Influence of Donor Factors on Early Function of Graft Kidneys

Transcription

1 Influence of Donor Factors on Early Function of Graft Kidneys J Am Soc Nephrol 10: , 1999 DEEPIKA SURI and TIMOTHY W. MEYER Departments of Medicine, Palo Alto Veterans Administration Health Care Service and Stanford University, Palo Alto, California. Abstract. Factors which influence graft function can be divided into donor factors that affect both kidneys from the same donor equally and postdonor factors that affect each kidney individually. This study assessed the influence of donor factors on graft function early after transplantation. Sixty-one donors who provided kidneys that were transplanted locally into two separate recipients were identified. Recipient creatinine clearance values were estimated from serum creatinine concentrations using a computer model. Pairwise ANOVA showed that donor factors accounted for 35 to 45% of the variation in recipient creatinine clearance from d to wk posttransplantation. Although donor factors had a large aggregate effect during this period, individual factors that influenced graft function could not be identified from analysis of donor medical records. At 6 mo after transplantation, the effect of donor factors on graft function was no longer discernible. These results show that the condition of the donor exerts an important influence on graft function early after transplantation. More detailed study is required to identify individual factors that contribute to this effect. Function of cadaver kidneys over the first few days after transplantation ranges from near zero to normal (1 4). Most of the kidneys that exhibit poor initial function eventually recover adequate function. Delayed function, however, has significant adverse consequences. It prolongs hospitalization and complicates immunosuppressive therapy. In addition, when defined by a requirement for dialysis during the first week after transplantation, delayed function is associated with an increased incidence of acute rejection and increased rate of graft loss over the first year (5,6). Some, although not all, studies have found that delayed function is also associated with an increased rate of late graft loss (5 9). Delayed graft function is generally attributed to reperfusion injury following renal ischemia (1 4). The factors that cause some grafts to exhibit delayed function while others function promptly, however, are poorly understood. Theoretically, these factors can be divided into two groups. The first group is composed of donor factors, which should affect both kidneys from the same donor equally. These could include features of the donor s medical condition before the injury which caused brain death, the nature of this injury, and events during the terminal hospitalization and procurement surgery. The second group is composed of post-donor factors, which are not expected to affect both kidneys from the same donor equally. These could include consequences of cold ischemia, features of the recipient s medical condition, and events during transplant Received September 14, Accepted December 15, Correspondence to Dr. Timothy Meyer, Departments of Medicine, Palo Alto VAHCS and Stanford University, Palo Alto VAHCS, 3801 Miranda Avenue, Palo Alto, CA Phone: , ext ; Fax: ; meyer.timothy_w@palo-alto.va.gov / Journal of the American Society of Nephrology Copyright 1999 by the American Society of Nephrology surgery and subsequent hospitalization. The current study compared the influence of donor and postdonor factors by analyzing the extent to which kidneys from the same donor exhibit similar function posttransplantation. Materials and Methods Records of the California Transplant Donor Network (CTDN) for 1996 were reviewed to identify donors who provided kidneys transplanted locally into two separate recipients. Of a total of 185 kidney donors during the year, 57 were excluded because one or both kidneys were transplanted outside the network, 37 were excluded because another organ was transplanted along with the kidney in at least one recipient, 14 were excluded because both kidneys were transplanted into the same recipient, 13 were excluded because one kidney was discarded, and an additional three were excluded because they were under 10 yr of age. The remaining 61 donors and the 1 recipients of their kidneys were included in this study. Donor clinical data were obtained from a computerized database maintained by CTDN. Donor creatinine clearance values were estimated using the formula of Cockcroft and Gault (10) for adults and the formula of Schwartz et al. (11) for adolescents. Recipient data were obtained from medical records maintained by the local transplant centers and referring nephrologists. Creatinine clearance during the period from 4 to 7 h after transplantation was estimated using a modification of the method described by Moran and Myers (1). The age, gender, and weight of the recipient, the time of implantation, and all recorded serum creatinine values and the times at which they were measured were entered into a computer program. The program then estimated serum creatinine values at 4, 48, and 7 h by interpolation and calculated the average serum creatinine concentration over 4 to 48 and 48 to 7 h. Body creatinine content was calculated as the product of serum creatinine concentration and body water content. Values for creatinine clearance during 4 to 48 h and 48 to 7 h posttransplantation were then obtained from the appropriate values for serum creatinine concentration, body creatinine content, and creatinine production as estimated by the formulas of Cockcroft and Gault and Schwartz et al. In recipients who were hemodialyzed, clearance

2 1318 Journal of the American Society of Nephrology J Am Soc Nephrol 10: , 1999 values were calculated after excluding the period between the last serum creatinine measurement before dialysis and the first creatinine measurement after dialysis. Records of dialysis time and/or serum creatinine levels were insufficient to allow this correction for the period from 4 to 48 h in three patients and for the period 48 to 7 h in nine patients. In these patients, clearance values were calculated without correcting for dialysis. When the uncorrected values were less than 10 ml/min, they were used in the analysis. In other patients, the clearance was set at 10 ml/min. In the two recipients who underwent peritoneal dialysis, the computer-generated creatinine clearance values were less than 1 ml/min, and no attempt to correct them for dialytic clearance was made. Creatinine clearance values at wk and 6 mo were estimated using the formulas of Cockcroft and Gault and Schwartz et al. The clearance at wk was calculated using the average of all serum creatinine values from day 13 to day 15 in 100 patients. When no creatinine values were available from this interval, values were averaged from day 1 to 16 (18 patients) or from day 9 to 19 (4 patients). The clearance at 6 mo was calculated using the average of all serum creatinine values from 4 to 7 mo excluding values obtained during episodes of acute rejection. One recipient who died and one recipient who was lost to follow-up were excluded from analysis so the number of pairs analyzed at 6 mo was 59. Graft creatinine clearance was recorded as zero in two patients who underwent transplant nephrectomy and had returned to dialysis at 6 mo. Episodes of acute rejection during the first 6 mo, established by biopsy or by use of pulse immunosuppressive therapy to reverse increases in serum creatinine, were identified by review of clinic records. Statistical Analyses The relation of function in kidneys from the same donor was assessed using a modification of the method described by Cosio et al. (13). Recipients of kidneys from the same donor were first randomly designated the A recipient and the B recipient. An ANOVA was then used to estimate the contribution of donor factors to the total variation observed in graft function. For this analysis, the difference between graft function in an individual recipient and the mean graft function of the study group was assumed to be the sum of two normally distributed variables. The first of these variables, F i, represented the portion of the difference ascribable to donor factors and thus had the same value for both kidneys from the ith donor. The second, E ij with j A or B, represented the portion of the difference ascribable to postdonor factors and thus had a different value for each kidney. The posttransplant clearance values x ia and x ib for the two kidneys of the ith donor were thus expressed as: and x ia F i E ia (1) x ib F i E ib. () The values of F i and E ij in individual patients could not be determined, but the average magnitude of F i and E ij could be obtained from the related variables f i and e i, where: and f i x ia x ib (3) e i x ia x ib. (4) It will be seen that f i reflected the degree to which the average function of a pair of kidneys differed from the grand mean and that e i reflected the degree to which function in two kidneys from the same donor differed from each other. Standard ANOVA calculations provided values for f i, e i, and the sum of squares, where: Sum of squares f i e i. (5) Since the values for E ij and F i were presumed to be normally distributed and the number of pairs was large, values for E ij and F i obeyed the relationships: and Sum of squares F i E i (6) E i e i. (7) The latter relationship reflects the tendency of the real influence of recipient factors E ij to have a greater magnitude than calculated values for e i. Relationships 6 and 7 were combined to obtain: F i Sum of squares e i. (8) The fraction of the overall variability of graft function that was attributable to donor factors was then estimated as: F i Sum of squares Sum of squares e i. (9) Sum of squares The test was used to determine whether there was a tendency for both recipients of kidneys from the same donor to be dialyzed during the first 4 d posttransplantation. The contribution of individual donor factors to graft function posttransplantation was assessed by linear regression for parametric variables and by unpaired t test for nonparametric variables. All statistical calculations were done with a standard software program (StatView 4.5, Abacus Concepts, Berkeley, CA). Values are presented as the mean 1 SD throughout. Results Clinical data for the donors are summarized in Table 1. The mean age was yr, and there were 1 women and 40 men. The serum creatinine value immediately before procurement was mg/dl. The maximum serum creatinine recorded during hospitalization was slightly higher, averaging mg/dl, but did not exceed. mg/dl in any patient. Body weight was 80 kg and the estimated creatinine clearance before procurement was ml/min. The Table 1. Clinical characteristics of the 61 donors a Age (yr) to 66 Gender (F/M) 4/80 Maximum serum creatinine to. (mg/dl) Final serum creatinine (mg/dl) to 1.9 Body weight (kg) 80 6 to 136 Estimated creatinine clearance to 171 (ml/min) Duration of hospitalization (h) to 13 a Values are the mean 1 SD and the range observed.

3 J Am Soc Nephrol 10: , 1999 Donor Effect on Early Graft Kidney Function 1319 duration of the terminal hospitalization was h. Brain death was attributed to trauma in 4 patients, to cerebrovascular accident in 9 patients, and to other causes in eight patients. Kidneys from the 61 donors were transplanted into 53 women and 69 men with an average age of yr. Graft function in the recipients is summarized in Table. Serum creatinine was mg/dl over the period from 4 to 48 h postimplantation and mg/dl over the period from 48 to 7 h postimplantation. The large SD in these values reflected a wide range of early graft function. Creatinine clearance values estimated from body size and the rate of change in serum creatinine varied from near zero to near normal. Thirtyfour of the 1 recipients were dialyzed over the first 4 d postimplantation. The average serum creatinine declined to.8.5 mg/dl at wk and mg/dl at 6 mo. Regression plots revealed that early function in kidneys obtained from the same donor tended to be similar, as depicted in Figure 1. By 6 mo after transplantation, this tendency was no longer apparent, as depicted in Figure. Estimates of the relative influence of donor and postdonor factors on graft function are summarized in Table 3. Values for F i were between 35 and 45% of the total sum of squares at 4 to 8 h, 48 to 7 h, and wk after transplantation. These results indicate that donor factors accounted for slightly less that half of the variability in graft kidney function during the early posttransplant period. In contrast, the value for F i was only 10% of the total sum of squares at 6 mo, indicating that the residual effect of donor factors accounted for very little of the variability in graft function observed at this interval. As illustrated in Figure 3, the influence of donor factors on early function could not be detected when dialysis was used as the only index of poor function. Both recipients of kidneys from the same donor were dialyzed during the first 4 d in only four patients. This number was not greater than that which would have resulted from chance alone given a 8% overall frequency of dialysis during this interval ( 0., P 0.6). Good graft function during the early posttransplant period was associated with a reduced incidence of acute rejection over the first 6 mo. The median estimated clearance at 4 to 8 h was ml/min. Acute rejection was observed in 19% of patients with clearance values greater than the median and in 38% of patients with clearance values less than or equal to the median ( 5.1, P 0.05). Very good early graft function was associated with Table. Graft function in the 1 recipients a Period Serum Creatinine (mg/dl) Creatinine Clearance (ml/min) 4 to 48 h to 7 h wk mo a Serum creatinine values for four recipients and creatinine clearance values for two recipients are not included in data at 6 mo. Figure 1. Early function of graft kidneys from the same donor. Creatinine clearance values for kidneys from the same donor tended to be similar during the first wk after transplantation. Linear regression yielded values of r 0.13, P at 4 to 48 h, r 0.16, P 0.00 at 48 to 7 h, and r 0.1, P at wk.

4 130 Journal of the American Society of Nephrology J Am Soc Nephrol 10: , 1999 observed between the postdonor factor cold ischemia time and early graft function (r 0.07, P 0.00). Figure. Function at 6 mo of graft kidneys from the same donor. The tendency for kidneys from the same donor to exhibit similar creatinine clearance values is no longer apparent. a still lower incidence of acute rejection. Acute rejection was observed in only 7% of patients whose estimated clearance values at 4 to 48 h fell in the upper quartile ( 4 ml/min, 8.8, P 0.01). The relation of graft function to individual donor factors is summarized in Table 4. The table presents creatinine clearance values at 4 to 48 h, but similar results were obtained when creatinine clearance values at 48 to 7 h and 14 d were analyzed. Grafts from donors without a history of hypertension appeared to function better than grafts from donors with such a history. This relation could not be assigned statistical significance by conventional criteria, however, because correcting for analysis of multiple variables would raise the P value above Other features of the donor medical history, including death at a young age and death due to trauma, did not exert a detectable influence on graft function. Graft function also was not correlated with recorded features of the donor condition in hospital. The authors had hypothesized that graft function would be correlated with donor kidney function before procurement, but this did not prove to be the case. Low systolic BP and the use of dopamine, which were considered potential indices of impaired donor hemodynamic function, did not predict poor function. Use of dopamine at a rate 10 g/kg per min (30 patients) or of pressors other than dopamine (3 patients) likewise did not predict poor function. Examination of donor laboratory values including hematocrit, platelet count, prothrombin time, liver function tests, and the anion gap also failed to identify factors that influenced graft function. In contrast, a significant inverse correlation was Discussion The chief aim of the current study was to assess the relative influence of donor and postdonor factors on graft function early after transplantation. Graft function was evaluated by modeling creatinine clearance rates rather than simply by analyzing serum creatinine values or the use of dialysis. Results indicated that early graft function varied continuously over a wide range. Statistical analysis was performed using the ANOVA as described by Cosio et al. (13) with a modification to prevent overestimation of the importance of donor factors. Application of these methods suggested that donor factors accounted for 35 to 45% of the variability in graft function over the period between 4 h and wk after transplantation. The donor effect on graft function could no longer be detected at 6 mo. Presumably, recovery from reperfusion injury reduced the magnitude of the donor effect. In addition, the influence of events between wk and 6 mo would reduce the relative importance of donor factors and make their effect hard to detect in a study of the present size. Good early graft function was associated with a reduced incidence of acute rejection, in accord with the findings of previous studies (6,7,14). Relatively few studies have previously compared graft function in recipients of kidneys from the same donor. Pfaff et al. (15) identified recipient pairs who received kidneys from 77 donors at a single center. As in the current study, analysis did not reveal an influence of donor factors on the requirement for dialysis during the early posttransplant period. It is not surprising that the effect of donor factors is obscured when dialysis is used as the sole index of poor graft function. The decision to use dialysis is influenced by features of the recipient s condition other than graft function, including extracellular fluid volume, electrolyte status, and the extent to which uremia was corrected by dialysis before transplantation. Moreover, the use of dialysis as an index of function requires that graft function be divided into two categories rather than considered as a continuous variable. This process in itself tends to obscure the effect of donor factors. Cosio et al. (13) addressed this problem by comparing serum creatinine values in recipients of kidneys from the same donor. They found a statistically significant correlation between serum creatinine values in 184 recipient pairs evaluated at 10 d and in 139 recipient pairs evaluated at 6 mo. Graft function at earlier intervals was not assessed. Our findings at 14 d appear similar to those obtained by Cosio et al. (13) at 10 d. Our findings at 6 mo, however, are different. We could not detect an effect of donor factors at this interval. Cosio et al. (13) concluded that most of the variation in serum creatinine at 6 mo was attributable to donor factors, although the correlation between creatinine values in recipient pairs was weak. The discrepancy between this result and that of the current study is due in part to a difference in statistical methods. As described in Materials and Methods, we corrected for the tendency of the variability within donor pairs to under-

5 J Am Soc Nephrol 10: , 1999 Donor Effect on Early Graft Kidney Function 131 Table 3. Aggregate influence of donor factors a Parameter 4 to 48 h 48 to 7 h wk 6 mo Sum of squares 48,714 66,95 91,983 89,47 E i 8,860 37,01 58,338 80,450 F i 19,854 9,940 33,645 8,797 % donor factors a Values for percentage of donor factors were calculated by dividing values for F i by the sum of squares. Figure 3. Dialysis during the first 4 d inrecipients of kidneys from the same donor. The influence of donor factors could not be detected when dialysis was used as the only index of poor function. estimate the influence of postdonor factors. This correction reduces the portion of the variability ascribed to donor factors. It should be emphasized that errors in the assessment of graft function will cause underestimation of the importance of donor factors. This is because such errors tend to exaggerate the difference in function of kidneys from the same donor. Estimation of creatinine clearance should provide a more accurate measure of graft function than serum creatinine alone. As used in the current study, however, this method requires calculation of creatinine production on the basis of age, gender, body weight, and height. Variations in muscle mass among people of the same age, gender, weight, and height, which may be greater among dialysis patients than healthy subjects, are ignored. Creatinine clearance, moreover, provides an imperfect measure of GFR when renal function is reduced (16,17). Our calculation that donor factors accounted for 35 to 45% of the variation in graft creatinine clearance from 4 h to wk posttransplantation may therefore have underestimated the influence of donor factors on graft function. The current study revealed a large aggregate effect of donor factors but failed to identify individual donor factors that affected graft function. Previous studies have likewise left most of the variation in early graft function unaccounted for. The largest of these studies have described data from the U.S. Renal Data System (18), the UNOS Scientific Renal Transplant Registry (6), the European Multicenter Study Group (19,0), and two individual centers (13,15). In most cases, delayed graft function has been defined by the requirement for dialysis during the first week posttransplantation. The only donor factor associated with an increased risk of delayed graft function in the majority of the studies has been older age. The strength of the age-associated risk has been moderate, which may explain why the inverse correlation between donor age and early graft function did not attain statistical significance in our smaller study. Two of the larger studies identified death due to cerebrovascular accident as an age-independent risk factor for delayed graft function and one identified donor obesity as a risk factor (15,19). Presumably, vascular disease associated with these factors could make the kidney more susceptible to ischemic injury. A remarkable feature of previous studies has been the absence of a strong association between donor hemodynamic state and the risk of delayed graft function. Hypotension and pressor use were associated with an increased risk of delayed graft function in two smaller studies (1,), but this result was not confirmed by the larger studies of Pfaff et al. (15) and Ploeg et al. (19). We also observed no correlation between graft function and recorded hemodynamic parameters or pressor use. Given the aggregate effect of donor factors, the failure to identify important individual factors could be attributed to two causes. First, many individual donor factors could combine to account for a large portion of the variability in graft function without any single factor having a large enough influence to be identified in a study of the present size. If this is the case, identification of donor factors that influence graft function will remain difficult. A second possibility is that important donor factors are not described in routine medical records. Some factors, such as the severity and duration of hypotension and associated evidence of impaired tissue perfusion, may be noted but not described in adequate detail. Other factors, including the structure of the donor kidney and the adequacy of its perfusion during procurement surgery, are not routinely evaluated. More detailed studies will be required to assess the extent to which such factors influence graft function.

6 13 Journal of the American Society of Nephrology J Am Soc Nephrol 10: , 1999 Table 4. Relation of graft function to individual factors a Type of Variable Recorded Value Creatinine Clearance at 4 to 48 h P Value Nonparametric donor variables Yes No history of hypertension history of smoking death due to trauma dopamine used Parametric donor variables Lower Tertile Mid Tertile Upper Tertile age (yr) creatinine clearance (ml/min) minimum SBP (mmhg) cold ischemia time (h) a Creatinine clearance values are given for recipients whose donors were in the yes and no categories for the nonparametric variables and in the lower, mid, and upper tertiles for the parametric variables. The P values given were obtained using the unpaired t test for nonparametric variables and linear regression for parametric variables and were not corrected for analysis of multiple variables. The cause of death was not determined in one patient. Histories of hypertension, smoking, and dopamine use were not obtained in two patients each. Acknowledgments This work was supported by the Research Service of the Veterans Administration and the Baxter Extramural Grant Program. Dr. Suri was supported by a Dean s Fellowship from Stanford University. The authors are indebted to the California Transplant Donor Network and to the transplant programs of the California Pacific Medical Center, Stanford University Medical Center, and University of California San Francisco for making data available for this analysis. References 1. Shoskes DA, Halloran PF: Delayed graft function in renal transplantation: Etiology, management and long-term significance. J Urol 155: , Tilney NL, Guttmann RD: Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation 64: , Samaniego M, Baldwin WM, Sanfilippo F: Delayed graft function: Immediate and late impact. Curr Opin Nephrol Hypertens 6: , Alejandro V, Scandling JD Jr, Sibley RK, Dafoe D, Alfrey E, Deen W, Myers BD: Mechanisms of filtration failure during postischemic injury of the human kidney: A study of the reperfused renal allograft. J Clin Invest 95: , Terasaki PI, Cecka JM, Gjertson DW, Takemoto S, Cho YW, Yuge J: Risk rate and long-term kidney transplant survival. In: Clinical Transplants, edited by Cecka JM, Terasaki PI, Los Angeles, UCLA Tissue Typing Laboratory, 1996, pp Scornik JC, Cecka JM: Immune responsiveness and renal transplantation. In: Clinical Transplants, edited by Cecka JM, Terasaki PI, Los Angeles, UCLA Tissue Typing Laboratory, 1996, pp Halloran PF, Aprile MA, Farewell V, Ludwin D, Smith EK, Tsai SSY, Bear RA, Cole EH, Fenton SS, Cattran DC: Early function as the principal correlate of graft survival. Transplantation 46: 3 8, Troppmann C, Gillingham KJ, Gruessner RWG, Dunn DL, Payne WD, Najarian JS, Matas AJ: Delayed graft function in the absence of rejection has no long-term impact. Transplantation 61: , Lehtonen SR, Isoniemi HM, Salmela KT, Taskinen EI, von Willebrand EO, Ahonen JP: Long-term graft outcome is not necessarily affected by delayed onset of graft function and early acute rejection. Transplantation 64: , Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16: 31 41, Schwartz GJ, Brion LP, Spitzer A: The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 34: , Moran SM, Myers BD: Course of acute renal failure studied by a model of creatinine kinetics. Kidney Int 7: , Cosio FG, Qui W, Henry ML, Falkenhain ME, Elkhammas EA, Davies EA, Bumgardner GL, Ferguson RM: Factors related to the donor organ are major determinants of renal allograft function and survival. Transplantation 6: , Troppmann C, Gillingham KJ, Benedetti E, Almond PS, Gruessner RWG, Najarian JS, Matas A: Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. Transplantation 59: , Pfaff WW, Howard RJ, Patton PR, Adams VR, Rosen CB, Reed AI: Delayed graft function after renal transplantation. Transplantation 65: 19 3, Shemesh O, Golbetz H, Kriss JP, Myers BD: Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 8: , Levy AS, Perrone RD, Madias NE: Serum creatinine and renal funciton. Annu Rev Med 39: , Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL: Delayed graft function: Risk factors and implications for renal allograft survival. Transplantation 63: , Ploeg RJ, van Bockel JH, Langendjik PTH, Groenewegen M, van der Woude FJ, Persijn GG, Thorogood J, Hermans J: Effect

7 J Am Soc Nephrol 10: , 1999 Donor Effect on Early Graft Kidney Function 133 of preservation solution on results of cadaveric kidney transplantation. Lancet 340: , Koning OH, Ploeg RJ, van Bockel JH, Groenewegen M, van der Woude FJ, Persijn GG, Hermans J: Risk factors for delayed graft function in cadaveric kidney transplantation: A prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. Transplantation 63: , Meruisse M, Albert A, Defraigne JO, Bonnet P, Honore P, Pirenne J, Henrivaux P, Mahieu P, Beaujean MA, Limet R, Jacquet N: Multiple risk factor analysis of non-immunological delayed graft function after kidney transplantation. Clin Transplant : , Ashan N, Holman MJ, Yang HC: Kidneys transplanted from inotropic supported donors develop higher post-op ATN and poor allograft function [Abstract]. J Am Soc Nephrol 7: 1901, 1996 This article can be accessed in its entirety on the Internet at along with related UpToDate topics.