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.

De novo use of everolimus with elimination or minimization of cyclosporine in renal transplant recipients.

BACKGROUND: The purpose of two similarly designed multicenter, prospective, parallel-group, open-label studies was to evaluate early cyclosporine (CsA) elimination versus minimization from an everolimus-CsA-steroid regimen in de novo renal transplant patients. METHODS: Within 24 hours after transplantation, 170 renal transplant patients received everolimus (trough levels 3-8 ng/mL), CsA, and steroids. Those eligible (n = 114) were randomized (1:1) at 3 months to have CsA elimination by month 4 to 6 (±1 week) with everolimus trough levels maintained at 6 to 12 ng/mL or CsA minimization, until 12 months. The randomized population excluded those who discontinued the study prior to randomization due to adverse events, acute rejection episodes of Banff grade IIb/III, or worsening renal function during the month prior to randomization. RESULTS: At 12 months, the estimated glomerular filtration rate (Nankivell) with CsA elimination was noninferior versus CsA minimization (P < .0001, α-level 0.05; 90% confidence interval 0.6-8.5) by 7 mL/min/1.73 m(2) (noninferiority margin). Composite efficacy failure was comparable with CsA elimination and CsA minimization (18.9% and 17.5%, respectively, P = 1.000) and no graft loss or death was reported after randomization. Cytomegalovirus infections were rare under everolimus treatment, and no pneumonitis episode was reported. CONCLUSION: In our selected randomized study population, immediate initiation of everolimus allowed CsA elimination. Renal function was stable on everolimus-based, CsA-free maintenance regimen without compromising efficacy.

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.

Use of the new proliferation signal inhibitor everolimus in renal transplant patients in Spain: preliminary results of the EVERODATA registry.

Everolimus (Eve) has shown good efficacy and safety profiles in clinical trials in combination with low doses of cyclosporine but there is limited experience in other modes, especially with calcineurin inhibitor elimination. We developed a retrospective study to analyze its clinical use after approval in Europe in 2005. Herein we have presented the results of a series of 272 patients followed for the first 6 months after Eve introduction. In 93.8% of cases Eve was introduced after the first month posttransplantation (conversion use), and 6 months after introduction, the CNI had been eliminated in 75% of cases. The main indication for Eve introduction was the diagnosis of a malignant neoplasm (42%), whereas the combined indication of prevention and/or treatment of toxicity, especially nephrotoxicity, accounted for 46.3% of cases. Initial doses were low (1.37 mg/d), but were progressively increased up to 2 mg/d at 6 months. Renal function remained unchanged during the follow-up period, whereas proteinuria moderately increased. Only 5 cases (2%) of acute rejection episodes were observed with excellent patient and graft survivals at 6 months after conversion. Further analysis of this extensive series of patients with a longer follow-up is needed.

[Kidney transplant]. / Trasplante renal.

The kidney transplant is the therapy of choice for the majority of the causes of chronic terminal kidney insufficiency, because it improves the quality of life and survival in comparison with dialysis. A kidney transplant from a live donor is an excellent alternative for the young patient in a state of pre-dialysis because it offers the best results. Immunosuppressive treatment must be individualised, seeking immunosuppressive synergy and the best safety profile, and must be adapted to the different stages of the kidney transplant. In the follow-up to the kidney transplant, cardiovascular risk factors and tumours must be especially taken into account, given that the death of the patient with a working graft is the second cause of loss of the graft following the first year of the transplant. The altered function of the graft is a factor of independent cardiovascular mortality that will require follow-up and the control of all its complications to postpone the entrance in dialysis.

Trasplante renal / Kidney transplant

El trasplante renal es la terapia de elección para la mayoría de las causas de insuficiencia renal crónica terminal porque mejora la calidad de vida y la supervivencia frente a la diálisis. El trasplante renal de donante vivo es una excelente alternativa para el paciente joven en situación de prediálisis porque ofrece mejores resultados. El tratamiento inmunosupresor debe ser individualizado buscando la sinergia inmunosupresora y el mejor perfil de seguridad, y debe adaptarse a las diferentes etapas del trasplante renal. En el seguimiento del trasplante renal hay que tener muy en cuenta los factores de riesgo cardiovascular y los tumores puesto que la muerte del paciente con injerto funcionante es la segunda causa de pérdida del injerto tras el primer año del trasplante. La función alterada del injerto es un factor de mortalidad cardiovascular independiente que requerirá seguimiento y control de todas sus complicaciones para retrasar la entrada en diálisis

The kidney transplant is the therapy of choice for the majority of the causes of chronic terminal kidney insufficiency, because it improves the quality of life and survival in comparison with dialysis. A kidney transplant from a live donor is an excellent alternative for the young patient in a state of pre-dialysis because it offers the best results. Immunosuppressive treatment must be individualised, seeking immunosuppressive synergy and the best safety profile, and must be adapted to the different stages of the kidney transplant. In the follow-up to the kidney transplant, cardiovascular risk factors and tumours must be especially taken into account, given that the death of the patient with a working graft is the second cause of loss of the graft following the first year of the transplant. The altered function of the graft is a factor of independent cardiovascular mortality that will require follow- up and the control of all its complications to postpone the entrance in dialysis

Preliminary results of the effect of treatment of hyperhomocysteinemia and its relationship with inflammation, coagulation status, and endothelial function after renal transplantation.

The aim of this study was to assess the relationship between total plasma homocysteine (tHC) and several markers of endothelial function, coagulation, and pro-inflammatory status in renal transplant recipients. Our own previous study demonstrated the efficacy of folic acid (FA) and vitamin B(12) (B(12)) treatment to reduce tHC. Using 70 stable recipients, 56 of whom showed hyperhomocisteinemia (HHC) (tHC > or = 14 micromol/L) and a control group (n = 14, tHC < 14 micromol/L), we treated 29 patients in the HHC group (10 mg FA and 500 mg B(12) daily) and determined their endothelial function, inflammatory activity, and coagulation status. We assessed plasma levels of von Willebrand Factor and fibrinogen as the prothrombotic profile and C-reactive protein and plasma albumin as inflammation markers. We performed Doppler sonography of the brachial artery to assess endothelial function. The mean value of plasma tHC of 19.05 +/- 3.70 micromol/L before treatment decreased to 13.45 +/- 3.25 micromol/L after 3 months of treatment (P < .001). The vWF was significantly correlated with tHC (P < .05) and was higher in the HHC patients (P < .05). The fibrinogen mean level was also significantly higher in HHC patients (P < .05). The C-reactive protein level was significantly higher and the albumin level was lower among patients with HHC. The endothelium-dependent dilation (EDD) correlated with baseline tHC (P < .05). In preliminary data we observed that homocysteine-lowering therapy may provide cardiovascular protection by enhancing endothelial function, limiting oxidative stress, and reducing procoagulation status.

Detection and treatment of post kidney transplant hyperglycemia: a Spanish multicenter cross-sectional study.

INTRODUCTION: The prevalence of diabetes mellitus (DM) is greater among patients with solid organ transplants than in the general population, although the factors associated with posttransplant DM (PTDM) are unknown. OBJECTIVES: The objective of this study was to estimate the prevalence of and assess the risk factors for PTDM. PATIENTS AND METHODS: We included outpatients with functioning isolated solid organ allografts (kidney, liver, heart, and lung). We collected demographic and posttransplant clinical data that included DM diagnostic ADA criteria, DM treatment, DM family history, presence of hepatitis C virus (HCV), immunosuppression treatment, hypertension, and dyslipidemia. RESULTS: A total of 2178 patients included, 1410 kidney recipients, 489 liver transplants, 207 heart transplants, and 72 lung recipients. Seventeen and four-tenths percent of the patients who did not have DM prior to transplantation, developed PTDM (median time: 79 days). A greater prevalence was observed among patients with a family history, HCV, and tacrolimus treatment (with or without steroids P < .05). By logistic regression analyses, OR for these factors were 1.51, 1.65, and 1.38, respectively. Of those patients who did not suffer PTDM, 55.2% showed basal blood glucose values under 100 mg/dL; only 68% presented with a hemoglobin Alc under 6. CONCLUSIONS: The prevalence of PTDM among kidney recipients was higher than that in the general population. DM family history, HCV positive, and tacrolimus were risk factors associated with this entity.

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.

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.

De novo hemolytic-uremic syndrome/thrombotic microangiopathy in renal transplant patients receiving calcineurin inhibitors: role of sirolimus.

The aim of this study was to evaluate the outcome of ten renal transplant recipients who developed de novo hemolytic uremic syndrome/thrombotic microangiopathy (DnHUS) after treatment with calcineurin inhibitors among 3,862 patients transplanted during the period 2000-2001 in Spain, and the results of switching to sirolimus for resolution of this pathologic condition. No patient had end-stage disease due to primary HUS. The criteria of diagnosis were decreased renal function, biopsy-proven thrombotic microangiopathy, and no signs of acute rejection. Calcineurin inhibitors were completely removed and immediate treatment with sirolimus started after diagnosis. The follow-up period was 19.0+/-4.3 months, at least 12 months after diagnosis. One patient died of sepsis shortly after starting sirolimus therapy. The serum creatinine level in the series decreased from 5.2+/-2.6 mg/dL at the time of biopsy to 2.15+/-1.9 mg/dL 1 month later (P=.011). All but one of the nine recipients, who lost his graft 3 months later (80% success) maintained function, with a serum creatinine of 2.1+/-1.4 mg/dL and Cockroft index of 61.3+/-34 mL/min at the end of follow up. During this time, none of the patients experienced an acute rejection episode and sirolimus was maintained without any remarkable secondary effect. Sirolimus seems to be a promising alternative for the treatment of renal transplant patients who develop calcineurin inhibitor-induced DnHUS.

Mast cells in chronic rejection of human renal allografts.

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.