Factors influencing the glomerular filtration rate increase after cadaveric renal transplantation: a multivariate analysis

Factors Influencing the Glomerular Filtration Rate Increase After Cadaveric Renal Transplantation: A Multivariate Analysis E. Bertoni, A. Rosati, M. Zanazzi, L. Di Maria, R. Marcucci, M. Biagini, L. Moscarelli, R. Piperno, M. Gallo, and M. Salvadori

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N THIS article we describe 80 recipients of cadaveric renal transplants with an actual follow-up of at least 1 year. As observed by others,22 we could document an increase in GFR in almost all patients. The main question rising from the observation of an increase of GFR after kidney transplantation is whether this increase is beneficial or is a maladaptive sign. Many reports3– 6,11 observe, even over a long period after transplantation, a well-preserved GFR without loss of RFR. In these cases we have observed an increase in GFR, without glomerular hyperfiltration. Other authors10 found a reduction of RFR after renal transplantation. The lack of RFR in kidney transplant recipients, according to these authors, might indicate a hyperfiltration of the transplanted kidney and such condition could contribute to chronic graft loss. Even if over a short time period, we observed a relevant GFR increase with respect to the baseline values in almost all recipients, this condition was stable at 1 year and was found in both young and older donors. Delayed graft function as well as acute rejection were the main causes of a reduced GFR increase. The lack of pathological 24-hour proteinuria as well as the well-preserved GFR increase seem to indicate the absence of glomerular injury in these observations. Cadaveric kidneys as well as living donor kidneys display increased glomerular filtration rate (GFR) after kidney transplantation which accounts for an improvement both in the living donor remnant and in the transplanted kidney after living donor transplantation.1–3 The GFR increase after transplantation may be ascribed to the renal functional reserve (RFR), which is defined as the difference between the basal GFR and the maximum achievable GFR, for example, under stimulation by an amino acid infusion. RFR may be documented either in healthy subjects or in donor candidates before transplantation.4,5 It has been assumed that tests of the existence of renal functional reserve (change in GFR, change in effective renal plasma flow) can be used to demonstrate hyperfiltration.6 The understanding of whether cadaveric kidneys can increase the GFR after transplantation because of a RFR is of outstanding relevance because it has been stated that kidneys with impaired renal function display a decreased RFR when compared to kidneys with normal function. The

complete absence of RFR, therefore, implies that the remaining nephrons are working at the limit of their capacity. In other words, such kidneys used in transplantation would be unable to increase their GFR.4,7 Several articles document that after transplantation there is an increase in GFR, which may last a long time. In several cases the GFR increase does not imply a reduction in RFR, since this has been found to be unchanged even 20 years after transplantation.3 In such patients it is not clear whether the GFR increase should be ascribed to hyperfiltration; according to some authors, the long-lasting RFR has an unknown significance.5,8 On the other hand, in physiological conditions such as pregnancy, the GFR increase does not reduce the RFR.9 In other transplanted patients, a GFR increase is associated with a reduction in RFR. In these patients the transplanted kidney is maximally hyperfiltrating.10 Finally, according to some articles the capacity to increase the GFR or maintain a RFR is not affected by calcineurin inhibitors.11,12 This also correlates with the finding that patients on cyclosporine therapy maintain a high RFR when treated with calcium channel blockers.13 The GFR increase that is often realized after kidney transplantation is relevant because several authors suggest that hyperfiltration is a cause of chronic allograft nephropathy.14 According to these authors, all kidneys with an inadequate nephron mass with respect to the recipients (pediatric as well as kidneys from older adults, female donors, and size mismatch between donor and recipient) undergo glomerular hypertension and hyperfiltration, with development of focal glomerulosclerosis and consequent reduced graft survival.15 More recent reports, however, suggest a role of programmed senescence, accelerated by immune-mediated and nonimmune injuries leading to proFrom the Renal Unit and Thrombosis Center, Department of Renal Transplantation, Careggi University Hospital, Florence, Italy. Address reprint requests to Maurizio Salvadori, MD, Renal Unit, Department of Renal Transplantation, Careggi University Hospital, viale Pieraccini 18, 50139, Florence, Italy. E-mail: [email protected]

0041-1345/02/$–see front matter PII S0041-1345(02)03564-9

© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710

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gressive loss of energy generation and membrane damage.16,17 In the case of living donors current knowledge fails to support the notion that adaptive hyperfiltration of the remnant kidney after donor nephrectomy is deleterious. Rather than being maladaptive, hyperfiltration appropriately compensates for the loss of functional renal mass. Moreover, according to some authors,18 the hyperfiltration theory challenged the view that GFR is a fixed function insofar as there is a good correlation between GFR and renal parenchymal damage. According to these authors, GFR is a dynamic parameter that is diet-dependent and can be altered by hemodynamic maneuvers. Therefore, it is not a good indicator of renal lesion. In the case of the transplanted kidney, many authors disagree with the fact that hyperfiltration per se could play a relevant role in chronic allograft nephropathy. According to these authors, clinical and experimental data support the hypothesis that chronic allograft nephropathy is mainly sustained by immunological factors. The hyperfiltration condition has a weak effect, with respect to the latter, on the chronic allograft nephropathy.16,17 The purpose of the present study was to prospectively evaluate the degree of GFR increase in patients who received cadaveric renal transplants during the first year after transplantation in order to analyze relevant factors. PATIENTS AND METHODS The 80 renal transplants performed in our center in 1999 had an actual follow-up of at least 1 year. Demographic recipient data were: mean age 47.70 ⫾ 11.4 years; 56 men, 24 women; and mean body weight 72.31 ⫾ 10.95 kg. We observe a 45% incidence of delayed graft function, as defined by need for dialysis in the first week after transplantation among older donors and 17.5% among younger donors. Of the patients 28.9% had a biopsy proven acute rejection. All patients were on double or triple therapy with Neoral and steroids with or without mycophenolate mofetil. Twenty patients received angiotensin-converting enzyme (ACE) inhibitors as antihypertensive therapy. Demographic donor data were: mean age 49.87 ⫾ 14.12; 52 men and 28 women; 24 dead from trauma and 56 dead from cerebrovascular accident. Twenty-seven (33.7%) donors had a history of hypertension. Mean cold ischemia time was 20 ⫾ 4.5 hours and longer than 24 hours in 18 transplants. Mean donor GFR was 80.78 ⫾ 24.05 mL/min. Both donor and recipient GFR were evaluated by CockcroftGault equation using the ideal body weight. Cockcroft-Gault was the only practical way to determine the GFR in cadaveric donors.19 All pairs of kidneys retrieved in our regional transplant program have been included. All pairs of kidneys had a similar histological score not differing by more than 1 point according to Karpinski20 and similar macroscopic appearances. The length of the 2 kidneys, as determined by ultrasonography, did not differ by more than 10 mm. Both kidneys had similar ultrasonographic patterns. Under these conditions, we assumed each donor kidney GFR to be equal to half the donor Cockcroft-Gault value. Both the absolute GFR increase at 6 months, and the GFR increase at 6 months and at 1 year were calculated with respect to the donor GFR and compared according to different variables. Both recipient GFR and 24-hour proteinuria were evaluated at 6 and 12 months after transplantation.

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Statistical Analysis ⌬ GFR increase and absolute increase at 6 months were compared in univariate and multivariate fashion versus covariates of donor age, cause of death, donor hypertension history, donor GFR, cold ischemia time, rejection and/or delayed graft function, ACE inhibitor therapy, and recipient weight at 6 months after transplantation. Results were expressed as mean values ⫾ standard deviation. Differences between means were evaluated with Student t test. An analysis of variance (ANOVA) test for repeated measures was used when appropriate. Correlations between variables as basal GFR, recipient weight, and GFR increase were established using linear regression with calculated correlation coefficient, r. P values ⬍ .05 were considered to be statistically relevant. A multiple regression analysis was performed with the Stata 6.0 software for Windows (Stata Corporation, College Station, Tex). To identify the main determinants of the increase in GFR, we performed a multivariate regression analysis using the absolute 6-month increase in GFR as the dependent variable and graft rejection, donor GFR, donor age, donor cause of death, patient weight, donor history of hypertension, and use of ACE inhibitors as the independent variables. All probability values reported are two-tailed with values less than .05 considered statistically significant.

RESULTS

The GFR increase was evaluated both as the absolute value and the change with respect to the baseline values. Almost all patients (90%) had a GFR increase, either considering absolute values or percentages of increment. The overall GFR increase at 6 months was 56.83% with respect to the baseline values and remained stable at 1 year (58.9%) (P ⬍ .0001). No relationship was observed between basal and 6-month GFR values (r ⫽ .189; P ⫽ NS), which implies that several factors operating in different ways in each recipient, influence the increased GFR. The main donor-related factors correlating with a greater GFR increase after transplantation were younger donor age, no history of hypertension (Fig 1), and low donor GFR (Fig 2). In the case of older donors, the 6-month GFR increase was 14.6 ⫾ 11.4 mL/min versus 23.19 ⫾ 23.26 mL/min (P ⬍ .03) for younger donors. In the case of positive versus negative donor history of hypertension, the GFR increase was 7.6 ⫾ 15.09 mL/min versus 24.13 ⫾ 20.18 mL/min (P ⬍ .001). The overall GFR increase with respect to the baseline at 6 months was strictly and inversely related to the baseline GFR (r ⫽ ⫺.719, P ⬍ .001). In particular, patients with a basal GFR ⬍35 mL/min had a higher GFR increase than patients with a basal GFR ⬎35mL/min (26.89 ⫾ 19.42 vs 15.11 ⫾ 17.21 mL/min; P ⬍ .007). Main recipient-related factors that determine higher GFR increases after transplantation were recipient 6-month body weight, use of ACE inhibitors, and freedom from rejection and/or delayed graft function (DGF) (Fig 3). The overall GFR increase at 6 months with respect to the baseline was strictly related to the recipient weight (r ⫽ .484; P ⬍ .001). Patients free from either acute rejection and/or DGF had greater GFR increases; 27.56 ⫾ 20.35 mL/min with respect to patients experiencing such events; 13.79 ⫾ 15.12 mL/min (P ⬍ .001). Also recipients treated with ACE inhibitors showed higher GFR increases: 30.42 ⫾

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Fig 1.

Donor-related factors influencing GFR after transplantation.

19.46 vs 14.2 ⫾ 15.94 mL/min (P ⬍ .001). No statistically significant effect on GFR increase was less for cold ischemia time (CIT) longer or shorter than 24 hours or death from cerebrovascular accident (CVA) versus trauma (P ⫽ NS for both). Table 1 shows the multiple regression analysis of the significant independent variables to determine higher absolute GFR increments. Ranking the variables in order of significance influencing the GFR increase, we found: low

donor GFR, freedom of rejection/DGF, recipient weight, donor age younger than 55 years, use of ACE inhibitors in the recipient, and absence of hypertension history in the donor. Cause of death was without significance. Besides determining 1 year GFR, we calculated 24-hour protein excretion rate at 1 year as a possible sign of glomerular injury. We found that almost all patients had a 24-hour proteinuria within the normal range (mean value of 235 mg/24 hours).

Fig 2. Relationship between overall change in GFR increase at 6 months and basal GFR.

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Table 1. Multiple Regression Analysis of Donor/Recipient Factors Influencing GFR Increase Independent Variables

Donor GFR Rejection DGF Recipient body weight Donor age ACE inhibitors History of donor hypertension Cause of death

P ⬍.0001 P ⬍.0001 P ⬍.0001 P ⬍.001 P ⬍.001 P ⬍.003 P ⫽ NS

DISCUSSION

Several articles state that the GFR of the transplanted kidney increase after kidney transplantation, an observation that is better documented in the case of living donors, because in such a condition it is possible to determine both the GFR and the RFR before kidney transplantation. In the case of cadaveric donors, it is not easy to determine these parameters in the donor due to the clinical condition of the donor, the scarcity of time, and technical difficulties. Nevertheless, several articles on cadaveric kidney donation refer to the occurrence of an increased GFR after transplantation with long-term persistence of a renal functional reserve. Questions arise concerning the relationship between the posttransplantation GFR increase and pre-existent RFR. According to some authors, the GFR increase may be completely ascribed to the RFR, since they observed a relevant reduction in RFR after kidney transplantation; in such cases the transplanted kidneys are maximally hyperfiltrating. Some articles, on the contrary, document an in-

creased GFR with a preserved RFR just as in physiological conditions, such as pregnancy, the GFR increase does not attenuate the RFR.9 Even more important is the understanding of whether the posttransplantation GFR increase determines glomerular hyperfiltration and hypertension, because this condition, according to the hyperfiltration theory, may be associated with glomerular sclerosis, chronic allograft nephropathy, and graft damage. In this article we documented an increase in GFR rate among 80 cadaveric renal transplants. The donor GFR as well as the recipient GFR were evaluated according to the Cockcroft-Gault formula. The use of the Cockcroft-Gault equation as used clinically (the lower of ideal or total body weight and the higher of the actual serum creatinine or serum creatinine concentration corrected to 1 mg/dL in cachectic patients) results in more accurate predictions of GFR in critically ill patients than urine creatinine clearance measurements.19 Almost all recipients displayed a GFR increase, which we documented at 6 months after transplantation and remained stable at 1 year. Only 8 among 80 patients did not show a GFR increase. We verified the GFR increase early after transplantation (even 1 month).2 We did not have the opportunity to verify whether the GFR increase after transplantation was influenced by cyclosporine therapy as all our patients were on cyclosporine-based immunosuppression. According to our data, cyclosporine-based therapy does not seem to significantly reduce the capacity to increase GFR after transplantation. Our findings were in agreement with those of Ader et al11 who observed that, even when maintained on cyclosporine therapy, renal trans-

Fig 3. Recipient-related factors influencing GFR after transplantation.

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plant recipients may have GFR increase without glomerular hyperfiltration because they retain RFR both at 1 and 8 months posttransplantation. Moreover, Ader found that kidney transplant patients retain a higher RFR with respect to the native kidneys in heart transplant recipients probably because of higher cyclosporine dosage in the latter patients.12 Dividing our cohort into organs from donor older than and younger than 55 years, we found that younger kidneys showed a greater GFR increase than older kidneys. This fact is not surprising, as it has been stated that subjects with a reduced renal function, as older donors, would have decreased functional glomerular reserve, which could account for a lower GFR increase in the case of older donors. Surprisingly, the GFR increase with respect to the baseline values at 6 months was strictly and inversely related to the donor baseline GFR. This observation was similar in younger and older donors and implies that kidneys with a lower GFR, such as small-size donors and older donors, may have a high RFR that accounts for a higher GFR increase after transplantation. Donor history of hypertension had a negative effect on the GFR increase although independent of the cause of death. Changes from GFR baseline values were strictly related to the recipient weight. Indeed, recipient weights at 6 months after transplantation were well correlated with the GFR increase, probably due to the stimulus of a larger body mass, to produce a greater increase in GFR. In our allocation criteria we did not account for donor/recipient size matching. According to the hyperfiltration theory, the increase in GFR related to the recipient weight could lead, over the long term to glomerulosclerosis and reduced graft survival. According to several articles, the effects of recipient size are small compared with those of other factors. Gaston et al, 21 in a multivariate analysis of 17 variables, found that donor-recipient body surface area mismatch, independent of other risk factors, did not affect the risk of allograft loss. All these data suggest that immune factors are more important than non-immune factors in determining chronic allograft nephropathy. In conclusion, the GFR increase was linked to body weight exibited by our patients, rather than being maladaptive, might be an expression of physiological remodeling. Twenty recipients were treated for hypertension with ACE inhibitors. These patients displayed a significantly higher GFR increase, an observation that may link to the renoprotective effect ascribed to these drugs.

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In our patients DGF and acute rejection were the most important limiting factors on the GFR increase, even if these patients did have a GFR increase, although lower than that of patients not experiencing these conditions. This is not surprising because both are well, recognized factors that reduce kidney functional tissue and strongly correlate with reduced graft survival. We determined the GFR increase 6 months after transplantation, after the occurrence of the acute rejection episode, but we could not document whether the kidneys with acute rejection had a high GFR increase before the acute rejection occurrence. All these factors were confirmed by the multivariate analysis.

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