poor prognostic indicator. Gubler et al found that all patients who had a poor clinical course had mild and/or intermittent proteinuria before the age of 3 to 13 years, frequently developed nephrotic syndrome accompanied by hypertension, and eventually had renal failure. 29 Most males present with ESRD between the ages of 20 and 40 years, but cases of death resulting from uremia have been noted in boys younger than 10 years of age. Other prognostic indicators of a poor clinical outcome in addition to male gender, split GBM, and proteinuria include ocular findings and sensorineural hearing loss.22 However, ·these two clinical signs are not usually dissociated from one another. For example, Habib et al noted that 77% of the patients they followed who had perimacular changes started dialysis before 30 years of age, in contrast to 13% of patients without perimacular changes. 31 In the former group, all the patients also had neural hearing loss. No definitive treatment, except for genetic counseling, has become available since Alport's time. In 1992, Callis et al reported on the use of cyclosporine A in eight patients with AS and massive proteinuria. 53 Using an average dose of 4.21 mg/kg/d of cyclosporine A, proteinuria abated in five patients by the third week of treatment and decreased from 183.3 mg/m 2/hr to 32.5 mg/m 2/hr in the remaining three patients. However, when cyclosporine A was discontinued in those who had enjoyed a full remission, proteinuria reappeared within 2 weeks. Renal allotransplantation may be considered a potential replacement therapy for AS patients who have ESRD. In 1975, the Advisory Committee to the Renal Transplant Registry reported 73 patients diagnosed with AS who had undergone allotransplantation. 54 Twenty-four of these patients lost allograft function to rejection (80%), sepsis (12%), or because of technical problems (8%). However, there was no account of recurrent disease nor the mention of the development of anti-GBM disease. Subsequently, Peten et al studied 30 patients diagnosed with AS who had undergone transplantation. When matched for age, sex, graft origin, and immunosuppressive regimen, overall graft survival and function in

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the AS group did not differ from those of a control group.55 Fifteen of 35 grafts were biopsied and examined by immunofluorescence at least 3 months following transplantation. Five of these grafts stained positive for linear immunoglobulin G along the GBM in the absence of crescentic glomerulonephritis, and in one of these cases circulating anti-GBM antibodies were detected. Peten et al concluded that despite the frequent occurrence of glomerular immunoglobulin G staining posttransplant (33% prevalence in this study), graft function is not necessarily affected. However, discretion must be used when considering transplanting a kidney from a living-related donor to an AS patient, especially if the donor candidate is female, since even electron microscopy of renal biopsy tissue from the donor may not exclude AS. In addition, the transplant nephrologist needs to be aware that posttransplant glomerulonephritis may occur in AS, albeit uncommonly, given that isolated cases of antiGBM-mediated glomerulonephritis have been reported. 56.58 Immunosuppressive therapy prescribed to prevent rejection may account for this rare occurrence. NAIL-PATELLA SYNDROME

The first reported case ofNPS was by Sedgwick (as cited by Little) in 1897, who described 18 members of a single family spanning four generations who lacked patellae and thumbnails. 59 Similar hereditary anomalies, however, may had been observed as early as 1820. 60 In 1951, Roeckerath heralded the term "hereditary osteoonychodysplasia," or HOOD, to describe this inherited syndrome, which affected the nails, knees, elbows, and pelvis of those aIDicted. 61 By 1939, Kieser had noted accompanying renal involvement in patients with NPS, while in 1950 Hawkins and Smith reported in the English literature the first cases of family members with NPS who also had proteinuria, cylindruria, and hematuria. 62 ,63 Definition and Epidemiology

Nail-patella syndrome is characterized by (1) dysplasia of the nailbeds, (2) presence of iliac horns, (3) hypoplasia or complete absence of the patellae, and (4) deformation or luxation of the head of the radius.

Carbonara and Alpert reviewed the literature on NPS in 1964. 64 They summarized the findings of studies published from 1948, which included 60 patients from 25 kindreds, to the date of their report. After including two additional cases, Carbonara and Alpert found that 39 of the 62 (63%) patients had the complete tetralogy of nail, elbow, knee, and pelvic changes; eight (13%) had nail, knee, and elbow changes without iliac horns; four (6%) had nail and knee deformities plus iliac horns; three (5%) had nail and elbow changes with iliac horns; and another three had knee, elbow, and iliac horns. The least frequent combinations included two cases with knee changes and iliac horns, two cases who had nail and elbow involvement, and one patient with only nail and knee changes. Genetics

Turner had already appreciated the genetic transmission ofNPS from parent to child in 1933 when he wrote, "It [NPS] appears to be transmitted in accordance with the laws that govern the inheritance of dominant characteristics, as described by Mendel. ,,65 Renwick and Lawler established a genetic linkage between NPS with the ABO blood group system in 1955.66 Both gene loci for NPS and ABO are present on the long arm of chromosome 9. Furthermore, Schleutermann et al also indicated that the NPS locus and that for adenylate kinase are also linked, with zero recombinations found among 29 kindreds studied. Their loci have been mapped to the region 9q34. 67 In an effort to provide genetic counseling to members of families with NPS who also had associated nephropathy (defined as protein excretion on several occasions exceeding 0.2 giL or 0.15 gld in the absence of leukocyturia and hematuria), Looji et al analyzed the clinical findings from 35 kindreds and concluded that the risk to a child developing NPS and nephropathy is approximately 1:4 and that the risk to a child developing NPS and renal failure is approximately 1: 10 if either parent had NPS plus nephropathy.68 These investigators therefore concluded that for a parent with NPS, having nephropathy or renal failure presents no "significant" risk that their offspring will contract similar renal involvement.

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Clinical Presentation

Carbonara and Alpert stated that the majority of cases (84%) they reviewed had been diagnosed with NPS only after having sought medical assistancefor condition(s) unrelated to NPS. 64 Interestingly, most of these patients' physical activity was noted to be unhampered. The male to female ratio and the ratio of affected to unaffected offspring were 1: 1. The diagnosis was usually made when the patients were in their second or third decades of life. In a review of 72 members from 11 kindreds with NPS, Bennett et al found 36 cases with characteristic skeletal deformities. 69 Of these 36 patients, 20 were found to manifest urinary abnormalities (urine protein greater the 1+ [17 cases]; the presence of red blood cells, white blood cells, or casts [12 cases]; overnight urinary concentration < 1.0 16 [seven cases]; 2-hour creatinine clearance <75 mL/min/1.73 m 2 [five cases]; or a urine pH >5.5 in the morning [two cases]). Furthermore, two of these 36 patients (5.5%) eventually died of progressive renal failure. These results differ somewhat from those of Simila et al, who showed an incidence of renal involvement of 30% (53 of 173 patients) and death due to nephropathy in 14 cases (8%).70 The incidence of nail dystrophy has been reported to be as high as 98% by Carbonara and Alpert. 64 Involvement of the nails is always symmetrical, as nails often are noted to be thin and longitudinally ridged. And for some still unknown reason, the degree of deformity diminishes from the first to the fifth digit. Changes on the toenails are similar, but found less frequently.65,7 1,72 Patellar involvement is found in approximately 90% of cases, with 11 % of the cases in one study lacking patellae bilaterally.64,71,73 There is often subluxation of the patellae (29%), which may eventually lead to a secondary chondromalacia or osteoarthritis. 74 Iliac horns were first described in the English literature by Fong in 1946 as an incidental finding following an intravenous pyelogram in a patient with NPS.75 On computed tomography, these horns have been reported to "appear very widebased or sessile with the bulk of the horn representing cortical bone. ,,76 On necropsy, Darlington and Hawkins reported finding the horns arising

from the site of attachment of the gluteus medius muscle. 77 Over 80% of cases with NPS have iliac horns, and approximately 70% of these may be palpated on clinical examination. The presence of iliac horns is considered pathognomic for NPS. 73 ,78 Elbow deformities usually result in an inability to fully extend, pronate, or supinate the arm, and result from hypoplasia of the radial head or radial bowing. Ninety percent of patients with NPS have elbow involvement. 64,65,71,72 One final clinical finding associated with NPS is Lester's sign. 79 Approximately 50% of patients have heterochromia of the iris, as the outer zone of the iris appears pale in contrast to a darker central portion, resulting in a "clover leaf' arrangement. Other sporadically associated deformities found in conjunction with NPS include lordosis, scoliosis, straightened clavicles, and cleft lip/ palate 72,80 (Table 2). H istopatho{ogy

The first renal biopsy results for a patient with NPS were reported by Muth in 1965. 60 (Brixey and Burke had previously reported finding evidence of chronic glomerulonephritis at necropsy in a 26-year-old man with NPS who had died with uremia. 7I) The patient was a teenage female with hypoplastic patellae and dystrophic nails who also had intermittent nephrotic-range proteinuria. These initial biopsy findings revealed localized thickening of the GBM with patchy areas of endothelial and epithelial cell proliferation on light microscopy. Ben-Bassat et al first reported finding collagen fibers deposited within the GBM, surrounded by electron-lucent areas, in a 19-year-old man with Nps.81 The lack of periodicity displayed by many of the fibers was suggestive of immature collagen. Other investigators have since reported similar findings of collagen fibers coupled to electronlucent areas, rendering an overall "moth-eaten" appearance to the GBM. 2,69,82 The mesangium is usually spared, save for minor collagen deposition, and varying degrees of epithelial foot process fusion have been noted (see Fig 1).69 In addition, immunofluorescent studies have yielded inconsistent findings from study to study.2,83 Monoclonal antibodies directed against the GBM have been-reported to fail to bind in some patients

614

with NPS, suggesting that the GP antigen is absent. 84 Bennett et al made an interesting observation concerning an unaffected sibling from a family with four members who had NPS.69 The GBMs of the affected members showed the characteristic ultrastructural lesions on electron microscopy, while the unaffected member had normal-appearing GBMs. In addition, Drut et al reported finding irregular thickening of GBMs with subendothelial fibrillar electron-dense deposits from the kidneys of an 18-week, spontaneously aborted fetus of a mother with NPS.85 Pathogenesis

Given the histopathologic findings of fibrillar collagen deposition within the GBM, several investigators have speculated that a connective tissue disorder may be the underlying process in NPS. 69 ,81 Greenspan et al have recently located the COL5A1 gene, which encodes the proal (V) chain of the fibrillar type V collagen, within the segment 9q34.2 - 9q34.3. 86 This places the COL5A 1 gene near the locus for NPS, which also maps to 9q34. Further work will be required to ascertain whether the COL5A1 gene is aberrant in patients with NPS. Course and Therapy

Looji et al reported that 29 of 104 patients with hereditary osteo-onychodysplasia and nephropathy later progressed to ESRD at a mean age of 33 years.68 Several cases have been reported in the literature over the past 20 years that relate the outcome of renal transplantation in patients with ESRD secondary to NPS nephropathy. The first report of renal transplantation performed on a patient with NPS was that of Eisenberg et al in 1972. 87 The patient was an 11-yearold boy who lacked patellae and had dislocated radial heads. He received a kidney transplant from an unaffected sister following renal failure accompanied by renal osteodystrophy. Two months posttransplantation all signs of active bone disease had resolved radiographically, but no mention was made of the patient's renal function. Uranga et al reported a 33-year-old man who had the skeletal stigmata of NPS and ESRD. 88 This patient received a renal transplant from his unaffected mother. One year after transplantation

BODZIAK, HAMMOND, AND MOLITOR IS

the patient reportedly had normal renal function, and the biopsied glomeruli appeared normal on light microscopy. More recently, Chan et al noted a 30-year-old man with NPS and ESRD who received a threeantigen matched kidney from an unaffected sister whose blood group differed from that of the patient (type 0 and type A, respectively).89 Eighteen months following transplantation, the biopsied graft revealed normal-appearing GBMs on electron microscopy. Additionally, the patient's dystrophic nails also had regrown completely. Speculation has arisen that perhaps an enzyme(s) deficient in NPS (eg, adenylate kinase) may be replenished on renal transplantation from an unaffected person. 89 In any event, these reports suggest that renal transplantation is a viahle therapeutic modality in the treatment of ESRD in patients with NPS. THIN BASEMENT MEMBRANE NEPHROPATHY

In 1926, Baehr reported 14 normotensive patients with a "benign and curable form of hemorrhagic nephritis" who had presented with painless hematuria and normal renal function in early adulthood. 90 Two classifications were made based on their clinical history. One group had suffered recurrent, short episodes of macroscopic hematuria, often precipitated by an acute upper respiratory infection, with a normal urinalysis or occasional microscopic hematuria between attacks. The other group had persistent microscopic hematuria unrelated to any infectious process and usually was discovered incidentally. Although Baehr failed to report a follow-up course of these patients, their prognoses were thought to be excellent. Similar reports of children and young adults were made subsequently by numerous investigators. Dische et al termed this entity "thin membrane nephropathy," while Yum and Bergstein suggested the term "basement membrane nephropathy.,,91.92 In earlier literature, "benign familial nephritis" or "benign familial hematuria" may have been ascribed to a similar process. 90,93,94 We refer to this clinical and pathologic process as "thin basement membrane nephropathy." Definition and Epidemiology

For patients who present with persistent microscopic hematuria or infrequent gross hema-

615

INHERITED DISEASES OF THE GBM

turia interposed between microhematuria, we will adopt the histologic definition put forth by Abe et al: "1) minor abnormalities seen in glomeruli by light microscopy-that is, which are apparently normal or show only minor changes by light microscopy; 2) diffuse thinning of the GBM to 200 nm, or less; 3) deposits of immunoglobulins and complement components that are not detectable by immunofluorescence microscopy; and 4) exclusion of Alport's syndrome or systemic diseases that accompany renal disease. ,,95 From a prospective study conducted from 1978 through 1983 in a circumscribed area of the Netherlands, Tiebosch et al found a prevalence rate of 31 % for TBMN among patients aged 16 to 65 years who underwent renal biopsy for persistent hematuria. 96 A similar prevalence rate of 31 % was found for immunoglobulin A nephropathy from among the same group of patients. The overall positive and negative predictive values in patients who presented with persistent microscopic hematuria and who were found to have TBMN were 31.5% and 96%, respectively. In contrast, only one patient from this same study had presented with macroscopic hematuria and was deemed to have TBMN. The overall positive and negative predictive values in patients who presented in such a manner and who were found to have TBMN were 4% and 68.5%, receptively. Thus, gross hematuria is rarely associated with TBMN. Genetics

Thin basement membrane nephropathy appears to be transmitted in an autosomal dominant mode as several reports have cited that approximately 50 percent of the offspring of one affected parent will similarly be affected, and a male-to-female ratio close to unity is frequently seen 3,94. This is only speculative, however, since the pathogenesis of TBMN remains to be elucidated. Clinical Presentation

Patients with TBMN usually present with asymptomatic microscopic hematuria, which is detected at the time of routine examination. 91 ,95,97,98 They lack the associated findings of AS (deafness, ocular deformities, platelet dyscrasias) and ofNPS (nail dystrophy, hypoplastic or absent patellae, Lester's sign, etc). These patients

rarely have macroscopic hematuria. 93 Earlier reports associated bouts of gross hematuria with a preceding upper respiratory infection in patients with benign familial hematuria. Whether these patients truly had TBMN is speculative given that immunofluorescence and electron microscopy evidence were lacking (Table 2). Histopathology

By light microscopy, glomeruli appear normal on renal biopsy specimens taken from patients with TBMN. Immunofluorescent studies are usually negative for staining of immunoglobulins, components, and fibrinogen. The histologic hallmark found in TBMN is marked, diffuse thinning of the GBM, often associated with focal epithelial foot process fusion (see Fig 1).3,91,94,97.99 The thinning is due to a decreased width of the lamina densa. Basta-Jovanovic et al found the arithmetic mean of the lamina densa in the GBMs of patients who had TBMN to be 71.4 to 147.0 nm versus an arithmetic mean of 174.4 to 235.5 nm in a control group. 100 The overall thickness of the GBMs ranged from 129 to 202 nm and 287 to 317 nm in the TBMN and control groups, respectively. Also noticeable on electron microscopy is the absence of focal thickening, lamellation, and deposits within the GBM, which are associated findings of AS. However, it may be difficult to differentiate TBMN from AS in a biopsy specimen taken from a young child since diffuse thinning of the GBM is often the only finding manifested on biopsy in the young AS patient. 97 Pathogenesis

To date, the etiology of TBMN remains undetermined. Savige et al reported that the GP antigen is present within the GBM of patients with TBMN, thus differentiating it from AS.101 These investigators also reported that the a 1 (IV) and 0'2 (IV) collagen chains do not appear to be defective. Further work is required to establish whether another collagen type(s) may be involved or whether a different component (eg, laminin) may be abnormal within the lamina densa. Course and Therapy

As its progenitor name (benign familial hematuria) implied, patients with TBMN have no apparent increase in morbidity or mortality. Sev-

BODZIAK, HAMMOND, AND MOLITORIS

616

eral studies, which have included follow-up periods of up to 10 years, have reported finding no deleterious effects on the renal function of patients with TBMN. 9I ,95

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