Keywords: Alport syndrome, Hereditary nephritis, Renal failure.
|How to cite this article:|
Cohan EP. Alport Syndrome: A Specific Case of Hereditary Nephropathy. Saudi J Kidney Dis Transpl 1999;10:1-6
Mr. R.S. was found to have microhematuria as a young child. During his youth, his urine would become darker during and after upper respiratory infections. By age 28, he required chronic dialysis. His mother has microhematuria but no loss of renal function. R.S. has had two kidney transplants. Now at age 53 years, he remains partially deaf, but can function with a hearing aid.
Hereditary diseases are an impotent part of nephrology today. The 18 th century pathologist, Morgagni, would not be surprised, because in his classic De Sedibus he said the "in cases where the causes of diseases are obscure the probability of a hereditary disease should be investigated".  Even in the absence of well defined hereditary disease such as cystic disease, Alport syndrome or Fabry disease, a familial tendency towards renal failure may be found upon close study of a family.  This familial tendency might be caused by diseases whose names are still unknown, or, alternatively, by common genetic traits such as polymorphism for the aghiotensinconverting-enzyme gene. This editorial is directed, however, at the much narrower problem of Alport syndrome, which accounts for about 10% of defined hereditary causes for end-stage renal disease.
| Definition|| |
Alport syndrome is a hereditary nephritis that is typically accompanied by deafness. The inheritance is x-linked in most cases, but both autosomal dominant and autosomal recessive patterns are described. Deafness is not uniformly present; over one third of cases described in a French series had normal hearing.  It classically presents with microhematurea, in a young or adolescent boy. Proteinuria also occurs, but the clinical syndrome is usually nephritic rather than nephrotic. Still, proteinuria may increase with time and nephrotic-range proteinuria can occur. Hypertension is present, much as is the case in most kidney diseases that evolve to scarring and renal failure.
| Progression to renal failure|| |
Progression of renal insufficiency to endstage renal disease (ESRD) is the rule in males with the typical x-linked Alport syndrome. This progression is said to occur at a variable rate.  In a recent case that I saw, when the rate of progression was graphed as the reciprocal of the plasma creatinine versus time,  the loss of glomerular filtration rate (GFR) was about 0.7 ml/min/month. This decline started at age 25. In another, this rate was much faster, at about 2 ml/min/month. This decline began when this patient was 17 years old. There are no systematic studies of the rate of progression in Alport syndrome, especially as relates to concurrent hypertension, proteinuria, or other genetic factors such as gene polymorphism. Carrier females, in the x-linked Alport syndrome, may have microhematuria but do not develop renal impairment.
We glibly ascribe loss of kidney function in Alport syndrome to genetic factors, yet it must be admitted that these are only dimly understood. A recent study has examined the role of proteolysis of type IV collagen in the glomerular basement membrane (GBM) of patients with x-linked Alport syndrome.  This study suggests that the fetal predominance of α l (IV) and α 2(IV) collagen persists in the GBM in Alport syndrome, leading to enhanced breakdown by proteolysis. This mechanism would help to explain the hematuria and proteinuria of Alport syndrome, but not the progression of glomerular or tubulointerstitial scarring. It would also not explain the clinical association between upper respiratory infection and worsening of hematuria, a feature that was noted by Alport himself.  It is possible that proteinuria itself is a factor in the progression of Alport syndrome as it may be in other kidney diseases,  but this idea has not been tested.
| Differential Diagnosis|| |
The differential diagnosis of Alport syndrome is not difficult in a typical case. Most cases are x-linked, as were 75 of 108 cases studied by Mazzuco et al.  It is the ones with autosomal recessive or, the even rarer autosotnal dominant inheritance that are more difficult. Ideally, the kidney biopsy clarifies the diagnosis, with the socalled basket weave pattern by electron microscopy [Figure - 1]. One study has shown evolution of thin GBM to a more typical basket weave pattern in serial biopsies of a child.  The finding of thin GBM may suggest the diagnosis of thin GBM nephropathy, a condition that is probably the pathological equivalent of benign familial hematuria.  Both Alport syndrome and thin GBM nephropathy involve gene abnormalities of the collagen IV gene, the α 5 chain being critical in Alport and α4 chain in thin GBM. In theory, these genetic defects could be specifically identified, leading to precise diagnosis, but the multiplicity of gene abnormalities that could lead to an abnormal collagen IV α5 chain makes it difficult to rule out Alport syndrome by mere genetic tests. Deafness is a useful feature if it is present but less useful for differential diagnosis if it is not present. The family history remains useful, because if a sibling or older family member has developed renal failure, Alport syndrome rather than thin GBM nephropathy is likely. IgA nephropathy may initially look like a case of Alport syndrome especially if there appears to be a familial pattern. 
Sensorineural deafness has even been described in such cases. Here, immunofluorescent studies of the kidney biopsy help to reach the true diagnosis see [Table - 1].
| Pathogenesis|| |
As a cause of ESRD, in the United States, Alport syndrome is only one tenth as common as cystic diseases.  Two recent studies showed that Alport syndrome is an infrequent diagnosis upon kidney biopsy in Saudi children with kidney disease, being less than 4% of all cases. , Yet most internists and pediatricians are at least aware of Alport syndrome, and it provides ample material for qualifying examinations. This interest results from our ability to define Alport syndrome from gene to protein to patient. Type IV collagen is formed by the combination of three sub-units, called enchains. These are six types from α l to α 6. They are the chains that make up basement membranes, including those of the eye, the liver, the placenta and the kidney. The α 5 chain is affected in classical, x-linked Alport syndrome, because of abnormalities in the gene that codes for the α.5 chain. This gene, COL4A5, is located on the long arm of the x chromosome (Xq22), and may be abnormal because of rearrangement, deletion, insertion or other chromosomal change. It is worth noting that up-to-date genetic studies could not show mutations in COL4A5 in more than half of the cases reported in a recent paper from Italy.  Genomic screening is therefore not reliable at present.
It is not clear why a defective α 5 chain would lead to an abnormal GBM and, ultimately, renal failure. Kashtan and Michael suggest that there is compensatory synthesis of collagen chains that do not contain α5, with consequent degradation.  Kalluri et al have provided evidence that the usual developmental switch from α1 and α2 chains to α3, α4 and α5 chains does not occur in classical Alport syndrome, and that lends to enhanced degradation of the GBM by glomerular endopiptidases.  These studies do not explain subsequent glomerular and tubulointerstitial scarring, nor do they explain why progression rates are variable.
| Treatment|| |
In this youth, patient R.S. was told to avoid strenuous sports and to observe bed rest if he were to have an upper repository infection. Correspondingly, there is no discussion of therapy for hereditary nephritis in an authoritative British text from 1962.  Even by 1998, as written in the Primer on Kidney Diseases,  there is no proven specific therapy for Alport syndrome, yet there may be room for cautious optimism. First, the natural variability of the rate of progression to chronic renal failure suggests the presence of modifiable factors or pathways in the progression of Alport syndrome to ESRD. Second, in three recent cases of hereditary nephropathy, we have shown that angiotensin-converting-enzyme (ACE) inhibitors may slow the rate of decline of renal function.  The genetic abnormalities in these three cases are not known, and they may not even be real cases of Alport syndrome. Still, the recent success of ACE-inhibition in many other progressive kidney disease may well be extended to Alport syndrome.
Gene therapy is an attractive topic today. Its premise is that by correcting the gene abnormality, one will cure the disease. At its simplest, the gene abnormality would be one base pair on the chromosomal DNA, and its correction would be painless, permanent, and cause complete healing. Clearly it is not so simple. The identification of he gene for polycystin has not enabled gene therapy for polycystic kidney disease. In that condition, as well as in Alport syndrome, there are multiple places where the gene may be abnormal. For gene therapy, for a particular patient, the particular mutation needs to be identified. Then, a way of correcting the gene, in the right tissues, and without catastrophic side effects, is required of course; damage already done by the gene is not corrected by such an approach. There difficulties emphasize that gene therapies are not the sole answer. A mechanistic understanding of pathogenesis may usefully point out ways to interfere in the cascade of injury, without tinkering with the genes. By way of example. One can treat the hereditary condition of Liddle syndrome very effectively with amiloride, and without gene therapy.
| Dialysis and Transplantation|| |
Survival on dialysis of patients with ESRD due to Alport syndrome is not known to differ from that of similar aged patients with chronic nephritis of other causes. Kidney transplantation is an obvious option for many patients with Alport syndrome, because of their youth. Donation of a kidney from a relative is possible, but careful urinalysis of the donor is important to prevent the donation of an organ from a heterozygous carrier of the Alport trait. Graft survival of kidneys transplanted into Alport patients is no different than that of appropriate control cases. In fact, published studies show that it is very good, being 70% at 5 years. [,20] At the Froedtert Hospital Transplant Center, data provided to me by Dr. Zhu showed a 90% graft survival at 5 years in-patients undergoing kidney transplantation for Alport syndrome since 1985.
The problem of post-transplant anti-GBM nephritis is much discussed but actually rare and may be asymptomatic, put simply, in x-linked Alport syndrome, the defective COL4A5 gene causes the α5 collagen chain to be absent from birth. This means that the transplantation of a normal kidney into that person may lead to antibody information against α5 (IV) antigen, which is viewed as "foreign" by the immune system of the Alport patient. Five of eighteen cases studied by Peten et al had linear GBM staining for IgG, but no clinical expression of this phenomenon.  In the series of 30 described by Gobel at al, circulating antiGBM antibodies and linear IgG deposits along the GBM did occur in one case, but without signs of anti-GBM nephritis. 
| Acknowledgment|| |
The helpful criticisms of Dr. Larry Greenbaum are greatly appreciated. Mrs. Laura Zimmer typed the manuscript.
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Eric P Cohan
Department of Medicine, Froedtert Memorial Lutheran Hospital, 9200 W. Wisconsin Ave, Milmaukee, WI 53226
[Figure - 1]
[Table - 1]