Living Kidney Donor With IgA Nephropathy?
Living Kidney Donor With IgA Nephropathy?
A 45-year-old woman was evaluated as a living kidney donor for her 21-year-old son. The evaluation was normal except for mild microhematuria. The full urinary tract work-up was normal. We proceeded with transplantation and a reperfusion biopsy showed IgA nephropathy with mild glomerular involvement. What is the expected donor and recipient outcome? Was a predonation donor kidney biopsy absolutely indicated?
Jose Benchimol, MD
This question raises a number of important and interesting questions, each of which could be the subject of a lengthy review. Pertinent issues include:
When a prospective kidney donor is discovered on routine urinalysis to have hematuria, the evaluation should proceed according to an algorithm that is similar to what one would follow in general practice. The first step is to be certain that if the donor candidate is female, the urine sample was not obtained during menses. If there is any doubt, repeat samples should be obtained in mid-cycle. Urinary infection is another common reason for microhematuria. Unless associated with structural abnormalities of the urinary tract, uncomplicated urinary infection would not be a reason to exclude a potential donor. Therefore, urinary culture would be indicated.
If persistent microhematuria continues after taking menstruation and infection into account, the next question to be addressed is whether the microhematuria is associated with proteinuria. If there is significant abnormal proteinuria, it is likely that there is an intrinsic renal source of the hematuria, and it is unlikely that donation could be recommended. Many transplant programs also now employ assays for "microalbuminuria" to assist in evaluation of donors with microhematuria, though the significance of microalbuminuria in nondiabetic, otherwise healthy individuals remains unknown.
The next step involves examination of the urinary tract to exclude lesions such as stones or tumors. This will generally require a combination of cystoscopy and an imaging study such as an intravenous urogram, a computerized tomography scan, or magnetic resonance imaging scan, depending on local practice. Complete work-up with all of these studies would not necessarily be indicated in the course of routine care for a younger individual with microhematuria, but in the context of donor evaluation full evaluation is generally believed to be necessary.
If at this point the work-up is completely negative and there are no other associated findings suggestive of renal disease (such as hypertension, proteinuria, or decreased renal function), most authors would describe the donor candidate as having "isolated hematuria." In a recent survey of donor evaluation practices, 37% of US transplant centers indicated that they would be willing to proceed with donor nephrectomy in such individuals, provided that a kidney biopsy was normal. I have personally always been reluctant to recommend biopsy and kidney donation in these individuals, for the following reasons. First, these are not individuals in whom a biopsy would be performed in the course of routine care by most nephrologists. Careful sequential follow-up would be the routine approach, so the biopsy and its attendant risks would have to be viewed as extra risks of kidney donation. Second, and perhaps most important, there are really no long-term follow-up data that support the position that a totally normal biopsy predicts a good long-term outcome after nephrectomy in persons with microhematuria. Others, however, would advocate the use of biopsy in this setting, and would proceed with kidney donation if a biopsy were normal. If this approach is taken, it is critically important that the biopsy be evaluated by immunofluorescence microscopy and electron microscopy.
In a single-center, Egyptian study, 37 of 300 potential living kidney donors were found to have microhematuria. Seven had stones or bladder pathology as the source of hematuria. The other 30, who had unremarkable cystoscopy and imaging studies, all underwent kidney biopsy. All 30 had abnormal biopsies, and 25 of the 30 had evidence for hereditary nephritis (Alport syndrome). None of these individuals were considered suitable as kidney donors, and the authors concluded that microhematuria was sufficient to exclude potential kidney donors from further consideration. However, it seems likely that the findings and recommendations of this study may not be generalizable, particularly considering the high incidence of hereditary nephritis in this group of potential donors and recipients.
When evaluating a potential donor with microhematuria, one of the single most important factors is the kidney disease of the recipient. If the recipient has a disease that can present fairly often with "isolated hematuria" as defined above, the level of concern about microhematuria in the donor should probably rise considerably. These diseases include hereditary nephritis/Alport syndrome, IgA nephropathy, and thin basement membrane syndrome. In most other forms of renal disease, affected individuals will usually have proteinuria, abnormal renal function, abnormal renal imaging studies, or some combination of these factors that will obviously rule them out during a standard donor evaluation.
If the kidney transplant recipient has a disorder which often presents with isolated microhematuria and the disorder is one that at least in some cases has a familial or genetic basis, the finding of isolated hematuria in a potential donor is obviously of great concern.
In the past, IgA nephropathy has probably been viewed as a sporadic, nonfamilial disorder by most nephrologists. However, recent studies in which family members have been more systematically and comprehensively examined indicate that the proportion of cases with familial involvement is fairly high. For example, a recent Italian study found that 14% of 185 probands with IgA disease had at least 1 other relative with the disease. The disease has not yet been linked to specific mutations, nor is the mode of inheritance clear. Most investigators note that the lack of a clear Mendelian pattern of inheritance in the large kindreds that have been studied suggests that the disease probably represents an interaction between a specific genetic predisposition and 1 or more environmental factors. Based on these recent studies, I would not proceed any further with consideration of a living-related donor for a recipient with IgA disease if the routine evaluation showed persistent hematuria.
Hereditary nephritis/Alport syndrome is obviously recognized as a disorder with a genetic basis. The most common and most intensively studied form is caused by a mutation in a basement membrane collagen alpha peptide gene on the X chromosome. There are also recessive forms attributable to mutations in other autosomal basement membrane collagen genes. A full discussion of these syndromes is beyond the scope of this article. In general, if one is dealing with a recipient with the X-linked form of the disease, evaluation of potential family member donors is reasonably straightforward, given our current understanding of the mode of inheritance. For example, the father of an Alport recipient can generally be expected to unaffected, while the mother is expected to be a heterozygous carrier of the mutation. In the United States, most males in these families who are old enough to be kidney donors will have clinical evidence of disease on routine screening, though this is not automatically true. One unanswered question is, could one consider a heterozygous female Alport mutation carrier with very mild disease and a normal routine work-up as a kidney donor, or will uninephrectomy expose these persons to an accelerated course of kidney disease?
Thin basement membrane syndrome, also often referred to as benign familial hematuria, is generally thought to be a benign condition which does not very often lead to end-stage renal failure. Therefore, it is uncommon that a prospective kidney recipient is identified as having renal failure due to this disorder. Nonetheless, it is mentioned here because it is a common condition and may affect up to 5% to 10% of the general population. Knowledge about the molecular and genetic basis for this condition is rapidly increasing, but is still incomplete. Of note, many of the individuals in these families who actually have hematuria have mutations in some of the basement membrane collagen peptide genes, as observed in hereditary nephritis/Alport syndrome, suggesting that thin basement membrane syndrome may at least in some cases represent a milder but related disorder. What seems to be completely unknown at present is whether removing a kidney in these individuals alters what otherwise seems to be a benign prognosis. I think one could proceed with donor nephrectomy, but only after an informed discussion about the uncertainties involved.
Obviously, anyone with evidence of IgA disease on routine evaluation, or perhaps on kidney biopsy, should not be considered as a donor. However, it is known that IgA nephropathy, at least as defined by pathologic examination, can occur without hematuria, proteinuria, or other clinical evidence of kidney disease. Thus, it should not be surprising that at least occasionally such kidneys are used in transplantation, either from cadaveric or living donors. The largest reported collection of such cases included long-term follow-up on 3 living donors with IgA deposits found on postimplantation allograft biopsy. While 2 of these donors had no clinical evidence of renal disease over 7 years of follow-up, the third donor developed progressive renal insufficiency. Of course, this poor outcome might have happened anyway even if the donor had retained his second kidney. However, these findings argue against kidney donation if biopsy evidence of IgA deposition is found.
In the report described above, the 3 recipients whose transplanted kidneys had IgA deposits did generally well. In 2 of the 3 cases, the deposits disappeared after 1-6 months. These findings suggest to me that in IgA disease, continued deposition of IgA-containing immune complexes is needed to cause renal injury in this disorder. If the recipient did not have native-kidney IgA disease, such continued deposition is unlikely, the mesangium clears the old deposits, and the patient does well.
On the other hand, the third patient did not clear the deposits with time, though they did seem to decrease. In retrospect, this individual probably had native-kidney IgA disease and probably continued to have new IgA deposits. I would conclude from this that IgA nephropathy is a systemic disease, and that the prognosis for a patient who receives a kidney with a few IgA deposits depends heavily upon whether that person had IgA disease to begin with. Recurrent IgA deposits after transplantation are common in IgA nephropathy recipients, and are sometimes associated with hematuria and proteinuria. While some of these patients may have premature graft failure due to IgA recurrence, graft survival in IgA recipients seems to be about average overall.
A 45-year-old woman was evaluated as a living kidney donor for her 21-year-old son. The evaluation was normal except for mild microhematuria. The full urinary tract work-up was normal. We proceeded with transplantation and a reperfusion biopsy showed IgA nephropathy with mild glomerular involvement. What is the expected donor and recipient outcome? Was a predonation donor kidney biopsy absolutely indicated?
Jose Benchimol, MD
This question raises a number of important and interesting questions, each of which could be the subject of a lengthy review. Pertinent issues include:
The evaluation and selection of potential kidney donors with hematuria;
The risk of familial involvement in renal disorders that present with isolated hematuria;
The outcome for an individual with IgA nephropathy who has undergone uninephrectomy; and
The outcome for a kidney recipient who has received a kidney with IgA deposits present at the time of transplantation.
When a prospective kidney donor is discovered on routine urinalysis to have hematuria, the evaluation should proceed according to an algorithm that is similar to what one would follow in general practice. The first step is to be certain that if the donor candidate is female, the urine sample was not obtained during menses. If there is any doubt, repeat samples should be obtained in mid-cycle. Urinary infection is another common reason for microhematuria. Unless associated with structural abnormalities of the urinary tract, uncomplicated urinary infection would not be a reason to exclude a potential donor. Therefore, urinary culture would be indicated.
If persistent microhematuria continues after taking menstruation and infection into account, the next question to be addressed is whether the microhematuria is associated with proteinuria. If there is significant abnormal proteinuria, it is likely that there is an intrinsic renal source of the hematuria, and it is unlikely that donation could be recommended. Many transplant programs also now employ assays for "microalbuminuria" to assist in evaluation of donors with microhematuria, though the significance of microalbuminuria in nondiabetic, otherwise healthy individuals remains unknown.
The next step involves examination of the urinary tract to exclude lesions such as stones or tumors. This will generally require a combination of cystoscopy and an imaging study such as an intravenous urogram, a computerized tomography scan, or magnetic resonance imaging scan, depending on local practice. Complete work-up with all of these studies would not necessarily be indicated in the course of routine care for a younger individual with microhematuria, but in the context of donor evaluation full evaluation is generally believed to be necessary.
If at this point the work-up is completely negative and there are no other associated findings suggestive of renal disease (such as hypertension, proteinuria, or decreased renal function), most authors would describe the donor candidate as having "isolated hematuria." In a recent survey of donor evaluation practices, 37% of US transplant centers indicated that they would be willing to proceed with donor nephrectomy in such individuals, provided that a kidney biopsy was normal. I have personally always been reluctant to recommend biopsy and kidney donation in these individuals, for the following reasons. First, these are not individuals in whom a biopsy would be performed in the course of routine care by most nephrologists. Careful sequential follow-up would be the routine approach, so the biopsy and its attendant risks would have to be viewed as extra risks of kidney donation. Second, and perhaps most important, there are really no long-term follow-up data that support the position that a totally normal biopsy predicts a good long-term outcome after nephrectomy in persons with microhematuria. Others, however, would advocate the use of biopsy in this setting, and would proceed with kidney donation if a biopsy were normal. If this approach is taken, it is critically important that the biopsy be evaluated by immunofluorescence microscopy and electron microscopy.
In a single-center, Egyptian study, 37 of 300 potential living kidney donors were found to have microhematuria. Seven had stones or bladder pathology as the source of hematuria. The other 30, who had unremarkable cystoscopy and imaging studies, all underwent kidney biopsy. All 30 had abnormal biopsies, and 25 of the 30 had evidence for hereditary nephritis (Alport syndrome). None of these individuals were considered suitable as kidney donors, and the authors concluded that microhematuria was sufficient to exclude potential kidney donors from further consideration. However, it seems likely that the findings and recommendations of this study may not be generalizable, particularly considering the high incidence of hereditary nephritis in this group of potential donors and recipients.
When evaluating a potential donor with microhematuria, one of the single most important factors is the kidney disease of the recipient. If the recipient has a disease that can present fairly often with "isolated hematuria" as defined above, the level of concern about microhematuria in the donor should probably rise considerably. These diseases include hereditary nephritis/Alport syndrome, IgA nephropathy, and thin basement membrane syndrome. In most other forms of renal disease, affected individuals will usually have proteinuria, abnormal renal function, abnormal renal imaging studies, or some combination of these factors that will obviously rule them out during a standard donor evaluation.
If the kidney transplant recipient has a disorder which often presents with isolated microhematuria and the disorder is one that at least in some cases has a familial or genetic basis, the finding of isolated hematuria in a potential donor is obviously of great concern.
In the past, IgA nephropathy has probably been viewed as a sporadic, nonfamilial disorder by most nephrologists. However, recent studies in which family members have been more systematically and comprehensively examined indicate that the proportion of cases with familial involvement is fairly high. For example, a recent Italian study found that 14% of 185 probands with IgA disease had at least 1 other relative with the disease. The disease has not yet been linked to specific mutations, nor is the mode of inheritance clear. Most investigators note that the lack of a clear Mendelian pattern of inheritance in the large kindreds that have been studied suggests that the disease probably represents an interaction between a specific genetic predisposition and 1 or more environmental factors. Based on these recent studies, I would not proceed any further with consideration of a living-related donor for a recipient with IgA disease if the routine evaluation showed persistent hematuria.
Hereditary nephritis/Alport syndrome is obviously recognized as a disorder with a genetic basis. The most common and most intensively studied form is caused by a mutation in a basement membrane collagen alpha peptide gene on the X chromosome. There are also recessive forms attributable to mutations in other autosomal basement membrane collagen genes. A full discussion of these syndromes is beyond the scope of this article. In general, if one is dealing with a recipient with the X-linked form of the disease, evaluation of potential family member donors is reasonably straightforward, given our current understanding of the mode of inheritance. For example, the father of an Alport recipient can generally be expected to unaffected, while the mother is expected to be a heterozygous carrier of the mutation. In the United States, most males in these families who are old enough to be kidney donors will have clinical evidence of disease on routine screening, though this is not automatically true. One unanswered question is, could one consider a heterozygous female Alport mutation carrier with very mild disease and a normal routine work-up as a kidney donor, or will uninephrectomy expose these persons to an accelerated course of kidney disease?
Thin basement membrane syndrome, also often referred to as benign familial hematuria, is generally thought to be a benign condition which does not very often lead to end-stage renal failure. Therefore, it is uncommon that a prospective kidney recipient is identified as having renal failure due to this disorder. Nonetheless, it is mentioned here because it is a common condition and may affect up to 5% to 10% of the general population. Knowledge about the molecular and genetic basis for this condition is rapidly increasing, but is still incomplete. Of note, many of the individuals in these families who actually have hematuria have mutations in some of the basement membrane collagen peptide genes, as observed in hereditary nephritis/Alport syndrome, suggesting that thin basement membrane syndrome may at least in some cases represent a milder but related disorder. What seems to be completely unknown at present is whether removing a kidney in these individuals alters what otherwise seems to be a benign prognosis. I think one could proceed with donor nephrectomy, but only after an informed discussion about the uncertainties involved.
Obviously, anyone with evidence of IgA disease on routine evaluation, or perhaps on kidney biopsy, should not be considered as a donor. However, it is known that IgA nephropathy, at least as defined by pathologic examination, can occur without hematuria, proteinuria, or other clinical evidence of kidney disease. Thus, it should not be surprising that at least occasionally such kidneys are used in transplantation, either from cadaveric or living donors. The largest reported collection of such cases included long-term follow-up on 3 living donors with IgA deposits found on postimplantation allograft biopsy. While 2 of these donors had no clinical evidence of renal disease over 7 years of follow-up, the third donor developed progressive renal insufficiency. Of course, this poor outcome might have happened anyway even if the donor had retained his second kidney. However, these findings argue against kidney donation if biopsy evidence of IgA deposition is found.
In the report described above, the 3 recipients whose transplanted kidneys had IgA deposits did generally well. In 2 of the 3 cases, the deposits disappeared after 1-6 months. These findings suggest to me that in IgA disease, continued deposition of IgA-containing immune complexes is needed to cause renal injury in this disorder. If the recipient did not have native-kidney IgA disease, such continued deposition is unlikely, the mesangium clears the old deposits, and the patient does well.
On the other hand, the third patient did not clear the deposits with time, though they did seem to decrease. In retrospect, this individual probably had native-kidney IgA disease and probably continued to have new IgA deposits. I would conclude from this that IgA nephropathy is a systemic disease, and that the prognosis for a patient who receives a kidney with a few IgA deposits depends heavily upon whether that person had IgA disease to begin with. Recurrent IgA deposits after transplantation are common in IgA nephropathy recipients, and are sometimes associated with hematuria and proteinuria. While some of these patients may have premature graft failure due to IgA recurrence, graft survival in IgA recipients seems to be about average overall.
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