Nicolae Leca

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.

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.

Racial differences in determinants of live donor kidney transplantation in the United States.

Few studies have compared determinants of live donor kidney transplantation (LDKT) across all major US racial‐ethnic groups. We compared determinants of racial‐ethnic differences in LDKT among 208 736 patients who initiated treatment for end‐stage kidney disease during 2005–2008. We performed proportional hazards and bootstrap analyses to estimate differences in LDKT attributable to sociodemographic and clinical factors. Mean LDKT rates were lowest among blacks (1.19 per 100 person‐years [95% CI: 1.12–1.26]), American Indians/Alaska Natives‐AI/ANs (1.40 [1.06–1.84]) and Pacific Islanders (1.10 [0.78–1.84]), intermediate among Hispanics (2.53 [2.39–2.67]) and Asians (3.89 [3.51–4.32]), and highest among whites (6.46 [6.31–6.61]). Compared with whites, the largest proportion of the disparity among blacks (20%) and AI/ANs (29%) was attributed to measures of predialysis care, while the largest proportion among Hispanics (14%) was attributed to health insurance coverage. Contextual poverty accounted for 16%, 4%, 18%, and 6% of the disparity among blacks, Hispanics, AI/ANs and Pacific Islanders but none of the disparity among Asians. In the United States, significant disparities in rates of LDKT persist, but determinants of these disparities vary by race‐ethnicity. Efforts to expand preESKD insurance coverage, to improve access to high‐quality predialysis care and to overcome socioeconomic barriers are important targets for addressing disparities in LDKT.

Eculizumab use in kidney transplantation.

Purpose of reviewEculizumab suppresses the effector functions of the complement system and represents a therapeutic breakthrough for patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome (aHUS). Safety monitoring is ongoing; so far, most notable is the expected increase in infection risk with encapsulated organisms. Despite potential applicability in multiple complement-mediated disorders, the off-label use of eculizumab has been limited, mainly by its prohibitive cost. The purpose of this review is to summarize the current data relevant to the use of eculizumab in kidney transplantation. Recent findingsIn aHUS, prone to high rates of recurrence and allograft loss, eculizumab has made the most notable therapeutic impact. Further clarification of complement defects may help predict therapeutic responses and hopefully guide treatment duration. In C3 glomerulopathies, the clinical response to eculizumab appears more heterogeneous and less effective in processes mediated by upstream to C5 complement deregulation. A large clinical trial of eculizumab for prevention of delayed graft function is ongoing. In antibody-mediated rejection, the role of eculizumab is unclear as its use has been limited to very complex, mostly presensitized, patients in mixed combinations of therapeutic modalities. SummaryOverall, eculizumab has raised awareness of complement-mediated disorders as an exciting, new therapeutic option with multiple potential applications in kidney transplantation. Further research is needed to develop a better understanding of eculizumab applicability, efficacy, and treatment monitoring and beyond, to future therapeutic tools targeting the complement.

Immunosuppressive Medications and Squamous Cell Skin Carcinoma: Nested Case‐Control Study Within the Skin Cancer after Organ Transplant (SCOT) Cohort

Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self‐report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23–5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29–0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32–0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus.

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.

Leflunomide use in renal transplantation.

Purpose of reviewLeflunomide has been used off-label in renal transplantation because of the attractive combination of antiviral and immunosuppressive effects. This study intends to review the clinical applications of leflunomide with interest to transplantation. Recent findingsIn renal transplantation, particularly in BK nephropathy, the use of leflunomide has attempted to model the in-vitro antiviral experimental data, leading to the use of higher dosages than those studied in the approved use in rheumatoid arthritis. Concerns of toxicity with this approach have been raised, and a newer association with hemolysis and thrombotic microangiopathy has been reported. By attempting to target levels, the use of leflunomide in transplantation has been difficult because of the long half-life of the drug and the high interpatient variability. Higher leflunomide levels may lead to disproportionate immunosuppressive effects and decrease the antiviral properties. Newer data suggest that the correlation between leflunomide levels and BK nephropathy outcome is unclear. SummaryThe available clinical data with leflunomide in renal transplantation are limited; however, it suggests positive outcomes and shows that the correlation between the drug exposure and its effects has not been well delineated. Further research is needed to refine the safety and efficacy of leflunomide in relation to its potential effects in a multitude of pathological entities in renal transplantation.

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.

Kidney Biopsies May Help Predict Renal Function After Liver Transplantation.

Background Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population. Methods We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed. Results Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK. Conclusions Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates.

Regulation of human interleukin 14 transcription in vitro and in vivo after renal transplantation.

Background. Alloantibodies and B lymphocytes are felt to contribute in increasingly important ways to the pathogenesis of both acute and chronic allograft injury. The mechanisms that lead to the formation of posttransplant alloantibodies despite immunosuppressive therapy have not been fully elucidated. Interleukin 14 (IL-14) or high molecular weight B cell growth factor secreted by activated T and B cells and follicular dendritic cells promotes B cell growth, survival and memory, and antibody production. The potential role of IL-14 in human transplantation has not been examined. Methods. Using quantitative polymerase chain reaction techniques, we examined IL-14 mRNA transcript levels in human cells and compared them to IL-2. Interleukin-14 mRNA levels were measured in isolated human T cells stimulated in vitro with mitogen and alloantigen in the presence or absence of immunosuppressive drugs. In vivo, IL-14 transcript levels were measured in peripheral blood leukocytes isolated from patients after renal transplantation. Results. In vitro, both IL-14 and IL-2 transcript levels increase after alloantigen and mitogen stimulation and are suppressed by currently used immunosuppressive agents. In vivo, IL-14 and IL-2 behave differently as IL-14 transcript levels are not reduced by immunosuppressive therapy. Interleukin-14 transcripts also increase after both immune and nonimmune injury to renal allografts. Conclusions. This is the first demonstration of human IL-14 mRNA regulation in vitro and in vivo. Given the important effects of IL-14 on B cell proliferation and antibody production, increases in IL-14 transcript levels may play a role in alloantibody formation after renal transplantation.