Patient-Centered Research and Outcomes in Cancer and Kidney Transplantation.

Cancer has been identified by kidney transplant recipients as a critically important outcome. The co-occurrence of cancer and kidney transplantation represents a complex intersection of diseases, symptoms, and competing priorities for treatments. Research that focuses on biochemical parameters and clinical events may not capture the priorities of patients. Patient-centered research can improve the relevance and efficiency of research and is particularly pertinent in the setting of cancer and kidney transplantation to facilitate shared decision-making in complex clinical situations. In addition, patient-reported outcomes can facilitate the assessment of patients' experiences, symptom burden, treatment side effects, and quality of life. This review discusses patient-centered research in the context of kidney transplantation and cancer, including consumer involvement in research and patient-centered outcomes and their measures and inclusion in core outcome sets.

Mendelian randomization for nephrologists.

Confounding is a major limitation of observational studies. Mendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. With the emergence of large-scale genome-wide association studies in nephrology over the past decade, MR has become a popular method to establish causal inferences. However, MR is a complex and challenging methodology that requires careful consideration to ensure robust results. This review article aims to summarize the basic concepts of MR, its application and relevance in nephrology, and the methodological challenges and limitations as well as discuss the current guidelines for design and reporting. With reference to a clinically relevant example of examining the causal relationship between the estimated glomerular filtration rate and cancer, this review outlines the key steps to conducting an MR study, including the key considerations and potential pitfalls at each step. These include defining the clinical question, selecting the data sources, identifying and refining appropriate genetic variants by considering linkage disequilibrium and associations with potential confounders, harmonization of variants across data sets, validation of the genetic instrument by assessing its strength, estimation of the causal effects, confirming the validity of the findings, and interpreting and reporting results.

Scope and Consistency of Cancer Outcomes Reported in Randomized Trials in Kidney Transplant Recipients.

Introduction: Cancer is an important outcome in kidney transplantation, but the scope and consistency of how cancer is defined and reported in trials involving kidney transplant recipients has not been evaluated. This study aimed to assess the range and variability of cancer outcomes in trials involving kidney transplant recipients. Methods: The ClinicalTrials.gov database was searched from February 2000 to July 2021 to identify all randomized controlled trials (RCTs) in adult kidney transplant recipients, and which included cancer as a specified outcome. The definition of cancer, types of cancer (if any), timepoint(s) of measurement and method of aggregation were extracted for each cancer outcome. Results: Of the 819 trials in kidney transplantation, only 84 (10%) included 1 or more cancer outcomes. Of these, 72 of 84 (86%) trials included cancer as a secondary outcome and 12 of 84 (14%) considered cancer as a primary outcome. The most frequent description of cancer was "malignancy" (n = 44, 43%), without reference to diagnostic criteria, histology, grade, or stage. The 2 most common cancer types were posttransplant lymphoproliferative disorder (PTLD) (n = 20, 20%) and nonmelanoma skin cancer (n = 10, 10%). Several methods of aggregation were identified, including incidence or rate (n = 47, 46%), frequency or proportion (n = 30, 29%), and time to event (n = 5, 5%). Approximately half the cancer outcomes were measured at a single time point (n = 44, 52%). Conclusion: Cancer is an infrequently reported outcome and is inconsistently defined in trials of kidney transplant recipients. Consistent reporting of cancer outcomes using standardized definitions would provide important information on the impact of cancer in patients after kidney transplantation.

Association Between Side of Living Kidney Donation and Post-Transplant Outcomes.

Background: Right-sided living donor kidneys have longer renal arteries and shorter veins that make vascular anastomosis more challenging. We sought to determine whether recipients of right-sided living donor kidneys have worse outcomes than left-sided kidney recipients. Methods: An observational analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) was undertaken. We used adjusted logistic regression to determine the association between side and delayed graft function (DGF) and time-stratified adjusted cox regression models for graft and patient survivals. Results: Between 2004 and 2018, 4,050 living donor kidney transplants were conducted with 696 (17.2%) using right kidneys. With reference to left kidneys, the adjusted OR (95% CI) for DGF was 2.01 (1.31-3.09) for recipients with right kidneys. Within 30 days, 46 allografts (1.4%) were lost, with major causes of overall graft loss being technical, primary non-function and death. Recipients of right donor kidneys experienced a greater risk of early graft loss (aHR 2.02 [95% CI 1.06-3.86], p = 0.03), but not beyond 30 days (aHR 0.97 [95% CI 0.80-1.19], p = 0.8]). Conclusion: Technical challenge is the most common cause of early graft loss. The risk of early graft loss among recipients who received right kidneys is doubled compared to those who received left living donor kidneys.

Encapsulation of OZ439 into Nanoparticles for Supersaturated Drug Release in Oral Malaria Therapy.

Malaria poses a major burden on human health and is becoming increasingly difficult to treat due to the development of antimalarial drug resistance. The resistance issue is further exacerbated by a lack of patient adherence to multi-day dosing regimens. This situation motivates the development of new antimalarial treatments that are less susceptible to the development of resistance. We have applied Flash NanoPrecipitation (FNP), a polymer-directed self-assembly process, to form stable, water-dispersible nanoparticles (NPs) of 50-400 nm in size containing OZ439, a poorly orally bioavailable but promising candidate for single-dose malaria treatment developed by Medicines for Malaria Venture (MMV). During the FNP process, a hydrophobic OZ439 oleate ion paired complex was formed and was encapsulated into NPs. Lyophilization conditions for the NP suspension were optimized to produce a dry powder. The in vitro release rates of OZ439 encapsulated in this powder were determined in biorelevant media and compared with the release rates of the unencapsulated drug. The OZ439 NPs exhibit a sustained release profile and several-fold higher release concentrations compared to that of the unencapsulated drug. In addition, XRD suggests the drug was stabilized into an amorphous form within the NPs, which may explain the improvement in dissolution kinetics. Formulating OZ439 into NPs in this way may be an important step toward developing a single-dose oral malaria therapeutic, and offers the possibility of reducing the amount of drug required per patient, lowering delivery costs, and improving dosing compliance.

Design and Solidification of Fast-Releasing Clofazimine Nanoparticles for Treatment of Cryptosporidiosis.

Clofazimine, a lipophilic (log P = 7.66) riminophenazine antibiotic approved by the US Food and Drug Administration (FDA) with a good safety record, was recently identified as a lead hit for cryptosporidiosis through a high-throughput phenotypic screen. Cryptosporidiosis requires fast-acting treatment as it leads to severe symptoms which, if untreated, result in morbidity for infants and small children. Consequently, a fast-releasing oral formulation of clofazimine in a water-dispersible form for pediatric administration is highly desirable. In this work, clofazimine nanoparticles were prepared with three surface stabilizers, hypromellose acetate succinate (HPMCAS), lecithin, and zein, using the flash nanoprecipitation (FNP) process. Drug encapsulation efficiencies of over 92% were achieved. Lyophilization and spray-drying were applied and optimized to produce redispersible nanoparticle powders. The release kinetics of these clofazimine nanoparticle powders in biorelevant media were measured and compared with those of crystalline clofazimine and the currently marketed formulation Lamprene. Remarkably improved dissolution rates and clofazimine supersaturation levels up to 90 times equilibrium solubility were observed with all clofazimine nanoparticles tested. Differential scanning calorimetry indicated a reduction of crystallinity of clofazimine in nanoparticles. These results strongly suggest that the new clofazimine nanoparticles prepared with affordable materials in this low-cost nanoparticle formulation process can be used as viable cryptosporidiosis therapeutics.