- Email: [email protected]
Changing Pattern of Mortality in Renal Transplant Recipients: A Single-Center, 30-Year Experience
Changing Pattern of Mortality in Renal Transplant Recipients: A Single-Center, 30-Year Experience K.-H. Shu, H.-C. Ho, M.-C. Wen, M.-J. Wu, C.-H. Chen, C.-H. Cheng, T.-M. Yu, Y.-W. Chuang, S.-T. Huang, S.-F. Tsai, Y.-C. Lo, and S.-C. Weng ABSTRACT Introduction. Patient survival among kidney transplant (KTx) recipients has improved remarkably in the past decades. The most common causes of death are cardiovascular disease in the West; in Taiwan, the answer remains uncertain. Methods. From 1983 to 2012, KTx patients who underwent transplantation and were followed at our hospital were recruited for the study. For comparison, patients were stratified according to the transplant time as group 1, 1983e1989 (the initial era); group 2, 1990e1998 (the cyclosporine era); and group 3, 1999e2012 (the modern era, in which tacrolimus and mycophenolate mofetil were available). Results. A total of 520 KTx patients (male:female ratio of 285:235) were performed in our hospital during the study period. A progressive improvement in patient survival rates (P < .0001) was noted among the 3 groups. At a mean follow-up duration of 9.55 8.20 years, 83 recipients had died. Overall, the most common cause of death was infection (44.6%), followed by cardiovascular disease (21.7%), malignancy (12.0%), and hepatic failure (10.8%). Infection was the main cause of death in groups 1 and 2 (44.1% and 52.6%, respectively) but not in Group 3 (18.2%), although this trend did not reach statistical significance. Death owing to cardiovascular diseases became the most common cause of death (27.3%) in the modern era (group 3). Conclusion. The pattern of mortality among Taiwanese KTx patients has changed over the past 30 years. Infection is no longer the commonest cause of death.
T
HE OUTCOME OF KIDNEY TRANSPLANTATION (KTx) has improved remarkably over the past several decades. The major cause of death among KTx recipients is cardiovascular diseases (CVD) in the West; in Taiwanese patients, it remains unclear. The present study aims to elucidate of causes of death during different eras over the past 30 years in our hospital.
METHODS KTx recipients who underwent transplantation and were followed at our hospital were recruited for the study. A retrospective analysis of patient demographics and outcomes was made through our computerized database. For comparison, patients were stratified according to the vintage of transplantation. Group 1 (the initial era, 1983e1989) was treated with high-dose steroids and azathioprine. Some patients also received cyclosporine [CsA] during this period. Group 2 (the CsA era, 1990e1998) received a standard regimen of low-dose steroids, CsA, and azathioprine. Group 3 (the modern era, 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.032 442
1999e2012) received a standard immunosuppressive regimen of low-dose steroids, tacrolimus (FK), and mycophenolic acid. In some recipients, interleukin-2 receptor blocker was given as induction therapy during this period. In group 1, the dose of steroid was 0.5 mg/kg/day for 3 months followed by a slow taper. The dose of
From the Division of Nephrology, Department of Internal Medicine (K.-H.S., M.-J.W., C.-H. Chen., C.-H. Cheng., T.-M.Y., Y.-W.C., S.-T.H., S.-F.T., Y.-C.L., S.-C.W.), the Division of Urology, Department of Surgery (H.-C.H.), the Department of Pathology (M.-C.W.), Taichung Veterans General Hospital, Taichung, Institute of Medicine, the Chung-Shan Medical University (K.-H.S., M.-J.W., C.-H. Cheng.), Taichung, School of Medicine, and the China Medical University (C.-H. Chen.) Taichung, Taiwan. Address reprint requests to Kuo-Hsiung Shu, MD, Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan. E-mail: khshu@vghtc. gov.tw ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 442e444 (2014)
PATTERN OF MORTALITY IN RENAL TRANSPLANTATION
443
Table 1. Patient Demographics (n [ 520) Transplantation Year Variable
Sex (male, %) Age at KTx (y) Duration of dialysis (y) Pre-KTx DM (%) Post-KTx DM (%) Hepatitis B (%) Hepatitis C (%) No. of HLA mismatches AB DR
1983e1988 (n ¼ 83)
1989e1998 (n ¼ 163)
1999e2012 (n ¼ 274)
Total (n ¼ 520)
P Value
66.3 33.5 8.1 2.2 3.1 0.0 9.6 16.9 26.5
55.2 35.3 8.6 2.9 2.5 2.2 8.9 10.4 28.8
51.1 42.6 12.7 4.0 3.9 9.1 8.8 6.9 10.6
54.8 38.8 11.6 3.3 3.6 6.0 8.9 9.6 18.8
.051 <.0001 <.0001 .003 .982 .034 <.0001
2.38 0.87 1.01 0.74
2.06 0.94 0.75 0.55
1.74 1.16 0.85 0.67
1.94 1.07 0.84 0.65
<.0001 .016
DM, diabetes mellitus; HLA, human leukocyte antigen; KTx, kidney transplantation.
azathioprine was 2e3 mg/kg/day, adjusted according to white blood cell count. The diagnosis of rejection was mainly based on clinical suspicion and a graft biopsy was rarely performed. In group 2, the dose of steroid was 0.5 mg/kg/day and tapered to 5 mg/day by the end of the third month; CsA was 10e15 mg/kg/day in 2 divided doses. A graft biopsy was sometimes performed to elucidate unexplained deterioration of graft function. In group 3, the doses of FK and mycophenolic acid were 0.2e0.3 mg/kg/d and 2 g/d, respectively. Some patients also received interleukin-2 receptor blocker as induction therapy. A graft biopsy was routinely performed for deterioration of renal function and heavy proteinuria. A KaplaneMeier plot was used to describe patient survival and a logrank test was used for comparison among the 3 groups. Causes of death were determined through chart review. Deaths occurred outside our hospital and without definite diagnosis were categorized as “other/unknown.”
RESULTS
From 1989 through 2012, a total of 520 cases (male:female ratio of 285:235) of KTx recipients were performed at our hospital. Demographic data are presented in Table 1. Group 3 patients were older at KTx, and had a longer duration of pre-KTx dialysis, more pre-KTx diabetes mellitus, but lower prevalence of hepatitis B virus and hepatitis C virus (HCV) infection. The 1-, 5-, and 10-year patient survival rates are 87.8%, 68.3%, and 53.4%, respectively, for group 1; 90.6%, 84.9%, and 79.1%, respectively for group 2; and 98.9%, 94.0%, and 89.6%, respectively, for group 3 (P < .0001). During a mean follow-up of 9.55 8.20 years, Table 2. Cause of Death According to Transplantation Year Transplantation Year Cause of Death
No. of deaths Infection (%) Malignancy (%) Hepatic failure (%) Cardiovascular disease (%) Others/unknown (%)
1983e1988 1989e1998 1999e2012 Total (n ¼ 83) (n ¼ 163) (n ¼ 274) (n ¼ 520) P Value
34 44.1 11.8 8.8 29.4
38 52.6 10.5 10.5 13.2
11 18.2 18.2 18.2 27.3
83 44.6 12.0 10.8 21.7
5.9
13.2
18.2
10.8
83 patients died. The causes of death in different transplant eras are presented in Table 2. The leading cause of death was infection in groups 1 and 2 patients (44.1% and 52.6% of total deaths, respectively). In contrast, CVD was the leading cause of death in group 3 (27.3%); infection accounted for only 18.2%. Table 3 shows a clear trend of noninfectious disease as the main cause of death in the modern era, although this difference was not statistically significant. Table 4 shows that age at transplantation and the time of transplantation were independent risk factors associated with mortality. To explore the predictive factors that were associated with infection or CVD as a cause of death, we performed univariate and multivariate logistic regression analyses. For infection, the only independent risk factor was HCV infection (odds ratio, 7.222; P ¼ .005; 95% CI, 1.837e28.400). For CVD, the only independent risk factor was number of mismatch in human leukocyte antigen HLA-A and -B loci (odds ratio, 2.209; P ¼ .032; 95% CI, 1.071e4.556).
DISCUSSION
The outcome of KTx has improved remarkably over the past several decades [1]. However, KTx patients face challenges posttransplant, such as infection, malignancy, CVD, and others owing to some inherent characteristics such as the side effects of immunosuppressive agents and suboptimal long-term graft function. Infection was the most common cause of death in the early years, but has decreased recently [2,3]. The current study showed that infection was the most common cause of death overall (44.6%; Table 2). However, when patients were stratified according to transplant era, Table 3. Infection as a Cause of Death Before and After 1999
.369
Transplant Year Cause of Death
Before 1999 (n ¼ 246)
After 1999 (n ¼ 274)
Total (n ¼ 520)
Number of deaths Infectious (%) Noninfectious (%)
72 48.6 51.4
11 18.2 81.8
83 44.6 55.4
P Value
.101
444
SHU, HO, WEN ET AL Table 4. Factors Associated With Death by Cox Regression Analysis Univariate
Multivariate
Factor
b
P Value
95% CI
b
P Value
95% CI
Sex (female) Transplant age Transplant year 1983e1988 1989e1998 Hepatitis B Hepatitis C Diabetes mellitus Dialysis duration HLA mismatch AB DR
0.182 0.019
.357 .042
0.567e1.227 1.001e1.039
0.205 11.144
.849 <.0001
0.15e10.1 4775e1,000,861
1.925 1.164 0.548 0.205 0.208 0.018
<.0001 .0004 .046 .463 .504 .600
3.57e13.14 1.67e6.14 1.01e2.97 0.71e2.12 0.67e2.27 0.95e1.09
2.680 2.426 0.974 1.624 1.757 0.055
<.0001 <.0001 .711 .134 .154 .700
6.804e31.281 5.210e24.557 0.02e459.4 0.61e42.5 0.52e65.0 0.80e1.40
0.164 0.299
.098 .057
0.97e1.43 0.99e1.84
0.650 0.751
.317 .348
0.54e6.85 0.44e10.2
DM, diabetes mellitus.
infection accounted for only 18.2% of death in the modern era, compared with 44.1% in group 1 and 52.6% in group 2 (Table 2). Although not statistically significant, there was a clear trend toward a decreased prevalence of infection as a cause of death (Table 3). Several reasons may account for this changing pattern. Group 1 and 2 patients had a greater prevalence of hepatitis B virus and HCV infection (Table 1). These viral infections are associated with higher susceptibility of infection. The association was further supported by the multivariate logistic regression showing that HCV infection was an the independent risk factor for infection as a cause of death. The development of newer generation of immunosuppressants, such as calcineurin inhibitors and mycophenolic acid, has allowed a more selective suppression on immune system and a reduction of steroid dose that in turn has decreased risk of infection in the modern era. Moreover, although newer drugs are more potent, modern transplant physicians have learned to better use these drugs based on past experience. We speculated that the inferior patient survival in groups 1 and 2 (Table 4) was most likely owing to the greater incidence of severe infection during these 2 periods. CVD was the second important cause of death in group 1 and has become the most important cause of death in the modern era (Table 2). Our Group 3 patients were older at KTx, and had a longer duration of pre-KTx dialysis and greater prevalence of pre-KTx diabetes; all of these characteristics are associated with a greater risk of CVD. Our finding is consistent with a recent report from Spain [4]. CVD is a common complication in patients with chronic kidney disease as well as in KTx recipients [5]. Although successful transplantation may ameliorate several risk factors, immunosuppressive agents such as corticosteroids,
calcineurin inhibitors, and mammalian target of rapamycin inhibitors are associated with hypertension, hyperglycemia, and hyperlipidemia, all of which are important contributing factors to CVD. A study of coronary artery and aorta calcification in KTx recipients showed a significant progression within 4 years posttransplant [6]. Interestingly, we found that the number of HLA-A and B loci mismatches was the independent risk factor for CVD as a cause of death. We speculated that the more mismatches of HLA might be associated with inferior long-term graft function and chronic renal failure per se is highly associated with CVD. In conclusion, infection is no longer the commonest cause of mortality among Taiwanese KTx patients. Death owing to CVD is increasing and requires intensive management.
REFERENCES [1] Hariharan S, McBride MA, Cherikh WS, et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311. [2] Schweitzer EJ, Matas AJ, Gillingham KJ, et al. Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s. Ann Surg 1991;214:679. [3] Howard RJ, Patton PR, Reed AI, et al. The changing causes of graft loss and death after kidney transplantation. Transplantation 2002;73:1923. [4] Morales JM, Marcen R, Del Castillo D, et al. Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study. Nephrol Dial Transplant 2012;27(suppl 4):iv39. [5] Murphy SW, Foley RN, Parfrey PS. Screening and treatment for cardiovascular disease in patients with chronic renal disease. Am J Kidney Dis 1998;32:S184. [6] Marechal C, Coche E, Goffin E, et al. Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients. Am J Kidney Dis 2012;59:258.
T
HE OUTCOME OF KIDNEY TRANSPLANTATION (KTx) has improved remarkably over the past several decades. The major cause of death among KTx recipients is cardiovascular diseases (CVD) in the West; in Taiwanese patients, it remains unclear. The present study aims to elucidate of causes of death during different eras over the past 30 years in our hospital.
METHODS KTx recipients who underwent transplantation and were followed at our hospital were recruited for the study. A retrospective analysis of patient demographics and outcomes was made through our computerized database. For comparison, patients were stratified according to the vintage of transplantation. Group 1 (the initial era, 1983e1989) was treated with high-dose steroids and azathioprine. Some patients also received cyclosporine [CsA] during this period. Group 2 (the CsA era, 1990e1998) received a standard regimen of low-dose steroids, CsA, and azathioprine. Group 3 (the modern era, 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.032 442
1999e2012) received a standard immunosuppressive regimen of low-dose steroids, tacrolimus (FK), and mycophenolic acid. In some recipients, interleukin-2 receptor blocker was given as induction therapy during this period. In group 1, the dose of steroid was 0.5 mg/kg/day for 3 months followed by a slow taper. The dose of
From the Division of Nephrology, Department of Internal Medicine (K.-H.S., M.-J.W., C.-H. Chen., C.-H. Cheng., T.-M.Y., Y.-W.C., S.-T.H., S.-F.T., Y.-C.L., S.-C.W.), the Division of Urology, Department of Surgery (H.-C.H.), the Department of Pathology (M.-C.W.), Taichung Veterans General Hospital, Taichung, Institute of Medicine, the Chung-Shan Medical University (K.-H.S., M.-J.W., C.-H. Cheng.), Taichung, School of Medicine, and the China Medical University (C.-H. Chen.) Taichung, Taiwan. Address reprint requests to Kuo-Hsiung Shu, MD, Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan. E-mail: khshu@vghtc. gov.tw ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 442e444 (2014)
PATTERN OF MORTALITY IN RENAL TRANSPLANTATION
443
Table 1. Patient Demographics (n [ 520) Transplantation Year Variable
Sex (male, %) Age at KTx (y) Duration of dialysis (y) Pre-KTx DM (%) Post-KTx DM (%) Hepatitis B (%) Hepatitis C (%) No. of HLA mismatches AB DR
1983e1988 (n ¼ 83)
1989e1998 (n ¼ 163)
1999e2012 (n ¼ 274)
Total (n ¼ 520)
P Value
66.3 33.5 8.1 2.2 3.1 0.0 9.6 16.9 26.5
55.2 35.3 8.6 2.9 2.5 2.2 8.9 10.4 28.8
51.1 42.6 12.7 4.0 3.9 9.1 8.8 6.9 10.6
54.8 38.8 11.6 3.3 3.6 6.0 8.9 9.6 18.8
.051 <.0001 <.0001 .003 .982 .034 <.0001
2.38 0.87 1.01 0.74
2.06 0.94 0.75 0.55
1.74 1.16 0.85 0.67
1.94 1.07 0.84 0.65
<.0001 .016
DM, diabetes mellitus; HLA, human leukocyte antigen; KTx, kidney transplantation.
azathioprine was 2e3 mg/kg/day, adjusted according to white blood cell count. The diagnosis of rejection was mainly based on clinical suspicion and a graft biopsy was rarely performed. In group 2, the dose of steroid was 0.5 mg/kg/day and tapered to 5 mg/day by the end of the third month; CsA was 10e15 mg/kg/day in 2 divided doses. A graft biopsy was sometimes performed to elucidate unexplained deterioration of graft function. In group 3, the doses of FK and mycophenolic acid were 0.2e0.3 mg/kg/d and 2 g/d, respectively. Some patients also received interleukin-2 receptor blocker as induction therapy. A graft biopsy was routinely performed for deterioration of renal function and heavy proteinuria. A KaplaneMeier plot was used to describe patient survival and a logrank test was used for comparison among the 3 groups. Causes of death were determined through chart review. Deaths occurred outside our hospital and without definite diagnosis were categorized as “other/unknown.”
RESULTS
From 1989 through 2012, a total of 520 cases (male:female ratio of 285:235) of KTx recipients were performed at our hospital. Demographic data are presented in Table 1. Group 3 patients were older at KTx, and had a longer duration of pre-KTx dialysis, more pre-KTx diabetes mellitus, but lower prevalence of hepatitis B virus and hepatitis C virus (HCV) infection. The 1-, 5-, and 10-year patient survival rates are 87.8%, 68.3%, and 53.4%, respectively, for group 1; 90.6%, 84.9%, and 79.1%, respectively for group 2; and 98.9%, 94.0%, and 89.6%, respectively, for group 3 (P < .0001). During a mean follow-up of 9.55 8.20 years, Table 2. Cause of Death According to Transplantation Year Transplantation Year Cause of Death
No. of deaths Infection (%) Malignancy (%) Hepatic failure (%) Cardiovascular disease (%) Others/unknown (%)
1983e1988 1989e1998 1999e2012 Total (n ¼ 83) (n ¼ 163) (n ¼ 274) (n ¼ 520) P Value
34 44.1 11.8 8.8 29.4
38 52.6 10.5 10.5 13.2
11 18.2 18.2 18.2 27.3
83 44.6 12.0 10.8 21.7
5.9
13.2
18.2
10.8
83 patients died. The causes of death in different transplant eras are presented in Table 2. The leading cause of death was infection in groups 1 and 2 patients (44.1% and 52.6% of total deaths, respectively). In contrast, CVD was the leading cause of death in group 3 (27.3%); infection accounted for only 18.2%. Table 3 shows a clear trend of noninfectious disease as the main cause of death in the modern era, although this difference was not statistically significant. Table 4 shows that age at transplantation and the time of transplantation were independent risk factors associated with mortality. To explore the predictive factors that were associated with infection or CVD as a cause of death, we performed univariate and multivariate logistic regression analyses. For infection, the only independent risk factor was HCV infection (odds ratio, 7.222; P ¼ .005; 95% CI, 1.837e28.400). For CVD, the only independent risk factor was number of mismatch in human leukocyte antigen HLA-A and -B loci (odds ratio, 2.209; P ¼ .032; 95% CI, 1.071e4.556).
DISCUSSION
The outcome of KTx has improved remarkably over the past several decades [1]. However, KTx patients face challenges posttransplant, such as infection, malignancy, CVD, and others owing to some inherent characteristics such as the side effects of immunosuppressive agents and suboptimal long-term graft function. Infection was the most common cause of death in the early years, but has decreased recently [2,3]. The current study showed that infection was the most common cause of death overall (44.6%; Table 2). However, when patients were stratified according to transplant era, Table 3. Infection as a Cause of Death Before and After 1999
.369
Transplant Year Cause of Death
Before 1999 (n ¼ 246)
After 1999 (n ¼ 274)
Total (n ¼ 520)
Number of deaths Infectious (%) Noninfectious (%)
72 48.6 51.4
11 18.2 81.8
83 44.6 55.4
P Value
.101
444
SHU, HO, WEN ET AL Table 4. Factors Associated With Death by Cox Regression Analysis Univariate
Multivariate
Factor
b
P Value
95% CI
b
P Value
95% CI
Sex (female) Transplant age Transplant year 1983e1988 1989e1998 Hepatitis B Hepatitis C Diabetes mellitus Dialysis duration HLA mismatch AB DR
0.182 0.019
.357 .042
0.567e1.227 1.001e1.039
0.205 11.144
.849 <.0001
0.15e10.1 4775e1,000,861
1.925 1.164 0.548 0.205 0.208 0.018
<.0001 .0004 .046 .463 .504 .600
3.57e13.14 1.67e6.14 1.01e2.97 0.71e2.12 0.67e2.27 0.95e1.09
2.680 2.426 0.974 1.624 1.757 0.055
<.0001 <.0001 .711 .134 .154 .700
6.804e31.281 5.210e24.557 0.02e459.4 0.61e42.5 0.52e65.0 0.80e1.40
0.164 0.299
.098 .057
0.97e1.43 0.99e1.84
0.650 0.751
.317 .348
0.54e6.85 0.44e10.2
DM, diabetes mellitus.
infection accounted for only 18.2% of death in the modern era, compared with 44.1% in group 1 and 52.6% in group 2 (Table 2). Although not statistically significant, there was a clear trend toward a decreased prevalence of infection as a cause of death (Table 3). Several reasons may account for this changing pattern. Group 1 and 2 patients had a greater prevalence of hepatitis B virus and HCV infection (Table 1). These viral infections are associated with higher susceptibility of infection. The association was further supported by the multivariate logistic regression showing that HCV infection was an the independent risk factor for infection as a cause of death. The development of newer generation of immunosuppressants, such as calcineurin inhibitors and mycophenolic acid, has allowed a more selective suppression on immune system and a reduction of steroid dose that in turn has decreased risk of infection in the modern era. Moreover, although newer drugs are more potent, modern transplant physicians have learned to better use these drugs based on past experience. We speculated that the inferior patient survival in groups 1 and 2 (Table 4) was most likely owing to the greater incidence of severe infection during these 2 periods. CVD was the second important cause of death in group 1 and has become the most important cause of death in the modern era (Table 2). Our Group 3 patients were older at KTx, and had a longer duration of pre-KTx dialysis and greater prevalence of pre-KTx diabetes; all of these characteristics are associated with a greater risk of CVD. Our finding is consistent with a recent report from Spain [4]. CVD is a common complication in patients with chronic kidney disease as well as in KTx recipients [5]. Although successful transplantation may ameliorate several risk factors, immunosuppressive agents such as corticosteroids,
calcineurin inhibitors, and mammalian target of rapamycin inhibitors are associated with hypertension, hyperglycemia, and hyperlipidemia, all of which are important contributing factors to CVD. A study of coronary artery and aorta calcification in KTx recipients showed a significant progression within 4 years posttransplant [6]. Interestingly, we found that the number of HLA-A and B loci mismatches was the independent risk factor for CVD as a cause of death. We speculated that the more mismatches of HLA might be associated with inferior long-term graft function and chronic renal failure per se is highly associated with CVD. In conclusion, infection is no longer the commonest cause of mortality among Taiwanese KTx patients. Death owing to CVD is increasing and requires intensive management.
REFERENCES [1] Hariharan S, McBride MA, Cherikh WS, et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311. [2] Schweitzer EJ, Matas AJ, Gillingham KJ, et al. Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s. Ann Surg 1991;214:679. [3] Howard RJ, Patton PR, Reed AI, et al. The changing causes of graft loss and death after kidney transplantation. Transplantation 2002;73:1923. [4] Morales JM, Marcen R, Del Castillo D, et al. Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study. Nephrol Dial Transplant 2012;27(suppl 4):iv39. [5] Murphy SW, Foley RN, Parfrey PS. Screening and treatment for cardiovascular disease in patients with chronic renal disease. Am J Kidney Dis 1998;32:S184. [6] Marechal C, Coche E, Goffin E, et al. Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients. Am J Kidney Dis 2012;59:258.