Commentary
The Real World Impact of APOL1 Variants on Kidney Transplantation Anil Chandraker, MD, FRCP1
I
t is well recognized that the risk of kidney failure among African Americans is higher than non-African Americans for both native kidneys and allografts. The estimate for cumulative lifetime risk of kidney failure amongst African Americans is 8% compared with 2% in whites.1 Although some of the excess risk in African Americans is associated with the traditional risk factors that disproportionately affect African Americans, such as obesity, smoking, socioeconomic position and diabetes, an additional genetic component has long been suspected. In a landmark article in 2010 using a case-control approach and data from the 1000 Genomes Project, individuals with high-risk variants of the APOL1 gene were first identified as having a significantly higher risk of renal failure. Subjects with 2 alleles of the high-risk APOL1 gene variants G1 or G2 were associated with a more than 7-fold risk of ESRD compared with zero-risk alleles.2 Although individuals with APOL1 high-risk variants are associated with a higher risk of renal failure, causality between these variants and renal disease has not been established. Although some data from animal models have indicated that the APOL1 gene itself may play a role in kidney development, the presence of the high-risk variants does not universally cause renal failure, but rather significantly increase the lifetime risk of kidney disease.3 This has lead some to speculate that in addition to genetic susceptibility, a “second hit” is also required to develop kidney injury. For example in a recently reported study conducted over a 20-year period, increased levels of the hemostatic factors VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with 2 APOL1 high-risk alleles.4 Even though there seems to be no difference in mRNA expression of APOL1 in the kidneys of affected individuals, the risk seems to be associated with the kidney itself rather than a circulating factor as it has been shown that there is no difference in allograft survival in the medium term for kidney transplant recipients transplanted with kidneys that have the high-risk APOL1 genotypes.5
Received 23 August 2015. Revision received 6 September 2015. Accepted 9 September 2015. 1 Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
The author declares no funding or conflicts of interest. Correspondence: Anil Chandraker, MD, FRCP, Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/10001-16 DOI: 10.1097/TP.0000000000000970
16
www.transplantjournal.com
As with native kidneys, renal transplantation donor kidneys carrying the high-risk variants of APOL1 are associated with worse outcomes. In this issue of Transplantation, Freedman et al6 analyzed a large group of renal transplant recipients and confirmed findings from previous studies, indicating that patients with 2 high-risk alleles of the APOL1 gene have shorter allograft survival and are more likely to have higher serum creatinine levels than recipients with 0/1 APOL1-renalrisk variant kidney. Although donor age is by itself associated with poorer outcomes the authors found no association between donor age and APOL1 genotype on renal allograft survival, and as in other studies, the high-risk APOL1 gene variant had no discernible effect on recipient survival. Based on their finding, the authors mulled whether rapid testing of the APOL1 status may help stratify deceased donor allocation.7 Introduction of the Kidney Donor Profile Index scoring system for allocation of deceased donor organs in the United States has helped place “better” organs into those most likely to benefit from transplantation, but by giving every deceased donor kidney a score, the KDPI score may also have had a negative effect on the discard rate of deceased donor kidneys. After all, who wants to take a kidney that is labeled as being in the bottom 5% of anything? So should APOL1 genotyping be incorporated into the allocation system? The disparity between those awaiting transplants and the number of available organs is increasing. This imbalance between those needing a transplant and available organs is worse among the African American community. As organs from African Americans donors go disproportionately to AA recipients, any further loss of donors would inevitably lengthen the time to transplantation for African Americans. Whether this would be beneficial as a whole or individually is still hard to say. As what constitutes the purported second hit is not understood, it is not even clear when that second hit occurs, is it programed into the kidney before transplantation? Does it occur in the perioperative period or postoperatively? As high-risk variants of APOL1 accelerate many causes of renal failure, the answer would seem to be all of the above. Hence making a decision to discard what is “on average” a worse kidney at the time of transplantation seems premature. In a recently published study looking at data from the Coronary Artery Risk Development in Young Adults study highrisk variants of the APOL1 gene were associated with both higher incident albuminuria and kidney function decline.8 The study had a 15-year follow-up and showed that among African American participants, the high-risk APOL1 gene variants were associated with 0.38% mL/min per 1.73 m2 per year faster estimated glomerular filtration rate based on serum cystatin C decline compared with African Americans with the low risk APOL1 variants. However, the estimated glomerular filtration rate based on serum cystatin C slopes Transplantation
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January 2016
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
■
Volume 100
■
Number 1
Chandraker
© 2015 Wolters Kluwer
did not significantly differ by APOL1 status before the onset of albuminuria. The majority of African Americans (78%) with albuminuria did not have the high-risk variants of APOL1. This study was also one of the few that also adjusted for socioeconomic position, an important risk factor for the development of kidney disease that is missing from most analyses. Although this study was carried out in nontransplanted patients and so we have to be cautious about extrapolating findings to the transplant setting, the findings do fit with the idea that high-risk variants of APOL1 are associated with acceleration of renal injury once present and that screening for and prevention of kidney disease may be the key to reducing the rate of renal decline regardless of APOL1 status in a nontransplant as well as a transplant setting. Although it is important to call for further future research in this area, we are still left with a very real dilemma as to what to do in the present to best serve our patients. Restricting the pool of potential donors does not appear to be the right answer, greater vigilance for changes in albuminuria and decline in glomerular filtration rate and appropriate and aggressive management may offer the best hope for prolonging allograft function regardless of the individual factors
17
responsible, while we await consensus and clarification of the mechanisms responsible. REFERENCES 1. Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc Nephrol. 2002;13:1635–1644. 2. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010; 329:841–845. 3. Anderson BR, Howell DN, Soldano K. In vivo modeling implicates APOL1 in nephropathy: evidence for dominant negative effects and epistasis under anemic stress. PLoS Genet. 2015;11:e1005349. 4. Tin A, Grams ME, Maruthur NM, et al. Hemostatic factors, APOL1 risk variants, and the risk of ESRD in the atherosclerosis risk in communities study. Clin J Am Soc Nephrol. 2015;10:784–790. 5. Lee BT, Kumar V, Williams TA, et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant. 2012;12:1924–1928. 6. Freedman BI, Pastan SO, Israni AK, et al. APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation. 2016;100:194–202. 7. Freedman BI, Julian BA, Pastan SO, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant. 2015;15:1615–1622. 8. Peralta CA, Bibbins-Domingo K, Vittinghoff E, et al. APOL1 genotype and race differences in incident albuminuria and renal function decline. J Am Soc Nephrol. July 15, 2015. (Epub ahead of print).
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Real World Impact of APOL1 Variants on Kidney Transplantation Anil Chandraker, MD, FRCP1
I
t is well recognized that the risk of kidney failure among African Americans is higher than non-African Americans for both native kidneys and allografts. The estimate for cumulative lifetime risk of kidney failure amongst African Americans is 8% compared with 2% in whites.1 Although some of the excess risk in African Americans is associated with the traditional risk factors that disproportionately affect African Americans, such as obesity, smoking, socioeconomic position and diabetes, an additional genetic component has long been suspected. In a landmark article in 2010 using a case-control approach and data from the 1000 Genomes Project, individuals with high-risk variants of the APOL1 gene were first identified as having a significantly higher risk of renal failure. Subjects with 2 alleles of the high-risk APOL1 gene variants G1 or G2 were associated with a more than 7-fold risk of ESRD compared with zero-risk alleles.2 Although individuals with APOL1 high-risk variants are associated with a higher risk of renal failure, causality between these variants and renal disease has not been established. Although some data from animal models have indicated that the APOL1 gene itself may play a role in kidney development, the presence of the high-risk variants does not universally cause renal failure, but rather significantly increase the lifetime risk of kidney disease.3 This has lead some to speculate that in addition to genetic susceptibility, a “second hit” is also required to develop kidney injury. For example in a recently reported study conducted over a 20-year period, increased levels of the hemostatic factors VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with 2 APOL1 high-risk alleles.4 Even though there seems to be no difference in mRNA expression of APOL1 in the kidneys of affected individuals, the risk seems to be associated with the kidney itself rather than a circulating factor as it has been shown that there is no difference in allograft survival in the medium term for kidney transplant recipients transplanted with kidneys that have the high-risk APOL1 genotypes.5
Received 23 August 2015. Revision received 6 September 2015. Accepted 9 September 2015. 1 Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
The author declares no funding or conflicts of interest. Correspondence: Anil Chandraker, MD, FRCP, Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/10001-16 DOI: 10.1097/TP.0000000000000970
16
www.transplantjournal.com
As with native kidneys, renal transplantation donor kidneys carrying the high-risk variants of APOL1 are associated with worse outcomes. In this issue of Transplantation, Freedman et al6 analyzed a large group of renal transplant recipients and confirmed findings from previous studies, indicating that patients with 2 high-risk alleles of the APOL1 gene have shorter allograft survival and are more likely to have higher serum creatinine levels than recipients with 0/1 APOL1-renalrisk variant kidney. Although donor age is by itself associated with poorer outcomes the authors found no association between donor age and APOL1 genotype on renal allograft survival, and as in other studies, the high-risk APOL1 gene variant had no discernible effect on recipient survival. Based on their finding, the authors mulled whether rapid testing of the APOL1 status may help stratify deceased donor allocation.7 Introduction of the Kidney Donor Profile Index scoring system for allocation of deceased donor organs in the United States has helped place “better” organs into those most likely to benefit from transplantation, but by giving every deceased donor kidney a score, the KDPI score may also have had a negative effect on the discard rate of deceased donor kidneys. After all, who wants to take a kidney that is labeled as being in the bottom 5% of anything? So should APOL1 genotyping be incorporated into the allocation system? The disparity between those awaiting transplants and the number of available organs is increasing. This imbalance between those needing a transplant and available organs is worse among the African American community. As organs from African Americans donors go disproportionately to AA recipients, any further loss of donors would inevitably lengthen the time to transplantation for African Americans. Whether this would be beneficial as a whole or individually is still hard to say. As what constitutes the purported second hit is not understood, it is not even clear when that second hit occurs, is it programed into the kidney before transplantation? Does it occur in the perioperative period or postoperatively? As high-risk variants of APOL1 accelerate many causes of renal failure, the answer would seem to be all of the above. Hence making a decision to discard what is “on average” a worse kidney at the time of transplantation seems premature. In a recently published study looking at data from the Coronary Artery Risk Development in Young Adults study highrisk variants of the APOL1 gene were associated with both higher incident albuminuria and kidney function decline.8 The study had a 15-year follow-up and showed that among African American participants, the high-risk APOL1 gene variants were associated with 0.38% mL/min per 1.73 m2 per year faster estimated glomerular filtration rate based on serum cystatin C decline compared with African Americans with the low risk APOL1 variants. However, the estimated glomerular filtration rate based on serum cystatin C slopes Transplantation
■
January 2016
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
■
Volume 100
■
Number 1
Chandraker
© 2015 Wolters Kluwer
did not significantly differ by APOL1 status before the onset of albuminuria. The majority of African Americans (78%) with albuminuria did not have the high-risk variants of APOL1. This study was also one of the few that also adjusted for socioeconomic position, an important risk factor for the development of kidney disease that is missing from most analyses. Although this study was carried out in nontransplanted patients and so we have to be cautious about extrapolating findings to the transplant setting, the findings do fit with the idea that high-risk variants of APOL1 are associated with acceleration of renal injury once present and that screening for and prevention of kidney disease may be the key to reducing the rate of renal decline regardless of APOL1 status in a nontransplant as well as a transplant setting. Although it is important to call for further future research in this area, we are still left with a very real dilemma as to what to do in the present to best serve our patients. Restricting the pool of potential donors does not appear to be the right answer, greater vigilance for changes in albuminuria and decline in glomerular filtration rate and appropriate and aggressive management may offer the best hope for prolonging allograft function regardless of the individual factors
17
responsible, while we await consensus and clarification of the mechanisms responsible. REFERENCES 1. Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc Nephrol. 2002;13:1635–1644. 2. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010; 329:841–845. 3. Anderson BR, Howell DN, Soldano K. In vivo modeling implicates APOL1 in nephropathy: evidence for dominant negative effects and epistasis under anemic stress. PLoS Genet. 2015;11:e1005349. 4. Tin A, Grams ME, Maruthur NM, et al. Hemostatic factors, APOL1 risk variants, and the risk of ESRD in the atherosclerosis risk in communities study. Clin J Am Soc Nephrol. 2015;10:784–790. 5. Lee BT, Kumar V, Williams TA, et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant. 2012;12:1924–1928. 6. Freedman BI, Pastan SO, Israni AK, et al. APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation. 2016;100:194–202. 7. Freedman BI, Julian BA, Pastan SO, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant. 2015;15:1615–1622. 8. Peralta CA, Bibbins-Domingo K, Vittinghoff E, et al. APOL1 genotype and race differences in incident albuminuria and renal function decline. J Am Soc Nephrol. July 15, 2015. (Epub ahead of print).
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
