These citations, from the three most recent editions of the large three-volume monograph "Diseases of the Kidney," refer to comprehensive clinical descriptions of Alport syndrome by our University of Utah group.
"Diseases of the Kidney" may be purchased from the publisher, but is readily found in medical school libraries. I, Curtis L. Atkin, have as yet been unable to obtain the publisher's permission to completely reprint here this copyrighted material. The following essay was adapted and condensed from these Chapters by Dr Martin C. Gregory for the HNF Newsletter No. 27, September 1995. My notes and emendations to Dr Gregory's piece are [bracketed].
Hereditary nephritis is a disparate group of often ill-defined conditions that are similar only in that they run in families and present many diagnostic difficulties. Because the incidence and diversity of such diseases are not generally recognized, opportunities for timely diagnoses and genetic counseling are lost. The most common and best known hereditary nephritis is Alport syndrome. In this chapter, Alport syndrome will be defined as progressive hereditary hematuric nonimmune glomerulonephritis characterized ultrastructurally by irregular thickening, thinning, and lamellation of the glomerular basement membrane (GBM). In some kindreds nonrenal features occur. These include hearing loss, various ocular defects, abnormalities of platelet number and function, granulocyte inclusions, and esophageal and genital leiomyomatosis (tumors). We regard nonrenal features as helpful diagnostic pointers in some kindreds, although they are not essential to the diagnosis.
Terminology and diagnostic criteria in many reports vary, and it is difficult to define exactly what Alport syndrome or progressive hereditary nephritis should include. Alport did not perform renal histological studies and as his kindred "has rid itself of Alport's disease," no means exist for defining the syndrome he described in modern terms. This kindred had dominantly inherited kidney disease that was characterized in both sexes by hematuria and urinary erythrocyte casts, variable proteinuria, and especially in males by progressive hearing loss and renal failure. Affected males had hearing loss, died in adolescence, and had no offspring. Progressive azotemia (excesses of urea and creatinine in the blood) and ESRD (end stage renal disease) especially in males, complex ultrastructural anomalies of GBM (glomerular basement membrane), and negative glomerular immunofluorescence studies are characteristics of all types of Alport syndrome. Eventual ESRD of nearly all affected males is a central feature. [Now that Type IV disease (below) is better understood, it has become clear that hearing loss essentially always accompanies renal failure in Alport syndrome]. Many reports have expanded the classic dyad of aural and renal symptoms to include other associated nonrenal anomalies and traits [such as] thrombocytopathia (bleeding disorder characterized by defective platelets), ocular abnormalities, or leiomyomatosis. [Anti-basement membrane collagen antisera that bind] normal GBM and epidermal basement membrane (EBM) fail to bind these membranes in many but not all Alport kindreds].
Chronic hematuria (blood in the urine) is the cardinal sign of Alport syndrome. Persons with hematuria and a gene for Alport syndrome are affected. Clinically normal gene carriers (preponderantly females) should be identified for genetic studies, counseling, and selection of kidney donors; it is, however, misleading to characterize them as affected persons. Our minimal criterion for affectedness is greater than or equal to 3 red cells per high-power field of the centrifuged fresh urine sediment (with rigorous exclusion of menstrual blood) but choice of [either 1 or more, or of 10 or more] erythrocytes per field would change few diagnoses. Urinary erythrocyte casts and proteinuria support the diagnosis of Alport syndrome, but are not necessary for it, whereas other urinary findings (pyuria, positive urine cultures, or proteinuria in the absence of hematuria) are not signs of Alport syndrome. The prime criterion for ascertainment of Alport syndrome in kindreds is the demonstration of a family history of chronic glomerulonephritis in multiple closely related persons.
Clinical features regularly displayed by affected persons in a kindred define the characteristic phenotype of Alport syndrome in that kindred. The severity [and timing] of symptoms may vary [amongst relatives] according to age and gender, [yet many kindreds show statistically distinct averages]. Kindreds clearly differ in [rates of progression of renal failure,] typical ages of ESRD, [rates of progression] of hearing loss, [and presence of] ocular abnormalities. Different phenotypes and different modes of inheritance [demonstrate genetic heterogeneity and phenotypic heterogeneity] of Alport syndrome.
Juvenile versus Adult Types of Alport Syndrome. Schneider first recognized that males in some kindreds with Alport syndrome experienced ESRD in childhood or adolescence, while in other kindreds, males that had ESRD were middle-aged. Bimodality of age of ESRD has been shown repeatedly; juvenile kindreds are those in which males develop ESRD at a mean age below 31 years; in adult types of Alport syndrome ESRD occurs in males at a mean age greater than 31 years.
Major Types of Alport Syndrome. Our analysis of 65 kindreds indubitably suffers from nonuniformity of diagnostic criteria in the original reports, but most fit the following classification well. [The scheme, however, grows ever more obsolete; in particular it does not include autosomal recessive inheritance. Nascent, improved classifications are based on DNA analyses and difficult but gradually improving discrimination of clinical features (phenotype).]
The estimated gene frequency [for X-linked Alport syndrome] is 1:5000 in the Intermountain West of the United States. Shaw and Kallen estimated Alport syndrome gene frequency 1:10,000 elsewhere in the United States. We could not estimate worldwide incidence of Alport syndrome. It has been reported in many races and is probably not associated with race or geography. We believe that the observed incidence of Alport syndrome in Utah is about twice that elsewhere, not because of the "founder principle", but because of the unusual extent of our studies. The origins and large founding size of the Utah population, and high rates of gene flow have resulted in gene frequencies that are similar to those in northern Europe.
[Dr David Barker tentatively estimates the frequency of autosomal recessive (COL4A3 and COL4A4) mutations at 1:250.]
Penetrance and Dominance. Hematuria and ESRD are both manifestations of Alport syndrome, with penetrances that eventually coincide in males, but may be widely disparate in females. Penetrance of hematuria and ESRD is 100% in males with types II, III, and IV disease. For types I, V, and VI hematuria and ESRD likely also approach 100%. For females with types III or IV disease prevalence of hematuria is 90% and eventual prevalence of ESRD in females approximates 15%. ESRD may supervene in close to 100% of females with type V disease. In both males and females the penetrance of hematuria remains constant with age.
[X-linked recessive inheritance has in past been implicated from observations of ESRD in most males and much less ESRD in females. In truly X-linked recessive traits such as hemophilia and colorblindness, males are affected and females are clinically normal. In Alport syndrome, however,] hematuria indicates nephritis in most gene-carriers of either [gender. Thus X-linked recessive Alport syndrome is a specious category].
X-linked Dominant Inheritance. Starting with the original studies of Utah Kindred P, forms of X-linked, sex-linked, or gender-influenced inheritance have been proposed in a minority of reports on Alport syndrome. In the large Utah kindreds there were numerous offspring of affected males but no male to male transmission when stringent diagnostic criteria were applied. Classical genetic analysis and likelihood analysis established X-linkage in several kindreds. X-linkage was proven for various kindreds with types II, III, and IV Alport syndrome by findings of close genetic linkage of the Alport locus ATS to restriction fragment length polymorphic markers in or near the Xq22 chromosomal region. Genetic linkage of nephritis with mutations in the COL4A5 gene proves X-linkage in some of the same and other kindreds. Similar linkage to highly polymorphic microsatellite markers within the COL4A5 proves X-linkage in still other families. [X-linkage characterizes roughly 85% of Alport families.]
[Autosomal Recessive Inheritance characterizes about 15% of Alport families. Regardless of gender, the full array of symptoms are suffered not only by homozygotes of COL4A3 or -4 mutations, but also by double heterozygotes of the COL4A3 and -4 genes. It is becoming clear that heterozygotes of either COL4A3 or COL4A5 may show some but decreased symptoms.]
Autosomal Dominant Inheritance. Male to male transmission established autosomal dominant inheritance of Alport syndrome in kindreds which may be categorized as having types V or VI Alport syndrome. [Autosomal dominance characterizes roughly 1% of Alport families. Some but not all of them have mutations of COL4A3 or COL4A4 genes.]
Dominant inheritance of Alport syndrome may be assumed even with minimal pedigree information. As a group, males with Alport syndrome have about 30% fewer children than normal; many males with juvenile type disease will have no offspring.
Incomplete penetrance of Alport syndrome in females must always be kept in mind. In kindreds with X-linkage, daughters of affected males will all be gene carriers regardless of their urinalysis results. Unless there is information from genetic markers or from urinalyses of the next generation, each clinically normal daughter of the three other sorts of gene carrier parents (mothers in kindreds with X-linkage, and parents of either sex in kindreds with autosomal dominance) stands a real probability of having an undetected nephritis gene.
Renal Symptoms. Hematuria is the cardinal feature, persistent and present from birth in males and in 80-90% of females who have a nephritis gene. The child's mother may note occasionally or persistently red diapers, but hematuria is usually inconspicuous in adult-type disease. Episodes of gross hematuria may follow sore throats or other infections in children and may be the presenting symptom. Macroscopic hematuria is not common in adults and perhaps a feature of juvenile types of disease. Red cell excretion rate is increased by acute infections and by pregnancy.
In adult types of Alport syndrome, renal function is typically normal for years and then wanes inexorably to renal failure. The reciprocal of serum creatinine falls linearly with time during this phase (roughly six years from early to end-state renal failure in adult-type Alport syndrome); hypertension appears, and worsens as renal function deteriorates. Crescentic glomerulonephritis may occur, especially in juvenile types of Alport syndrome, and be accompanied by rapidly progressive renal failure.
With either juvenile or adult type Alport syndrome, renal failure is inevitable for affected males, but few females become uremic, and then generally when elderly. ESRD of females in kindreds with type V Alport syndrome may be as frequent as for the males.
Sensorineural Hearing Loss. Kindreds with type IV Alport syndrome and some with indeterminate type Alport syndrome have socially normal hearing, whereas progressive and ultimately profound, bilateral, sensorineural hearing loss distinguishes kindreds with all other types. Patients can be unaware of a high frequency loss that is readily shown by audiometry (hearing test). Hearing loss generally occurs later, less severely, and less frequently in females, although some women and girls may have a profound loss. In some families with Alport syndrome and hearing loss, affected members may have apparently normal hearing even after ESRD, but as a rule those family members without hearing loss have less severe renal disease. In Utah Kindred P with type III Alport syndrome, noticeable hearing loss generally coincides with the onset of renal failure.
Ocular Features. Eye defects appear limited to kindreds with juvenile type nephritis with hearing loss. In start contrast to hearing loss, which is common in hereditary nephritis, but not specific for it, anterior lenticonus [protrusion of the substance of the crystalline lens] is uncommon though nearly pathognomonic. All cases of anterior lentinconus reported between 1964 and 1982 have been associated with nephritis and/or hearing loss. Lenticonus is more common in males and is usually, but not invariably, bilateral.
The path to the correct diagnosis lies through a carefully extended family history and personal examination of the urinary sediment, specifically for hematuria. The proband will commonly be a child with unexplained hematuria or an adolescent to middle-aged male with ESRD, with a vague history of kidney disease in brothers or relatives on the maternal side. Systematic urinalyses may reveal several relatives with hematuria.
Of great interest are the forthcoming genetic methods of diagnosis. It appears that probing with cDNAs from COL4A5 will reveal mutations in equal to or less than 10% of kindreds. Emerging techniques with microsatellite markers within COL4A5, exon scanning, single stranded DNA fragment conformational analyses, etc., should soon provide specific genetic tests for gene-carrier status in most families.
No specific treatment is known to affect the underlying pathological process or to alter the clinical course. Antibiotics, anticoagulants, steroids, and immunosuppressives have wrought no benefit. Control of hypertension is mandated on general grounds and protein restriction may prove to be of value once nephron loss gives rise to hyperfiltration. Management of advancing renal failure is along conventional lines. When terminal uremia occurs, dialysis and transplantation pose no particular problems, although the lack of certain GBM antigens invites a slender risk of de novo anti-GBM nephritis after transplantation. Except for one unconvincing example, the glomerular defect of Alport syndrome has not recurred after transplantation. Particular care must be taken in selection of living donors: meticulous and repeated urinalysis for hematuria is the most important step.
Great care should be taken to avoid adding insults from drug ototoxicity to the advancing aural injury. Improvement or stabilization of hearing loss has occasionally been noted after transplantation of Alport patients; others have noted no benefit nor have we. Interpretation of these findings is difficult because dialysis or the uremic state have been held culpable for reversible hearing loss. When hearing loss worsens the patient will become more dependent on lip-reading and other visual cues. We have observed poor to fair success with hearing aids. Visual acuity should be monitored at intervals in those with or at risk of lenticonus and consideration given to early lens extraction and intra-ocular lens implantation. Keep steroid doses low after transplantation and monitor regularly for cataracts; poor vision is a disproportionate handicap to the deaf.