- Email: [email protected]
More Than 25 Years Together: Basis for a Long-Lifespan Kidney Transplant
More Than 25 Years Together: Basis for a Long-Lifespan Kidney Transplant L.S. Díaza,*, M.G. Frailea,b, A.C.A. Lópeza, M.L.S. Fernándeza,b, N.R. Canoa, and C. Díaz-Cortea,b a
Nephrology Department, HUCA, Oviedo, Spain; and bRed Investigación Renal (REDINREN), Madrid, Spain
ABSTRACT Patients with graft survival for 20 years or more are not uncommon; they are called ultralong kidney recipients. It is interesting to know if there are patterns in donors and recipients that could be reproduced. A retrospective cohort with 22 adult patients with a kidney renal transplant performed more than 25 years ago is analyzed. The mean of age of the donors was 24 years (median, 21 years); 82% were men and the cause of death was mainly acute traumatic brain injury. Recipients had a mean age of 34 years (median, 36 years) at the time of transplant; the most common underlying renal disease was glomerular, without evidence of recurrence. A total of 16 patients had compatibility in HLA II (1 in 11 cases; 2 in 5 cases). Only 6 patients have had any episode of acute rejection; 3 of them have developed antibodies class I, but no donor-specific antibodies. In this retrospective cohort, increases in donor age are associated with poor renal function. The mean creatinine is 1.43 mg/dL (range, 0.97e2.14 mg/dL) and mean proteinuria is 653.43 mg/g (range, 55e3722 mg/g). The characteristics common in ultralong kidney recipients are young male donors, a shortage of episodes of rejection, and good HLA compatibility, especially in class II antigens.
K
IDNEY transplantation is the treatment of choice for end-stage renal disease. Immunosuppressive therapies introduced in the 2000s have increased the survival of grafts by decreasing the rates of acute rejection. Other factors have contributed to the trend, such as better surgical techniques and immunologic advances in HLA [1,2]. There are patients with long-term survival of renal grafts, more than 20 years, called ultralong term kidney recipients, with good functionality and simple protocol immunosuppressive regimens of treatment. Traynor et al [3] found that old recipient age, male sex, acute rejection, and deceased donor transplant were associated with graft loss. La Manna et al [4] described that renal function at 1 year after transplant was a fundamental variable for predicting long-term outcome of kidney transplant, and this group suggests that there are genetic factors, molecular features, and graft-related characteristics that may affect graft survival. It is interesting to know if there are patterns we can reproduce in this emerging population of ultralong-term kidney recipients. PATIENTS AND METHODS We conducted an observational, retrospective, and descriptive study of kidney adult transplant patients with functioning graft more than 25 years after transplant and follow-up in our hospital. 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.10.007
334
A review of the database of the hospital registry was made considering the demographic, clinical, and immunologic variables of the donor and the recipient. The study of the retrospective cohort included 22 patients.
RESULTS
The study cohort included 22 patients. The characteristics of the population are summarized in Table 1. A total of 21 were deceased donors and 1 was a living donor (mother to son). For donors the mean age was 24 years (median, 21 years) and 82% were men. Mean graft survival was 29.61 years (range, 26.7e36.4 years). The recipients at the time of transplant had a mean age of 34 years (median, 36 years) and 59% were men. The mean age difference between donors and recipients is 11.9 years, with younger donors. The renal base disease of the recipients is distributed in 10 cases of glomerular disease, not identified chronic kidney Grant information: No grant. *Address correspondence to Lucía Sobrino Díaz, MD, PhD, Nefrology Department, HUCA, Av. Roma s/n, 33011, Oviedo, Asturias, España. Tel: þ34985108000, Fax: þ34985667143. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 334e336 (2019)
LONG-LIFESPAN KIDNEY TRANSPLANT
335 Table 1. Characteristics of the Study Population
Donor Age
Age at KTx
Compatibility
ABs anti-HLA II
Graft Age
Acute Rejection
Serum Cr, mg/dL
P/Cr Ratio, mg/g
Immunosuppressive Therapy
16 39 40 17 53 35 15 32 45 40 16 33 33 55 37 46 24 43 39 29 38 24
1B 1A1B1DR ND ND 2B1DR ND ND 1A1DR 1DR1B 2DR ND 1DR1B 1B2DR 2B1DR 1DR 1A1B1DR 1A1B1DR 1A1B2DR 1A2B2DR 1A2B2DR 1B1DR 1A1B1DR
þ (no DSA) þ (no DSA) þ (no DSA)
34 27 29 34 29 36 28 27 32 27 26 29 29 32 26 27 26 28 25 26 28 27
no no no no no yes no no no no yes yes no no yes no no no no No Yes Yes
0.86 0.90 0.95 0.97 1.06 1.06 1.09 1.11 1.12 1.24 1.32 1.40 1.48 1.53 1.62 1.71 1.79 1.85 2.06 2.10 2.13 2.14
260 3722 102 2042 181 219 111 55 101 157 287 130 84 ND 1305 780 219 264 114 1157 674 1758
PredþAZA CSA PredþAZA PredþTACþMMF CSA PredþAZA PredþCSAþAZA PredþCSA PredþAZA CSA PredþCSAþAZA TACþMMF CSAþAZA PredþCSAþAZA PredþCSAþMMF CSAþMMF PredþCSAþMMF CSAþAZA CSAþAZA PredþCSAþMMF CSAþMMF PredþCSA
25 15 27 17 11 18 ND 12 29 17 ND 52 11 9 ND 42 20 23 32 42 40 ND
Abbreviations: AZA, azathioprine; Cr, creatinine; CSA, cyclosporine; DSA, donor-specific antibodies; KTx, kidney transplant; ND, no data; P, proteinuria; Pred, prednisone; MMF, mycophenolate mofetil; TAC, tacrolimus.
disease in 1, diabetic nephropathy in 2, urologic pathology in 6, uremic hemolytic syndrome in 1, and polycystic kidney disease in 2. Causes of death of donors were not documented in 11 cases, traumatic brain injury in 10 cases, and a living donor from mother to child in 1 case. The compatibility in HLA II antigens was very frequent. Only 1 case had no compatibility in class II antigens. HLA matching was in 2 antigens class II in 5 cases and in 1 antigen in 11 cases. The current renal function is mean creatinine of 1.43 mg/ dL (range, 0.97e2.14 mg/dL) with mean proteinuria of 653.43 mg/g (range, 55e3722 mg/g). The relationship between donor age and estimated glomerular filtration rate (eGFR) was as follows: patients with eGFR >60 mL/min had a donor with a mean age of 20.3 years, patients with eGFR 30 to 60 mL/min had a donor with a mean age of 26.1 years, and patients with an eGFR <30 mL/min had a donor with a mean age of 32.5 years. Recipients have good adherence to medical treatment. There were 6 patients who have had acute episodes of rejection. Only 3 cases developed class II antibodies, but not donor-specific antibodies. The current treatment is based on classic protocols: 72.7% are treated with cyclosporine, 40.9% with azathioprine, and 59.1% with prednisone. Seven are in triple combination therapy, 12 are in biotherapy, and 3 are in monotherapy with cyclosporine. DISCUSSION
Factors that influence the survival of the graft are well documented [5]. In the short term, there are long periods of
cold ischemia involving initial graft dysfunction, HLA sensitization, donor type (live, no expanded criteria), factors dependent on the transplant center, donor age, comorbidity of both the donor and recipient, and even the type of dialysis prior to transplant. In the long term, the factors that affect the functionality of the graft are episodes of severe acute rejection, HLA compatibility, repeated infections, inadequate immunosuppression, and anti-HLA sensitization. Finally, there are independent factors: tissue damage (cerebral death, cold ischemia, and infections such as cytomegalovirus), inadequate renal mass, therapeutic failure, decrease in immunosuppression, hypertension, dyslipidemia, diabetes mellitus, recurrence of glomerular disease or development of de novo glomerulonephritis, hyperhomocysteinemia, and development of proteinuria >1 g/24 h. In our retrospective cohort, main characteristics for ultralong kidney transplant are young donors and recipients, few episodes of acute rejection, good compatibility, and adherence to medical treatment. It is remarkable that most of the patients have a glomerular disease without evidence of recurrence. Most of them have little proteinuria and there were only 2 cases of diabetes as underlying disease. These results support a previous study [4] in which serum creatinine at 1 year was strongly predictive of graft survival at 5, 10, and 20 or more years, and supports other studies in which immunologic factors were related to early graft loss [6]. In some studies women have more predisposition to have ultralong graft survival, but in our cohort there are more men [4,7].
336
A trend is observed in the relationship between the age of the donor and the survival of the renal graft, so that with lower ages of the donor, higher rates of graft survival are observed. This fact is described previously in numerous studies [8e10]. Our study has limitations, as we were not able to investigate all factors after transplant because data of our patients are limited. In summary, this is a favorable cohort in whom recipients and donors are young with low comorbidity, good compatibility, and few episodes of rejection, which are all factors described as predictive of good outcome for long-term graft survival. CONCLUSIONS
In our retrospective cohort, young male donors, few episodes of rejection, and good HLA compatibility, especially in class II antigens, are characteristics common to ultralongterm kidney recipients. REFERENCES [1] Karcz M, Kusztal M, Boratynska M, Klinger M. Very long survival transplanted kidney characteristics of recipients. Transplant Proc 2018;50:1730e2. https://doi.org/10.1016/j.transproceed.2018.02.114.
DÍAZ, FRAILE, LÓPEZ ET AL [2] Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McInstosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States 1988-1996. N Engl J Med 2000;342:605e12. [3] Traynor C, Jenkinson A, Williams Y, O’Kelly P, Hickey D. Twenty-year survivors of kidney transplantation. Am J Transplant 2012;12:3289e95. [4] Le Manna G, Capelli I, Gasperoni L, Comai G, Ravaioli M, Marchetti A. Long term outcomes of kidney transplant: characteristics if recipients with 20 or more years of graft survival. J Med Surg Pathol 2016;1:109. [5] Moreso F, Hernández D. Has the survival of the graft improved after renal transplantation in the era of the modern immunosuppression? Nefrologia 2013;33:14e26. [6] Banasik M, Botatinska M, Koscielska-Kasprzak K, Maranozowska O, Krajewska M, et al. The impact of de novo donor-specific-HLA antibodies leukocyte antigen antibodies on 5year renal transplant outcome. Transplant Proc 2013;45:1449e52. [7] Adey DB. Women and kidney transplantation. Adv Chronic Kidney Dis 2013;20:427e32. [8] Øien CM, Reisaeter AV, Leivestad T, Dekker FW, Line PD, Os I. Living donor kidney transplantation: the effects of donor age and gender on short and long term outcomes. Transplantation 2007;15:600e6. [9] Prommool S, Jhangri G, Cockfield S, Halloran P. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 1999;11:565e73. [10] Legendre C, Canaud G, Marínez F. Factors influencing long-term outcome after kidney transplantation. Transpl Int 2014;27:19e27.
Nephrology Department, HUCA, Oviedo, Spain; and bRed Investigación Renal (REDINREN), Madrid, Spain
ABSTRACT Patients with graft survival for 20 years or more are not uncommon; they are called ultralong kidney recipients. It is interesting to know if there are patterns in donors and recipients that could be reproduced. A retrospective cohort with 22 adult patients with a kidney renal transplant performed more than 25 years ago is analyzed. The mean of age of the donors was 24 years (median, 21 years); 82% were men and the cause of death was mainly acute traumatic brain injury. Recipients had a mean age of 34 years (median, 36 years) at the time of transplant; the most common underlying renal disease was glomerular, without evidence of recurrence. A total of 16 patients had compatibility in HLA II (1 in 11 cases; 2 in 5 cases). Only 6 patients have had any episode of acute rejection; 3 of them have developed antibodies class I, but no donor-specific antibodies. In this retrospective cohort, increases in donor age are associated with poor renal function. The mean creatinine is 1.43 mg/dL (range, 0.97e2.14 mg/dL) and mean proteinuria is 653.43 mg/g (range, 55e3722 mg/g). The characteristics common in ultralong kidney recipients are young male donors, a shortage of episodes of rejection, and good HLA compatibility, especially in class II antigens.
K
IDNEY transplantation is the treatment of choice for end-stage renal disease. Immunosuppressive therapies introduced in the 2000s have increased the survival of grafts by decreasing the rates of acute rejection. Other factors have contributed to the trend, such as better surgical techniques and immunologic advances in HLA [1,2]. There are patients with long-term survival of renal grafts, more than 20 years, called ultralong term kidney recipients, with good functionality and simple protocol immunosuppressive regimens of treatment. Traynor et al [3] found that old recipient age, male sex, acute rejection, and deceased donor transplant were associated with graft loss. La Manna et al [4] described that renal function at 1 year after transplant was a fundamental variable for predicting long-term outcome of kidney transplant, and this group suggests that there are genetic factors, molecular features, and graft-related characteristics that may affect graft survival. It is interesting to know if there are patterns we can reproduce in this emerging population of ultralong-term kidney recipients. PATIENTS AND METHODS We conducted an observational, retrospective, and descriptive study of kidney adult transplant patients with functioning graft more than 25 years after transplant and follow-up in our hospital. 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.10.007
334
A review of the database of the hospital registry was made considering the demographic, clinical, and immunologic variables of the donor and the recipient. The study of the retrospective cohort included 22 patients.
RESULTS
The study cohort included 22 patients. The characteristics of the population are summarized in Table 1. A total of 21 were deceased donors and 1 was a living donor (mother to son). For donors the mean age was 24 years (median, 21 years) and 82% were men. Mean graft survival was 29.61 years (range, 26.7e36.4 years). The recipients at the time of transplant had a mean age of 34 years (median, 36 years) and 59% were men. The mean age difference between donors and recipients is 11.9 years, with younger donors. The renal base disease of the recipients is distributed in 10 cases of glomerular disease, not identified chronic kidney Grant information: No grant. *Address correspondence to Lucía Sobrino Díaz, MD, PhD, Nefrology Department, HUCA, Av. Roma s/n, 33011, Oviedo, Asturias, España. Tel: þ34985108000, Fax: þ34985667143. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 334e336 (2019)
LONG-LIFESPAN KIDNEY TRANSPLANT
335 Table 1. Characteristics of the Study Population
Donor Age
Age at KTx
Compatibility
ABs anti-HLA II
Graft Age
Acute Rejection
Serum Cr, mg/dL
P/Cr Ratio, mg/g
Immunosuppressive Therapy
16 39 40 17 53 35 15 32 45 40 16 33 33 55 37 46 24 43 39 29 38 24
1B 1A1B1DR ND ND 2B1DR ND ND 1A1DR 1DR1B 2DR ND 1DR1B 1B2DR 2B1DR 1DR 1A1B1DR 1A1B1DR 1A1B2DR 1A2B2DR 1A2B2DR 1B1DR 1A1B1DR
þ (no DSA) þ (no DSA) þ (no DSA)
34 27 29 34 29 36 28 27 32 27 26 29 29 32 26 27 26 28 25 26 28 27
no no no no no yes no no no no yes yes no no yes no no no no No Yes Yes
0.86 0.90 0.95 0.97 1.06 1.06 1.09 1.11 1.12 1.24 1.32 1.40 1.48 1.53 1.62 1.71 1.79 1.85 2.06 2.10 2.13 2.14
260 3722 102 2042 181 219 111 55 101 157 287 130 84 ND 1305 780 219 264 114 1157 674 1758
PredþAZA CSA PredþAZA PredþTACþMMF CSA PredþAZA PredþCSAþAZA PredþCSA PredþAZA CSA PredþCSAþAZA TACþMMF CSAþAZA PredþCSAþAZA PredþCSAþMMF CSAþMMF PredþCSAþMMF CSAþAZA CSAþAZA PredþCSAþMMF CSAþMMF PredþCSA
25 15 27 17 11 18 ND 12 29 17 ND 52 11 9 ND 42 20 23 32 42 40 ND
Abbreviations: AZA, azathioprine; Cr, creatinine; CSA, cyclosporine; DSA, donor-specific antibodies; KTx, kidney transplant; ND, no data; P, proteinuria; Pred, prednisone; MMF, mycophenolate mofetil; TAC, tacrolimus.
disease in 1, diabetic nephropathy in 2, urologic pathology in 6, uremic hemolytic syndrome in 1, and polycystic kidney disease in 2. Causes of death of donors were not documented in 11 cases, traumatic brain injury in 10 cases, and a living donor from mother to child in 1 case. The compatibility in HLA II antigens was very frequent. Only 1 case had no compatibility in class II antigens. HLA matching was in 2 antigens class II in 5 cases and in 1 antigen in 11 cases. The current renal function is mean creatinine of 1.43 mg/ dL (range, 0.97e2.14 mg/dL) with mean proteinuria of 653.43 mg/g (range, 55e3722 mg/g). The relationship between donor age and estimated glomerular filtration rate (eGFR) was as follows: patients with eGFR >60 mL/min had a donor with a mean age of 20.3 years, patients with eGFR 30 to 60 mL/min had a donor with a mean age of 26.1 years, and patients with an eGFR <30 mL/min had a donor with a mean age of 32.5 years. Recipients have good adherence to medical treatment. There were 6 patients who have had acute episodes of rejection. Only 3 cases developed class II antibodies, but not donor-specific antibodies. The current treatment is based on classic protocols: 72.7% are treated with cyclosporine, 40.9% with azathioprine, and 59.1% with prednisone. Seven are in triple combination therapy, 12 are in biotherapy, and 3 are in monotherapy with cyclosporine. DISCUSSION
Factors that influence the survival of the graft are well documented [5]. In the short term, there are long periods of
cold ischemia involving initial graft dysfunction, HLA sensitization, donor type (live, no expanded criteria), factors dependent on the transplant center, donor age, comorbidity of both the donor and recipient, and even the type of dialysis prior to transplant. In the long term, the factors that affect the functionality of the graft are episodes of severe acute rejection, HLA compatibility, repeated infections, inadequate immunosuppression, and anti-HLA sensitization. Finally, there are independent factors: tissue damage (cerebral death, cold ischemia, and infections such as cytomegalovirus), inadequate renal mass, therapeutic failure, decrease in immunosuppression, hypertension, dyslipidemia, diabetes mellitus, recurrence of glomerular disease or development of de novo glomerulonephritis, hyperhomocysteinemia, and development of proteinuria >1 g/24 h. In our retrospective cohort, main characteristics for ultralong kidney transplant are young donors and recipients, few episodes of acute rejection, good compatibility, and adherence to medical treatment. It is remarkable that most of the patients have a glomerular disease without evidence of recurrence. Most of them have little proteinuria and there were only 2 cases of diabetes as underlying disease. These results support a previous study [4] in which serum creatinine at 1 year was strongly predictive of graft survival at 5, 10, and 20 or more years, and supports other studies in which immunologic factors were related to early graft loss [6]. In some studies women have more predisposition to have ultralong graft survival, but in our cohort there are more men [4,7].
336
A trend is observed in the relationship between the age of the donor and the survival of the renal graft, so that with lower ages of the donor, higher rates of graft survival are observed. This fact is described previously in numerous studies [8e10]. Our study has limitations, as we were not able to investigate all factors after transplant because data of our patients are limited. In summary, this is a favorable cohort in whom recipients and donors are young with low comorbidity, good compatibility, and few episodes of rejection, which are all factors described as predictive of good outcome for long-term graft survival. CONCLUSIONS
In our retrospective cohort, young male donors, few episodes of rejection, and good HLA compatibility, especially in class II antigens, are characteristics common to ultralongterm kidney recipients. REFERENCES [1] Karcz M, Kusztal M, Boratynska M, Klinger M. Very long survival transplanted kidney characteristics of recipients. Transplant Proc 2018;50:1730e2. https://doi.org/10.1016/j.transproceed.2018.02.114.
DÍAZ, FRAILE, LÓPEZ ET AL [2] Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McInstosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States 1988-1996. N Engl J Med 2000;342:605e12. [3] Traynor C, Jenkinson A, Williams Y, O’Kelly P, Hickey D. Twenty-year survivors of kidney transplantation. Am J Transplant 2012;12:3289e95. [4] Le Manna G, Capelli I, Gasperoni L, Comai G, Ravaioli M, Marchetti A. Long term outcomes of kidney transplant: characteristics if recipients with 20 or more years of graft survival. J Med Surg Pathol 2016;1:109. [5] Moreso F, Hernández D. Has the survival of the graft improved after renal transplantation in the era of the modern immunosuppression? Nefrologia 2013;33:14e26. [6] Banasik M, Botatinska M, Koscielska-Kasprzak K, Maranozowska O, Krajewska M, et al. The impact of de novo donor-specific-HLA antibodies leukocyte antigen antibodies on 5year renal transplant outcome. Transplant Proc 2013;45:1449e52. [7] Adey DB. Women and kidney transplantation. Adv Chronic Kidney Dis 2013;20:427e32. [8] Øien CM, Reisaeter AV, Leivestad T, Dekker FW, Line PD, Os I. Living donor kidney transplantation: the effects of donor age and gender on short and long term outcomes. Transplantation 2007;15:600e6. [9] Prommool S, Jhangri G, Cockfield S, Halloran P. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 1999;11:565e73. [10] Legendre C, Canaud G, Marínez F. Factors influencing long-term outcome after kidney transplantation. Transpl Int 2014;27:19e27.