Perioperative Normal Saline Administration and Delayed Graft Function in Patients Undergoing Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: Perioperative normal saline administration remains common practice during kidney transplantation. The authors hypothesized that the proportion of balanced crystalloids versus normal saline administered during the perioperative period would be associated with the likelihood of delayed graft function. METHODS: The authors linked outcome data from a national transplant registry with institutional anesthesia records from 2005 to 2015. The cohort included adult living and deceased donor transplants, and recipients with or without need for dialysis before transplant. The primary exposure was the percent normal saline of the total amount of crystalloids administered perioperatively, categorized into a low (less than or equal to 30%), intermediate (greater than 30% but less than 80%), and high normal saline group (greater than or equal to 80%). The primary outcome was the incidence of delayed graft function, defined as the need for dialysis within 1 week of transplant. The authors adjusted for the following potential confounders and covariates: transplant year, total crystalloid volume, surgical duration, vasopressor infusions, and erythrocyte transfusions; recipient sex, age, body mass index, race, number of human leukocyte antigen mismatches, and dialysis vintage; and donor type, age, and sex. RESULTS: The authors analyzed 2,515 records. The incidence of delayed graft function in the low, intermediate, and high normal saline group was 15.8% (61/385), 17.5% (113/646), and 21% (311/1,484), respectively. The adjusted odds ratio (95% CI) for delayed graft function was 1.24 (0.85 to 1.81) for the intermediate and 1.55 (1.09 to 2.19) for the high normal saline group compared with the low normal saline group. For deceased donor transplants, delayed graft function in the low, intermediate, and high normal saline group was 24% (54/225 [reference]), 28.6% (99/346; adjusted odds ratio, 1.28 [0.85 to 1.93]), and 30.8% (277/901; adjusted odds ratio, 1.52 [1.05 to 2.21]); and for living donor transplants, 4.4% (7/160 [reference]), 4.7% (14/300; adjusted odds ratio, 1.15 [0.42 to 3.10]), and 5.8% (34/583; adjusted odds ratio, 1.66 [0.65 to 4.25]), respectively. CONCLUSIONS: High percent normal saline administration is associated with delayed graft function in kidney transplant recipients.

Contrast Administration to the Deceased Kidney Donor Has No Impact on Post-Transplant Outcomes.

BACKGROUND: Contrast-induced acute kidney injury may occur in patients undergoing imaging studies. This study reviews all deceased kidney donors at a single center during a 15-y period to determine if donor contrast exposure results in contrast-induced acute kidney injury in the donor or is associated with worse outcomes in the transplant recipient. METHODS: Donor and recipient renal functions were recorded, including donor serum creatinine and recipient delayed graft function, creatinine clearance at 1 y, and early and late graft survival. Donor contrast exposure was recorded as the number of preprocurement contrasted studies. RESULTS: Donor and recipient records were available for 1394 transplants (88%). There were 51% of donors who received any contrasted study (38%, one study; 12%, two studies, and 1%, three studies). Donor contrast exposure was not associated with significant differences in preprocurement serum creatinine levels. Post-transplant, donor contrast exposure was associated with risk of neither delayed graft function (4% for all) nor early kidney graft loss. Creatinine clearance at 1 y was equivalent. Five-year Cox regression demonstrated higher graft survival for contrast-exposed grafts (P = 0.03). CONCLUSIONS: There is no negative effect of donor contrast administration on early and late kidney graft function. These findings included donor kidneys exposed to as many as three contrasted studies.

Early Postoperative Use of Diuretics After Kidney Transplantation Showed Increase in Delayed Graft Function.

PURPOSE: In acute renal injury, diuretics are widely considered to be harmful. Nevertheless, they are used frequently after kidney transplantation. We hypothesized that diuretics administered in the early postoperative treatment after kidney transplantation increase the incidence of delayed graft function (DGF). METHODS: In this monocentric, retrospective cohort analysis, we screened the closed files of all consecutive patients who underwent kidney transplantation from 2011 to 2017. The outcome variable was DGF, defined as at least 1 hemodialysis within 7 days postoperatively. To stratify for baseline characteristics such as waiting time or cold ischemic period, we employed a propensity score-matched analysis. Further statistical processing included basic descriptive statistics, Mann-Whitney U test, and binary logistic regression analysis. RESULTS: The unmatched cohort included 445 patients and showed a significantly increased rate of DGF for patients who received either furosemide or mannitol or a combination of both (5% vs 25%; P < .001). Mannitol (odds ratio [OR]: 4.094) and furosemide (OR: 2.915) showed a significant correlation with DGF in the multivariate regression analysis. Propensity score-based matching resulted in a matched cohort of 214 patients with balanced baseline risk variables. In this matched cohort, the rate of DGF was significantly increased in patients who received diuretics in the early postoperative treatment (7% vs 16%; P = .031). CONCLUSION: Our results show that postoperatively administered diuretics are associated with an increased rate of DGF even in a cohort with balanced preoperative risk variables. This study supports recently published reviews, which call diuretics in the transplantation process into question.

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients.

AIMS: Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype-guided tacrolimus doses. METHODS: This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype-guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. RESULTS: The genotype-guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over-therapeutic concentration patients was noted in the genotype-guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype-guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37-month follow-up period. CONCLUSIONS: Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.

The organ preservation and enhancement of donation success ratio effect of extracorporeal membrane oxygenation in circulatory unstable brain death donor.

Between 2010 and 2013, we recorded 66 cases of failed organ donation after brain death (DBD) due to the excessive use of the vasoactive drugs resulting in impaired hepatic and/or renal function. To investigate the effect of extracorporeal membrane oxygenation (ECMO) in donor management, ECMO was used to provide support for DBD donors with circulatory and/or respiratory failure from 2013 to 2015. A retrospective cohort study between circulatory non-stable DBD with vasoactive drugs (DBD-drug) and circulatory non-stable DBD with ECMO (DBD-ECMO) was designed to compare the transplant outcomes. A total of 19 brain death donors were supported by ECMO. The incidence rate of post-transplant liver primary non-function (PNF) was 10% (two of 20) in DBD-drug group and zero in DBD-ECMO group. Kidney function indicators, including creatinine clearance and urine production, were significantly better in DBD-ECMO group, as well as the kidney delayed graft function (DGF) rate was found to be decreased by the use of ECMO in our study. Donation success rate increased steadily from 47.8% in 2011 to 84.6% in 2014 after the ECMO intervention. The use of ECMO in assisting circulatory and respiratory function of DBD can reduce liver and kidney injury from vasoactive drugs, thereby improving organ quality and reducing the organ discard rates.

Tako-tsubo cardiomyopathy on the first day after renal transplantation - case report and literature review.

BACKGROUND: The etiology of tako-tsubo cardiomyopathy, defined as a transient left ventricular dysfunction in the absence of significant coronary artery stenosis, still remains unclear. This syndrome mainly occurs in postmenopausal women and is often associated with emotional stress or miscellaneous diagnostic and therapeutic procedures. Estimated prevalence of tako-tsubo cardiomyopathy is found in 1% to 2% of patients presenting with suspected acute coronary syndrome. So far there has been only one case report of tako-tsubo cardiomyopathy in a renal transplant recipient. CASE REPORT: We describe the case of a 68-year-old woman with a history of coronary artery disease and coronary artery bypass grafting in whom unspecific transient chest pain and hypotension were observed on the first day after renal transplantation. After transplantation, the patient was anuric with pulmonary congestion and toxic tacrolimus concentrations were observed. Electrocardiogram showed sinus rhythm with left bundle branch block (LBBB) that has not been described before. Plasma cardiac necrosis markers troponin I and creatine kinase MB were mildly elevated. Echocardiography showed severe left ventricular function impairment with characteristic shape of left ventricle. Subsequent cardiac catheterization revealed the absence of angiographic evidence of acute plaque rupture within both coronary arteries and bypass grafts. During the next few days there was marked clinical improvement with resolution of LBBB and full recovery of all biochemical parameters. On discharge, full functional recovery of the left ventricle in echocardiography was observed. Postulated mechanisms of tako-tsubo cardiomyopathy include catecholamine excess, coronary artery spasm, and microvascular dysfunction. On the other hand calcineurin inhibitors are known factors causing coronary epicardial endothelial dysfunction and negatively affecting vasomotor function. CONCLUSIONS: Tako-tsubo cardiomyopathy in patients after renal transplantation may be at least in part a manifestation of calcineurin inhibitor cardiotoxicity.

mTOR inhibitors and renal allograft: Yin and Yang.

Mammalian target of rapamycin inhibitors (mTOR-I), everolimus and sirolimus, are immunosuppressive drugs extensively used in renal transplantation. Their main mechanism of action is the inhibition of cell signaling through the PI3 K/Akt/mTOR pathway. This interesting mechanism of action confers to these medications both great immunosuppressive potential and important anti-neoplastic properties. Although the clinical utility of this drug category, as with other antineoplastic/immunosuppressants, is clear, the use of mTOR-I commonly results in the development of several complications. In particular, these agents may determine severe renal toxicity that, as recent studies report, seems clearly correlated to dose and duration of drug use. The mTOR-I-induced renal allograft spectrum of toxicity includes the enhanced incidence of delayed graft function, nephrotoxicity in particular when co-administered with calcineurin inhibitors (CNI) and onset of proteinuria. The latter effect appears highly frequent in patients undergoing mTOR-I treatment and significantly associated with a rapid graft lost. The damage leading to this complication interests both the glomerular and tubular area. mTOR-I cause an inhibition of proliferation in podocytes and the epithelial-to-mesenchymal transition in tubular cells. Interestingly, all these side effects are mostly reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to maximize their important and specific therapeutic effects while minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in a CNI-free immunosuppressive protocol.

Is it safe to withdraw steroids within seven days of renal transplantation?

BACKGROUND: The safety of very early steroid withdrawal (VESW) in renal transplant recipients remains unclear. METHODS: Literature searches for all randomized controlled trials comparing VESW with steroid maintenance regimens were performed using MEDLINE, EMBASE, and the Cochrane Library. Quality assessment was performed in each trial. Meta-analyses were performed to demonstrate the pooled effects of relative risk (RR) and weighted mean difference with 95% confidence intervals (CI). RESULTS: A total of 3520 participants from 15 RCTs were included. VESW regimen increased the incidence of acute rejection (AR) over controls (RR = 1.46, CI = 1.20-1.79, p = 0.04). Subsequent analysis demonstrated that such difference lost significance in patients receiving tacrolimus (p = 0.16), but remained significant in patients with cyclosporin (p < 0.00001). The increased AR episodes were predominantly mild. VESW was associated with an increased incidence of delayed graft function (DGF) when steroids were withdrawn within three d post-transplantation. Cardiovascular risk factors, including incidence of new onset diabetes and total cholesterol, were significantly reduced under VESW regimen. CONCLUSIONS: It is safe and practical to withdraw steroids very early after renal transplantation. However, a three- to seven-d course of steroids may decrease the risk for DGF relative to steroid withdrawal in <3 d. Antibody induction is effective in preventing early AR.

Association of pre-transplant statin use with delayed graft function in kidney transplant recipients.

BACKGROUND: Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function. METHODS: All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times. RESULTS: Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 - 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56). CONCLUSIONS: The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.

The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients.

OBJECTIVE: Cyclosporine A (CsA) is a substrate of cytochrome P450 3A4 (CYP3A4). Recently, a newly discovered intron 6 single-nucleotide polymorphism in CYP3A4 (rs35599367 C>T), defining the CYP3A4*22 allele, has been linked to reduced hepatic expression and activity of CYP3A4. In the present study, the clinical impact of this single-nucleotide polymorphism was investigated in a cohort of patients receiving a CsA-based immunosuppressive regimen. MATERIALS AND METHODS: A total of 172 de-novo kidney transplant recipients, receiving CsA/mycophenolate mofetil as immunosuppressive therapy and participating in the Fixed-Dose Concentration Controlled study, were genotyped for the new CYP3A4*22 allele. CsA C(0) and/or C(2) levels were measured on days 3 and 10 and in months 1, 3, 6, and 12 after transplantation. Plasma creatinine concentrations, delayed graft function (DGF), and biopsy-proven acute rejection were recorded. RESULTS: The CYP3A4*22 allele was significantly associated with a higher risk of DGF compared with the CYP3A4*1/*1 patients after adjustment for known risk factors [odds ratio (OR)=6.34, confidence interval (CI(95%): 1.38-29.3), P=0.015]. Mixed-model analysis demonstrated that the overall creatinine clearance was 20% lower in CYP3A4*22 allele carriers compared with CYP3A4*1/*1 patients [CI(95%) (-33.1 to -7.2%), P=0.002]. For ABCB1 3435C>T, T-variant carriers had a decreased risk of developing DGF compared with CC patients [CT: OR=0.30, CI(95%) (0.11-0.77), P=0.011; TT: OR=0.18, CI(95%) (0.05-0.67), P=0.011]. CONCLUSION: CYP3A4*22 constitutes a risk factor for DGF and worse creatinine clearance in patients receiving CsA-based immunosuppressive therapy. Therefore, pretransplant genotyping for the CYP3A4*22 allele might help clinicians to identify patients at risk of DGF and poor renal function when treated with CsA.

A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients.

BACKGROUND: Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]). New-onset diabetes after transplantation (NODAT) is a known adverse effect of tacrolimus therapy and has been associated with DGF. OBJECTIVES: The impact of DGF on tacrolimus C(min) and dose requirements was evaluated in renal transplant recipients in the first postoperative week. The effects of the CYP3A5*3 A6986G polymorphism on initial mean tacrolimus C(min) and dose requirements in the presence and absence of DGF were assessed. This study also tested the hypothesis that if DGF influences early tacrolimus exposure, this would lead to a higher risk for NODAT (defined as the need for glucose-lowering medication for an uninterrupted period of ≥ 26 weeks). METHODS: This prospective, open-label, observational clinical cohort study enrolled renal allograft recipients aged ≥ 18 years. Tacrolimus was administered as an oral loading dose of 0.2 mg/kg/d and adjusted to achieve a target mean daily tacrolimus C(min) between 12 and 15 ng/mL. C(min) values and oral dose requirements in the first postoperative week were compared between patients with and without DGF. Patients were genotyped for the CYP3A4*1B -290A>G, CYP3A5*3 A6986G, ABCB1 Exon26 C3435T, ABCB1 Exon21 G2677T, and ABCB1 Exon21 G2677A single nucleotide polymorphisms. NODAT that occurred within the first 12 weeks after transplantation was confirmed using an oral glucose tolerance test. RESULTS: A total of 304 patients were enrolled (184 men, 120 women; mean [SD] age, 52.9 [14.1] years). Through day 3 after transplantation, mean (SD) 12-hour tacrolimus C(min) values were significantly higher in recipients experiencing DGF despite identical loading doses of 0.2 mg/kg. Mean tacrolimus dose requirements were significantly lower in patients with DGF during the first week. After recovery of DGF, mean tacrolimus dose requirements were not significantly different between recipients with and without DGF. In homozygous CYP3A5*3 carriers (n = 252), mean (SD) tacrolimus dose requirements remained significantly lower during DGF, while in CYP3A5*1 carriers with DGF (n = 52), lower mean dose requirements were observed only after postoperative day 4. The proportion of patients in whom NODAT developed was significantly greater in patients with DGF and tacrolimus C(min) >15 ng/mL on the first day after transplantation (27.2%) compared with recipients who remained free of DGF and had C(min) ≤15 ng/mL on day 1 (6.5%) (P = 0.016). On logistic regression analysis, greater recipient age (odds ratio [OR] = 1.044; 95% CI, 1.009-1.080), higher tacrolimus C(min) on day 1 (OR = 1.048; 95% CI, 1.017-1.080), and DGF (OR = 2.968; 95% CI, 1.107-7.959) were associated with an increased risk for NODAT. CONCLUSION: In this open-label, observational study, DGF was associated with higher initial mean tacrolimus C(min) values and lower daily dose requirements predominantly in CYP3A5 nonexpressers.

Sirolimus for calcineurin inhibitors in organ transplantation: contra.

Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin inhibitors for the prevention of acute rejection in renal transplantation. Despite initial encouraging results, enthusiasm faded with large trials showing an increased risk of acute rejection with this molecule that did not provide superior graft function over cyclosporin or tacrolimus. Recent data showed that SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a paradoxical stimulatory effect on innate immunity, which may explain its incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a concerning safety profile including high risk of delayed graft function and onset of proteinuria. This adds to many other adverse effects, including dyslipidemia, diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, and mouth ulcers, that further limit the use of this molecule. Severe cases of interstitial pneumonia have also been reported with this therapy, raising additional concerns. Incomplete control of immune response, along with a poor tolerability, makes SRL far from being the ideal antirejection drug. Progressive restrictions of SRL indication in renal transplantation have, however, been paralleled by evidence showing mTOR abnormalities involved in many pathogenic conditions, thus opening the avenue to new possible applications of this molecule.

Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF.

Sirolimus is associated with prolonged delayed graft function (DGF) following renal transplantation and exacerbation of proteinuria. We assessed renal allograft biopsies from DGF patients treated with de novo sirolimus (n = 10) for renal tubular cell and podocyte apoptosis and expression of activated caspase-3, Bcl-2, and mTOR and compared them to biopsies from DGF patients not receiving sirolimus (n = 15). Both groups received mycophenolate mofetil, prednisone and antibody induction. Apoptosis was assessed using terminal deoxynucleodidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Caspase-3, Bcl-2, and mTOR expression were assessed by immunohistochemistry. Sirolimus treated patients had 334+/-69 TUNEL positive cells per 5 high power fields compared to 5.5+/-2.9 TUNEL positive cells in control patients (p<0.001). The number of TUNEL positive cells correlated with tubular architectural disruption. Expression of activated caspase-3, Bcl-2, or activated mTOR did not differ between groups. 60% of biopsies from sirolimus treated patients compared to 7% of biopsies from controls showed diffuse podocyte apoptosis (p = 0.007). There was no podocyte expression of activated mTOR, activated caspase-3, or Bcl-2 in either group. These data suggest that DGF patients treated with sirolimus have increased renal tubular cell apoptosis and podocyte apoptosis.

The combination of sirolimus and cyclosporine does not delay initial renal graft function recovery.

BACKGROUND: Sirolimus has been considered to be a non-nephrotoxic agent. It may delay graft function due to a potential hindrance of the recovery from acute tubular necrosis. It remains controversial as to whether the concomitant administration of sirolimus (SRL) with calcineurin inhibitors delays graft function in Asian patients. METHOD: This study enrolled 61 patients who received primary renal transplantation. Twenty-one patients aged 38.9 +/- 11 years received early treatment with 6 mg/day sirolimus, 8 mg/kg/day cyclosporine (CsA) and prednisolone (SRL group). Forty patients with a mean age of 36.7 +/- 9 years in the control group were treated with the standard immunosuppressive therapy (8 mg/kg/day CsA, mycophonolate mofetil and prednisolone). RESULTS: The creatinine level at one week following transplantation in the SRL group was not significantly different from that in the control group (4.7 +/- 1.0 versus 2.7 +/- 0.4 mg/dL, p = 0.17). Similarly, there was no significant difference in the creatinine level at week 2 (3.4 +/- 0.7 versus 2.7 +/- 0.3 mg/dL, p = 0.36), week 3 (2.0 +/- 0.3 versus 2.1 +/- 0.2 mg/dL, p = 0.76), and week 4 (1.8 +/- 0.2 versus 1.8+/-0.1 mg/dL, p = 0.92) between SRL and control groups, respectively. Similarly, the number of the patients with renal function impairment in both groups was not significantly different. The one-year patient and graft survival was 100% and 96%, respectively, in the SRL group and 100% and 98%, respectively, in the control group. CONCLUSION: The combination of sirolimus and cyclosporine did not prolong the recovery from transplantation-associated ischemic injury in kidney graft recipient. Our study demonstrated the safety of early usage of the concomitant administration of sirolimus and cyclosporine in kidney transplantation.

Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen.

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.