Pedro Errasti

Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience.

BACKGROUND The mammalian target of rapamycin inhibitors (mTORi) sirolimus (Si) and everolimus (Ev) induce pneumonitis, an unusual but potentially fatal adverse effect. We report 8 cases of suspected mTORi-induced pneumonitis over a 9-years experience from 2000 to 2009. METHODS The switch from a calcineurin inhibitor (CNi) was made due to chronic transplant nephropathy, tumors, nephrotoxicity, or for rejection prophylaxis. RESULTS One hundred six patients were switched from CNi to Si (n=29) or Ev (n=134). Twenty-five additional patients were treated de novo with mTORi. The 8 patients (3 Si, 5 Ev) who developed pneumonitis included 5 females and 3 males of median age, 59.1 years (range, 40-68). The median time from switch to pneumonitis onset was 292 days (range, 60-982). The clinical presentation included fatigue (n=6), fever (n=7), dyspnea (n=6), dry cough (n=6), and weight loss (n=5). In most cases, imaging tests (chest radiograph, computerized tomography) revealed bilateral lower lobe involvement. Bronchoalveolar lavage showed a lymphocytic alveolitis in 5 subjects with negative cultures. All patients recovered after mTORi withdrawal. All patients were treated with antibiotics and five with steroids. CONCLUSION mTORi associated pneumonitis is not a rare disease. It is equally induced by Si or Ev. Pneumonitis was not apparently dependent on the drug dose or the blood levels. Discontinuation of mTORi seems to be the safest treatment option to avoid pulmonary fibrosis or a fatal outcome.

Mast cells in chronic rejection of human renal allografts.

Abstract An increased number of mast cells (MCs) is found in renal specimens of patients with diseases associated with persistent chronic inflammation. MCs proliferation is partly dependent on the presence of T lymphocytes. Both chronic inflammation and T-lymphocytes are essential in the development of chronic rejection (CR), and probably for the infiltration of MCs. MC-derived products such as heparin, histamine, and serine proteases may be responsible for endothelial proliferation and excess collagen production by fibroblasts. In this study, a quantitative evaluation of the MCs infiltration in kidney allografts with CR is performed. The extent of renal fibrosis was analysed in samples stained with Masson’s trichrome. To evaluate the potential relationship between MCs and fibrosis in CR we analysed 30 kidneys with CR (25 from nephrectomies and 5 from autopsies). Ten transplanted kidneys obtained from patients died by causes not related with rejection were used as controls. CR was graded according to the Banff schema, which assesses the degree of vasculopathy, tubular atrophy, interstitial fibrosis and transplantation glomerulopathy. Giemsa-stained sections and immunohistochemistry using anti-MC tryptase and c-kit monoclonal antibodies were used to detect MCs. The mean number of MCs per 20 high-power fields (HPF) in the transplanted kidney with CR was 101.8±15.3 in the renal cortex and 46.60±6.52 in the medulla. MCs were significantly more numerous in CR with respect to normal kidneys, both in the cortex (P<0.01; Mann-Whitney U test) and in the medulla (P<0.01; Mann-Whitney U test). There was a positive correlation between the number of MCs and extent of fibrosis (P<0.01; Kruskal-Wallis one-way anova test) and tubular atrophy (P<0.01). These results suggest that MCs may play a role in the process of development of interstitial fibrosis in CR.

Loss of renal graft due to recurrent IgA nephropathy with rapidly progressive course: an unusual clinical evolution.

Recurrence of IgA nephropathy following renal transplantation has been described in 40-50% of patients, and it usually has a good outcome. We present the case of a 54-year-old man with IgA nephropathy who developed terminal renal failure in 1985, 3 years after the onset of the disease. In March 1986 he received a cadaveric renal allograft following treatment with ciclosporin and steroids. Eight months later he developed microhaematuria and proteinuria and 10 months later he developed acute nephritic syndrome and rapidly progressive renal failure. Renal biopsy disclosed an IgA nephropathy with epithelial crescents in 60% of glomeruli. Treatment with plasma exchange and cyclophosphamide was unsuccessful and the patient lost his graft and returned to regular haemodialysis 15 months after renal transplantation.

Autosomal-dominant polycystic kidney disease: high prevalence of graft loss for death-related malignancies and cardiovascular risk factors

Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease with multiple extrarenal manifestations. It accounts for 7% to 11% of patients receiving dialysis or renal transplantation (RT) for end-stage renal disease (ESRD) in Europe. We analyzed retrospectively the causes of death, the prevalence of cardiovascular risk factors (CVRF) and the patient and graft survivals in 62 consecutive ADPKD patients who received 63 cadaveric grafts (29 men and 34 women), of the 600 RTs performed between 1980-2001. The diagnosis of ADPKD was established by family history and ultrasound techniques. At present, 50 patients (79.4%) have functioning grafts, with a mean follow-up of 84.7 months (range, 12-255), and 13 patients have lost their grafts. The main cause of failure was patient death with a functioning graft (9 cases). Malignancies occurred in 5 patients, including 2 lymphomas, 1 renal carcinoma, 1 pancreas sarcoma, and 1 lung cancer associated with infection. Three patients died of cardiocerebrovascular events, and 1 patient of pneumonia. One patient lost the graft after decreasing the immunosuppression for an obstructing colon cancer. Three additional patients now on dialysis lost their grafts due to chronic rejection in 2 cases and primary nonfunction in 1 case. The prevalence of cardiovascular risk factors among the 50 patients with functional grafts were: hypertension, 70%; hypercholesterolemia, 62%; hyperhomocysteinemia, 30%; hyperfibrinogenemia, 68%; increased lipoprotein (a), 18%; microalbuminuria, 22%; hyperuricemia, 48%; hyperparathyroidism, 24%; overweight status, 24%; and nonlethal myocardial infarction, 10%. We conclude that ADPKD patients have good graft and patient survivals, and that the presence of malignancy is the main cause of death and graft failure at our center.

Reduction in blood cyclosporine concentration by Orlistat in two renal transplant patients

OBESITY DISPLAYS a high incidence after renal transplantation and presents as a cardiovascular risk factor. Medical treatment includes limitation of caloric intake, behavior modification, and an aerobic exercise program, with frequent follow-up by the health-care team. Sometimes treatment with agents such as fenfluramine or phentermin is successful. Orlistat (Xenical, Roche Ldt, Switzerland), is a gastrointestinal lipase inhibitor that promotes weight loss in obese patients. Orlistat interferes with the absorption of fat soluble vitamins, but no data are available about interfering with cyclosporine (CyA) absorption in the manufacturer’s brochure.

Decrease of Apoptosis Rate in Patients with Renal Transplantation Treated with Mycophenolate Mofetil

Background/Aims: Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF prevents acute graft rejection in organ transplants. The aim of this investigation is to study whether MMF has any influence on apoptosis and proliferation rates of cells other than lymphocytes. Methods: We conducted a retrospective study of renal allograft biopsies taken during the 1st week after transplantation in 25 patients receiving triple therapy with prednisone, ciclosporin and azathioprine 75 mg/day and in 25 patients treated with MMF at a dose of 2 g/day instead of azathioprine, in order to investigate the differences in the proliferation and apoptosis rates of the glomerular, tubular, interstitial and endothelial cells of the kidney. Twelve normal kidneys were used as controls. Conventional histopathological techniques were applied as usual for pathological diagnosis. Proliferative activity was assessed by use of MIB-1 antibody. Sections of formalin-fixed, paraffin-embedded tissue blocks were stained for the presence of apoptotic cells by TUNEL assay. Evaluation of proliferative or apoptotic rates was made by counting the number of positive cells in 10 glomeruli and in 10 transversely cut tubuli in each biopsy. The positive cells in the interstitium were counted in ten high-power fields. Positive cells in the endothelium were scored semiquantitatively from 0 to 3: 0 = none, 1 = isolated cells, 2 = small groups of cells, 3 = most endothelial cells. Mann-Whitney U and chi-square tests were used for intergroup comparisons. Results: All biopsies were normal or had borderline (Banff classification) acute rejection. MIB–1 rates were similar in both groups, without statistical differences (p > 0.05) between them. Significantly lower apoptotic rates were found in the group treated with MMF in tubular epithelium (23.41 ± 8.86 vs. 57.4 ± 13.42; p = 0.021), in glomerular (1.25 ± 0.78 vs. 5.3 ± 1.66; p = 0.027), and interstitial cells (1.58 ± 0.6 vs. 5.8 ± 1.54; p = 0.043). Apoptosis in endothelial cells (p > 0.05) was similar in both groups. Conclusion: We conclude that treatment with MMF of kidney transplant patients does not affect the proliferative rate of cells of the allograft, but decreases the number of apoptotic cells in tubular epithelium.

New Immunosuppressive Therapies and Surgical Complications After Renal Transplantation

BACKGROUND To analyze the association between the principal immunosuppressive drugs (mycophenolate mofetil, calcineurin inhibitors and mammalian target of rapamycin [mTOR] inhibitors) used in the routine management of kidney transplant patients and the development of postoperative surgical complications. MATERIALS AND METHODS We analyzed 415 kidney transplants, studying the influence of various immunosuppressive regimens on the main postoperative surgical complications. RESULTS The mean follow-up for the entire group was 72.8 months (± 54.2 SD). Patients treated with myeophonolate mofetil (MMF) and cyclosporine (n = 121) experienced a higher frequency of wound eventration odds ratio [OR], 5.2; 95% confidence interval [CI], 1.2-23.5; P = .03) compared with azathioprine and cyclosporine (n = 71). Compared with transplant recipients treated with tacrolimus and MMF (n = 181), transplant recipients treated with cyclosporine and MMF (n = 121) had a significantly greater frequency of wound eventration (OR, 3.7; 95% CI, 1.5-9.5; P = .005), urologic (OR, 2; 95% CI; 1.02-3.9; P = .04), wound (OR; 2.2; 95% CI; 1.07-4.6; P = .03), late (OR, 1.7; 95% CI; 1.01-3.03; P = .04), and Clavien grade 3 surgical complications (OR; 1.9; 95% CI, 1.1-3.37; P = .01). Patients treated with mTOR inhibitors (n = 26) had higher rates of lymphocele (OR, 3.6; 95% CI, (1.1-11.4; P = .002) compared with those who received tacrolimus (n = 197). CONCLUSIONS New immunosuppressive drugs have improved short-term functional results; however, in some cases they seem to increase surgical complications rates.

Treatment of hyperhomocysteinemia after renal transplantation.

INTRODUCTION Several epidemiologic prospective studies have provided strong evidence that hyperhomocysteinemia (HHC) is a risk factor for cardiovascular disease (CVD) due to its role in producing endothelial damage due to oxidation stress. Several studies show that combined folic acid (FA) and vitamin B12 (B12) treatment decreases fasting total homocysteine (HC) levels in renal transplant recipients (RTR). The aim of the study was to determine the efficacy and safety during one year of combined FA and B12 treatment in 89 RTR, as well as the relationship between HHC with other known risk factors for CVD and the intrinsic characteristics of the transplantation. METHODS Among 193 RTR in whom we determined the baseline levels of HC, FA, B12, creatinine, and CV risk factors, 81 had normal (HC < 14 micromol/L) and 112 elevated (HC > or = 14 micromol/L) HC levels, 89 of whom were included in a treatment group (23 nontreated). Analytic measures were performed at baseline and 1, 3, and 12 months. RESULTS We observed a decrease in HC levels among the treatment group (P<.05) after 12 months without differences in the other groups. There were no differences in age, hypertension, hypercholesterolemia, smoking, presence of diabetes, or type of immunosuppression between the groups. There was a significant correlation between basal creatinine and HC level (P<.05). A higher prevalence of CVD was observed in the HHC group (P<.05). CONCLUSION HHC is associated with worse renal function and a higher prevalence of CVD. FA and B12 treatment normalize HC levels, representing a safe treatment that could improve the long-term vascular prognosis of RTR.

Predictive value of the Luminex single antigen panel for detecting flow cytometry cross-match positivity

Anti-human leukocyte antigen (HLA) antibodies are a major cause of allograft loss. Solid-phase immunoassays, notably Luminex technology, have lately begun to replace traditional techniques for detecting these antibodies. This platform, however, carries some restrictions in the type of antibodies it detects. For this reason, results using these new technologies must be correlated with results using traditional techniques that have proven clinical significance. We have correlated flow cytometry cross-match (FCXM) outcomes with results from Luminex assays. Serum samples from patients awaiting transplantation who had known anti-HLA antibodies as detected by Luminex were incubated with lymphocytes expressing (a) 1 of the HLA antigens detected by the sera or (b) several of them. Of the 169 T-cell FCXMs we performed, in 92 cases the target cell expressed only 1 of the HLA antigens detected by the serum. The results obtained correlated well with Luminex data (r = 0.84). A cutoff mean fluorescence intensity value of 6,500 for the Luminex single antigen assay yielded a sensitivity of 85% and specificity of 82% for detecting a positive FCXM. In the other 77 cases, the target cell expressed 2 or more of the HLA antigens detected by the serum. In this situation, the same cutoff proved a useful tool for differentiating negative from positive FCXMs.

First-line use of rituximab correlates with increased overall survival in late post-transplant lymphoproliferative disorders: retrospective, single-centre study

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single‐centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29–69), median time to diagnosis 50 months (range 0–100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B‐cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non‐rituximab; P = 0.5). R‐CHOP‐like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31–96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58–79 months; non‐rituximab 1–30 months). Post‐transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single‐centre series, and it should be considered as first‐line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.