Elizabeth Kendrick

Sirolimus-associated pulmonary toxicity

Background. Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. Methods. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. Results. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. Conclusion. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure

The histologic associations and clinical implications of peritubular capillary C4d staining from long-term renal allografts are unknown. We identified 99 renal transplant patients who underwent an allograft biopsy for renal dysfunction at least 10 yr after transplantation, 25 of whom were C4d-positive and 74 of whom were C4d-negative. The average time of the index biopsy from transplantation was 14 yr in both groups. Compared with C4d-negative patients, C4d-positive patients were younger at transplantation (29 +/- 13 versus 38 +/- 12 yr; P < 0.05) and were more likely to have received an allograft from a living donor (65 versus 35%; P < 0.001). C4d-positive patients had more inflammation, were more likely to have transplant glomerulopathy, and had worse graft outcome. The combined presence of C4d positivity, transplant glomerulopathy, and serum creatinine of >2.3 mg/dl at biopsy were very strong predictors of rapid graft loss. C4d alone did not independently predict graft loss. Retrospective staining of historical samples from C4d-positive patients demonstrated C4d deposition in the majority of cases. In summary, these data show that in long-term renal allografts, peritubular capillary staining for C4d occurs in approximately 25% of biopsies, can persist for many years after transplantation, and strongly predicts graft loss when combined with transplant glomerulopathy.

Renal disease in hepatitis C-positive liver transplant recipients.

Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.

Higher Levels of Leflunomide Are Associated with Hemolysis and Are not Superior to Lower Levels for BK Virus Clearance in Renal Transplant Patients

BACKGROUND AND OBJECTIVES Leflunomide use in renal transplantation has been increasing. Outcome correlation and safety data are still to be refined. The goals of this study were to report one centers experience with leflunomide, specifically the correlation of leflunomide levels with the outcomes of BK nephropathy and the observed toxic effects during the treatment with leflunomide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Leflunomide was used in 21 patients with BK nephropathy. These patients were divided into two groups on the basis of the leflunomide levels achieved: Low-level group (<40 microg/ml) and high-level group (>40 microg/ml). RESULTS During 13 mo of follow-up, there was no difference in the rate of serum BK viral clearance between the groups. There were three graft losses in the low-level group and one in the high-level group; however, creatinine levels were higher at the time of starting leflunomide in the low-level group. Leflunomide was also used in six patients with chronic allograft injury. No graft loss was observed during the follow-up period of 16 mo. Treatment with leflunomide seemed to be associated with a new toxicity, hemolysis, seen in four of the 27 patients so treated. Patients with hemolysis had high leflunomide levels (81.4 +/- 14 microg/ml) and worsening allograft function. Two patients had histologic evidence of thrombotic microangiopathy, which led to graft loss in one patient. CONCLUSIONS The clinical correlation between leflunomide levels and outcomes needs to be further refined. This study described a possible association of leflunomide with thrombotic microangiopathy, especially at higher levels.

Donor-recipient size matching influences early but not late graft function after pediatric en-bloc kidney transplantation.

Background. Pediatric en-bloc kidney transplantation into adult recipients is an accepted technique to expand the donor pool. Concerns about adequate “nephron dosing” have traditionally favored placing these kidneys into smaller recipients. Methods. We reviewed 20 pediatric en-bloc transplants performed at our institution between 2002 and 2008. We examined the impact of donor age, donor weight, recipient sex, combined kidney length, recipient weight, recipient-to-donor weight ratio, and recipient weight gain on serum creatinine over time using regression analysis. Results. Patient survival was 100%. Two grafts were lost early from vascular thrombosis. Of the remaining 18 recipients, all had immediate and excellent long-term function with average creatinine of 0.91±0.38 mg/dL at a mean follow-up of 1257±656 days. For 17 patients with 1 year follow-up, recipient weight, recipient-to-donor weight ratio, and recipient male sex negatively influenced renal function at 1 month. However, this relationship was lost by 1 year with increasing function in the smallest donors and largest size mismatches. Between 1 month and 1 year posttransplant, estimated creatinine clearance improved from 59±13 mL/min at 1 month posttransplant to 88±41 mL/min (P<0.015). Weight gain after transplant was associated with improved creatinine clearance, suggesting continued adaptation over time. Conclusions. We conclude that donor or recipient size matching up to a recipient-to-donor weight ratio of 7.5 does not significantly impact later renal function after pediatric en-bloc kidney transplantation into adults.

Outcomes of simultaneous liver and kidney transplantation in relation to a high level of preformed donor-specific antibodies

Background The protective effect of the liver allograft when simultaneously transplanted with a kidney in the setting of allosensitization is unclear. Methods We analyzed the significance of sensitization, defined based on positive cytotoxicity crossmatches, positive flow cytometry crossmatches, and/or the presence of high levels of donor-specific antibodies, on the outcomes of simultaneous liver and kidney (SLK) transplantation. We reviewed 56 SLK performed at our center through December 31, 2011 and identified 13 patients who met high sensitization criteria. Results Median patient survival was not significantly different: 86 months (95% confidence interval [CI], 47–135) for nonsensitized patients versus 151 months (95% CI, 4 to ∞) for sensitized patients (P=0.5). The 5-year survival was 67% (95% CI, 0.5–0.8) in the nonsensitized group and 64% (95% CI, 0.3–0.9) in the sensitized group. There were six renal allograft failures in the nonsensitized group but none in the sensitized group. The adjusted hazard ratios associated with the risk of death or the combined risk of death or renal allograft failure were 0.7 (95% CI, 0.1–3.8) and 0.4 (95% CI, 0.1–2.2) for sensitized versus nonsensitized patients. There were significantly more renal allograft rejections in the sensitized group (5 vs. 1; P=0.002) in the first year after transplantation, only one showing C4d positivity. Creatinine levels at 1 year after transplantation were similar: 1.5 mg/dL in the nonsensitized group versus 1.36 mg/dL in the sensitized group (P=0.6). Conclusion Sensitization does not appear to have a significant negative impact on the survival of SLK patients.

Managing the Failing Allograft

Managing the failing allograft juxtaposes immunosuppressive management and routine chronic kidney disease care. The complications of immunosuppression can be more pronounced in those with renal failure (infection, anemia, bone disease). The withdrawal of immunosuppression may be associated with acute allograft rejection, arthralgias, and the development of antidonor antibodies. Likewise depression is prevalent. Improving well‐being and overall survival necessitates proper titration of immunosuppressive medications and control of blood pressure, anemia, lipids, and glucose along with attention to treatment of depression.

CYCLOSPORINE C2 PEAK MONITORING IN LIVING AND DECEASED DONOR KIDNEY TRANSPLANTATION REDUCES THE INCIDENCE OF BIOPSY PROVEN ACUTE REJECTION.

Aims: To assess the effectiveness of using cyclosporine C2 monitoring in 100 kidney transplant recipients immunosuppressed with basiliximab induction and cyclosporine (Neoral), mycophenolate mofetil and prednisone. We report the initial results obtained for the first 75 of these patients, and compare these to those achieved using trough C0 cyclosporine monitoring. Methods: 75 patients transplanted from August 31 2003 to March 9 2004 were included in this protocol. Of these 22 (age 25-67, mean 51 yr.) were recipients of living donor transplants and 53 (age 25-77, mean 52 yr.) of deceased donor transplants. Patients received the initial 20-mg dose of basiliximab at the time of surgery and a second 20-mg dose on the 4 post-operative day prior to discharge. Prednisone was given according to a standard taper, mycophenolate mofetil as 1000 mg twice daily, and cyclosporine was adjusted to achieve predetermined target C2 levels. These targets were: 0-4 weeks 1300 ng/ml (1150-1550), 5-8 weeks 1000 ng/ml (800-1200), 8-12 weeks 825 ng/ml (750-900), 4-12 months 750 ng/ml ( 650). Results: Graft Survival is 98.7%, and Patient Survival 100%. To date 8/75 patients have had an acute rejection (10.7%). Of these rejections 4 were Borderline Cellular Rejection, 2 Mild Cellular Rejection, 1 Vascular Cell Mediated Rejection, and 1 had C4d positive Humoral Rejection. Of the 74 patients with functioning allografts, 2 patients were converted to tacrolimus, the other 72 are maintained on cyclosporine using C2 monitoring. The mean serum creatinine level in those that experienced a rejection is 2.5 mg%, as compared to 1.7 mg% in those that have not had a rejection. Conclusions: The use of peak C2 cyclosporine monitoring has reduced the rate of rejection in this group of patients to 10.7%, as compared to an historical cohort in which an otherwise identical protocol was used with C0 trough monitoring that resulted in a rejection rate of 16% by 6 months.