Acute Renal Failure after Lung Transplantation


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Acute Renal Failure after Lung Transplantation

  1. 1. American Journal of Transplantation 2005; 5: 1469–1476 Copyright C Blackwell Munksgaard 2005 Blackwell Munksgaard doi: 10.1111/j.1600-6143.2005.00867.x Acute Renal Failure after Lung Transplantation: Incidence, Predictors and Impact on Perioperative Morbidity and Mortality Paulo N. Rochaa, ∗ , Ana T. Rochab , Scott M. Introduction Palmerb , R. Duane Davisc and Stephen R. Smitha In the 2 decades since the performance of the first suc- Duke University Medical Center, Departments of cessful lung transplant (LT) by the Toronto group (1), lung Medicine and Surgery, Divisions of a Nephrology, transplantation (LTx) has become the preferred treatment b Pulmonology and c Cardiothoracic Surgery, Durham, NC modality for patients with end-stage pulmonary disease 17710, USA (2,3). According to the 21st annual registry of the Inter- ∗ Corresponding author: Paulo N. Rocha, national Society for Heart and Lung Transplantation, 1655 LTs were performed worldwide in the year 2002 (4). A sig- nificant proportion of these patients develop chronic renal The incidence, predictors and clinical significance of dysfunction after LTx (5,6), a phenomenon frequently at- acute renal failure (ARF) after lung transplantation tributed to the toxicity of calcineurin inhibitors. However, are not well described. We retrospectively collected data on the incidence and clinical implications of acute renal data on 296 patients transplanted at our center be- failure (ARF) following LTx are scarce. tween April 1992 and December 2000; follow-up was extended until December 2002. Patients were initially divided into two groups: ARF (doubling of baseline cre- Several factors peculiar to LTx might act in synergism to atinine within 2 weeks after surgery) and NoARF. The place recipients at increased risk for ARF. First, it has been ARF group was subdivided into ARFD (dialyzed) and suggested that patients with respiratory failure may experi- ARFnD (not dialyzed). The incidence of ARF was 56% ence renal hypoperfusion (7,8), which could potentiate the (166/296), but most cases were ARFnD (n = 143). In- nephrotoxic effects of hemodynamic instabilities that may dependent predictors of ARFD (n = 23) were: baseline occur during thoracic surgery. Second, the calcineurin in- GFR (OR 0.98, CI 0.96–0.99, p = 0.012), pulmonary di- hibitors used in the immediate postoperative period cause agnosis other than COPD (OR 6.80, CI 1.5–30.89, p = renal vasoconstriction and reduce renal perfusion (9–11). 0.013), mechanical ventilation > 1 d (OR 6.16, CI 1.70– Third, the ‘leaky capillaries’ of freshly transplanted lungs 22.24, p = 0.006) and parenteral amphotericin B use lead to the use of diuretics to reduce pulmonary edema, (OR 3.04, CI 1.03–8.98, p = 0.045). Both ARFnD and ARFD were associated with longer duration of me- which may, in turn, decrease circulating blood volume and chanical ventilation, increased hospital stay and in- further aggravate renal hypoperfusion. The intense renal creased early mortality. One-year patient survival was vasoconstriction that ensues might then augment the risk 92.3%, 81.8% and 21.7% in the NoARF, ARFnD and of ARF caused by antibiotics, antifungals and antivirals that ARFD groups, respectively (p < 0.0001). After control- are frequently used in this setting. ling for important covariates, ARFD remained associ- ated with an increased hazard of dying (HR 6.77, CI Navis and coworkers studied the renal hemodynamics be- 4.00–11.44, p < 0.0001). In conclusion, ARF occurs com- fore and after LTx in 44 patients and showed that a reduc- monly after lung transplantation and affects important clinical outcomes, especially when dialysis is required. tion in glomerular filtration rate (GFR) could be detected as early as 1 month postoperatively (8). In a subsequent Key words: Acute renal failure, amphotericin B, dialy- report, the same group showed that the long-term renal sis, lung transplantation, mechanical ventilation, risk outcome following LTx could be predicted by the 1-month factors GFR (12). More recently, Ishani et al. documented a decline in renal function in 91.3% of lung or combined heart–lung Received 7 November 2004, revised 3 January 2005 and transplant recipients by 6 months (13). However, none of accepted for publication 19 January 2005 these studies examined ARF occurring immediately after surgery. Therefore, the incidence, predictors and impact of ARF on perioperative morbidity and mortality after LTx are presently unknown. To address these issues, we con- This work was presented as a mini oral session at the 2004 Amer- ducted a retrospective review of 296 consecutive patients ican Transplant Congress, Boston, MA. that underwent LTx at our center over an 8-year period. 1469
  2. 2. Rocha et al. Materials and Methods Retrospective review of all lung transplants performed at DUMC between 4/92 – 12/00 Study design, inclusion and exclusion criteria We performed a retrospective cohort study using a convenience sample. All N = 312 transplants Excluded: consecutive patients that underwent LTx at Duke University Medical Cen- Retransplants ter (DUMC) between April 1992 (first LT performed at DUMC) and Decem- Died within 24 hours ber 2000 (n = 312) were included. Combined heart–lung transplants were N = 296 patients Missing critical data not included. Retransplants (n = 10), recipients that died within the first 24 hours (n = 5) and those for whom critical data were missing (n = 1) were excluded. The remaining 296 patients comprised our study group. Follow-up extended until 12/02 Data acquisition was extended until December 2002 to allow for at least 2 years (maximum of 10 years) of follow-up. Mean follow-up = 3.3 ± 2.4 years Data acquisition ARFnD Information on patient demographics, predictor variables and outcomes of N = 143 interest were obtained from electronic medical records and clinic paper NoARF ARF charts. All cyclosporine A (CsA) levels obtained within the first week and N = 130 N = 166 ARFD all serum creatinine levels obtained within the first 2 weeks of LTx were N = 23 collected. We also collected follow-up data on serum creatinine and CsA levels for three clinic visits during the first year posttransplant (first visit postdischarge, then 3 and 12 months later) and yearly thereafter. Figure 1: Study flow chart. Retrospective review of all LTs per- formed at Duke University Medical Center between April 1992 and December 2000. Two hundred ninety-six patients were identified Definitions and mean follow-up for the entire group was 3.3 ± 2.4 years. Most ARF was defined according to the RIFLE criteria (acronym indicating Risk patients (n = 166) had ARF, but only a minority (n = 23) required of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of dialysis. kidney function and End-stage kidney disease) (14). We used the RIFLE-I criterion (injury) of doubling of the baseline serum creatinine within the first 2 weeks of LTx. Patients who did not meet this criterion comprised the NoARF group. The ARF group was further divided into ARFD (dialyzed) and (Figure 1). One hundred sixty-six patients (56%) experi- ARFnD (not dialyzed). GFR was estimated using the abbreviated Modifi- enced ARF approximately 1 week (7.3 ± 3.8 d) after LTx. cation of Diet in Renal Disease study equation (15). Estimated GFR was The majority of these cases, however, were not dialyzed defined as normal (≥ 90 mL/min/1.73 m2 ), decreased (60–89 mL/min/1.73 (ARFnD, n = 143). The incidence of ARF requiring dialysis m2 ), or consistent with chronic kidney disease (CKD, GFR < 60 mL/min/1.73 was 8% (ARFD, n = 23). m2 ) according to recently published guidelines (16). The mean age for the entire population was 47 ± 14 years. Statistical analysis Interestingly, mean age was significantly lower in the Data were summarized with mean ± standard deviation (SD) or median ARFnD than in the NoARF group (44 ± 15 vs. 51 ± 13, and interquartile range (IQR). Continuous variables were compared among p = 0.0007); ARFD patients were also younger than those groups using ANOVA or the Kruskal–Wallis test; post hoc multiple com- parisons were performed using Bonferroni or Dunnett’s T3 methods. Pro- without ARF, but this difference was not statistically sig- portions were compared using the chi-square or Fisher’s exact test. Logis- nificant (Table 1). The majority of patients studied were tic regression analyses were performed to identify covariates associated white (90%). However, 30% of those who required dialy- with ARFD. Covariates assessed on univariate analyses were: age, race, sis for ARF were non-white. The racial distribution of pa- underlying pulmonary diagnosis, type of LT, pre-LT diabetes mellitus, pre- tients in the three outcome groups was thus significantly LT hypertension, baseline GFR, duration of mechanical ventilation (MV), different at the p = 0.002 level. The most common pul- antimicrobials and diuretics used perioperatively. A multivariate analysis monary diagnoses leading to transplantation were chronic with backward selection was then performed to identify covariates inde- obstructive pulmonary disease (COPD, 45%), cystic fibro- pendently associated with ARFD. Patient mortality was analyzed using the sis (CF, 21%) and idiopathic pulmonary fibrosis (IPF, 10%). Kaplan–Meier method and survival curves were compared using the log- This order of frequency was maintained in the NoARF and rank test. The effect of different covariates on mortality was evaluated using Cox proportional-hazards models. Variables assessed on univariate ARFnD groups, but not in the ARFD group. In this latter analyses were: age, underlying pulmonary diagnosis, race, type of LT, gen- group, pulmonary hypertension and IPF were the predom- der and ARFD. Variables that achieved statistical significance on univariate inant diagnoses (22% each), followed by sarcoidosis, a1 analysis were included in a multivariate model to identify independent pre- antitrypsin and CF (13% each). In addition, COPD was a rel- dictors of mortality. Statistical analyses were performed using SAS (version atively uncommon diagnosis (9%) among ARFD patients. 8.2) and SPSS (version 13.0). p-values <0.05 were considered statistically Overall, bilateral LTx was the most common surgical proce- significant. dure (53%), but a disproportionately high frequency of bilat- eral LTx was performed in patients who developed ARFD Results (83%). Mean preoperative GFR was 103 ± 39 mL/min/1.73 m2 . Baseline GFR varied significantly with pulmonary di- The study group consisted of 296 patients transplanted agnosis, with the highest values encountered in CF and over an 8-year period and followed up for 3.3 ± 2.4 years the lowest in pulmonary hypertension (135 ± 51 vs. 1470 American Journal of Transplantation 2005; 5: 1469–1476
  3. 3. Acute Renal Failure after Lung Transplantation Table 1: Baseline characteristics ARF Baseline variables NoARF (n = 130) ARFnD (n = 143) ARFD (n = 23) p-value Age, years (mean ± SD) 51 ± 131,2 44 ± 153 45 ± 12 0.0009 Gender Male 57% (74) 48% (68) 48% (11) 0.28 Female 43% (56) 52% (75) 52% (12) Race White 94% (122) 90% (128) 70% (16) 0.002 Non-white 6% (8) 11% (15) 30% (7) Diagnosis COPD 59% (77) 38% (55) 9% (2) <0.0001 Cystic fibrosis 12% (15) 30% (43) 13% (3) Idiopathic pulmonary fibrosis 10% (13) 9% (13) 22% (5) a1-antitrypsin 6% (8) 5% (7) 13% (3) Pulmonary hypertension 5% (6) 4% (6) 22% (5) Sarcoidosis 2% (3) 5% (7) 13% (3) Bronchiectasis 3% (4) 2% (3) 4% (1) Others 3% (4) 6% (9) 4% (1) Type of lung transplant Right lung 25% (32) 12% (17) 4% (1) 0.0003 Left lung 35% (56) 29% (41) 13% (3) Bilateral 40% (42) 59% (85) 83% (19) Pretransplant medical conditions Diabetes mellitus 3% (4) 3% (5) 13% (3) 0.07 Systemic hypertension 25% (32) 28% (40) 35% (8) 0.56 Baseline creatinine, mg/dL 0.884,5 ± 0.22 0.776 ± 0.21 0.97 ± 0.23 <0.0001 Baseline GFR, mL/min/1.73 m2 95 ± 327,8 113 ± 429 87 ± 28 <0.0001 GFR categories (in mL/min/1.73 m2 ) Normal (≥90) 53% (69) 71% (102) 35% (8) 0.0002 Decreased (60–89) 41% (53) 28% (40) 52% (12) CKD (<60) 6% (8) 1% (1) 13% (3) Percentages may not add up to 100% due to rounding. COPD = chronic obstructive pulmonary disease; GFR = glomerular filtration rate; CKD = chronic kidney disease. 1 p = 0.0007 for NoARF vs. ARFnD; 2 p = 0.2491 for NoARF vs. ARFD; 3 p = 1.0 for ARFnD vs. ARFD; 4 p = 0.0002 for NoARF vs. ARFnD; 5 p = 0.1375 for NoARF vs. ARFD; 6 p = 0.0001 for ARFnD vs. ARFD; 7 p = 0.0002 for NoARF vs. ARFnD; 8 p = 1.0 for NoARF vs. ARFD; 9 p = 0.0067 for ARFnD vs. ARFD. 77 ± 15 mL/min/1.73 m2 , p < 0.0001). Interestingly, and ARFD (182 ± 53 ng/mL) groups, respectively. Antivi- patients who developed ARF had higher preoperative rals and diuretics were commonly used in the immedi- GFR than patients who did not (110 ± 42 vs. 95 ± 33 ate postoperative period; utilization of these drugs was mL/min/1.73 m2 , p = 0.001). This apparent contradiction similar among the groups. Aminoglycoside and parenteral was due to the high baseline GFR of ARFnD patients (113 ± amphotericin B, however, were more commonly used by 42 mL/min/1.73 m2 ); patients who developed ARFD ac- patients who developed ARF. Combined use of aminogly- tually had the lowest baseline GFR of all groups studied. coside and amphotericin B was not common; we only Other variables such as height, weight, body mass index had four patients that used both drugs concomitantly. and the presence of diabetes mellitus or systemic hyper- Interestingly, all developed ARF (two ARFnD and two tension were similar among groups. ARFD). CsA was the initial calcineurin inhibitor used by 95% of pa- Two hundred four patients had at least one episode of tients (n = 278) (Table 2). In the year 2000, we moved biopsy-proven acute lung rejection (ALR) during follow-up to tacrolimus as the primary agent based on accumu- (mean 1.6 ± 1.7 episodes/patient). The median time to the lated data for its improved efficacy in LTx; this change in first ALR episode was 29 (IQR 18–84) d. To investigate a protocol accounts for the remaining 5% of patients who possible relationship between ALR and ARF, we stratified were started on tacrolimus. During follow-up, 33% of pa- ALR episodes into those occurring within (≤14 d) or after tients (n = 92) were converted from CsA to tacrolimus. the first 2 weeks (>14 d). The incidence of ALR in the first Somewhat surprisingly, mean CsA levels during the first 2 weeks of LTx was similar among groups (11.5%, 11.9% week after LTx were highest in the NoARF group (244 and 13% in the NoARF, ARFnD and ARFD groups, respec- ± 57 ng/mL), followed by the ARFnD (222 ± 51 ng/mL) tively; p = NS). American Journal of Transplantation 2005; 5: 1469–1476 1471
  4. 4. Rocha et al. Table 2: Posttransplant characteristics ARF Postoperative variables NoARF (n = 130) ARFnD (n = 143) ARFD (n = 23) p-value Initial choice of calcineurin inhibitor Cyclosporine A (CsA) 89% (116) 85% (121) 91% (21) 0.43 Tacrolimus (FK506) 11% (14) 15% (22) 9% (2) CsA to FK506 conversion during follow-up 25% (29) 35% (38) 25% (2) 0.25 Average CsA level during 1st week 244 ± 571,2 222 ± 513 182 ± 53 <0.0001 Medication use Ganciclovir 87% (113) 87% (124) 96% (22) 0.47 Acyclovir 12% (15) 15% (21) 4% (1) 0.34 Tobramycin 6% (8) 25% (36) 13% (3) <0.0001 Amphotericin B 3% (4) 12% (17) 30% (7) <0.0001 Loop diuretics 87% (113) 90% (128) 83% (19) 0.59 Thiazide diuretics 36% (47) 47% (67) 43% (10) 0.20 1p = 0.0009 for NoARF vs. ARFnD; 2 p < 0.0001 for NoARF vs. ARFD; 3 p = 0.0370 for ARFnD vs. ARFD. a) b) 1000 1000 Mechanical Ventilation, days 100 Hospital Stay, days 100 10 10 1 1 2 13 11 17 35 (1 – 2) (1 – 9) (8 – 28) (8 – 17) (11 – 44) (19 – 95) 0,1 1 NoARF ARFnD ARFD NoARF ARFnD ARFD Figure 2: Duration of MV and hospital stay according to group distribution. (A) Development of ARF was associated with longer duration of mechanical ventilation (p < 0.0001 for the comparison among the three groups; p = 0.0263 for NoARF vs. ARFnD; p = 0.0022 for NoARF vs. ARFD; p = 0.124 for ARFnD vs. ARFD). (B) Development of ARF was associated with longer hospital stay (p < 0.0001 for the comparison among the three groups; p = 0.0148 for NoARF vs. ARFnD; p = 0.0099 for NoARF vs. ARFD; p = 0.0659 for ARFnD vs. ARFD). Numbers below boxes represent median (IQR). Typically, recipients were extubated on day 1 after LTx. As in one). Five patients initiated dialysis on CVVHD; in three shown in Figure 2A, the development of ARF was asso- of these, HD followed CVVHD. Only one patient initiated ciated with a significantly longer stay on MV (p = 0.0263 dialysis on HD. for ARFnD vs. NoARF; p = 0.0022 for ARFD vs. NoARF). Duration of hospital stay was similarly affected by the pres- To identify predictor variables associated with ARFD, we ence of ARF. Overall, the median hospital stay was 15 d. As performed univariate (Table 3, Panel A) and multivariate lo- shown in Figure 2B, the median hospital stay was 11 (IQR gistic regression analysis. As shown in Panel B of Table 3, 8–17) d for NoARF patients, 17 (IQR 11–44) for ARFnD and the independent predictors of ARFD (n = 23) were: base- 35 (IQR 19–95) d for ARFD patients (p = 0.0148 for ARFnD line GFR (OR 0.98, CI 0.96–0.99, p = 0.012), pulmonary vs. NoARF; p = 0.0099 for ARFD vs. NoARF). diagnosis other than COPD (OR 6.80, CI 1.5–30.89, p = 0.013), MV > 1 d (OR 6.16, CI 1.70–22.24, p = 0.006) and Peritoneal dialysis (PD) was the most commonly used parenteral amphotericin B use (OR 3.04, CI 1.03–8.98, p = dialysis modality, followed by continuous veno–venous 0.045). hemodialysis (CVVHD) and conventional hemodialysis (HD). PD was the initial modality used by 17 patients; in There were 55 deaths in the NoARF group (42%), 66 5 of these PD was followed by a second dialysis modality in the ARFnD (46%) and 20 deaths in the ARFD group (HD in two, CVVHD in one and CVVHD followed by HD (87%) (p = 0.0004). Median times to death were: 792 (IQR 1472 American Journal of Transplantation 2005; 5: 1469–1476
  5. 5. Acute Renal Failure after Lung Transplantation Table 3: Predictors of ARFD Discussion Variables OR CI p-value (A) Univariate logistic regression The main findings of our study were that ARF occurred Race (non-white vs. white) 4.76 1.78–12.74 0.002 commonly after LTx (56%), but the majority of episodes Diagnosis (other vs. COPD) 9.83 2.26–42.71 0.002 did not require dialysis and had a small influence on peri- Type of transplant (BL vs. SL) 4.72 1.56–14.22 0.006 operative morbidity and mortality. Conversely, ARFD was Pretransplant DM (yes vs. no) 4.40 1.10–17.55 0.036 much less common (8%) but greatly affected all clinical Baseline GFR 0.98 0.96–0.99 0.031 outcomes studied, including mortality. MV (> 1 vs. ≤ 1 d) 8.01 2.33–27.59 0.001 Amphotericin B (yes vs. no) 5.25 1.94–14.18 0.001 In a study of ARF, the criterion used to define ARF is directly related to the incidence encountered. Until recently, how- (B) Multivariate Logistic Regression Baseline GFR 0.98 0.96–0.99 0.012 ever, there was no consensus definition of ARF (17). Given Diagnosis (other vs. COPD) 6.80 1.50–30.89 0.013 this lack of standardization, it is difficult to compare the inci- Mechanical ventilation 6.16 1.70–22.24 0.006 dence of ARF encountered herein to that of other studies. (> 1 vs. ≤ 1 d) The efforts of the Acute Dialysis Quality Initiative Group Amphotericin B (yes vs. no) 3.04 1.03–8.98 0.045 culminated in the publication of a consensus definition of BL = bilateral; SL = single lung; DM = diabetes mellitus; COPD ARF based on the RIFLE criteria (14,18–20). We used the = chronic obstructive pulmonary disease; GFR = glomerular RIFLE-I criterion of doubling of the baseline serum creati- filtration rate; MV = mechanical ventilation. nine because it offers a good combination of sensitivity and specificity. With this definition, we found that more than half (56%) of our patients met criteria for ARF. This is likely the result of a combination of factors peculiar to LTx: pre- operative hypoxic respiratory failure, episodes of renal hy- poperfusion during thoracic surgery, and postoperative use of calcineurin inhibitors, diuretics and (sometimes) nephro- toxic antimicrobials. Despite the high incidence of ARF, only a minority of patients required acute dialysis. This suggests that most renal insults in this setting are mild and perhaps caused by reversible hemodynamic-mediated reductions in GFR. However, we identified four variables that were in- dependently associated with ARFD: pulmonary diagnoses other than COPD, lower baseline GFR, postoperative use of parenteral amphotericin B and duration of MV greater than 1 d. Patients with ‘other’ pulmonary diagnoses had 6.8 greater Figure 3: Impact of ARF on patient survival. The Kaplan–Meier odds of developing ARFD than patients with COPD. Al- curves show patient survival over time according to group distribu- though we cannot rule out that unmeasured variables pe- tion: NoARF (solid line), ARFnD (dashed line), ARFD (dotted line). culiar to certain diagnoses might underlie this observation, Patient survival in the ARFD group was significantly worse than we believe that the association between pulmonary diag- in the ARFnD and NoARF groups (p < 0.0001 for the comparison nosis and ARFD was related, at least in part, to the type of among the three curves). surgery performed. In the ARFD group, patients with other pulmonary diagnoses were much more likely to have re- ceived bilateral LTx (19/21) than were patients with COPD 595–1192), 531 (IQR 152–1336), 33 (IQR 19–82) in the (0/2). On univariate analysis, bilateral LTx was a strong pre- NoARF, ARFnD and ARFD, respectively (p < 0.0001). Of dictor of ARFD, but it did not remain in the final multivariate note, 16/20 deaths in the ARFD group occurred during the model likely due to redundancy with underlying diagnosis. initial hospitalization. A survival analysis is shown in Fig- ure 3. One-year patient survival was 92%, 82% and 22% A lower baseline GFR was also independently associated in the NoARF, ARFnD and ARFD groups, respectively (p < with ARFD. This finding appears to contradict those of 0.0001). At 5 years, patient survival was 61%, 58% and Navis and coworkers who showed pronounced reductions 13%, and at 10 years, 59%, 55% and 13% in the NoARF, in renal function 1 month after LTx in patients with normal ARFnD and ARFD groups, respectively. In a multivariate or elevated baseline GFR and only modest decreases in Cox proportional-hazards regression, ARFD (HR 6.77, CI GFR in those with renal impairment prior to surgery (8). 4.00–11.44, p < 0.0001) and single LTx (HR 1.78, CI 1.24– The renal impairment in the latter group was character- 2.55, p = 0.0018) were the only variables independently ized by a marked reduction in renal perfusion, as indicated associated with an increased hazard of dying. by a low effective renal plasma flow, an elevated filtration American Journal of Transplantation 2005; 5: 1469–1476 1473
  6. 6. Rocha et al. fraction and an elevated renal vascular resistance. The au- and lowest in the ARFD group. This likely represents the thors concluded that renal function impairment character- reaction of physicians to reduce the CsA dose in light of ized by intense renal vasoconstriction should not be con- worsening renal function rather than a renoprotective ef- sidered a contraindication for transplantation (8). However, fect of higher CsA levels. Since we did not have data on the above-mentioned study by Navis et al. does not ad- CsA dose, this hypothesis could not be confirmed. It should dress perioperative ARF or need for acute dialysis. In our be noted that CsA levels were relatively high in all groups. study, baseline GFR was also higher in recipients who de- Moreover, trough CsA levels correlate poorly with drug veloped ARF than in those who did not, but this was due exposure as measured by the area under the curve (25). to the higher GFR encountered in the ARFnD group, which Therefore, given all the accumulated data on the nephro- had the highest proportion of CF patients. In contrast, 65% toxicity of CsA, our results should be interpreted with cau- of patients who developed ARFD had a baseline GFR that tion and do not suggest that CsA is free of renal toxicitiy was either decreased or consistent with CKD. For each after LTx. 1 mL/min/1.73 m2 increase in baseline GFR, we observed a 2% reduction in the odds of developing ARFD. Therefore, PD was used by 74% (17/23) of the patients that were dia- transplant physicians do need to be wary of a low baseline lyzed. PD was used as the sole modality in 13 patients and GFR when selecting patients for LTx. This is a complex is- as the initial modality in four. In this retrospective analysis, sue because some patients have hemodynamic-mediated we could not ascertain the factors influencing the choice of reductions in GFR that might actually improve after LTx, as dialysis modality but we hypothesize that PD was favored shown by Navis et al. (8). Therefore, a thorough nephro- due to the following factors. PD is a slow, continuous pro- logic evaluation should be performed in all candidates that cedure well suited for unstable ICU patients. In addition, exhibit a decreased baseline GFR to define the nature of it does not require anticoagulation, a clear advantage for renal impairment and help judge the potential risk for renal recipients that may still have productive thoracic drains. complications after LTx. Lastly, this study was performed before CVVHD became the preferred continuous modality at our institution. Given Treatment with parenteral amphotericin B increased the that most patients used PD, we could not determine if the odds of developing ARFD (OR 3.04, CI 1.03–8.98). Ampho- choice of dialysis modality influenced outcome. Some sug- tericin B is known to be nephrotoxic, especially when com- gest that PD may provide insufficient solute clearance for bined with CsA (21). We also observed a potential syner- hypercatabolic patients in the ICU (26). In an open, ran- gism between amphotericin B and aminoglycoside but the domized comparison of CVVHD and PD in patients with low number of patients using this combination precluded infection-associated ARF in Vietnam, Phu and coworkers us from formally addressing this interaction. Transplant found that assignment to PD was associated with a 5.1 physicians must be cautious when using amphotericin B in times higher odds of death and a 4.7 times higher odds of LT recipients; when acceptable, agents such as voricona- need for future dialysis (27). However, small, uncontrolled zole (22) and caspofungin (23) should be preferred. studies have shown that PD adequately controls fluid and metabolic derangements in hypercatabolic patients with Compared to patients who stayed on MV for ≤1 d, those ARF (28–33). More recently, a prospective, randomized who remained on MV for >1 d were 6.16 times more likely crossover study of 87 patients with hypercatabolic ARF to have ARFD. The direction of causality in the association showed that tidal PD achieved the standards of adequacy between length of MV and ARFD, however, is not com- as per National Kidney Foundation guidelines (34). Over pletely clear. Although, chronologically, MV precedes renal the last 5 years, our institution as well as many others has failure by a week this does not imply that it causes ARFD. It shifted to CVVHD as the preferred dialysis modality for is certainly possible that evolving ARF might impair wean- unstable ICU patients (35). This decision was more likely ing from MV due to difficulties in maintaining adequate influenced by commodity and ease of use CVVHD than by fluid balance. Furthermore, in patients undergoing PD, the objective data that CVVHD is superior to PD (36). We be- presence of large volumes of dialysis fluid in the peritoneal lieve the poor outcome of our ARFD patients resulted from cavity might compromise respiratory mechanics, or even factors unrelated to the type of dialysis used. This assertion interfere with proper patient positioning for weaning. An is supported by a recent meta-analysis (37). alternative possibility is that the association between MV and ARFD is indirect: for example, critically ill patients are Survival analysis showed a marked increase in early mortal- at risk for both prolonged MV and ARFD. In this light, pro- ity in the ARFD group. Sixteen of these patients died during longed MV remains a good predictor of ARFD because the initial hospitalization for LTx, for an in-hospital mortal- it represents several variables associated with disease ity of 70%. This falls within the reported range of 50–80% severity. mortality for patients with dialysis requiring ARF in the ICU (38–41), post-CT surgery (42–45) and after heart transplan- Since CsA can cause ARF in other settings (9), we hypoth- tation (46,47). In a Cox proportional-hazards model, ARFD esized that higher CsA trough levels would be associated was strongly associated (HR 6.71) with mortality. However, with ARF after LTx (24). However, mean CsA levels within we could not ascertain whether ARFD had a direct effect the first week after LTx were highest in the NoARF group on mortality or simply represented a marker for severity 1474 American Journal of Transplantation 2005; 5: 1469–1476
  7. 7. Acute Renal Failure after Lung Transplantation of disease. Theoretically, adequate dialysis should be able tality is direct or related to disease severity. Finally, the to control volume status, electrolyte and acid–base dis- influence of dialysis modality on the outcome of patients turbances and avoid mortality directly attributable to ARF. who develop ARFD after LTx warrants further investigation. Nonetheless, it has been shown that dialysis-requiring ARF In the mean time, efforts should be concentrated on reno- greatly increases mortality in the ICU (48) and following car- protective strategies to avoid ARFD in high-risk patients. diac surgery (42), even when adjusted for comorbidity and postoperative complications. It should be noted that cri- teria for dialysis adequacy in the ARF setting are lacking References (49,50). Moreover, it might be presumptuous to assume that current renal replacement modalities are able to com- 1. Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314: 1140–1145. pletely reverse the abnormalities caused by the uremic mi- 2. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; lieu. For example, it is possible that immune alterations per- 155: 789–818. sist even after what we consider adequate dialysis (51,52). 3. Lau C, Palmer S, D’amico T, Tapson V, Davis R. Lung transplanta- There could also be morbidity related to dialysis access and tion at Duke University Medical Center. In: JM Cecka, PI Terasaki, the dialytic procedure (53–57). Still, these data should not eds. Clinical transplants. Los Angeles, California: UCLA Tissue be interpreted to mean that dialysis ought to be withheld Typing Laboratory, 1998: 327–340. patients with severe ARF after LTx; rather, standard indica- 4. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, tions for the initiation of renal replacement therapy should Hertz MI. The Registry of the International Society for Heart and continue to be used in this population. Lung Transplantation: twenty-first official adult lung and heart- lung transplant report—2004. J Heart Lung Transplant 2004; 23: 804–815. We have shown that single LTx is associated with lower 5. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after trans- early mortality, yet worse overall survival than bilateral LTx plantation of a nonrenal organ. N Engl J Med 2003; 349: 931–940. (3,58). In concert with these findings, we now show that 6. Rocha AT, Rocha PN, Smith SR, Palmer SM. Chronic kidney dis- single LTx is associated with lower odds of ARFD, but ease after lung transplantation. Am J Transplant 2004; 4(Suppl 8): higher hazard of dying than bilateral LTx. Theoretically, bilat- 226. eral LTx provides greater functional reserve than single LTx 7. Kilburn KH, Dowell AR. Renal function in respiratory failure. Ef- while avoiding complications associated with the native fects of hypoxia, hyperoxia, and hypercapnia. Arch Intern Med lung, such as hyperinflation or infection. However, bilateral 1971; 127: 754–762. and single LT recipients differ in several ways, including 8. Navis G, Broekroelofs J, Mannes GP et al. Renal hemodynamics underlying pulmonary diagnosis; therefore, the difference after lung transplantation. A prospective study. Transplantation 1996; 61: 1600–1605. in survival cannot be attributed to the type of procedure 9. Greenberg A, Egel JW, Thompson ME et al. Early and late forms alone. of cyclosporine nephrotoxicity: studies in cardiac transplant recip- ients. Am J Kidney Dis 1987; 9: 12–22. Our work has limitations. First, this single-center, retro- 10. Puschett JB, Greenberg A, Holley J, McCauley J. The spectrum spective cohort does not reflect changes in practice that oc- of ciclosporin nephrotoxicity. Am J Nephrol 1990; 10: 296–309. curred in the last 5 years, such as the switch to tacrolimus- 11. Zaltzman JS, Pei Y, Maurer J, Patterson A, Cattran DC. Cy- based immunosuppression and use of CVVHD for acute closporine nephrotoxicity in lung transplant recipients. Transplan- dialysis. Second, we did not have information on variables tation 1992; 54: 875–878. that are important to an analysis of risk factors for ARF: 12. Broekroelofs J, Navis GJ, Stegeman CA et al. Long-term renal intraoperative hypotension, use of and time on cardiopul- outcome after lung transplantation is predicted by the 1-month postoperative renal function loss. Transplantation 2000; 69: 1624– monary bypass and disease severity scores in the imme- 1628. diate postoperative period. Therefore, the results of our 13. Ishani A, Erturk S, Hertz MI, Matas AJ, Savik K, Rosenberg ME. predictive model should be interpreted with caution. How- Predictors of renal function following lung or heart-lung transplan- ever, we propose that one of the variables included in our tation. Kidney Int 2002; 61: 2228–2234. model, MV > 1 d, could be seen as a marker for over- 14. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute all disease severity. Finally, we did not have invasive data renal failure: definition, outcome measures, animal models, fluid on volume status to assess if the practice of ‘keeping pa- therapy and information technology needs: the Second Interna- tients dry’ postoperatively has a detrimental effect on kid- tional Consensus Conference of the Acute Dialysis Quality Initia- ney function. Nevertheless, we tested for but did not find tive (ADQI) Group. Crit Care 2004; 8: R204–R212. an association between diuretic use and ARF. 15. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet In summary, this is the first study to describe the inci- in Renal Disease Study Group. Ann Intern Med 1999; 130: 461– dence, predictors and impact of ARF on perioperative mor- 470. bidity and mortality after LTx. We found that ARF occurred 16. National Kidney Foundation. K/DOQI clinical practice guidelines commonly in this setting but only those episodes that re- for chronic kidney disease: evaluation, classification, and stratifi- quired acute dialysis greatly influenced all outcomes stud- cation. Am J Kidney Dis 2002; 39(2 Suppl 1): S1–266. ied. Prospective studies are needed to confirm our findings 17. Bellomo R, Kellum J, Ronco C. Acute renal failure: time for con- and determine if the relationship between ARFD and mor- sensus. Intensive Care Med 2001; 27: 1685–1688. American Journal of Transplantation 2005; 5: 1469–1476 1475
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