Anthony Langone

Urinary tract infections after renal transplantation: a retrospective review at two US transplant centers

Abstract:  Urinary tract infections (UTIs) are the most common infectious complication following renal transplantation. Previous studies uniformly report that renal transplant recipients develop UTIs more often than the general population, but widely differ on how frequently UTIs occur after transplantation. These studies also disagree on the risk factors associated with developing post‐transplant UTIs, as well as the effect that UTIs may have on graft outcomes and patient mortality. We performed a retrospective cohort study including all the adult patients who received a renal transplant at two US transplant centers from January 1996 to December 2002 (500 patients). Two hundred and thirteen (43%) patients developed one or more post‐transplant UTIs over a mean follow‐up period of 42 months. Significant risk factors for post‐transplant UTIs were advanced age, female gender, reflux kidney disease, use of azathioprine and cadaveric donor. UTIs did not increase risk for renal graft loss, but were associated with increased mortality (3.5 odds ratio, 95% confidence interval 1.68–7.23). We conclude UTIs may be associated with an increased mortality risk in renal transplant recipients. Prevention of UTIs in high‐risk renal transplant patients or those with recurrent UTIs may possibly decrease post‐transplant mortality.

EFFECT OF RENAL TRANSPLANTATION ON BIOMARKERS OF INFLAMMATION AND OXIDATIVE STRESS IN END-STAGE RENAL DISEASE PATIENTS

Background. Chronic kidney disease patients have a high prevalence of inflammation and oxidative stress, and this has been associated with the excess cardiovascular morbidity and mortality observed in this population. Because maintenance hemodialysis is ineffective in controlling these factors, we hypothesized that restoration of kidney function by transplantation would be required to improve uremic inflammation and oxidative stress. Methods. This was a prospective cohort study evaluating time-dependent changes in biomarkers of inflammation and oxidative stress before and after renal transplantation. Nineteen end-stage renal disease (ESRD) patients (age 38.3±13.7 years, 58% male, 95% white, 21% diabetic) undergoing living-donor renal transplantation were enrolled. C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, protein-associated carbonyl content, and F2-isoprostanes were assessed at 1 week pretransplantation and at 1 week and 2 months posttransplantation. Results. Pretransplant levels of the pro-inflammatory proteins IL-6, TNF-α, and CRP, as well as the oxidative stress markers plasma protein carbonyls and F2-isoprostanes, were significantly elevated in ESRD patients compared with healthy control subjects. We observed rapid and significant declines in all of these biomarkers after transplantation that persisted for 2 months. Conclusions. Our findings indicate that restoration of renal function by transplantation improves the chronic inflammation and increased oxidative stress associated with uremia, which may contribute to the improved survival afforded to ESRD patients by renal transplantation.

Improvement in 3-Month Patient-Reported Gastrointestinal Symptoms After Conversion From Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium in Renal Transplant Patients

Background. The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in terms of gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect of conversion over time, and the potential impact of concomitant calcineurin inhibitor. Methods. In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with gastrointestinal symptoms receiving cyclosporine or tacrolimus were converted to equimolar doses of EC-MPS. Change in gastrointestinal symptom burden was evaluated using a validated Gastrointestinal Symptom Rating Scale (GSRS). Results. A significant improvement in GSRS score was observed from baseline (2.61, 95% CI 2.54–2.68) to month 1 (1.87, 95% CI 1.81–1.93) after conversion to EC-MPS and was sustained to month 3 (1.81, 95% CI 1.74–188; both P<0.0001 versus baseline). The mean change in overall GSRS score from baseline to month 1 was −0.74 overall (cyclosporine: −0.73 and tacrolimus: −0.74; all P<0.0001 versus baseline), with a slight further improvement (−0.79) at month 3 (cyclosporine: −0.82 and tacrolimus: −0.78; all P<0.0001 versus baseline). A significant improvement in GSRS subscale scores was also observed in the total population regardless of calcineurin inhibitor at month 1, sustained to month 3 (all P<0.0001 versus baseline). The improvement in GSRS score postconversion was similar in African-American and non-African-American patients, and in diabetic and nondiabetic patients. Conclusions. This exploratory study in 728 patients demonstrates that following conversion from MMF to EC-MPS, regardless of concomitant calcineurin inhibitor, GSRS is improved and sustained over 3 months.

mTOR inhibitor-associated dermatologic and mucosal problems

Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E, Stockfleth E. mTOR inhibitor‐associated dermatologic and mucosal problems.
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2010.01232.x.
© 2010 John Wiley & Sons A/S.

A pilot protocol of a calcineurin-inhibitor free regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function

Abstract: Background: The worsening shortage of cadaver donor kidneys has prompted use of expanded or marginal donor kidneys (MDK), i.e. older age or donor history of hypertension or diabetes. MDK may be especially susceptible to calcineurin‐inhibitor (CI) mediated vasoconstriction and nephrotoxicity. Similarly, early use of CI in patients with delayed graft function may prolong ischaemic injury. We developed a CI‐free protocol of antibody induction, sirolimus, mycophenolate mofetil, and prednisone in recipients with MDK or DGF.

Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus

Aphthous ulceration is a common side effect of sirolimus. These lesions of the oral mucous membranes are often painful and debilitating, leading to either dose reduction or discontinuation of sirolimus in a significant number of patients. We report that the direct application of clobetasol, a high potency topical steroid, led to prompt resolution of the aphthous ulcers that developed in our renal transplant patients on sir‐olimus‐based immunosuppression.

Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study.

Background. Two open-label studies demonstrated that conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) significantly reduces gastrointestinal (GI) symptom burden and improves GI-specific health-related quality of life. Using a randomized design, this study evaluated changes in GI symptoms and health-related quality of life in patients converted from MMF to EC-MPS versus patients who continued with MMF-based treatment. Methods. In this 4-week, multicenter, randomized, prospective, double-blind, parallel-group trial, renal transplant recipients with GI symptoms receiving MMF plus a calcineurin inhibitor±corticosteroids were randomized to an equimolar dose of EC-MPS+MMF placebo or continue on their MMF-based regimen+EC-MPS placebo. The primary efficacy outcome was a change from baseline in total Gastrointestinal Symptom Rating Scale score of a minimally important difference of more than or equal to 0.3. Results. Three hundred ninety-six patients (EC-MPS group: n=199; MMF group: n=197) were included. A greater proportion of EC-MPS patients (62%) reached the primary efficacy outcome compared with MMF patients (55%); however, the difference was not statistically significant (P=0.15). EC-MPS patients had a significantly greater decrease in the Gastrointestinal Symptom Rating Scale indigestion syndrome dimension versus MMF patients. Within the subgroups of patients with diabetes, patients transplanted 6 to 12 months of study enrollment, and patients on steroids, a statistically significant greater proportion of EC-MPS versus MMF patients reached the primary efficacy outcome. Conclusions. Conversion from MMF to EC-MPS may be associated with improvements in presence and severity of GI symptoms, particularly in patients with indigestion, diabetes, on steroids, and in patients converted between 6 and 12 months posttransplantation.

Ezetimibe in renal transplant patients with hyperlipidemia resistant to HMG-CoA reductase inhibitors.

Hyperlipidemia affects the majority of renal transplant patients. Multiple risk factors contribute to elevated serum cholesterol including the use of certain immunosuppressant agents. HMG-Co A reductase inhibitors have become the preferred class of cholesterol-lowering medication with an increasing body of evidence to support their safety, efficacy, and outcomes in both the normal and renal transplant populations. New guidelines recommend lowering previous LDL-c goals as outcomes appears to continually improve. As a result, ezetimibe has been added to patients with persistently elevated triglycerides and/or LDL-c in individuals who possessed a renal transplant and were deemed to be on a maximum safe dose of statin agent. After the addition of ezetimibe, total cholesterol, LDL-c, and triglycerides fell by 21%, 31%, and 13%, respectively. Creatinine phosphokinase, liver enzyme serum levels, and renal function were not affected to any level of clinical significance with the addition of ezetimibe. Large interpatient variability of measurable immunosuppressant levels was seen but no serious adverse events were attributed to a change in levels.

Polyclonal antibody-induced serum sickness in renal transplant recipients: treatment with therapeutic plasma exchange.

Serum sickness is an immune-complex mediated illness that frequently occurs in patients after polyclonal antibody therapy (ATGAM or thymoglobulin). Serum sickness presents with significant morbidity but is self-limited and resolves with prolonged steroid therapy. We present five renal transplant patients who developed serum sickness after polyclonal antibody treatment with severe symptoms that persisted after being started on systemic steroids. These patients underwent one or two courses of therapeutic plasma exchange (TPE) with subsequent complete resolution of their symptoms. Renal transplant recipients with serum sickness after polyclonal antibody therapy may benefit from TPE by accelerating their time to recovery and thereby reducing overall morbidity.

Assessing Long-Term Nephron Loss: Is It Time to Kick the CAN Grading System?

Despite progress in decreasing rejection and improving short-term survival (1), much of it through improved immunosuppression and anti-infective agents, late kidney allograft loss remains a problem. With close to 5000 kidney transplants failing per year and returning the recipient to dialysis in the United States, kidney transplant failure is a leading cause of end-stage renal disease. Recent analyses of large databases reveal that late renal loss has not significantly changed despite improvements in reducing rejection (1–3). The causes of late allograft loss are not well defined. One common phenotype is loss of function with tubular atrophy (TA) and interstitial fibrosis (IF), a set of findings termed chronic allograft nephropathy or ‘CAN’. Although some have interpreted CAN as a disease (analogous to the old concept of chronic rejection), in fact these features mean only loss of nephrons. It seems likely that transition of epithelial cells to mesenchymal cells contributes to TA and IF, explaining why TA and IF are so strongly linked (4).