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Early diagnosis of chronic allograft nephropathy by means of protocol biopsies
Early Diagnosis of Chronic Allograft Nephropathy by Means of Protocol Biopsies D. Seron ABSTRACT Chronic allograft nephropathy (CAN) is the first cause of graft failure. Since graft survival has improved and the incidence of rejection decreased, these outcomes cannot be employed as primary efficacy variables in clinical trials due to the need for a large sample size. The presence of CAN in protocol biopsies is an independent predictor of graft survival. Thus, it has been proposed that chronic lesions in protocol biopsies be considered a primary efficacy variable. Power calculations have confirmed this hypothesis, especially if CAN is evaluated using a morphometric technique. Moreover, it has been demonstrated that in vivo glomerular number (Ng) can be estimated by combining a protocol biopsy with magnetic resonance imaging. Ng correlates with graft function in stable grafts. Taken together, these data suggest that protocol biopsies constitute a fundamental tool to improve the design of clinical trials and to define parameters that are crucial to the understanding of mechanisms leading to CAN.
C
HRONIC ALLOGRAFT NEPHROPATHY (CAN) is the most common cause of late graft loss.1 This condition is suspected by a progressive decline of renal function. However, once the diagnosis is histologically confirmed, the degree of renal scarring is rather advanced, and accordingly the probability to modify the natural history of CAN at this stage is rather low. The mechanisms leading to CAN are only partially understood, but it has been shown that both alloimmune and nonimmune mechanisms are involved. Various centers have performed protocol biopsies to diagnose this condition at early stages. Between 25% and 50% of patients already display CAN in protocol biopsies performed during the first 6 months. A consistent finding is that the presence of CAN in protocol biopsies is associated with poorer allograft survival. The predictive value of protocol biopsies for graft outcome is independent of that of other predictors of graft survival such as serum creatinine.2– 4 This observation is not surprising, considering the poor correlation between structure and function in well-functioning grafts.5
acute rejection episodes documented the superiority of a CsA and mycophenolate mofetil regimen over CsA and azathioprine.6 The last decade has witnessed a steady improvement in graft survival and a decreased incidence of acute rejection to less than 20%. Thus, graft survival or acute rejection cannot be employed as primary efficacy variables for clinical trials, since minimum sample size to detect a significant difference between treatment groups is too large.7 The presence of CAN in protocol biopsies performed during the first year is associated with poorer graft survival. Power calculations have been performed to estimate the minimum sample size for an hypothetical trial to prevent progression of CAN during the first months after transplantation. Protocol biopsies might allow one to reduce the minimum sample size to a large extent compared to other clinical parameters, such as serum creatinine, especially when chronic tubulointerstitial damage or intimal thickening are measured by a morphometric technique.3,8
PROTOCOL BIOPSIES AS A PRIMARY EFFICACY VARIABLE IN CLINICAL TRIALS
From the Nephrology Department, Hospital de Bellvitge, Barcelone, Spain. This work was supported by a Fundacio´ La Marato´ TV3 grant. Address reprint requests to Prof D. Sero´n, Nephrology Department, Hospital de Bellvitge, C/ Feixa llarga s/n, L’Hospitalet 08907, Barcelona, Spain.
In the early 1980s, 1-year graft survival was sufficient to demonstrate the superiority of cyclosporine (CsA) over azathioprine. In the early 1990s, a reduced incidence of © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 763–764 (2004)
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.037 763
764
PROTOCOL BIOPSIES AND THE ESTIMATION OF GLOMERULAR NUMBER IN STABLE GRAFTS
Surrogate parameters of reduced renal mass such as donor age, sex, or race are associated with attenuated allograft survival. Experimentally, it has been shown that the amount of transplanted renal mass is a major determinant of outcome. However, total glomerular number (Ng) has not been measured in a clinical setting. Estimates of three parameters are needed to calculate Ng: total cortical renal volume, mean glomerular volume, and glomerular volume fraction in the renal cortex. The first parameter is estimated by magnetic resonance imaging. However, this parameter can only be estimated in well-functioning kidneys since the difference between cortex and medulla disappears as renal scarring progresses. The other two parameters can be estimated in a renal biopsy. Thus, we employed protocol biopsies performed in stable grafts to estimate Ng. For this purpose we considered only well-functioning grafts with serum creatinine values of less than 200 mol/L and proteinuria of less than 1 g/24hours. However, the selection of well-functioning grafts decreased the possibility to correlate structure and function. In spite of this limitation we observed that Ng was a major determinant of glomerular filtration rate.9
SERON
In summary, the study of protocol biopsies suggests their utility as a primary efficacy variable in trials aimed to modify the natural history of CAN. Furthermore, protocol biopsies can be employed to obtain measures that are believed to be crucial for the understanding of the mechanisms leading to CAN.
REFERENCES 1. Racusen LC, Solez K, Colvin RB, et al: Kidney Int 55:713, 1999 2. Sero ´n D, Moreso F, Fulladosa X, et al: Kidney Int 61:727, 2002 3. Sero ´n D, Moreso F, Ramo ´n JM, et al: Transplantation 69:1849, 2000 4. Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, et al: Transplantation 71:515, 2001 5. Fulladosa X, Moreso F, Torras J, et al: Am J Kidney Dis 41:1065, 2003 6. Halloran P, Tomlanovich MT, Groth S, et al: Transplantation 63:39, 1997 7. Hariharan S, McBride MA, Cohen EP: Am J Transplant 3:933, 2003 8. Moreso F, Lopez M, Vallejos A, et al: Am J Transplantation 1:82, 2000 9. Fulladosa X, Moreso F, Narva´ez JA, et al: J Am Soc Nephrol 14:2662, 2003
C
HRONIC ALLOGRAFT NEPHROPATHY (CAN) is the most common cause of late graft loss.1 This condition is suspected by a progressive decline of renal function. However, once the diagnosis is histologically confirmed, the degree of renal scarring is rather advanced, and accordingly the probability to modify the natural history of CAN at this stage is rather low. The mechanisms leading to CAN are only partially understood, but it has been shown that both alloimmune and nonimmune mechanisms are involved. Various centers have performed protocol biopsies to diagnose this condition at early stages. Between 25% and 50% of patients already display CAN in protocol biopsies performed during the first 6 months. A consistent finding is that the presence of CAN in protocol biopsies is associated with poorer allograft survival. The predictive value of protocol biopsies for graft outcome is independent of that of other predictors of graft survival such as serum creatinine.2– 4 This observation is not surprising, considering the poor correlation between structure and function in well-functioning grafts.5
acute rejection episodes documented the superiority of a CsA and mycophenolate mofetil regimen over CsA and azathioprine.6 The last decade has witnessed a steady improvement in graft survival and a decreased incidence of acute rejection to less than 20%. Thus, graft survival or acute rejection cannot be employed as primary efficacy variables for clinical trials, since minimum sample size to detect a significant difference between treatment groups is too large.7 The presence of CAN in protocol biopsies performed during the first year is associated with poorer graft survival. Power calculations have been performed to estimate the minimum sample size for an hypothetical trial to prevent progression of CAN during the first months after transplantation. Protocol biopsies might allow one to reduce the minimum sample size to a large extent compared to other clinical parameters, such as serum creatinine, especially when chronic tubulointerstitial damage or intimal thickening are measured by a morphometric technique.3,8
PROTOCOL BIOPSIES AS A PRIMARY EFFICACY VARIABLE IN CLINICAL TRIALS
From the Nephrology Department, Hospital de Bellvitge, Barcelone, Spain. This work was supported by a Fundacio´ La Marato´ TV3 grant. Address reprint requests to Prof D. Sero´n, Nephrology Department, Hospital de Bellvitge, C/ Feixa llarga s/n, L’Hospitalet 08907, Barcelona, Spain.
In the early 1980s, 1-year graft survival was sufficient to demonstrate the superiority of cyclosporine (CsA) over azathioprine. In the early 1990s, a reduced incidence of © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 763–764 (2004)
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.037 763
764
PROTOCOL BIOPSIES AND THE ESTIMATION OF GLOMERULAR NUMBER IN STABLE GRAFTS
Surrogate parameters of reduced renal mass such as donor age, sex, or race are associated with attenuated allograft survival. Experimentally, it has been shown that the amount of transplanted renal mass is a major determinant of outcome. However, total glomerular number (Ng) has not been measured in a clinical setting. Estimates of three parameters are needed to calculate Ng: total cortical renal volume, mean glomerular volume, and glomerular volume fraction in the renal cortex. The first parameter is estimated by magnetic resonance imaging. However, this parameter can only be estimated in well-functioning kidneys since the difference between cortex and medulla disappears as renal scarring progresses. The other two parameters can be estimated in a renal biopsy. Thus, we employed protocol biopsies performed in stable grafts to estimate Ng. For this purpose we considered only well-functioning grafts with serum creatinine values of less than 200 mol/L and proteinuria of less than 1 g/24hours. However, the selection of well-functioning grafts decreased the possibility to correlate structure and function. In spite of this limitation we observed that Ng was a major determinant of glomerular filtration rate.9
SERON
In summary, the study of protocol biopsies suggests their utility as a primary efficacy variable in trials aimed to modify the natural history of CAN. Furthermore, protocol biopsies can be employed to obtain measures that are believed to be crucial for the understanding of the mechanisms leading to CAN.
REFERENCES 1. Racusen LC, Solez K, Colvin RB, et al: Kidney Int 55:713, 1999 2. Sero ´n D, Moreso F, Fulladosa X, et al: Kidney Int 61:727, 2002 3. Sero ´n D, Moreso F, Ramo ´n JM, et al: Transplantation 69:1849, 2000 4. Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, et al: Transplantation 71:515, 2001 5. Fulladosa X, Moreso F, Torras J, et al: Am J Kidney Dis 41:1065, 2003 6. Halloran P, Tomlanovich MT, Groth S, et al: Transplantation 63:39, 1997 7. Hariharan S, McBride MA, Cohen EP: Am J Transplant 3:933, 2003 8. Moreso F, Lopez M, Vallejos A, et al: Am J Transplantation 1:82, 2000 9. Fulladosa X, Moreso F, Narva´ez JA, et al: J Am Soc Nephrol 14:2662, 2003