The effect of co-trimoxazole on serum potassium concentration: safety evaluation of a randomized controlled trial

AIMS: Co-trimoxazole maintains a well-established role in the treatment of Pneumocystis jirovecii and Toxoplasma gondii, as well as urinary tract infections. Observational studies report hyperkalemia associated with co-trimoxazole which may stem from an amiloride-like potassium sparing effect. Our study reports on changes in serum potassium on patients without acute infections, and the influence of concomitant anti-kaliuretic drugs on this effect.  METHODS: Post-hoc analysis of a randomised controlled trial in patients with interstitial lung disease who were assigned to placebo or 960 mg twice daily co-trimoxazole. Serum potassium and creatinine were measured at baseline, six weeks, 6, 9 and 12 months. Primary outcome was difference in mean serum potassium concentrations between co-trimoxazole and placebo at six weeks.  RESULTS: Mean serum potassiums were similar at baseline, 4.24 (±0.44) mmol/L in the 87 co-trimoxazole group participants and 4.25 (±0.39) mmol/L in the 83 control participants. Co-trimoxazole significantly increased mean serum potassium at 6 weeks, difference between means compared to placebo of 0.21 mmol/L (95% Confidence Intervals [CI] 0.09-0.34; p = 0.001). This significant increase in serum potassium was detectable even after exclusion of patients on anti-kaliuretic drugs, difference between means for co-trimoxazole compared to placebo 0.23 mmol/L (95% CI 0.09-0.38, p = 0.002). There were 5/87 (5.7%) patients on co-trimoxazole whose serum potassium reached concentrations ≥5.5 mmol/L during the study period.  CONCLUSIONS: Co-trimoxazole significantly increases serum potassium concentration, even in participants not using anti-kaliuretic drugs. Whilst the magnitude of increase is often minor, a small proportion in our outpatient cohort developed hyperkalaemia of clinical importance

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Kinetics of urinary cell cycle arrest markers for acute kidney injury following exposure to potential renal insults

Objectives: Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure. Design: In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]center dot[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam). Setting: Thirty-five sites in North America and Europe between September 2010 and June 2012. Patients: Seven hundred twenty-three critically ill adult patients admitted to the ICU. Interventions: None. Measurements and Main Results: We compared the urinary [tissue metalloproteinase-2]center dot[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2-3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2-3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]center dot[insulin-like growth factor binding protein 7] from the day of exposure to 24-48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]center dot[insulin-like growth factor binding protein 7]. Conclusions: Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2-3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]center dot[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast

Nephrotoxicity of HAART

Highly active antiretroviral therapy (HAART) and other medical therapies for HIV-related infections have been associated with toxicities. Antiretroviral therapy can contribute to renal dysfunction directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or indirectly via drug interactions. With the increase in HAART use, clinicians must screen patients for the development of kidney disease especially if the regimen employed increases risk of kidney injury. It is also important that patients with chronic kidney disease (CKD) are not denied the best combinations, especially since most drugs can be adjusted based on the estimated GFR. Early detection of risk factors, systematic screening for chronic causes of CKD, and appropriate referrals for kidney disease management should be advocated for improved patient care. The interaction between immunosuppressive therapy and HAART in patients with kidney transplants and the recent endorsement of tenofovir/emtricitabine by the Centers for Disease Control (CDC) for preexposure prophylaxis bring a new dimension for nephrotoxicity vigilance. This paper summarizes the common antiretroviral drugs associated with nephrotoxicity with particular emphasis on tenofovir and protease inhibitors, their risk factors, and management as well as prevention strategies

Onco-nephrology : a decalogue

Onco-nephrology is an evolving subspecialty that focuses on the complex relationships existing between kidney and cancer. In this opinion piece, we propose a 'decalogue of onco-nephrology', in order to highlight the areas where the nephrologist and oncologist should work closely over the ensuing years to provide cutting-edge care for patients afflicted with cancer and kidney disease. The 10 points we have highlighted include (1) acute kidney injury and chronic kidney disease in cancer patients; (2) nephrotoxic effects of anticancer therapy, either traditional chemotherapeutics or novel molecularly targeted agents; (3) paraneoplastic renal manifestations; (4) management of patients nephrectomized for a kidney cancer; (5) renal replacement therapy and active oncological treatments; (6) kidney transplantation in cancer survivors and cancer risk in ESRD patients; (7) oncological treatment in kidney transplant patients; (8) pain management in patients with cancer and kidney disease, (9) development of integrated guidelines for onco-nephrology patients and (10) clinical trials designed specifically for onco-nephrology. Following these points, a multidisciplinary onco-nephrology team will be key to providing outstanding, cutting-edge care in both the acute and chronic setting to these patients

Onco-nephrology: A decalogue

Onco-nephrology is an evolving subspecialty that focuses on the complex relationships existing between kidney and cancer. In this opinion piece, we propose a 'decalogue of onco-nephrology', in order to highlight the areas where the nephrologist and oncologist should work closely over the ensuing years to provide cutting-edge care for patients afflicted with cancer and kidney disease. The 10 points we have highlighted include (1) acute kidney injury and chronic kidney disease in cancer patients; (2) nephrotoxic effects of anticancer therapy, either traditional chemotherapeutics or novel molecularly targeted agents; (3) paraneoplastic renal manifestations; (4) management of patients nephrectomized for a kidney cancer; (5) renal replacement therapy and active oncological treatments; (6) kidney transplantation in cancer survivors and cancer risk in ESRD patients; (7) oncological treatment in kidney transplant patients; (8) pain management in patients with cancer and kidney disease, (9) development of integrated guidelines for onco-nephrology patients and (10) clinical trials designed specifically for onco-nephrology. Following these points, a multidisciplinary onco-nephrology team will be key to providing outstanding, cutting-edge care in both the acute and chronic setting to these patients

Bisphosphonate nephrotoxicity

Bisphosphonates are valuable agents for the treatment of post-menopausal osteoporosis (PMO), hypercalcemia of malignancy, and osteolytic bone metastases. Oral bisphosphonates are used mainly to treat PMO and are not associated with significant nephrotoxicity. In contrast, nephrotoxicity is a significant potential limiting factor to the use of intravenous (IV) bisphosphonates, and the nephrotoxicity is both dose-dependent and infusion time-dependent. The two main IV bisphosphonates available to treat hypercalcemia of malignancy and osteolytic bone disease in the United States are zoledronate and pamidronate. Patterns of nephrotoxicity described with these agents include toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis, respectively. With both of these agents, severe nephrotoxicity can be largely avoided by stringent adherence to guidelines for monitoring serum creatinine prior to each treatment, temporarily withholding therapy in the setting of renal insufficiency, and adjusting doses in patients with pre-existing chronic kidney disease. In patients with PMO, zoledronate and pamidronate are associated with significantly less nephrotoxicity, which undoubtedly relates to the lower doses and longer dosing intervals employed for this indication. Ibandronate is approved in the US for treatment of PMO and in Europe for treatment of PMO and malignancy-associated bone disease. Available data suggest that ibandronate has a safe renal profile without evidence of nephrotoxicity, even in patients with abnormal baseline kidney function

Drug-related glomerular phenotypes: a global pharmacovigilance perspective

Introduction: Adverse drug reactions are a significant problem in modern society, stemming from the increase in prescribed medications, over-the-counter drugs, and overall polypharmacy. Glomerular disorders are one of the frequently reported renal conditions associated with medication use. VigiBase is a significant tool for evaluating events associated with drug use, and, to the authors’ knowledge, no study has yet assessed this database to identify the primary medications associated with glomerular disorders. Materials and Methods: We collected data from VigiBase for 54 years and evaluated data based on global frequencies, disproportionality (IC025 values), nephrotoxic potential, and physiopathological mechanisms. Results: Over the evaluation period, 33.932.051 spontaneous notifications of adverse drug reactions reported in VigiBase were assessed, from which 106.775 notifications of drug-associated glomerular disorders were extracted. The isolated medications were classified as ‘potential nephrotoxins’ (47.0%), with 40% of the medications lacking scientific references to report any association with the development of glomerular disorders. Among the evaluated medications, Inotersen (IC025 of 8.3), Penicillamine (IC025 6.8), Bevacizumab (IC025 5.9) and Lenvatinib (IC025 5.4) were identified as having the strongest association with these glomerular disorders. For medications classified as ‘non-nephrotoxic’, a high disproportionality index was observed, suggesting drugs that might be considered as new potential nephrotoxins. Conclusions: Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential.info:eu-repo/semantics/publishedVersio