Michael T. Burke

Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single‐center studies to date has been inconsistent. We aimed to resolve the issue of azathioprines carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty‐seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11–2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66–1.40) or KC (0.84, 95% CI 0.59–1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.

Relapsing and Recurrent Peritoneal Dialysis–Associated Peritonitis: A Multicenter Registry Study

BACKGROUND The causes, predictors, treatment, and outcomes of relapsed and recurrent peritoneal dialysis (PD)-associated peritonitis are poorly understood. STUDY DESIGN Observational cohort study using Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry data. SETTING & PARTICIPANTS All Australian PD patients between October 1, 2003, and December 31, 2007, with first episodes of peritonitis. PREDICTORS Demographic, clinical, and facility variables and type of peritonitis; relapse (same organism or culture-negative episode occurring within 4 weeks of completion of therapy of a prior episode or 5 weeks if vancomycin used); recurrence (different organism occurring within 4 weeks of completion of therapy of a prior episode or 5 weeks if vancomycin used); control (first peritonitis episode without relapse or recurrence). OUTCOMES & MEASUREMENTS Hospitalization, catheter removal, hemodialysis therapy transfer, death. RESULTS Of 6,024 PD patients studied, first episodes of relapsed, recurrent, and control peritonitis occurred in 356, 165, and 2,021 patients, respectively. Coagulase-negative staphylococci and Staphylococcus aureus accounted for 48% of relapsing peritonitis (adjusted OR, 1.26 [95% CI, 0.94-1.70] and 1.54 [95% CI, 1.08-2.19], respectively), but were much less likely to be isolated in recurrent peritonitis. Recurrent peritonitis was associated more frequently with fungi (13%; OR, 2.16; 95% CI, 1.12-4.17). The empirical antimicrobial approaches to relapsing and recurrent peritonitis were similar and their subsequent clinical outcomes were comparable. Compared with uncomplicated peritonitis, relapsed and recurrent peritonitis were associated with higher rates of catheter removal (22% vs 30% vs 37%, respectively; P < 0.001) and permanent hemodialysis therapy transfer (20% vs 25% vs 32%; P < 0.001), but similar rates of hospitalization (73% vs 70% vs 70%) and death (2.8% vs 2.0% vs 1.2%). LIMITATIONS Limited covariate adjustment. Residual confounding and coding bias could not be excluded. CONCLUSIONS Relapsed and recurrent peritonitis are caused by different spectra of micro-organisms, but are not readily clinically distinguishable at presentation. Empirical treatment with broad-spectrum antibiotics and subsequent adjustment according to antimicrobial susceptibilities results in similar clinical outcomes, albeit with appreciably higher rates of catheter removal and hemodialysis therapy transfer than for uncomplicated peritonitis.

Does the nature of residual immune function explain the differential risk of non-melanoma skin cancer development in immunosuppressed organ transplant recipients?

Patients receiving immunosuppression to prevent organ transplant rejection are at a greatly increased risk of developing nonmelanoma skin cancer. In recent years a correlation has been identified between the class of immunosuppressant that these patients receive and their subsequent cancer risk; in particular, patients switched from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors not only displayed a dramatic reduction in new tumor formation but also in some cases a regression of their existing lesions. Studies of cancer models in mice and cell lines in the laboratory have attributed these discrepancies in cancer risk to the ability of immunosuppressants such as mTOR inhibitors to elicit direct anticancer effects, including suppressing angiogenesis and increasing autophagy‐mediated DNA repair. Recent evidence from the immunological literature however, suggests a significant alternative contribution of mTOR inhibitors; namely the promotion of memory T‐cell function. Recent advances in understanding memory T‐cell establishment and the demonstration of their critical role in long‐term immunity make it timely to review the available evidence as to whether the improved nonmelanoma skin cancer outcome shown by patients switched to mTOR inhibitor treatment regimens may be associated with the retainment of memory T‐cell function.

Atypical fractures associated with bisphosphonate use post-renal transplantation

Bone disease is a major cause of morbidity post renal transplantation. The authors present a case of adynamic bone disease and atypical fractures associated with the use of bisphosphonates following renal transplantation. The uncertain role of parathyroidectomy and bone mineral density scans is also reviewed.

Kidney disease health literacy among new patients referred to a nephrology outpatient clinic

Knowledge about kidney disease among the general population is poor but has not been assessed in the population selected for referral to nephrology care.

Patient kidney disease knowledge remains inadequate with standard nephrology outpatient care

Background Chronic kidney disease (CKD) knowledge among patients newly referred to a nephrology clinic is limited. This study aimed to determine if CKD knowledge 1 year after initial consultation in a nephrology clinic improves with standard care. Methods Patients newly referred to a nephrology outpatient clinic received standard care from nephrologists, and had access to educational pamphlets, relevant internet sites and patient support groups. Those with estimated glomerular filtration rate <20 mL/min/1.73 m2 received individual education from a multi-disciplinary team. Knowledge was assessed by questionnaire at first visit and after 12 months. Results Of 210 patients at baseline, follow-up data were available at 12.7 (±1.7) months for 95. Median age was 70 [interquartile range (IQR) 60–76] years and 54% were male. Baseline median creatinine of the follow-up cohort was 137 (IQR 99–179) µmol/L. Eighty per cent had seen a nephrologist at least three times, 8% saw a CKD nurse, 50% reported collecting pamphlets and 16% reported searching the internet. At 12 months, fewer patients reported being uncertain why they had been referred (5 versus 20%, P = 0.002) and fewer reported being unsure of the meaning of CKD (37 versus 57%, P = 0.005). Unknown (44%) and alcohol (23%) remained the most common causes of CKD identified. Fewer patients responded ‘unsure’ regarding the treatment of CKD (38 versus 57%, P = 0.004). Conclusions After a year of standard care at nephrology outpatient clinics there were some minor improvements in patient knowledge; however, patient understanding of CKD remained poor.

Genetics and nonmelanoma skin cancer in kidney transplant recipients

Kidney transplant recipients (KTRs) have a 65- to 250-fold greater risk than the general population of developing nonmelanoma skin cancer. Immunosuppressive drugs combined with traditional risk factors such as UV radiation exposure are the main modifiable risk factors for skin cancer development in transplant recipients. Genetic variation affecting immunosuppressive drug pharmacokinetics and pharmacodynamics has been associated with other transplant complications and may contribute to differences in skin cancer rates between KTRs. Genetic polymorphisms in genes encoding the prednisolone receptor, GST enzyme, MC1R, MTHFR enzyme and COX-2 enzyme have been shown to increase the risk of nonmelanoma skin cancer in KTRs. Genetic association studies may improve our understanding of how genetic variation affects skin cancer risk and potentially guide immunosuppressive treatment and skin cancer screening in at risk individuals.

A Difficult Decision: Atypical Jc Polyomavirus Encephalopathy in a Kidney Transplant Recipient

Background A number of cerebral manifestations are associated with JC polyomavirus (JCPyV) which are diagnosed by detection of JCPyV in cerebrospinal fluid (CSF), often with the support of cerebral imaging. Here we present an unusual case of a kidney transplant patient presenting with progressive neurological deterioration attributed to JCPyV encephalopathy. Methods Quantitative polymerase chain reaction JCPyV was used prospectively and retrospectively to track the viral load within the patient blood, urine, CSF, and kidney sections. A JCPyV VP1 enzyme-linked immunosorbent assay was used to measure patient and donor antibody titers. Immunohistochemical staining was used to identify active JCPyV infection within the kidney allograft. Results JC polyomavirus was detected in the CSF at the time of presentation. JC polyomavirus was not detected in pretransplant serum, however viral loads increased with time, peaking during the height of the neurological symptoms (1.5E9 copies/mL). No parenchymal brain lesions were evident on imaging, but transient cerebral venous sinus thrombosis was present. Progressive decline in neurological function necessitated immunotherapy cessation and allograft removal, which led to decreasing serum viral loads and resolution of neurological symptoms. JC polyomavirus was detected within the grafts collecting duct cells using quantitative polymerase chain reaction and immunohistochemical staining. The patient was JCPyV naive pretransplant, but showed high antibody titers during the neurological symptoms, with the IgM decrease paralleling the viral load after graft removal. Conclusions We report a case of atypical JCPyV encephalopathy associated with cerebral venous sinus thrombosis and disseminated primary JCPyV infection originating from the kidney allograft. Clinical improvement followed removal of the allograft and cessation of immunosuppression.

Sirolimus increases T-cell abundance in the sun exposed skin of kidney transplant recipients

Background Kidney transplant recipients (KTRs) receiving the mammalian target of rapamycin inhibitor sirolimus may display a reduced risk of skin cancer development compared to KTRs receiving calcineurin inhibitors. Despite studies investigating the effects of these 2 drug classes on T cells in patient blood, the effect these drugs may have in patient skin is not yet known. Methods Fifteen patients with chronic kidney disease (not recipients of immunosuppressive drugs), and 30 KTRs (15 receiving a calcineurin inhibitor, and 15 receiving sirolimus) provided matched samples of blood, sun exposed (SE) and non-SE skin. The abundance of total CD8+ and CD4+ T cells, memory CD8+ and CD4+ T cells, and regulatory T (Treg) cells in each sample was then assessed by flow cytometry. Results Sirolimus treatment significantly increased absolute numbers of CD4+ T cells, memory CD8+- and CD4+ T cells, and Treg cells in SE skin versus paired samples of non-SE skin. No differences were found in the absolute number of any T cell subset in the blood. Correlation analysis revealed that the percentage of T cell subsets in the blood does not always accurately reflect the percentage of T-cell subsets in the skin of KTRs. Furthermore, sirolimus significantly disrupts the balance of memory CD4+ T cells in the skin after chronic sun exposure. Conclusions This study demonstrated that immunosuppressive drug class and sun exposure modify the abundance of multiple T-cell subsets in the skin of KTRs. Correlation analysis revealed that the prevalence of Treg cells in KTR blood does not accurately reflect the prevalence of Treg cells in KTR skin.

Tacrolimus Toxicity due to Biliary Obstruction in a Combined Kidney and Liver Transplant Recipient

The immunosuppressant tacrolimus has a narrow therapeutic window, necessitating therapeutic drug monitoring to maintain efficacy and minimise toxicity. There are very few reports examining the impact of impaired biliary excretion on tacrolimus blood levels or toxicity. We report the case of a 26-year-old combined liver and kidney transplant recipient, who developed acute biliary obstruction leading to tacrolimus toxicity with very high blood tacrolimus levels. Despite a careful evaluation, no alternative cause was found for her acute kidney injury, and her kidney function returned to previous baseline within several days following treatment of the biliary obstruction and temporary withdrawal of tacrolimus.