Nicholas B. Cross

Comparative survival and economic benefits of deceased donor kidney transplantation and dialysis in people with varying ages and co-morbidities

Background Deceased donor kidneys for transplantation are in most countries allocated preferentially to recipients who have limited co-morbidities. Little is known about the incremental health and economic gain from transplanting those with co-morbidities compared to remaining on dialysis. The aim of our study is to estimate the average and incremental survival benefits and health care costs of listing and transplantation compared to dialysis among individuals with varying co-morbidities. Methods A probabilistic Markov model was constructed, using current outcomes for patients with defined co-morbidities treated with either dialysis or transplantation, to compare the health and economic benefits of listing and transplantation with dialysis. Findings Using the current waiting time for deceased donor transplantation, transplanting a potential recipient, with or without co-morbidities achieves survival gains of between 6 months and more than three life years compared to remaining on dialysis, with an average incremental cost-effectiveness ratio (ICER) of less than

Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials.

50,000/LYS, even among those with advanced age. Age at listing and the waiting time for transplantation are the most influential variables within the model. If there were an unlimited supply of organs and no waiting time, transplanting the younger and healthier individuals saves the most number of life years and is cost-saving, whereas transplanting the middle-age to older patients still achieves substantial incremental gains in life expectancy compared to being on dialysis. Conclusions Our modelled analyses suggest transplanting the younger and healthier individuals with end-stage kidney disease maximises survival gains and saves money. Listing and transplanting those with considerable co-morbidities is also cost-effective and achieves substantial survival gains compared with the dialysis alternative. Preferentially excluding the older and sicker individuals cannot be justified on utilitarian grounds.

A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial.

In nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. We performed a systematic review including random effects meta-analysis of randomized controlled trials, using Cochrane Collaboration methodology. We identified 60 trials, enrolling 3802 recipients. Twenty-nine trials (2262 patients) compared calcium channel blockers (CCB) with placebo or no treatment, 10 trials (445 patients) compared angiotensin-converting enzyme inhibitors (ACEi) with placebo or no treatment, and seven studies (405 patients) compared CCB with ACEi. CCB compared with placebo or no treatment (plus additional agents in either arm as required) reduced graft loss (risk ratio [RR] 0.75, 95% confidence intervals [CI] 0.57–0.99) and improved glomerular filtration rate (GFR; mean difference [MD] 4.5 mL/min, 95% CI 2.2–6.7). Data on ACEi versus placebo or no treatment were inconclusive for GFR (MD −8.1 mL/min, 95% CI −18.6–2.4) and inconsistent for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD 11.5 mL/min, 95% CI 7.2–15.8), proteinuria (MD 0.28 g/day, 95% CI 0.10–0.47), hemoglobin (MD 11.5 g/L, 95% CI 7.2–15.8), and increased hyperkalemia (RR 3.7, 95% CI 1.9–7.7). Graft loss data were inconclusive (RR 7.4, 95% CI 0.4–140). These data suggest that CCB may be preferred as first-line agents for hypertensive kidney transplant recipients.

Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cells

BACKGROUND Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI. STUDY DESIGN Multicenter, single-blind, randomized, placebo-controlled, parallel-group study. SETTING & PARTICIPANTS Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37). INTERVENTIONS Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days. OUTCOMES & MEASUREMENTS Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained. RESULTS Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients. LIMITATIONS Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses. CONCLUSIONS GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.

The experiences of commercial kidney donors: thematic synthesis of qualitative research

BACKGROUND Cancer, particularly cutaneous squamous cell carcinoma (SCC), is a major cause of mortality in renal transplant recipients (RTRs). Myeloid-derived suppressor cells (MDSC) play a central role in suppressing cancer immunosurveillance but their potential mobilisation in RTRs and levels relative to those of other immunoregulatory dendritic cell (DC) populations have not been analysed. METHODS The circulating frequencies of MDSC and DC were analysed by multicolour flow cytometry in immunocompetent patients without (n = 13) or with (ICI-SCC(Pos), n = 14) current SCC, normal donors (NDs, n = 34), chronic kidney disease patients (CKD patients, n = 22) and RTRs (n = 31). RESULTS Compared to NDs, RTRs had significantly elevated levels of both CD14(Neg) and CD14(Pos) MDSC subsets (P < 0.001), while CKD patients and ICI-SCC(Pos) had significantly elevated levels of only the CD14(Neg)-MDSC subset. DC frequencies were significantly decreased in RTRs and CKD patients but were at normal levels in ICI-SCC(Pos). The MDSC/DC ratio was significantly elevated (P < 0.05) in RTRs (median = 5.7), CKD patients (median = 3.2) and ICI-SCC(Pos) (median = 3.5) relative to NDs (median = 0.7). The use of immunosuppressive drugs in CKD patients and past/current occurrence of SCC in RTRs was associated with significantly increased CD14(Neg)-MDSC frequencies. MDSC enriched from RTRs, when co-cultured with activated NDs T cells significantly suppressed extracellular IL-10 levels and can, when activated with formyl-methionyl-leucyl-phenylalanine, inhibit T-cell proliferation. CONCLUSIONS RTRs, CKD patients and ICI-SCC(Pos) have increased MDSC frequencies and MDSC/DC ratios. These changes may impact on cancer immunosurveillance. Therefore, MDSC represent both a potential therapeutic target and prognostic marker in these patients, with respect to the development of SCC and other malignancies.

KHA‐CARI guideline: KHA‐CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Commercial transplantation has expanded because of the shortage of kidneys for transplantation. This study aims to synthesize qualitative studies on the experiences and perspectives of living commercial kidney donors. We conducted a comprehensive literature search in electronic databases to April 2011 and consulted experts to identify unpublished studies. Thematic synthesis was used to analyze the findings. Seven studies involving over 676 commercial kidney donors were included. Three major themes were identified: desperation (the participants’ decision to sell their kidney was forced by poverty, debt, or to fulfill a family obligation); despair (destroyed body integrity, shame and secrecy, dehumanized and dispirited, loss of livelihood, heightened sense of vulnerability, disappointment, and regret); and debasement (deception by brokers and recipients, victimized by the hospital, stigmatized by community, and rejected by family). Commercial kidney transplantation is reported to result in ramifications for the donors’ mental, physical, and social well‐being. Not only do they remain in poverty, they lose dignity, sense of purpose, respect, relationships, and livelihood. Review of this published literature supports the need for effective implementation of the WHO guiding principles and legislated regulation to deter potential recipients and healthcare providers from pursuing commercial transplantation.

Effect of activated human polymorphonuclear leucocytes on T lymphocyte proliferation and viability

The latest Caring for Australians with Renal Impairment (CARI) guideline detailing renal transplant care, developed as a local modification of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.

It was just an unconditional gift. Self reflections of non-directed living kidney donors.

Human polymorphonuclear leucocytes (PMN) are thought to be immunosuppressive. The suppressive mechanism(s) used by PMN are, however, not well defined and in this study they were analysed using T‐cell responses to CD3+ CD28 monoclonal antibodies (mAb) as a readout. We demonstrate that in vitro activated PMN (PMNact) can, without any T‐cell interaction, induce apparent T‐cell suppression by inhibiting the stimulatory capacity of the CD3 mAb. However, a cell‐directed suppression of T‐cell proliferation was observed when PMNact were added to pre‐activated T cells that are already committed to polyclonal proliferation. This suppression was partially reversed by catalase addition (P < 0·01) and largely reversed by addition of exogenous interleukin‐2 (P < 0·001) but was not significantly reduced by nitric oxide synthase inhibition, myeloperoxidase inhibition or addition of excess arginine. Following removal of PMNact, suppressed T cells could respond normally to further stimulation. In addition to suppressing proliferation, co‐culture with PMNact also induced a significant decrease in T‐cell viability that was reversed by catalase addition (P < 0·05). The addition of the arginase inhibitor N‐hydroxy‐nor‐l‐arginine induced both a further significant, catalase‐sensitive, loss in T‐cell viability and increased nitrite release (P < 0·001). These data demonstrate that PMN, when activated, can both induce T‐cell death and reversibly inhibit proliferation of activated T cells. The mechanisms underlying these distinct processes and the effects of arginase inhibitors on PMN induced cytotoxicity merit further investigation.

Asking the right question and finding the right answers

Tong A, Craig JC, Wong G, Morton J, Armstrong S, Schollum J, Cross N. “It was just an unconditional gift.” Self reflections of non‐directed living kidney donors.

Toxicity profile of lithium

Clinical consultations generate questions that can be informed by published (and unpublished) evidence. This is the basis for evidence‐based practice. Finding answers involves searching available electronic databases. We describe a method for rephrasing or ‘framing’ clinical questions into population, intervention, comparator and outcome terms that helps to determine the best type of study to search for, and aids in the design of search strategies.