Chronic Calcineurin Inhibitor Research Articles

Longitudinal analysis of chronic allograft nephropathy: Clinicopathologic correlations

Loss of the allograft from chronic allograft nephropathy and death of the patient from vascular, malignant, or infective disease are the major problems in renal transplantation today. Protocol biopsy of the long-term kidney has provided new data with which to develop strategies for prevention and treatment of chronic allograft nephropathy. Two series of long-term protocol biopsies are reviewed. In the first, renal biopsies were obtained at time 0, and at 3 months and 12 months, and the recipients of the renal allografts were followed up for up to 15 years. In the second, the kidneys of recipients of simultaneous pancreas kidney transplants were biopsied annually for 10 years, and the results correlated with clinical events. Chronic allograft nephropathy is caused by acute and chronic immune-mediated damage, as well as by chronic calcineurin inhibitor nephrotoxicity. Both immune and nonimmune mechanisms exacerbate pre-existing donor disease and ischemia-reperfusion injury. Established interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerular sclerosis and eventual loss of the graft. Protocol biopsies have shown that clinical parameters of renal function underestimate the severity of chronic graft damage. Strategies for preventing or treating chronic renal allograft dysfunction and subsequent graft loss must better control rejection and simultaneously avoid nephrotoxicity.

Freedom From Graft Vessel Disease in Heart and Combined Heart- and Kidney-transplanted Patients Treated With Tacrolimus-based Immunosuppression

In end-stage cardiomyopathy where concomitant chronic renal failure is a contraindication for cardiac transplantation (HTx), simultaneous heart and kidney transplantation (HKTx) may be the only feasible therapeutic option. Due to the increased donor shortage, the clinical outcome of combined HKTx patients on tacrolimus-based immunosuppression was assessed and compared with a group of HTx patients. Three hundred forty-nine HTxs, including 13 (4%) combined HKTxs, were performed since 1995. Two hundred twenty-one HTx and all HKTx recipients received tacrolimus-based immunosuppression. Acute rejection episodes (AREs), infections, renal function and clinical outcome were evaluated. Pre-operative renal diagnoses for HKTx patients included cystic nephropathy (n = 4), glomerulonephritis (n = 4), cytostatica-induced nephropathy (n = 1), chronic rejection after renal transplant (n = 1), reflux nephropathy (n = 2) and chronic calcineurin-inhibitor -induced nephropathy after HTx (n = 1). Twelve patients (92%) were on hemodialysis pre-operatively, 1 underwent implantation of a left ventricular assist device (LVAD) before HKTx. After 4.7 +/- 2 years, 92% of HKTx compared with 85% of HTx patients had survived (p = 0.42). Acute cardiac rejection episodes were more frequent in HTx than in HKTx patients (0.04 +/- 0.09 vs 0.02 +/- 0.04 ARE/100 patient-days; p = 0.07). Incidence of infection was comparable (0.3 +/- 0.2 vs 0.5 +/- 0.4 infection/100 patient-days). Freedom from transplant vasculopathy was 100% in the HKTx group compared with 71% in the HTx group after 4 years (p = 0.04). Tacrolimus-based immunosuppression yields promising long-term results in HKTx and HTx. The incidence of transplant vasculopathy seems to be lower after HKTx than after HTx. If these results are secondary to a protective effect of tacrolimus-induced tolerance or of tolerance-associated co-transplantation they will need to be investigated in prospective multicenter trials.

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal

Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus

Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients. In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion. After a mean post-conversion follow-up of 27+/-1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4+/-14.9 to 53+/-16.3 ml/min at D30 (P = 0.01), and to 54.7+/-20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7+/-21.7, 52.8+/-20 and 51.7+/-20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P < 0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30. Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.

Sirolimus‐Induced Thrombotic Microangiopathy is Associated with Decreased Expression of Vascular Endothelial Growth Factor in Kidneys

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.

Is chronic calcineurin inhibitor toxicity responsible for long-term deterioration of renal function in transplant recipients?

Dose reduction or discontinuation of calcineurin inhibitors (CIs) in renal allograft recipients results in a measurable improvement in renal function, as assessed by a decrease in serum creatinine or improvement in glomerular filtration rate. In general, this effect has been presumed to result from a discontinuation of the acute vasoconstrictive action of CIs on the afferent arteriole. Does it reflect the resolution of chronic CI toxicity? Does chronic CI toxicity explain part of the syndrome of chronic allograft nephropathy (CAN)? We have observed evidence of a continued improvement in renal function or a lack of further deterioration after CI dose reduction or discontinuation in patients with CAN. This improvement in renal function remains evident for up to several years after the intervention and is observed even when the period of acute vasoconstriction (6 months after intervention; the period when the greatest rate of change occurs) is taken into account. These findings suggest a detrimental effect of CIs on renal function that may be, at least in part, reversible and independent of vasoconstriction. In this review, we examine the data concerning the relationship between CI and chronic graft dysfunction.

IV.2.1 Differential diagnosis of chronic graft dysfunction

A. Any significant deterioration in graft function should be investigated using the appropriate diagnostic tools and, if possible, therapeutic interventions should be initiated. The usual causes of a decline in glomerular filtration rate after the first year include transplant‐specific causes such as chronic allograft nephropathy, acute rejection episodes, chronic calcineurin inhibitor nephrotoxicity, transplant renal artery stenosis and ureteric obstruction, as well as immunodeficiency‐related causes and non‐transplant‐related causes, such as recurrent or de novo renal diseases and bacterial infections.

Calcineurin inhibitors and chronic renal allograft dysfunction: Not enough or too much?

The calcineurin inhibitors cyclosporin A and tacrolimus are currently the most widely prescribed drugs for maintenance immunosuppression after renal transplantation. The dose-limiting side effect is their nephrotoxicity. Because chronic calcineurin inhibitor nephrotoxicity resembles chronic rejection, we sought to describe the differences between these 2 conditions. We furthermore consider the value of the current practice to dose calcineurin inhibitors on trough levels, and the possibility that part of the graft's loses in the late posttransplant period are because of chronic calcineurin-inhibitor toxicity rather than chronic rejection. However, although long-term calcineurin inhibitors cause structural and functional impairment, calcineurin-inhibitor nephrotoxicity alone is rarely the cause of graft failure in renal transplant recipients after several years of follow-up.

Histopathological evaluation of renal allograft biopsies in Nepal: interpretation and significance

Background: Renal allograft biopsy remains the gold standard for the diagnosis of graft dysfunction. Protocol renal allograft biopsies have provided insights into pathogenesis of early and late allograft injury and guided clinical management. The aim of this study was to find out the causes of early and late graft dysfunction in renal allograft biopsies taken at different time points after transplantation. Materials and Methods: Between August 2008 and February 2011, a total of 98 renal allograft biopsies from 62 kidney transplants recipients were received in the department of Pathology, KIST Medical College and Teaching Hospital. Renal allograft biopsies were interpreted according to the Schemes of Banff ’09 update. Results: The maximum numbers of recipients were in the age group of 31-40 years. Age ranges from 16 to 61 years. Out of 62 recipients, there were 47(75.8%) males and 15 (24.2%) females. The time of biopsy ranges from 0 hour to 6 years after transplantation. There were 9 (9.18%) cases of acute T cell-mediated rejection, 8 (8.16%) cases of acute antibody-mediated rejection, 6 (6.12%) cases of acute ischemic injury, 6 (6.12%) cases of borderline lesions and 4 (4.08%) cases of chronic calcineurin inhibitor toxicity. Conclusion: In the early post-transplant period (0-6 months), acute antibody-mediated rejection, acute ischemic injury and T cell-mediated rejection are the major causes for graft dysfunction. In the late post transplant period (&gt; 6 months after transplant), transplant glomerulopathy, chronic calcineurin inhibitor toxicity, viral infections and graft senescence including donor derived disease result in poor late graft survival.DOI: http://dx.doi.org/10.3126/jpn.v2i3.6016 JPN 2012; 2(3): 172-179