Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus.

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3-8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. TRIAL REGISTRATION: NCT01025817.

Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients.

This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by

Investigator Assessment of the Utility of the TruGraf Molecular Diagnostic Test in Clinical Practice.

BACKGROUND: TruGraf v1 is a well-validated DNA microarray-based test that analyzes blood gene expression profiles as an indicator of immune status in kidney transplant recipients with stable renal function. METHODS: In this study, investigators assessed clinical utility of the TruGraf test in patient management. In a retrospective study, simultaneous blood tests and clinical assessments were performed in 192 patients at 7 transplant centers, and in a prospective observational study they were performed in 45 subjects at 5 transplant centers. RESULTS: When queried regarding whether or not the TruGraf test result impacted their decision regarding patient management, in 168 of 192 (87.5%) cases the investigator responded affirmatively. The prospective study indicated that TruGraf results supported physicians' decisions on patient management 87% (39/45) of the time, and in 93% of cases physicians indicated that they would use serial TruGraf testing in future patient management. A total of 21 of 39 (54%) reported results confirmed their decision that no intervention was needed, and 17 of 39 (44%) reported that results specifically informed them that a decision not to perform a surveillance biopsy was correct. CONCLUSIONS: TruGraf is the first and only noninvasive test to be evaluated for clinical utility in determining rejection status of patients with stable renal function and shows promise of providing support for clinical decisions to avoid unnecessary surveillance biopsies with a high degree of confidence. TruGraf is an invaluable addition to the transplant physician's tool kit for managing patient health by avoiding painful and invasive biopsies, reducing health care costs, and enabling frequent assessment of patients with stable renal function to confirm immune quiescence.

Application of TruGraf v1: A Novel Molecular Biomarker for Managing Kidney Transplant Recipients With Stable Renal Function.

TruGraf v1 is a laboratory-developed DNA microarray-based gene expression blood test to enable proactive noninvasive serial assessment of kidney transplant recipients with stable renal function. It has been previously validated in patients identified as Transplant eXcellence (TX: stable serum creatinine, normal biopsy results, indicative of immune quiescence), and not-TX (renal dysfunction and/or rejection on biopsy results). TruGraf v1 is intended for use in subjects with stable renal function to measure the immune status as an alternative to invasive, expensive, and risky surveillance biopsies. MATERIALS AND METHODS: In this study, simultaneous blood tests and clinical assessments were performed in 192 patients from 7 transplant centers to evaluate TruGraf v1. The molecular testing laboratory was blinded to renal function and biopsy results. RESULTS: Overall, TruGraf v1 accuracy (concordance between TruGraf v1 result and clinical and/or histologic assessment) was 74% (142/192), and a result of TX was accurate in 116 of 125 (93%). The negative predictive value for TruGraf v1 was 90%, with a sensitivity 74% and specificity of 73%. Results did not significantly differ in patients with a biopsy-confirmed diagnosis vs those without a biopsy. CONCLUSIONS: TruGraf v1 can potentially support a clinical decision enabling unnecessary surveillance biopsies with high confidence, making it an invaluable addition to the transplant physician's tool kit for managing patients. TruGraf v1 testing can potentially avoid painful and risky invasive biopsies, reduce health care costs, and enable frequent assessment of patients with stable renal function to confirm the presence of immune quiescence in the peripheral blood.

A blinded retrospective analysis of renal allograft pathology using the Banff schema: implications for clinical management.

BACKGROUND: We sought to determine whether diagnoses established through the Banff schema for evaluation of renal allograft pathology have implications for clinical management, compared with diagnoses established using descriptive terminology. METHODS: All patients included in this study had mild to severe allograft rejection diagnosed, and, as part of a therapeutic protocol, they received OKT3 as primary anti-rejection therapy. We conducted a retrospective review of their renal allograft biopsy specimens and reclassified them, using the Banff schema, without knowledge of clinical information, laboratory data, or previous biopsy interpretation. Although there is no strict correspondence between descriptive diagnostic terminology and the criteria used in the Banff schema, for the purpose of comparisons, the following approximation was used: mild and mild to moderate rejection=Banff borderline and Banff grade 1, moderate and moderate to severe rejection=Banff grades 2A and 2B, and severe rejection=Banff grade 3. The diagnosis was considered concordant when the diagnosis by descriptive terminology and Banff grading were within the adopted approximation. RESULTS: Of 96 biopsies specimens with mild to severe allograft rejection, 10 were insufficient for diagnosis, and three had changes of chronic allograft rejection. Of the remaining 83 biopsy specimens, 34 (41%) were concordant in interpretation of rejection grades, whereas 49 (59%) were discrepant. The greatest degree of concordance was in grades 2A (66.7%, 18 of 27) and 2B (64.7% 11 of 17), and the lowest was in the borderline category (11.8%, 2 of 17). The greatest degree of discrepancy was in normal and grade 3 (100%, 3 of 3 and 2 of 2, respectively), and the lowest was in grade 2A (33.3%, 9 of 27). Although primary anti-rejection therapy with OKT3 resulted in a high reversal rate of rejection (98%), there were 5 deaths, 12 graft loses, six episodes of serious infections, and three malignancies in this group of patients during a mean follow-up period of approximately 38 months. CONCLUSIONS: Because patients with borderline changes and grades 1 and 2A rejection may be treated differently from patients with higher grades (2B and 3), the use of the Banff schema may allow for better adjustment of immunosuppressive therapy in response to specific grades of acute allograft rejection and may result in decreased complications of immunosuppressive therapy.

Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection.

BACKGROUND: OKT3 is often used as primary treatment for acute renal allograft rejection. In a retrospective study, we sought to determine the efficacy of OKT3 as a first-line agent in reversing histologically confirmed acute renal allograft rejection. METHODS: Patients with mild to moderate, moderate, or severe acute cellular and acute vascular rejection who had not received any other anti-rejection treatment were included in this analysis. A total of 88 patients, who received OKT3 between 1987 and 1995, fulfilled these criteria. RESULT: Seventy of these patients were renal transplant recipients, and 18 were combined kidney and pancreas transplant recipients. The median time to the diagnosis of rejection from transplantation was 32 days (range, 6 days to 13 years). On histology, 6 were graded as mild to moderate, 36 as moderate, 29 as moderate to severe, and 17 as severe rejection. The mean baseline serum creatinine was 1.62 mg/dl (range, 0.7-10.1 mg/dl), and the mean serum creatinine at the time of diagnosis of rejection was 2.60 mg/dl (range, 1.4-12.7 mg/dl) (P=<0.0001). The mean duration of OKT3 treatment was 11.2 days (range, 8-18 days). The mean serum creatinine at the end of OKT3 treatment was 1.73 mg/dl (range, 0.6-5.0 mg/dl; P=0.24 compared with baseline serum creatinine). Rejection was reversed in 86 (98%) patients. Graft survival at 1 year after OKT3 therapy was 87.5% (77 of 88). At a mean follow-up of 38 months, 8 patients had died and 26 grafts were lost. The mean serum creatinine level in the 64 patients with a functioning graft was 1.76 mg/dl (range, 0.8-4.0 mg/dl) at the last follow-up. CONCLUSION: OKT3 when utilized as first-line therapy reversed 98% of the acute rejection episodes, with a 1-year post-OKT3 graft survival of 87.5%.

MALToma: a Helicobacter pylori-associated malignancy in transplant patients: a report from the Israel Penn International Transplant Tumor Registry with a review of published literature.

BACKGROUND: Mucosa-associated lymphoid tissue lymphoma (MALToma) is a Helicobacter pylori-related tumor of B-cell origin, the malignant potential for which remains to be defined in immunosuppressed patients. METHODS: Review of the Israel Penn International Transplant Tumor Registry identified six cases of gastric MALToma. Patient demographics, management, and outcomes were compared and published literature was reviewed. RESULTS: MALToma developed in six transplant recipients (three kidney, two heart, one kidney-pancreas). All were treated with immunosuppression minimization and therapy for H. pylori, resulting in disease regression in five patients. One patient developed progression to high-grade MALToma despite documented H. pylori eradication, required surgery and chemotherapy, and died, with significant disease at autopsy. CONCLUSIONS: Treatment of MALToma with immunosuppression minimization and anti-H. pylori therapy results in a majority of patients becoming disease free. Observation of malignant degeneration into an aggressive, high-grade lymphoma in one patient indicates the malignant potential. Diligent follow-up of these patients with endoscopy and biopsy is therefore indicated.

Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR).

INTRODUCTION: Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS: From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION: In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

Characteristics of long-term renal transplant survivors.

Despite the high rates of rejection, allograft failure, and patient death in the early years of renal transplantation, some patients have done remarkably well. Forty-three (17 living related donor and 26 cadaver donor recipients) such patients with an allograft that functioned for 19 years or more (range, 19 to 29 years) were followed up at this center. The patients included 24 men and 19 women, with a mean age at transplantation of 29 years, of whom 39 were white and four were black. At most recent follow-up, the mean daily dose of azathioprine was 104 mg (range, 50 to 175 mg) and that of prednisone was 10 mg (range, 5 to 20 mg). Mean serum creatinine level was 1.6 mg/dL (range, 0.7 to 5.4 mg/dL). Acute rejection occurred in 14 (33%) patients. Nine patients had one episode and five patients had two episodes of acute rejection. Long-term risks to the recipients appeared in the form of coronary artery disease in 10 (23%) patients; malignancy in 13 (30%) patients, which included nine patients with skin malignancy; and chronic hepatitis C virus (HCV) infection in four patients, two of whom died of complications of liver failure. Other complications included avascular bone necrosis in five patients, which required total hip replacement in two patients; hyperlipidemia requiring treatment in 16 (37%) patients; posttransplantation diabetes mellitus in 10 (23%) patients after a median of 17.5 years (range, 1 to 23 years); and hypertension in 23 (53%) patients. There were seven deaths (three of coronary artery disease, two of liver failure, one each of sepsis and malignancy) and eight graft losses (five to death with function, two to chronic rejection, and one to focal and segmental glomerulosclerosis). Although long-term allograft success results in patients receiving minimal amounts of immunosuppression and having good renal function, long-term renal transplant survivors are at risk for significant morbidity even in the third decade posttransplantation.

Immediate allograft dysfunction due to atheroembolic disease.

Atheroembolic disease is a known cause of renal failure following invasive vascular procedures in patients with atherosclerosis. It is, however, not generally associated with renal transplant dysfunction. We report on a case of donor-transmitted atheroembolic renal disease, which led to an immediate loss of the transplant kidney in the operating room. Risk factors associated with this condition and methods to prevent this complication are discussed.

Recurrent and de novo renal diseases after renal transplantation: a report from the renal allograft disease registry.

Recurrent or de novo glomerular disease is an important cause of graft dysfunction and eventual loss. Cyclosporine A (CyA) has improved short-term renal allograft outcome but has not altered long-term graft survival. The purpose of the current study is to determine the prevalence of such disease and its impact on graft function in the CyA era. From 1984 to 1994, 1,557 renal allografts were performed at the Medical College of Wisconsin and the University of Cincinnati. Patients were followed up for an average of 7.2 years (minimum, 1 year). Recurrent disease was diagnosed by renal biopsy in 98 (6.3%) patients after an average of 36 months. Demographic characteristics of patients with and without recurrent disease were similar. Glomerulonephritis was the most common finding, occurring in 73 patients, and included focal segmental glomerulosclerosis (FSGS), 25; IgA nephropathy (IgAN), 11; membranous (MN), 11; proliferative, 11; membranoproliferative glomerulonephritis (MPGN), 10; glomerular basement membrane (anti-GBM), 3; and systemic lupus erythematosus (SLE), two. Diabetic nephropathy was present in 22, hemolytic uremic syndrome (HUS) in two, and oxalosis in one. Graft loss occurred in 60 of 98 (61%) recipients. Half-life of the allograft was diminished in patients with recurrent disease, 2,038 +/- 225 versus 3,135 +/- 385 days, P = 0.002. The actuarial allograft survival at 1, 3, 5, and 8 years posttransplantation with recurrence was 88%, 74%, 57%, and 34%, respectively; and the corresponding graft survival for patients without recurrent disease was 80%, 70%, 64%, and 53%, respectively (P = 0.003). The risk of recurrent disease increased with length of graft survival from 2.8% at 2 years to 9.8% and 18.5% at 5 and 8 years, respectively. We conclude that recurrent disease is a significant problem after renal transplantation and is associated with decreased graft survival.

Primary care of patients with renal transplants.

The number of renal transplant recipients in the community continues to rise due to improved organ and patient survival. With increasing emphasis on primary care, more organ transplant recipients are being cared for by primary care physicians. This article outlines the management of renal transplant recipients and reviews the problems unique to this group of patients.