Calcineurin Inhibitor Withdrawal Research Articles

Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies.

Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.

Prospective Study of Everolimus With Calcineurin Inhibitor-Free Immunosuppression After Heart Transplantation: Results at Four Years

Immunosuppression is necessary after transplantation but it is associated with distinct adverse side effects. These negative effects could at least partially be overcome with the mammalian target of Rapamycin (mTOR) inhibitor everolimus. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients (HTx). In this prospective, single-arm, single-center study, maintenance patients after HTx were converted from CNI to everolimus. They were followed for 48 months. Primary endpoints were kidney-function and arterial hypertension. Forty-eight patients were recruited (mean post-transplant time 5.4 ± 3.5 years). Of these, 36 were followed for the entire 4-year period. Median calculated glomerular filtration rate increased from 40.7 (32.4 to 59.1) mL/minute at baseline to 48.9 (29.7 to 67)) mL/minute at month 48 (p = not significant). Median systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol, did not change significantly in a comparison of the values at baseline and at 48 months. Early resolution of most non-renal CNI-related adverse events was sustained. Due to adverse events, CNI therapy had to be reintroduced in 6 patients (12.5%). No significant changes in cardiac function parameters were observed. Calcineurin inhibitor-free immunosuppression with everolimus is an effective and safe option in selected maintenance HTx patients. Most adverse effects under everolimus occurred early after conversion and in most cases resolved without intervention within a few weeks. Refining selection criteria may help both in identifying patients who will profit most from switching and in alleviating the need to reintroduce CNI therapy.

Long‐term clinicopathological impact of calcineurin inhibitor cessation without specific cytoreductive induction in kidney transplantation

Calcineurin inhibitors (CNIs) have considerably improved renal allograft survival. However, their chronic use has various adverse effects, including hypertension, hyperlipidemia, and nephrotoxicity. We conducted a retrospective study of kidney transplant recipients using a CNI withdrawal protocol. Eleven of 13 patients who had stable graft function on triple-drug therapy including a cyclosporine (CsA) were enrolled in this study. The dose of CsA was reduced by 20% every two wks until complete withdrawal. The mean period between the baseline and last biopsies was 97 (range: 21-123) months. No patient had an acute rejection episode during follow-up. Progression of interstitial fibrosis and tubular atrophy was seen in five and six cases, respectively. Arteriolar hyalinosis improved in three cases, but worsened in four. No patient lost his graft during the study. The mean serum creatinine level was 1.30 ± 0.26 mg/dL at baseline and stable for 10 yr after elimination (1.26 ± 0.11 mg/dL). At the end of the study, four of the eleven patients had reduced their antihypertensive drugs, and one patient had stopped hyperlipidemia treatment. CNI withdrawal can be implemented safely in stable renal transplant recipients and might lead to improved patient outcomes. Additional specific evidence of CNI nephrotoxicity should be elucidated.

Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor–dependent idiopathic nephrotic syndrome

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Impact of Late Calcineurin Inhibitor Withdrawal on Ambulatory Blood Pressure and Carotid Intima Media Thickness in Renal Transplant Recipients

Calcineurin inhibitors (CNIs) have an unfavorable cardiovascular risk profile in renal transplant recipients. The aim of this substudy was to assess the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on ambulatory blood pressure monitoring and carotid intima media thickness. A total of 119 stable renal transplant recipients on triple regimen with steroids, a CNI and MMF were randomized into either the concentration-controlled CNI or MMF withdrawal groups. Patients were treated for traditional cardiovascular risk factors according to predefined targets. Ambulatory blood pressure monitoring and measurements of intima media thickness were performed at baseline and after 1, 2, and 3 years after randomization. CNI withdrawal resulted in a significant decline in both ambulatory day- and nighttime blood pressures (daytime: systolic blood pressure, -1.6 mm Hg/y, P=0.018; diastolic blood pressure, -1.3 mm Hg/y, P=0.002; nighttime systolic blood pressure: -1.9 mm Hg/y, P=0.008; diastolic blood pressure: -1.3 mm Hg/y, P=0.014), which was not observed after MMF withdrawal. There was no difference in the proportion of nocturnal nondippers (both groups, 69%, P=0.95). Despite the reduction in ambulatory blood pressure, no effect of CNI withdrawal on carotid intima media thickness was found. In stable renal transplant recipients, late CNI withdrawal from a triple drug regimen decreased blood pressure in comparison with MMF withdrawal but had no specific impact on carotid intima media thickness. Considering the high prevalence of hypertension in patients on CNI therapy, most stable renal transplant recipients may benefit from late CNI withdrawal by improved blood pressure control.

Calcineurin Inhibitor Conversion to Rapamycin Can Improve Graft Function in Living Donor Kidney Transplantation With Older Donors

BackgroundRecipients of living donor kidney transplantations from older donors often experience a lower glomerular filtration rate (GFR) than those from young donors. Calcineurin inhibitors (CNI) may cause nephrotoxicity, especially in recipients of older donor organs. The aim of this study was to investigate whether CNI withdrawal and conversion to rapamycin improved graft function among transplantation recipients of living donor kidneys from older donors. MethodsWe collected 83 living donor kidney transplantations using donors aged >50 years from January 2004 to December 2009, including 25 who underwent conversion to rapamycin at the end of 3 months, while 58 cases were maintained on CNI. Baseline characteristics, complications, and graft functions were compared between the groups. ResultsDonor age, recipient age, body weight, human leukocyte antigen mismatch, delayed graft function, acute rejection rate, serum creatinine, and estimated GFR were comparable between the 2 groups at the end of 3 months. The 1-year serum creatinine were 111.8 ± 25.5 μmol/L in CNI withdrawal versus 132.5 ± 35.9 μmol/L in the CNI-maintained group (P = .013) with 1-year estimated GFR of 86.9 ± 8.2 mL/min versus 77.4 ± 7.2 mL/min and 3-year estimated GFR of 76.1 ± 7.8 mL/min versus 67.0 ± 6.4 mL/min, respectively (both P < .001). The rates of acute rejection were 24% versus 22.4%, and chronic rejection, 4.0% versus 10.3% respectively (P > .05). One CNI withdrawal patient (4.0%) lost the graft function while 4 (6.9%) did so in the CNI-maintained group (P > .05). Logistic multivariate regression showed that maintained CNI usage, acute rejection episodes, and female donors to male recipients were independent risk factors for abnormal 1-year serum creatinine levels (P < .05). ConclusionCNI withdrawal with conversion to rapamycin improved graft function in living donor kidney transplantations from older donors.

Late Calcineurin Inhibitor Withdrawal Prevents Progressive Left Ventricular Diastolic Dysfunction in Renal Transplant Recipients

Late Calcineurin Inhibitor Withdrawal Prevents Progressive Left Ventricular Diastolic Dysfunction in Renal Transplant Recipients

Are There Differences in the Development of Proteinuria after Everolimus Initiation and Calcineurin Withdrawal or Not in Heart Transplantation?

Purpose Proliferation signal inhibitors(PSI) used after heart transplantation(HT) are useful in long-term complications. Proteinuria associated with use of PSI and possible deterioration of renal function may be related to use of calcineurin inhibitors (CNI). Purpose To determine the incidence of proteinuria after 1year of initiation everolimus (EVE) and analyze its relationship with CNI withdrawal and type of CNI. Methods and Materials Retrospective study of 54HT patients receiving EVE in late phase. 4patients were excluded due to basal pathological proteinuria and 7patients for CNI reintroduction. Immunosuppression was Cyclosporine (CyA) vs Tacrolimus (FK), MMF vs Azathioprine and prednisone. Proterinuria was determined using urine dipstick method and value Results 43HT patients analyzed(91% men, mean age 61±11 years), mean time between HT-EVE starting 5,5±4,8 years, CNI was discontinued in 10patients. Mean time of CNI withdrawal 24.7±17,4 days. Mean initial proteinuria(pre-EVE): 13’1 mg/dl(1,5-29,8). Incidence of proteinuria after EVE starting in patients with CNI/non-CNI at 3, 6 and 12 months was: 6(18%)/2(20%); 7(21%)/2(22%); 10(31%)/5(56%),p=NS; and with a median of 15,5(4-93)/25’5 (4-61); 15(7-53)/14(4-98); 19(7,7-93)/27(5-132), p=NS. Regarding to the CNI type (n=33; CyA12 and FK21), the incidence of proteinuria at 3,6 and 12 months in patients with CyA/FK was: 3(25%)/3(14%); 3(25%)/4(19%); 4(33%)/6(30%); and with a median of 19(8-33)/15(4-93); 14(9-52)/18(7-48); 22(8-92)/16(8-64), p=NS. Conclusions Incidence of proteinuria after 1year of EVE initiation in long-term HT is 34,8%. Combination of CNI with EVE does not increase significantly the development of proteinuria, although an increasing trend in the CNI withdrawal is observed. Comparison between CyA/FK also showed no significant differences. Further studies are needed to corroborate this hypothesis.

Long-Term Renoprotective Effect of Sirolimus-Based Calcineurin Inhibitor-Free Immunosuppression after Cardiac Transplantation

Purpose There are few data about long-term renal effect of calcineurin inhibitor (CNI) withdrawal and substitution with sirolimus (SRL) after heart transplantation (HTPL). We evaluated long-term effect of SRL-based CNI-free immunosuppression using iothalamate clearance (Ci) test. Methods and Materials We evaluated 199 patients whose Ci was followed regularly after HTPL. We excluded patients with combined other organ transplantation, systemic renal disease, irregular follow-up and age 40 months and as CNI group (n=77) if CNI was not discontinued. Patients who used CNI and SRL simultaneously (n=11) or who used SRL 60 months later. Results Baseline Ci of SRL group was not significantly different between groups. In SRL group, Ci was significantly increased at 12 month (63±23 ml/min/m²) compared to baseline (54±21 ml/min/m², p=0.019) and maintained thereafter. However, Ci was significantly reduced at 30 month (51±16 ml/min/m²) compared to baseline (60±18 ml/min/m², p=0.001) in CNI group. [ figure 1 ] Among 166 patients who tried SRL substitution for CNI, 38 (22.9%) could not tolerate SRL and major causes were lung infiltration (5.4%) and diarrhea (5.4%) followed by malaise (4.8%) and edema (2.4%). Conclusions Sirolimus-based CNI-free regimen is useful for the preservation of renal function in long-term follow-up after HTPL. However, as intolerance rate of SRL is significant, careful assessment of side effect in individual patient is mandatory.

End of the Line for Sirolimus in Liver Transplant Recipients With Hepatitis C Virus?

We read with interest the article by Watt et al.1 about the impact of sirolimus (SRL)-based immunosuppression on patient and graft survival among recipients of liver transplantation (LT) with hepatitis C virus (HCV), and we commend their efforts in trying to shed some light on the mechanisms linking immunosuppression to the risk of HCV-related graft failure. However, we are convinced that the results of their analysis do not provide evidence against the use of SRL and mammalian target of rapamycin (mTOR) inhibitors in general in HCV-positive LT recipients. Despite Watt et al.'s attempt,1 capturing the complexity of posttransplant immunosuppression is a challenging task that cannot be remedied by the use of propensity score matching analysis alone. Concerns about the use of propensity score matching have been raised recently: hidden bias may increase because the matching of patient samples by observed variables (ie, HCV versus non-HCV) may generate further bias on account of latent, unobserved, and/or underestimated confounders.2 Because of the Food and Drug Administration's black-box warning for SRL in LT, its use may deliberately have been reserved for patients with poorer prognoses and/or multiple risk factors beyond HCV infection, such as renal failure, expanded criteria donors, hepatocellular carcinoma (eg, grade, stage, and microvascular invasion), de novo and recurrent malignancies, and cardiovascular/metabolic complications at any time during the posttransplant period. Furthermore, information on SRL trough levels, overall patient exposure, and the mode of calcineurin inhibitor withdrawal is missing in Watt et al.'s analysis, as are histological data on the severity of HCV recurrence. Evidence against the dismissal of mTOR inhibitors in HCV-positive LT recipients is accumulating in the international literature. A recent retrospective analysis of HCV patients on SRL showed significantly less advanced fibrosis (stage ≥ 2) in comparison with an HCV control group at 1 and 2 years (30.1% versus 50.5%, P = 0.001), with no difference in patient survival at 1 year (92.5% versus 87.9%, P = 0.15) and 5 years.3 A recent prospective randomized controlled trial of using everolimus (EVR) to minimize tacrolimus (TAC) in de novo LT recipients has shown that the use of EVR is associated with fewer and less severe acute rejection episodes, similar patient and graft survival, and superior renal function at 12 months in comparison with standard-exposure TAC.4 HCV-positive patients on EVR fared as the overall population did with respect to efficacy and renal function, and there were comparable changes in the viral load from the time of randomization to month 12 in comparison with the TAC group. EVR with minimized TAC was also associated with numerically (but not statistically) more stable liver fibrosis and comparable necroinflammatory scores.4, 5 Altogether, these results challenge Watt et al.'s conclusions1 and argue for cautiously interpreting data derived from large databases and for addressing the need for more properly designed longitudinal studies before the use of mTOR inhibitors in HCV-positive patients is dismissed. We believe that transplant physicians have acquired experience with mTOR inhibitors over the last years and that the results of Watt et al.'s study reflect a learning-curve effect and an initial misuse of mTOR inhibitors in the patients with poorest outcomes. Paolo De Simone, M.D.1 Faouzi Saliba, M.D., Ph.D.2 Lutz Fischer, M.D.3 1Hepato-Biliary Surgery and Liver Transplantation University of Pisa Medical School Hospital Pisa, Italy 2Hepato-Biliary Center Paul Brousse Hospital (Public Hospital System of Paris) University of Paris-Sud Villejuif, France 3Department of Hepatobiliary and Transplant Surgery University Medical Center Hamburg-Eppendorf, Germany

Safety and efficacy of everolimus in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is a major cause of late kidney allograft loss. Everolimus, a novel proliferation signal inhibitor, ameliorates CAN by its antiproliferative or apoptosis-enhancing effects. This study aims to evaluate the safety and efficacy of everolimus in renal transplant recipients with calcineurin inhibitor (CNI) withdrawal either due to CAN or cal-cineurin inhibitor toxicity (CNIT). A total 21 patients with CAN or CNIT converted from CNI to everolimus were prospectively studied from 2006 to 2009. There were 19 males and two females, with a mean age of 32.9 ± 10.7 years. Eight patients had chronic interstitial nephritis, three had diabetes mellitus, nine had end-stage renal disease and one had focal segmental glomerulosclerosis as native kidney disease. The mean duration of dialysis was 10.7 ± 7 months. 57.2% of the patients had CAN and 42.8% had CNIT. Everolimus was started within six months of post-transplantation in six patients, within 6-12 months in two patients, within 1-2 years in four patients and after more than 2 years in nine patients. The mean dose at first month was 1.25 mg/day, at six month was 1.028 ± 0.3 mg/day and at 12 th month was 0.97 ± 0.2 mg/day, with a mean trough level of 6.35 ± 3 ng/dL, 5.18 ± 3 ng/dL and 6.43 ± 1.7 ng/dL, respectively. At the 12 th month, serum creatinine declined from 2.07 ± 0.58 mg/dL to 1.65 ± 0.81 mg/dL. The mean calculated glomerular filtration rate improved from 40.85 ± 8.8 mL/min to 56.84 ± 11.4 mL/min. No major side-effects were observed. Everolimus along with mycophenolate mofetil or azathioprine and prednisolone as a maintenance immunosuppressive therapy was found to be effective and safe in patients with CNIs withdrawal either due to CAN or CNIT.

Improvement of Renal Graft Function After Conversion From a Calcineurin Inhibitor Including Immunosuppression to a Mycophenolate Sodium Including Regimen: A 4-year Follow-up

BackgroundThe most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs. MethodsIn the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test. ResultsThe mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects. ConclusionThese data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.

Modern Immunosuppressive Therapy in Kidney Transplantation

Immunosuppressive therapy is a key component for successful kidney transplantation. It is commonly believed that more intensive immunosuppression is needed initially to prevent rejection episodes and less immunosuppression is subsequently maintained to minimize the overall risk of infection and malignancy. The selection of drugs should be guided by a comprehensive assessment of the immunologic risk, patient comorbidities, financial cost, drug efficacy and adverse effects. Lymphocyte-depleting antibody induction is recommended for patients with high immunologic risk, while IL-2R antibody can be used for low or moderate risk patients. Patients with very low risk may be induced with intravenous steroids without using an antibody. A maintenance regimen typically consists of a low-dose of steroid combined with two of the four class drugs: calcineurin inhibitor (tacrolimus or cyclosporine), antimetabolite (mycophenolate mofetil or enteric coated mycophenolate sodium), mTOR inhibitor (sirolimus or everolimus) and costimulation blocker (belatacept). Currently in the USA, the most popular maintenance is the combination of corticosteroid, mycophenolic acid and tacrolimus. Steroid minimization, or calcineurin inhibitor free or withdrawal should be limited to the highly selected patients with low immunological risk. Recently, the novel biological agent belatacept-based maintenance has demonstrated a significantly better renal function and improved cardiovascular and metabolic profile, which may provide hope for an ultimate survival benefit.

Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

Michael R. Lucey, Norah Terrault, Lolu Ojo, J. Eileen Hay, James Neuberger, Emily Blumberg, and Lewis W. Teperman Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Gastroenterology Division, Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI; Mayo Clinic, Rochester, MN; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Surgery, NYU Transplant Associates, New York, NY

Renal Function Improvement After Conversion to Proliferation Signal Inhibitors During Long-Term Follow-up in Heart Transplant Recipients

IntroductionThe use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function. MethodsThis prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion. ResultsNinety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04). ConclusionDespite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

Renal Function of an Everolimus Based Therapy after Calcineurin Inhibitor Withdrawal in Maintenance Renal Transplant Recipients: 3 Year Data of the APOLLO Trial

Objective: Assessment of renal function, safety and efficacy of an Everolimus (EVE) regimen after Calcineurin-Inhibitor (CNI) withdrawal in maintenance kidney allograft recipients. Methods: In an open-label, randomized, controlled, multi-center study 93 patients on a stable immunosuppressive therapy consisting of CNI, Enteric-Coated Mycophenolate Sodium (EC-MPS) with or without corticosteroids were randomized to either continue CNI treatment and EC-MPS or convert to an EVE/EC-MPS based regimen. After completion of the core study at Mo 12, patients were included in an observational follow-up study. Results: 93 pts with a mean time since the most recent transplantation of 6.4 years were randomized to either EVE/EC-MPS (n=46) or CNI/EC-MPS (n=47), 74 (79.6%) pts completed the 36 month visit. Trough levels were 98.1 ± 48.8 ng/ml in CsA, 5.4 ± 1.9 ng/ml in Tacrolimus and 6.4 ± 1.9 ng/ml in EVE treated pts. At Month 36 after randomization mean calculated GFR (Nankivell) was higher by 3.8 mL/min/1.73m2 for the EVE compared to the CNI group (60.5 ± 21.0 vs 56.7 ± 19.6 mL/min/1.73m2; p=n.s.). EVE pts remaining on their assigned treatment had a better renal function (7.9 min/1.73m2, 68.0 ± 19.9 (n=25) vs 60.1 ± 14.7 mL/min/1.73m2(n=31); p=0.08). The observed GFR change from conversion to month 36 was +5.2 [95% CI: -0.6;+10.9] for EVE/EC-MPS and 0.3 [95% CI: -4.7;+5.2] mL/min/1.73m2 for CNI/EC-MPS pts. Three deaths and one graft loss were observed in the CNI/EC-MPS group, one death and one graft loss in the EVE/EC-MPS group and no BPAR was observed in either group. The number of patients with infections was 9 pts (19.6%) in the EVE vs. 8 pts (17.0%) in the CsA group. Four (8.5%) malignancies occurred in the CNI group compared to one (4.3%) case in the EVE group. Conclusions: The late conversion to an EVE/EC-MPS treatment in maintenance renal transplant patients after CNI withdrawal is safe and associated with a tendency towards better renal function after 3 years. [cmy1].

Improved Renal Function of an Everolimus/Enteric-Coated Mycophenolate Sodium Regimen after Calcineurin Inhibitor Withdrawal in de Novo Renal Transplant Patients: 4 Years Follow-Up of the ZEUS Trial

Improved Renal Function of an Everolimus/Enteric-Coated Mycophenolate Sodium Regimen after Calcineurin Inhibitor Withdrawal in de Novo Renal Transplant Patients: 4 Years Follow-Up of the ZEUS Trial

Late Calcineurin Inhibitor Withdrawal Prevents Progressive Left Ventricular Diastolic Dysfunction in Renal Transplant Recipients

Calcineurin inhibitor (CNI)-based therapy is associated with adverse cardiovascular effects. We examined the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on echocardiographic parameters. This study was conducted as a substudy of a randomized trial in stable renal transplant recipients who were on a triple CNI-based regimen with prednisone and MMF that evaluated late concentration-controlled withdrawal of CNI or MMF on renal function. A total of 108 patients (age, 52.3±11.5 years; 67% male; at a median of 2.0 years post-transplantation, (interquartile range 1.3-3.3 years); estimated glomerular filtration rate, 57±16 mL/min/1.73 m; 66% on cyclosporine and 34% on tacrolimus) entered the cardiovascular substudy examining echocardiographic parameters at baseline and 2 years after randomization. In all patients, traditional cardiovascular risk factors were treated according to predefined targets. Late CNI withdrawal prevented progressive development of left ventricular (LV) diastolic dysfunction, as assessed by markers of LV diastolic function (mitral deceleration time and mitral annular e' velocity). Conversely, in the MMF-withdrawal group, the left atrial volume index (an indicator of chronic LV diastolic dysfunction) was significantly increased at 2 years (from 24.1±6.7 to 27.0±7.0 mL/m, P<0.05). In addition, CNI withdrawal resulted in a higher proportion of patients achieving the predefined blood pressure targets (<130/85 mm Hg: 41.5% vs. 12.7%, P=0.001) at 2 years while requiring less antihypertensive drugs. Changes in the left atrial volume index were significantly associated with treatment arm (P=0.03) and changes in systolic (P=0.005) and diastolic (P=0.005) blood pressure. Late CNI withdrawal, from a triple-drug regimen in stable renal transplant recipients, prevented progressive deterioration of LV diastolic function and facilitated better blood pressure control.