The Modification of Diet in Renal Disease (MDRD) and the Prediction of Kidney Outcomes After Lung Transplantation

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1 CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION The Modification of Diet in Renal Disease (MDRD) and the Prediction of Kidney Outcomes After Lung Transplantation Nadine Al-Naamani, MD, a Omar H. Maarouf, MD, a Jessie S. Wilt, MD, a Matthew Bacchetta, MD, b Frank D Ovidio, MD, PhD, b Joshua R. Sonett, MD, b Selim M. Arcasoy, MD, a David J. Lederer, MD, MS, a Thomas L. Nickolas, MD, MS, a and Steven M. Kawut, MD, MS a,c Background: Methods: Results: Conclusions: Chronic kidney disease (CKD) is prevalent after lung transplantation. This study evaluated the ability of the 24-hour urine creatinine clearance (CrCl) and the Modification of Diet in Renal Disease (MDRD) equation at the time of listing to predict CKD after lung transplantation and to determine risk factors for CKD. This was a retrospective cohort study of 122 patients who underwent lung transplantation at Columbia Presbyterian Medical Center between May 2002 and August The primary end point was CKD Stage 3 or higher, defined as glomerular filtration rate (GFR) 59 ml/min/1.73 m 2 or renal replacement therapy, for at least 3 months. Patients were a mean age of years, 55% women, and 83% non-hispanic white. CKD developed in 62% by 1 year after lung transplantation. Older age, female gender, a diagnosis of sarcoidosis, and diabetes mellitus independently increased the risk of CKD (all p 0.05). The MDRD equation was significantly better than CrCl at predicting CKD Stage 3 or higher at 1 year after transplantation, with an area under the receiver operating characteristic curve of 0.71 for MDRD (95% confidence interval [CI], ) and 0.51 for CrCl (95% CI, ) (P 0.001). Older age, female gender, and diabetes mellitus increased the risk of developing CKD after lung transplant. The MDRD estimate of GFR at listing was a better predictor of CKD than CrCl. MDRD estimates should be used during lung transplant evaluation for risk stratification for CKD. J Heart Lung Transplant 2008;27: Copyright 2008 by the International Society for Heart and Lung Transplantation. The survival of patients undergoing lung transplantation has improved in the past decade. Increased post-lung transplant survival has subsequently led to increases in the prevalence of chronic diseases in recipients, notably chronic kidney disease (CKD). Within 5 years of receiving a lung allograft, 38% of patients will present with abnormal serum creatinine, undergo chronic hemodialysis, or require kidney transplantation. 1 Although important postoperative risk factors include chronic calcineurin inhibitor use, 2 8 the pre-operative predictors of CKD are not well characterized. Because CKD leads to volume dysregulation, uremia, hypertension, increased risk of cardiovascu- From the Departments of a Medicine and b Surgery, College of Physicians and Surgeons, and the c Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. Submitted April 10, 2008; revised June 20, 2008; accepted July 29, Reprint requests: Steven M. Kawut, MD, MS, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, PH 8E, Room 101, 622 W 168th St, New York, NY Telephone: Fax: sk2097@columbia.edu Copyright 2008 by the International Society for Heart and Lung Transplantation /08/$ see front matter. doi: / j.healun lar complications, and in severe cases, necessitates renal replacement therapy (RRT), it is important to identify those lung transplant candidates who are potentially at increased risk of developing this complication. The glomerular filtration rate (GFR) is the best measure of kidney function. However, exact determination of GFR using radioactively labeled markers is expensive and impractical for routine clinical use. Most lung transplant centers use 24-hour urine collections for measurement of creatinine clearance (CrCl) in the evaluation for lung transplantation. However, the CrCl may be inaccurate due to difficulties in collection and has not been validated for the prediction of CKD after transplantation. On the other hand, the Modification of Diet in Renal Disease (MDRD) estimate of GFR (egfr) is easy to calculate, has been validated in patients with CKD against 24-hour urine iothalamate clearance, 9 11 is a more accurate measure of kidney function than 24-hour CrCl, 12 is used in most other populations where accurate determination of kidney function is required, and may have better validity for clinically important outcomes. 13 We have shown that egfr predicts CrCl before lung transplant, 14 but it is not known whether the egfr is clinically useful for predicting CKD after 1191

2 1192 Al-Naamani et al. The Journal of Heart and Lung Transplantation November 2008 lung transplantation. Such validation is imperative before recommending the egfr for clinical use in this population. 15 We aimed to identify pre-transplant risk factors for CKD after transplantation. We also aimed to compare the ability of the CrCl and egfr by MDRD at listing for lung transplantation to predict the development of CKD after transplantation. We hypothesized that egfr would better discriminate which patients would have CKD within 1 and 3 years after transplantation. METHODS AND MATERIALS Study Design This was a retrospective cohort study of consecutive lung transplant recipients at the Columbia Presbyterian Medical Center (CPMC) between May 2002 and August The study was approved by the CPMC Institutional Review Board. Study Subjects During the study period, 151 subjects underwent a first lung transplantation. Of these, 4 patients died in the first 3 months after transplantation and were excluded, as done in previous studies. 16 Pre-transplantation CrCl data were missing for 17 patients, and they were also excluded. Of the remaining 130 patients, 8 had an egfr 59 ml/min/1.73 m 2 before transplantation and were excluded. The remaining 122 patients constituted the study sample. Each patient was followed up until death or January 1, 2008, whichever occurred first. The routine post-transplant regimen included a calcineurin inhibitor, an anti-metabolite, and a corticosteroid. Tacrolimus was routinely initiated after transplantation, targeting a level of 12 to 15 ng/ml for the first year and a level of 6 to 8 ng/ml thereafter, as determined by microparticle enzyme immunoassay. Cyclosporine A emulsion was the alternative, targeting a level of 200 to 300 ng/ml for the first year and then 100 to 200 ng/ml thereafter, as determined by fluorescence polarization immunoassay. These targets were generally maintained unless there was evidence of significant and progressive CKD. Azathioprine was routinely used; however, patients may have switched to mycophenolate mofetil. Cytomegalovirus prophylaxis was instituted with either intravenous ganciclovir or valganciclovir based on risk of disease. Data Collection and Measurements Baseline demographic and clinical data were collected from medical records. Laboratory values were obtained for serum creatinine, blood urea nitrogen, and serum albumin for each of the patients in the cohort from the Data Warehouse of CPMC. Our data file was linked to the CPMC hemodialysis database to identify the patients who received RRT after lung transplantation. All lung transplant recipients at CPMC who need RRT are initiated at our center. We calculated CrCl from the 24-hour urine collection performed at evaluation for transplantation as the urine creatinine excretion divided by the serum creatinine. We used the MDRD equation 17 to estimate GFR at the time of evaluation and after transplantation from the available data: egfr 170 [serum creatinine] [age] [0.762 if patient was female] [1.180 if patient was black] [blood urea nitrogen] [serum albumin] CKD was defined as an egfr 59 ml/min/1.73 m 2 or RRT for 3 months. CKD was stratified into stages based upon the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines as CKD Stage 3 (egfr ml/min/1.73 m 2 ), Stage 4 (egfr ml/min/1.73 m 2 ), and Stage 5 (egfr 15 ml/ min/1.73 m 2 or RRT). The primary end point was CKD Stage 3 or higher or initiation of RRT after 30 days from transplant for 3 months. CKD Stage 4 or higher or initiation of RRT after 30 days from transplant for 3 months was considered as a secondary end point. Statistical Analysis Continuous variables are presented as mean standard deviation. Categoric variables are summarized using frequencies and percentages. Bivariate and multivariate Cox regression models were used to analyze predictors of the time from transplant to CKD Stage 3. We included those factors that were significantly associated with outcome in bivariate models (p 0.20) in the multivariate model and retained those which remained significant (p 0.05). Patients were censored at death in this analysis. To assess the ability of CrCl and the MDRD to discriminate between patients who developed CKD at 1 and 3 years after transplantation, we used receiver operating characteristic (ROC) curves. We compared the areas under the curves (AUCs) using chi-square tests. Patients whose follow-up ended or who died before 1 or 3 years were excluded from these respective analyses. We then assessed the sensitivity, specificity, and positive and negative predictive values for our egfr cut off (derived previously) 14 to predict CKD Stage 3 or greater at 1 year after transplantation. SPSS software (SPSS Inc, Chicago, IL) was used for all analyses.

3 The Journal of Heart and Lung Transplantation Al-Naamani et al Volume 27, Number 11 Table 1. Baseline Characteristics of Lung Transplant Recipients Characteristic Study sample (n 122) Excluded (n 29) Age, mean SD, year Female, No. (%) 67 (55) 15 (52) Race/ethnicity, No. (%) Non-Hispanic white 101 (83) 28 (97) Black 10 (8) 1 (3) Hispanic 8 (7)... Asian 3 (2)... Body mass index, mean SD, kg/m Diagnosis, No. (%) COPD 37 (30) 10 (34) Diffuse parenchymal lung disease 44 (36) 8 (28) Cystic fibrosis 21 (17) 9 (31) Sarcoidosis 5 (4)... Other 15 (13) 2 (7) Pre-transplantation variables Hypertension, No. (%) 22 (18) 8 (28) Diabetes mellitus, No. (%) 16 (13) 3 (10) Total cholesterol, mean SD, mg/dl egfr, mean SD, ml/min/1.73 m COPD, chronic obstructive pulmonary disease; egfr, estimated glomerular filtration rate; SD, standard deviation. Baseline characteristics of the study sample and excluded patients are shown in Table 1. The patients were a mean age of years at the time of transplantation, 55% were women, and 83% were non-hispanic white. Most had either chronic obstructive pulmonary disease or diffuse parenchymal lung disease. Hypertension was present in 18% of patients and diabetes mellitus in 13%. The mean GFR before transplantation was ml/min/1.73 m 2. Excluded patients were more likely to be non-hispanic white and to have cystic fibrosis and hypertension compared with the study sample. Pre-operative egfr was virtually identical between included and excluded patients. The median follow-up was 32 months. Twenty-four patients (20%) died during the study period. Survival was 94% (95% confidence interval [CI], 90% to 98%) at 1 year after lung transplantation and 69% (95% CI, 55% 83%) at 5 years. Double-lung transplantation was performed in 101 patients (83%) and single-lung transplantation in 21(17%). In the first year after transplantation, 62% (95% CI, 52% 71%) developed CKD Stage 3 or higher (n 72) or received RRT (n 3); at 3 years, 71% (95% CI 60% 82%) had CKD Stage 3 or higher (Figure 1A, Table 2). Within 1 year after transplantation, 30% of patients (95% CI, 22% 38%) developed CKD Stage 4 or higher (n 34) or received RRT (n 3), and by 3 years, 44% (95% CI, 32% 56%) reached this outcome (Figure 1B). No patient was considered a candidate for kidney transplantation. Table 3 summarizes the relationship of demographic and pre-transplant clinical variables with the risk of CKD Stage 3 or higher or RRT after lung transplantation. Bivariate analyses showed that older age and higher body mass index were associated with increased risk of CKD. Patients with diffuse parenchymal lung disease, cystic fibrosis, pulmonary arterial hypertension, and other diagnoses were less likely to have CKD than patients with chronic obstructive pulmonary disease. Lower egfr before transplantation was associated RESULTS Figure 1. Cumulative incidence of chronic kidney disease (A) Stage 3 or higher and (B) Stage 4 or higher after lung transplantation.

4 1194 Al-Naamani et al. The Journal of Heart and Lung Transplantation November 2008 Table 2. Comparison of Chronic Kidney Disease Stages Pretransplantation and at 1 Year Post-transplantation CKD Stage (ml/min/1.73 m 2 ) Pre-Tx, No. (%) 1-year post-tx, No. (%) 1( 90) 83 (68) 1 (1) 2 (60 89) 39 (32) 46 (38) 3 (30 59) 0 (0) 38 (31) 4 (15 29) 0 (0) 26 (21) 5( 15) 0 (0) 11 (9) CKD, chronic kidney disease; Tx, transplantation. with a higher risk of CKD after transplantation; a 10-ml/min/1.73 m 2 lower egfr conferred a 20% increase in the risk of CKD. Age, gender, diabetes mellitus, and sarcoidosis were independently associated with the risk of CKD after transplantation (Table 4). The addition of pre-transplantation egfr to the multivariate Cox regression model did not significantly change these results, although lower egfr also predicted an increased risk of posttransplant CKD (adjusted hazard ratio per 10 ml/min/ 1.73 m 2 decrease in egfr, 1.1; 95% CI, ; p 0.08). Pre-transplant egfr from the MDRD was significantly more discriminating than CrCl for the prediction of CKD Stage 3 (or higher) at 1 year after transplantation, with an AUC of 0.71 for egfr (95% CI, ) and 0.51 for CrCl (95% CI, ), (p 0.001; Figure 2A). The egfr was also more discriminating than CrCl for the prediction of CKD Stage 3 (or higher) at 3 years after transplantation and CKD Stage 4 (or higher) at 1 Table 4. Multivariate Model Predicting Risk Factors Associated With Chronic Kidney Disease in Lung Transplant Recipients Variable HR (95% CI) p-value Age, per 5-year 1.3 ( ) increase Female sex 1.6 ( ) 0.03 Diagnosis Other diagnoses 1 Sarcoidosis 3.2 ( ) 0.01 Diabetes mellitus pre-tx 2.5 ( ) CI, confidence interval; HR, hazard ratio; Tx, transplantation. and 3 years, but these differences were not statistically significant (Figures 2B, 3A, and 3B). In a previous study, we determined that an egfr cut off of 95 ml/min/1.73 m 2 was a sensitive predictor of CKD at the time of evaluation for lung transplantation. 14 We assessed the ability of this cut off to predict CKD Stage 3 or greater at 1 year after transplantation in the current cohort. The sensitivity of this cut off (egfr Table 3. Risk Factors Associated With Chronic Kidney Disease in Lung Transplant Recipients Variable HR (95% CI) p value Age per 5-year increase 1.2 ( ) Female sex 1.3 ( ) Race/ethnicity Other 1 Black 1.5 ( ) 0.29 Body mass index, per 5 kg/m 2 increase 1.4 ( ) Diagnosis COPD 1 Diffuse parenchymal lung disease 0.6 ( ) 0.02 Sarcoidosis 1.6 ( ) 0.32 Cystic fibrosis 0.3 ( ) Pulmonary arterial hypertension 0.2 ( ) 0.04 Other 0.3 ( ) 0.05 Pre-transplantation variables Hypertension 1.3 ( ) 0.29 Diabetes mellitus 1.6 ( ) 0.1 Total cholesterol 200 mg/dl 1.3 ( ) 0.21 egfr, per 10 ml/min/1.73 m 2 decrease 1.2 ( ) CI, confidence interval; COPD, chronic obstructive pulmonary disease; egfr, estimated glomerular filtration rate; HR, hazard ratio. Figure 2. Receiver operating characteristic curves for the ability of creatinine clearance (CrCl, gray line) and estimated glomerular filtration rate (egfr, black line) to predict chronic kidney disease (A) Stage 3 or higher and (B) Stage 4 or higher at 1 year after lung transplantation.

5 The Journal of Heart and Lung Transplantation Al-Naamani et al Volume 27, Number 11 Figure 3. Receiver operating characteristic curves for the ability of creatinine clearance (CrCl, gray line) and estimated glomerular filtration rate (egfr, black line) to predict chronic kidney disease (A) Stage 3 or higher and (B) Stage 4 or higher at 3 years after lung transplantation. 60 ml/min/1.73 m 2 and 95 ml/min/1.73 m 2 ) for predicting CKD Stage 3 (or higher) 1 year after transplantation in this cohort was 49% (95% CI, 38% 61%), the specificity was 74% (95% CI, 61% 87%), the negative-predictive value was 45% (95% CI, 33% 57%), and the positive-predictive value was 77% (95% CI, 65% 89%). DISCUSSION CKD is common after lung transplantation. We found that the cumulative incidence of CKD Stage 3 or higher at 1 and 3 years after lung transplantation was 62% and 71%, respectively. The cumulative incidence of CKD Stage 4 or higher was 30% at 1 year of follow-up and 44% at 3 years. We found the pre-transplantation risk factors associated with an increased risk that CKD would develop after transplantation included older age, female gender, sarcoidosis, diabetes mellitus, and lower egfr before transplantation. MDRD-derived estimates of GFR at listing were significantly better than CrCl at discriminating patients who presented with CKD Stage 3 within 1 year of transplantation and possibly Stage 4 at 1 and 3 years after transplantation from those who did not. At 1 year after transplantation, 62% of our lung transplant recipients had CKD Stage 3 or higher. Although less severe CKD than previously studied, 3,16,18 this level of kidney dysfunction may be associated with significant adverse systemic effects such as anemia, hypertension, and bone disease. 3,5,18 21 More severe Stage 4 CKD had developed in about one-third of our cohort by 1 year and in one-half by 3 years. Most CKD occurred in the first year after transplantation, and the incidence of new cases declined thereafter. Other authors have reported similar results. 18,22 The identification of pre-transplant risk factors for developing CKD may lead to preventative and therapeutic strategies. The most consistently identified associated risk factor, not surprisingly, is a low GFR before transplantation. 18,23 In our cohort, transplant candidates who had a 10 ml/min/1.73 m 2 lower GFR had a 20% increased risk that CKD would develop after lung transplantation. We also found that increasing age was associated with a higher risk that CKD would develop after transplantation, after adjustment for other factors (even pre-transplant kidney function). The increased burden of atherosclerotic vascular disease in older patients may account for this association. 2 Whether intensive treatment of cardiovascular risk factors is warranted before lung transplantation in older patients or those with lower pre-operative egfr should be studied. We also found that diabetes mellitus before transplant was associated with a higher risk for CKD independent of age and other factors. Diabetes mellitus is a well-established risk factor for the development of kidney dysfunction in the population at large, and diabetic nephropathy is more likely to occur in those with poor glycemic control, hypertension, glomerular hyperfiltration, or with a genetic predisposition. 24 Studies in other solid organ transplant populations have shown that pre-transplant diabetes mellitus increased the risk of requiring RRT after transplantation. 25 The addition of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker to achieve blood pressure goals, lower protein excretion, and delay the progression of albuminuria to overt proteinuria in patients with an established diagnosis of diabetes mellitus before transplantation may help prevent CKD after transplantation. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been established to be safe in both heart 26 and kidney 27 allograft recipients and may offer some protection against the long-term effects of calcineurin inhibitor

6 1196 Al-Naamani et al. The Journal of Heart and Lung Transplantation November 2008 therapy. 28 Clinical trials of these medications might be useful to answer these questions in lung transplantation. Finally, female gender was a risk factor for CKD even though typically male gender has been associated with CKD in the general population. 29 This finding could be due to differential effects of medications with renal toxicity. Gender-related differences in renal toxicity of immunosuppressive therapies should be investigated. Assessment of kidney function before transplant is necessary before deciding on suitability for lung transplant or the best immunosuppressive regimen. We have demonstrated that the egfr calculated from the MDRD equation at the lung transplant evaluation is as good as (or better than) the 24-hour CrCl, which is currently used in most lung transplant programs. Because patients actually undergoing lung transplant are a highly selected group (excluding candidates with significant CKD), our study sample of allograft recipients likely has a truncated distribution of the actual patient population of interest in terms of renal function, making it difficult to assess the true sensitivity and specificity of the MDRD. To perform the definitive study, the MDRD would be calculated and CrCl performed in all patients evaluated for a lung allograft; then, all eligible candidates (irrespective of the MDRD or CrCl results) would undergo transplantation, and the outcome of CKD would be monitored. Because such a design is not feasible, we must use those patients who actually received an allograft to assess the utility of the MDRD. The egfr cutoff 95 ml/min/1.73 m 2 before transplantation was relatively specific for CKD within 1 year after transplantation. This subgroup might be amenable to clinical trials of preventative strategies or transition to less nephrotoxic immunosuppressive medications. 30 Because egfr may be easily calculated from available laboratory results routinely obtained during the lung transplant evaluation, whereas CrCl costs $100 (at our center), there is a potential cost-savings with this approach as well. This study has some potential limitations. First, it was a retrospective, single-center study. Prospective, multicenter studies should be performed to confirm these findings. Second, data from I 125 -iothalamate clearance, which is the gold standard measure for GFR, were not available. However, our aim was to validate a clinically useful and easily performed prediction equation for CKD outcomes from variables available for all lung transplant candidates. Third, markers of CKD, such as albuminuria and proteinuria, were not readily available. Fourth, the severity and duration of medical comorbidities and other unmeasured variables that were potential confounders were not available for analysis. Fifth, our outcome measure was based on the egfr calculated from the MDRD, one of the equations under study, possibly leading to bias. In addition, there are other novel markers of kidney function, such as cystatin C, 15,31 or methods of immunosuppression level monitoring that may be useful but were not available in this study. Finally, the study population consisted of lung transplant recipients who were selected for this procedure based on CrCl, thus biasing toward a study sample with better kidney function than the actual population of lung transplant candidates evaluated for an allograft. That being said, we still detected better discrimination of outcomes by MDRD than by CrCl. In conclusion, we have demonstrated that the MDRD permits identification of lung transplant candidates at high risk for CKD after transplantation. The MDRD equation is a readily available, simple, and inexpensive method to stratify patients according to their risk. Particularly impressive was the large number of patients who developed CKD after transplantation. We have also shown that age, female gender, diabetes mellitus, and sarcoidosis independently predict the development of CKD. Preventative and therapeutic strategies should be implemented to retard the progression of CKD. Modifiable risk factors should be optimized before proceeding to lung transplant. Future research should focus on slowing the progression of CKD after lung transplant. REFERENCES 1. Trulock EP, Christie JD, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: twentyfourth official adult lung and heart-lung transplantation report J Heart Lung Transplant 2007;26: Barraclough K, Menahem SA, Bailey M, Thomson NM. Predictors of decline in renal function after lung transplantation. 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