Diagnosis and treatment of acute humoral kidney allograft rejection.

Acute humoral rejection (AHR) is a severe form of rejection associated with poor graft survival. Prompt diagnosis and rapid institution of therapy are crucial to improve the prognosis. A therapeutic approach based on plasmapheresis, intravenous imunoglobulin, and rituximab seems to be effective in refractory cases. Herein we have described our experience with 11 patients with biopsy-proven AHR who were treated between January 2005 and June 2008. Seven of these patients had panel reactive antibodies titers more than 50%. The diagnosis was based on Banff 2001 criteria; treatment consisted of a combination of plasmapheresis and intravenous immunoglobulin. Four refractory cases were also treated with a single dose of rituximab. One graft was lost due to thrombosis. All other patients recovered graft function with an average creatinine level of 1.6 mg/dL at 8.6 +/- 2.7 months of follow-up.

Pancreas-kidney transplantation and the evolution of pancreatic autoantibodies.

The recurrence or persistence of pancreatic autoantibodies after pancreas-kidney transplantation (PKT) is an intriguing finding. We prospectively analyzed 77 PKTs, searching for risk factors for the expression of these autoimmune markers and their impact on pancreas graft function. Among the 77 PKTs, 24.7% had 0 HLA matches, 20.8% displayed delayed graft function, and 14.3% had acute rejection episodes. Immunosuppression included antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and steroids. Sixty-five patients had both grafts functioning as a follow-up of more than 6 months. In 11 patients anti-glutamic acid decarboxylase (GAD) positivity persists (n = 8) or has recurred (n = 3), 4 of whom show increasing titers. Two patients maintain positive islet cell antibodies (ICA) and anti-GAD antibodies. The 9 patients positive for ICA included 2 who were negative before PKT and 7 who remain positive. The "positive" group (22 patients with positive ICA and/or anti-GAD) did not differ from the global group of 65 functioning PKT in terms of acute rejection episodes, HLA match, and steroid withdrawal. Among the positive patients, there were 2 with borderline glucose levels; however, among the entire "positive" group, the mean fasting glucose, HbA1c, and C-peptide measurements were not significantly different, when compared with the other 65 PKTs. In conclusion, pancreatic autoantibodies may be persistently positive or recur after PKT, despite appropriate immunosuppression. Its impact on long-term pancreas graft survival is unknown. We could not identify risk factors for their expression. An extended follow-up with monitoring and search for other risk factors may be necessary to increase our knowledge in this field.

The influence of HLA mismatches and immunosuppression on kidney graft survival: an analysis of more than 1300 patients.

New immunosuppressive drugs used in kidney transplantation decreased the incidence of acute rejection. It was hypothesized that, with their power, the importance of HLA matching was decreased. To evaluate the influence of HLA matching, immunosuppression, and other possible risk factors, we analyzed data of 1314 consecutive deceased donor kidney transplantation. We divided the patient population into 4 cohorts, according to the era of transplantation: era 1, before 1990, azathioprine (Aza) and cyclosporine (Csa) no microemulsion; era 2, between 1990 and 1995, Csa microemulsion; era 3, between 1996 and 2000, wide use of mycophenolate mofetil (MMF) and anti-thymocyte globulin (ATG); and era 4, after 2000, marked by sirolimus and tacrolimus (TAC) use. Multivariate analysis compared death-censored graft survival. Using as reference the results obtained with 0 HLA mismatches, we verified, during era 1 and era 2, an increased risk of graft loss for all of the subgroups with HLA mismatch >0. However, during era 3 and era 4, the number of HLA mismatches did not influence graft survival. Although acute rejection and delayed graft function, which decreased in the later periods, remained as prognostic factors for graft loss. Considering the immunosuppressive protocol with Csa+Aza+Pred as reference, protocols used after 1995 with Pred+Csa+ATG, with Pred+Csa+MMF, and with Pred+Tac+MMF presented better survival results. Results showed that the significance of HLA matching decreased while the results improved with the new immunosuppressant drugs. These observations support the hypothesis that the weakened importance of HLA matching may be a consequence of the increasing efficacy of the immunosuppression.

Renal transplantation in patients over 60 years of age: a single-center experience.

The prevalence of end-stage renal disease (ESRD) increases with advancing age. In most countries renal transplant recipients are getting older, too. Transplantation must be considered for ESRD patients older than 60 years; however, there are few data regarding outcomes in this population. We retrospectively reviewed the clinical course of recipients aged > or =60 years (n = 43) who underwent primary or repeated grafts from August 1988 to December 2004. We then compared recipient and donor characteristics as well as graft and patient survivals with recipients aged 18 to 59 years (n = 1058) who were transplanted during the same time. Donor age tended to be higher among the oldest recipient group (P < .001). Mean follow-up was significantly shorter in the group aged > or =60 years (P < .001), as our institution only recently has frequently accepted patients > or =60 years. Older recipients showed more frequent delayed graft function (P = .007), longer initial hospitalization (P = .005), and a significantly lower incidence of posttransplant acute rejection episodes (P = .015). Patient (P = .057), graft (P = .407), and death-censored graft (P = .649) survivals were not different between the two groups. Seven recipients aged > or =60 years died; the main cause of which was cardiovascular in origin. The loss of organs (n = 11) in the older patients was mainly due to death with a functioning kidney (54.5%). Our results confirm that renal transplant must be considered in selected patients older than 60 years as patient and graft survivals are similar to those of younger patients.

Impact of hepatitis C virus on renal transplantation: association with poor survival.

Data concerning the effect of hepatitis C virus (HCV) infection on the long-term outcome of patient and allograft survival are conflicting. We performed a retrospective study including all renal transplant recipients who underwent the procedure at our center between July 1983 and December 2004. We compared HCV-positive (n = 155) versus HCV-negative (n = 1044) recipients for the prevalence of anti-HCV, patient/donor characteristics, and graft/patient survival. The prevalence of HCV-positive patients was 12%. The anti-HCV positive recipients displayed a longer time on dialysis (P < .001), more blood transfusions prior to transplant (P < .001), and a higher number of previous transplants (P < .001). There were no differences in the incidence of acute rejection between the two groups. Patient (P = .006) and graft survival (P = .012) were significantly lower in the HCV-positive than the HCV-negative group. Graft survival censored for patient death with a functioning kidney did not differ significantly between HCV-positive and HCV-negative recipients (P = .083). Death from infectious causes was significantly higher among the HCV-positive group (P = .014). We concluded that HCV infection had a significant detrimental impact on patient and renal allograft prognosis. Death from infectious causes was significantly more frequent among HCV-positive than the non-HCV population.

Simultaneous pancreas-kidney transplantation: five-year results from a single center.

We report the 5-year results of our simultaneous pancreas-kidney transplantation (SPKT) program, started on May 2, 2000. Forty-two SPKT were performed on 42 type I diabetic patients with chronic renal failure. The procedure was performed with enteric diversion and vascular anastomosis to the iliac vessels. Immunosuppressive protocol included antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. The 24 women and 18 men had a mean age of 33.5 +/- 6.3 years and mean 22.8 +/- 14.2 years time of diabetes evolution. Forty patients had been on dialysis for 34.3 +/- 24.1 months, and two were preemptive transplantations. Acute rejection episodes were treated in eight patients (19.1%): in three cases they affected both organs; in two only the kidney was affected; and the other three were pancreas graft rejections. The incidence of postoperative complications requiring re-operation was 42.9%, mostly pancreas graft related. Two patients died, one due to cardiovascular disease; the other was transplant related. Three kidney grafts were lost, and the causes were immunologic, thrombosis, and patient death. Pancreas graft loss occurred in seven patients: thrombosis (n = 3); infection (n = 3); immunologic (n = 1). The patients with surviving grafts were doing well, with normal kidney and pancreas function: serum creatinine = 0.89 +/- 0.15 mg/dL; fasting blood glucose = 79 +/- 16 mg/dL; HbA1c = 4.7 +/- 1.1%. The 1-year patient, kidney, and pancreas survival rates were 97.3%, 94.6%, and 83.8% and 5-year values, 91.7%, 89.2%, and 78.7%, respectively. In conclusion, these results are similar to the most recent UNOS/IPTR reports, leading us to consider our experience with SPKT very positive.

Immunosuppression with antithymocyte globulin in renal transplantation: better long-term graft survival.

We analyzed the impact of antithymocyte globulin (ATG) in renal transplantation. We retrospectively studied 1217 recipients performed from July 83 to December 03. ATG-Fresenius-S (ATG-F) was used for induction therapy in 492 patients (40.4%; group I) and compared with group II, 725 patients (59.6%), without antilymphocyte induction. Groups were comparable in terms of recipient gender and race distribution; time on dialysis; cause of renal disease; number of human leukocyte antigen (HLA) mismatches; donor age, gender, and creatinine; and cold ischemia time. Patients with ATG-F were younger (35.8 +/- 13.8 vs 38.9 +/- 12.5 years, P < .001), more frequently hypersensitized (10% vs 3%, P < .001), and had more second transplants (15.7% vs 5.8%, P < .001). The incidence of acute rejection episodes was lower among ATG-F patients (23.6% vs 32.1%, P = .004). Admission time and incidence of delayed graft function (DGF) were similar in the two groups. Graft survival at 1, 5, 10, and 15 years was 88.9%, 80.7%, 71.3%, and 64.9% in group I and 86.4%, 77.4%, 60.7%, and 48.4% in group II (P = .003). The difference in patient survival over the same follow-up did not reach statistical significance. Multivariate analysis showed that the risk of graft failure was higher for those who did not receive ATG-F (HR = 1.51; 95% CI, 1.14 to 2.00; P = .004). Donor age and DGF were also independent predictors of graft failure. Our results showed a better long-term graft survival among patients who received ATG-F, despite their higher immunological risk. The absence of induction with ATG-F, donor age, and DGF were independent risk factors for graft failure.

Conversion to sirolimus in a population of kidney and kidney-pancreas transplant recipients.

INTRODUCTION: Calcineurin inhibitors (CI) are associated with nephrotoxicity that might reduce long-term graft survival. We report our experience with sirolimus (SRL) conversion among a population of kidney and kidney pancreas transplant recipients. METHODS: Thirty transplant recipients (6 women, 24 men; age 41 +/- 10.5 years old) were converted to SRL therapy at 25.97 +/- 32.5 months after transplantation. Indications for conversion were: intolerance to mycophenolate mofetil (n = 13), diabetes mellitus (n = 3), CI nephrotoxicity (n = 11), CI nephrotoxicity with chronic allograft rejection (n = 2), and side effects of azathioprine (n = 1). Follow-up after conversion is 3 to 45 months. RESULTS: No significant changes were observed in the 3 months postconversion in renal function, hematological profile, and mean arterial blood pressure. In contrast there was a significant increase in cholesterol values (pre: 198.7 +/- 49.4, versus post 221.2 +/- 60.8, P = .018). At a follow-up of 15.2 +/- 9.9 months after conversion two patients (6.7%) died with functioning allograft (one because of infection and one to myocardial infarct) three kidney allografts (10.7%) have been lost: two chronic rejection; one infection. In two patients SRL therapy was discontinued (one infection, one refractory edema). Neither significant change in renal function nor episodes of acute rejection were observed. CONCLUSIONS: Conversion to SRL was safe. There was no deterioration in renal function nor episodes of acute rejection. There was a significant increase in cholesterol values after conversion. The size of the sample and the time of follow-up may have determined our results.

Impact of homocysteinemia on long-term renal transplant survival.

AIM: We prospectively followed a cohort of 202 renal transplant recipients for 5 years to examine the impact of fasting homocysteinemia on long-term patient and renal allograft survival. METHODS: Cox proportional hazards regression analysis was used to identify independent predictors of all-cause mortality and graft loss. RESULTS: Hyperhomocysteinemia (tHcy >15 micromol/L) was present in 48.7% of the 202 patients, predominantly among men (55.8%) as opposed to women (37.1%). At the end of the follow-up period, 13 (6.4%) patients had died including 10 from cardiovascular disease, and 23 had (11.4%) had lost their grafts. Patient death with a functioning allograft was the most prevalent cause of graft loss (13 recipients). Levels of tHcy were higher among patients who died than among survivors (median 23.9 vs 14.3 micromol/L; P = .005). Median tHcy concentration was also higher among the patients who had lost their allografts than those who did not (median 19.0 vs 14.1 micromol/L; P = .001). In a Cox regression model including gender, serum creatinine concentration, transplant duration, traditional cardiovascular risk factors, and associated conditions, such as past cardiovascular disease, only tHcy concentration (ln) (HR = 5.50; 95% CI, 1.56 to 19.36; P = .008) and age at transplantation (HR = 1.07; 95% CI, 1.02 to 1.13; P = .01) were independent predictors of patient survival. After censoring data for patient death, tHcy concentration was not a risk factor for graft loss. CONCLUSIONS: This prospective study shows that tHcy concentration is a significant predictor of mortality, but not of graft loss, after censoring data for patient death.

Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity?

Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side effects and toxicities. The data concerning their nephrotoxicity are few and conflicting. A retrospective study was performed in 2 groups of renal transplant recipients treated with cyclosporine or tacrolimus to evaluate graft function and side effects. All patients had completed at least 6 months of follow-up before inclusion in the study. Group I included 10 patients who were converted from cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft dysfunction with creatinine values <3 mg/dL. After conversion, there was a significant reduction in creatinine values (from 2.43 +/- 1.21 to 1.86 +/- 0.72 mg/dL; P =.023) and an improvement in creatinine clearance (from 47.5 +/- 19.2 to 56.1 +/- 18.9 mL/min; P =.047). The lipid profile did not change, but there was a trend to better blood pressure control with less antihypertensive drugs. Group II compared 2 subgroups of patients receiving kidneys from the same donor, one treated with cyclosporine and the other with tacrolimus. Tacrolimus patients showed better renal function; namely, creatinine was 1.15 +/- 0.27 versus 1.44 +/- 0.33 mg/dL (P =.029) and creatinine clearance was 87.7 +/- 27.1 versus 60.3 +/- 25.9 mL/min (P =.043). Lipid and blood pressure values were not different between the 2 subgroups, but tacrolimus patients tended to need a lower number of antihypertensive medications. The incidence of de novo diabetes mellitus was approximately 20% among patients using tacrolimus. We concluded that tacrolimus may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better graft function and easier blood pressure control, but a high incidence of posttransplantation diabetes mellitus.

[Influence of Gilbert's syndrome on serum bilirubin levels and gallstone formation in children with chronic hemolytic disease]. / Influencia del síndrome de Gilbert en los valores de bilirrubina sérica y presencia de litiasis vesicular en pacientes con hemólisis crónica congénita.

To determine whether Gilbert's syndrome increases the risk of gallstone formation in children with chronic hemolytic disease, we studied 44 children with this diagnosis. Gallstones were detected by abdominal ultrasonography. This took place annually in scheduled examinations or in the context of acute abdominal pain. In all patients, the mean values of hemoglobin, reticulocyte and serum bilirubin in the chronic phase were recorded. In addition, TA insertion in the A(TA)nTATAA motif within the promoter region of the enzyme uridine-diphosphate-glucuronyl transferase (UGT1A1) was screened, since this is typically associated with GS.We found 10 (22.7 %) homozygotes for the mutated allele TA*7/TA*7, 12 (27.3 %) TA*6/TA*6 heterozygotes and 22 (50 %) homozygotes for the wild-type allele TA*6/TA*6. No statistically significant differences were found in the values of hemoglobin (Kruskal-Wallis test 2.496; p > 0.05) or in reticulocyte count (Kruskal-Wallis test 1.696; p > 0,05) between the three groups of patients, suggesting a similar degree of hemolysis. Patients with the UGT1A1 TA*7/TA*7 genotype showed higher mean serum bilirubin levels than did patients who were homozygous for the wild-type allele (Mann-Whitney test 35.5; p < 0.05). None of the patients with the TA*6/TA*6 genotype developed gallstones, whereas this complication was found in 2 of 12 (16.6 %) heterozygotes and 6 of 10 (60 %) homozygotes for the allele with TA insertion. In this latter group, 4 patients presented acute pancreatitis as a consequence of gallstone formation.The association between increased bilirubin load due to chronic hemolytic disease and diminished hepatic conjugation leads to raised serum bilirubin levels and consequently to an increased risk of gallstone formation. Therefore, we recommend screening for Gilbert's syndrome in children in the initial phases of chronic hemolytic diseases.