Dotinurad restores exacerbated kidney dysfunction in hyperuricemic patients with chronic kidney disease.

BACKGROUND: In this study, we aimed to clarify the beneficial effects of urate-lowering treatment with the novel agent dotinurad on renal function in patients with chronic kidney disease (CKD) and hyperuricemia (HUA). METHODS: Thirty-five patients with CKD (mean age 65.4 ± 14.8 years, 23 men) diagnosed with HUA were recruited. Changes in eGFR before and after dotinurad administration were assessed. Patients first underwent a 3-month observation period and then 3 months treatment with dotinurad. RESULTS: During the observation period, mean eGFR (mL/min/1.73 m2) declined significantly. The baseline eGFR was 31.8 ± 16.4 and the serum urate level (sUA, mg/dL) was 8.1 ± 1.7. During the treatment period, eGFR recovered to 36.5 ± 17.5 and sUA decreased to 6.7 ± 1.0. The increase in eGFR after dotinurad administration was correlated with a decrease in sUA (R = 0.375, p = 0.0263). CONCLUSION: Dotinurad administration to patients with CKD and HUA appears to be beneficial in restoring kidney function. Dotinurad may represent a potential medication for the prevention of kidney function decline caused by HUA.

Physiologically Based Pharmacokinetic Modeling of Lacosamide in Patients With Hepatic and Renal Impairment and Pediatric Populations to Support Pediatric Dosing Optimization.

PURPOSE: Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment. METHODS: This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data. FINDINGS: Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults. IMPLICATIONS: The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.

Smaller nadroparin dose reductions required for patients with renal impairment: A multicenter cohort study.

BACKGROUND: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. AIMS: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. METHODS: A retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. RESULTS: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m2, respectively. In eGFR 15-29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. CONCLUSION: We advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes.

Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.

Long-term cisplatin nephrotoxicity after childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Cisplatin is a chemotherapeutic drug commonly used in the treatment of many childhood solid malignancies. It is known to cause long-term nephrotoxicity, most commonly manifesting as reduced glomerular filtration rate and hypomagnesaemia. Existing literature regarding the epidemiology of long-term nephrotoxicity in childhood cancer describes large variation in prevalence and risk factors. OBJECTIVES: This study is to evaluate the prevalence of, and risk factors for, long-term cisplatin nephrotoxicity after treatment for childhood cancer. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they: (i) evaluated participants treated with cisplatin who were diagnosed with cancer < 18 years of age; (ii) investigated any author-defined measure of nephrotoxicity; and (iii) performed this evaluation 3 or more months after cisplatin cessation. Studies whose scope was broader than this were included if appropriate subgroup analysis was performed. RESULTS: Prevalence of reduced glomerular filtration rate (GFR) ranged between 5.9 and 48.1%. Pooled prevalence of reduced GFR using studies with a modern consensus threshold of 90 ml/min/1.73 m2 was 29% (95% CI 0.0-58%). Prevalence of hypomagnesaemia ranged between 8.0 and 71.4%. Pooled prevalence of hypomagnesaemia was 37% (95% CI 22-51%). Substantial heterogeneity was present, with I2 statistics of 94% and 73% for reduced GFR and hypomagnesaemia respectively. All large, long-term follow-up studies described increased risk of reduced GFR with increasing cumulative cisplatin dose. Included studies varied as to whether cisplatin was a risk factor for proteinuria, and whether age was a risk factor for cisplatin nephrotoxicity. LIMITATIONS: A wide range of study methodologies were noted which impeded analysis. No studies yielded data from developing health-care settings. No non-English studies were included, further limiting generalisability. CONCLUSIONS: Both of the most common manifestations of long-term cisplatin nephrotoxicity have a prevalence of approximately a third, with increasing cumulative dose conferring increased risk of nephrotoxicity. Further work is needed to characterise the relationship between reduced GFR and hypomagnesaemia, investigate other risk factors and understand the interindividual variation in susceptibility to nephrotoxicity.

When should targeted therapies be used in the treatment of lupus nephritis: Early in the disease course or in refractory patients?

Although the prognosis of lupus nephritis (LN) has improved over the last few decades, 5-20% of patients still progress to kidney failure. Hence, there is an unmet need to improve the management of LN. Two novel drugs, belimumab and voclosporin, have been recently approved for LN and obinutuzumab is in the late stage of development. In randomised controlled trials (RCTs), all these drugs, added to the standard-of-care, were more effective than standard-of-care alone in achieving renal response. Now the question is: should these new drugs be used early in the disease course or just in refractory patients? The main reasons supporting the early use are based on the RCTs that demonstrated benefits when combinatory regimen was initiated early in incident and relapsing patients leading to a higher proportion of patients to achieve renal response, hence reducing nephron loss and the risk of kidney failure. The main reasons supporting the use of the combinatory regimens primarily in relapsing/refractory patients acknowledge that many patients responded well even without add-on medications, allowing a more economic use of innovative and costly drugs. However, good predictors of renal response to standard-of-care are lacking and, thus, the decision of adding new treatments early or just in refractory or relapsing patients has to consider drug access, risks of over or undertreatment, and preservation of kidney function in high-risk individuals.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

A 51-Year-Old Woman with Advanced Peritoneal Mesothelioma and Stage 3b Chronic Kidney Disease Treated with Cytoreductive Surgery and Bidirectional Intraperitoneal Cisplatin and Ifosfamide Chemotherapy: A Case Report.

BACKGROUND Malignant mesotheliomas are rare, yet highly malignant tumors. Mesotheliomas are tumors that develop from mesothelial surfaces, with the pleura being the most common, followed by the peritoneum. The diagnosis of malignant peritoneal mesothelioma (MPM) is usually established when the disease is advanced, owing to the nonspecific clinical appearance and abdominal symptoms. Initially, MPM was treated with palliative systemic chemotherapy, with or without palliative surgery. However, cytoreductive surgery (CRS) combined with bidirectional intraoperative chemotherapy (BDIC) has recently emerged as a treatment option for MPM. BDIC creates a bidirectional chemotherapy gradient in the peritoneal tumor cells through the simultaneous use of intraperitoneal and intravenous chemotherapy. CRS, combined with BDIC (CRS-BDIC), allows the complete elimination of residual tiny tumor cells after complete removal of the visible tumor nodules. CASE REPORT Herein, we present a case of a 51-year-old woman with MPM and chronic kidney disease (CKD) stage 3b. Her treatment consisted of neoadjuvant chemotherapy and immunotherapy, followed by CRS-BDIC using intraperitoneal cisplatin and doxorubicin, and intravenous ifosfamide. The surgery was successful, with no immediate complications or decline in the patient's kidney function. On follow up 2 months later, the patient denies suffering any chemotherapy-related adverse effects, and her kidney profile remains stable. CONCLUSIONS In conclusion, nephrotoxicity, a known adverse effect of cisplatin and ifosfamide, might not be a contraindication for the use of these potentially nephrotoxic drugs in CRS-BDIC in patients with renal impairment.

Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort.

OBJECTIVES: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). METHODS: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. RESULTS: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P <0.01) and previous renal failure (57.9%, P <0.01). Patients treated with cloxacillin presented higher rates of septic shock (25%, P = 0.033) and new-onset or worsening renal failure (47.3%, P = 0.024) with significantly higher rates of in-hospital mortality (38.5%, P = 0.017). One-year IE-related mortality and rate of relapses were similar between treatment groups. None of the treatments were identified as risk or protective factors. CONCLUSION: Our results suggest that cefazolin is a valuable option for the treatment of MSSA IE, without differences in 1-year mortality or relapses compared with cloxacillin, and might be considered equally effective.

The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients.

PURPOSE: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. METHODS: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. RESULTS: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. CONCLUSION: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation.

[Translated article] Influence of augmented renal clearance in the lower incidence of linezolid-related haematological toxicity.

OBJECTIVES: Linezolid is an oxazolidin commonly related to the development of haematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced haematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. MATERIAL AND METHODS: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Haematological toxicity was defined as a decrease of 25% in platelets, of 25% in haemoglobin, and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of haematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentage diminution of all 3 parameters was calculated and compared by Mann-Whitney test and treatment interruption and transfusion requirements were registered. RESULTS: 30 ARC patients and 38 reference patients were included. Haematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (P=.014); thrombocytopenia in 13.33% vs 36.84% (P=.051), anaemia in 3.3% vs 10.52% (P=.374) and neutropenia in 10% vs 23.68% (P=.204). Median percentage of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (P=.333), while haemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (P=.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (P=.093). 10.5% of normal renal function patients reported at least 1 adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had transfusion requirements. No major events or interruptions were reported in ARC patients. CONCLUSION: Our findings suggest a lower incidence and clinical relevance of haematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

Influence of augmented renal clearance on the lower incidence of linezolid-related hematological toxicity. / Influencia de la hiperfiltración glomerular en la menor toxicidad hematológica inducida por linezolid.

OBJECTIVES: Linezolid is an oxazolidin commonly related to the development of hematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced hematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. MATERIAL AND METHODS: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Hematological toxicity was defined as a decrease of 25% in platelets, of 25% in hemoglobin and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of hematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentaje disminution of all three parameters was calculated and compared by Mann-Whitney test and treatment interruption and tranfusion requirements were registered. RESULTS: 30 ARC patients and 38 reference patients were included. Hematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (p = 0.014); thrombocytopenia in 13.33% vs 36.84% (p = 0.051), anemia in 3.3% vs 10.52% (p = 0.374) and neutropenia in 10% vs 23.68% (p = 0.204). Median percentaje of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (p = 0.333), while hemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (p = 0.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (p = 0.093). 10.5% of normal renal function patients reported at least one adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had tranfusion requirements. No major events or interruptions were reported in ARC patients. CONCLUSION: Our findings suggest a lower incidence and clinical relevance of hematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

Association of Metformin, Dipeptidyl Dipeptidase-4 Inhibitors, and Insulin with Coronavirus Disease 2019-Related Hospital Outcomes in Patients with Type 2 Diabetes.

OBJECTIVE: The effects of diabetes medications on COVID-19 hospitalization outcomes have not been consistent. We sought to determine the effect of metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), and insulin on admission to the intensive care unit (ICU), need for assisted ventilation, development of renal insufficiency, and mortality in patients admitted with COVID-19 infection after controlling for clinical variables and other relevant diabetes-related medications in patients with type 2 diabetes mellitus (DM). METHODS: This was a retrospective study of patients hospitalized with COVID-19 from a single hospital system. Univariate and multivariate analyses were performed that included demographic data, glycated hemoglobin, kidney function, smoking status, insurance, Charlson comorbidity index, number of diabetes medications, and use of angiotensin-converting enzyme inhibitors and statin prior to admission and glucocorticoids during admission. RESULTS: A total of 529 patients with type 2 DM were included in our final analysis. Neither metformin nor DPP4i prescription was associated with ICU admission, need for assisted ventilation, or mortality. Insulin prescription was associated with increased ICU admission but not with need for assisted ventilation or mortality. There was no association of any of these medications with development of renal insufficiency. CONCLUSIONS: In this population, limited to type 2 DM and controlled for multiple variables that have not been consistently studied (such as a measure of general health, glycated hemoglobin, and insurance status), insulin prescription was associated with increased ICU admission. Metformin and DPP4i prescriptions did not have an association with the outcomes.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Normal 24-hour urine calcium concentrations after long-term daily oral intake of vitamin D in doses ranging from 5000 to 50,000 international units in 14 adult hospitalized psychiatric patients.

Many controversies exist regarding vitamin D3 supplementation. These include not only diseases that are responsive to vitamin D supplementation, but also the long-term safety of prolonged daily oral vitamin D3 intake above 4000-10,000 International Units (IU). In particular, supplementation levels that do not result in adverse events, and the upper limits of safe serum 25-hydroxyvitamin D (25OHD) concentrations. Adverse reactions reported to occur with excessive vitamin D intake include hypercalcemia, renal failure, calcium crystal formation, undetectable parathyroid hormone concentrations, and hypercalciuria, all of which are reported to be reversible. To address the long-term safety of vitamin D supplementation, we previously reported data from patients in our hospital who have been voluntarily supplemented with vitamin D3 ranging from 5,000 to 10,000 IU/day since July 2011 as a standard of care for the prevention and treatment of vitamin D deficiency. Historically 90% of patients have agreed to daily supplementation, with most taking 10,000 IU/day. These data indicate no evidence for hypercalcemia, renal failure, calcium crystal formation, nephrolithiasis. or undetectable parathyroid hormone concentrations in patients taking 5000 or 10,000 IU/day for extended periods of time. As another measure for potential vitamin D toxicity, we retrospectively assessed 24-hour urine calcium excretion in 14 individuals on long-term daily oral vitamin D intake ranging from 5000 to 50,000 IU/day to further assess the safety of supplementation using these doses. This included patients taking either 5000 (4), 10,000 (9), or 50,000 (1) IU/day. Time on supplementation ranged from 10 to 102 months. A patient taking 400 IU/day and getting frequent sun exposure was also included. All fifteen 24-hour urine calcium measurements were normal. The current findings complement our experience with over 7000 patients in the past 13 years, indicating that prolonged daily oral intake of vitamin D3 ranging from 5000 to 10,000 IU/day is safe.

Patient safety outcomes for continuous infusion vancomycin as outpatient parenteral antimicrobial therapy.

BACKGROUND: Administration of vancomycin as a continuous infusion has been associated with reduced nephrotoxicity. Given limited published experience with continuous infusion vancomycin in outpatient parenteral antimicrobial therapy (OPAT) programs, we reviewed outcomes from our center. METHODS: This was a retrospective, single-center study of adult patients receiving vancomycin OPAT as continuous or intermittent infusion for an intended treatment duration of at least 7 days. The primary outcome was time to nephrotoxicity with continuous versus intermittent infusion vancomycin while on OPAT; additional outcomes included time to any vancomycin-associated adverse event, time to 60-day death or readmission, and time to 60-day emergency department encounter. Proportional hazards modeling was used to identify variables independently associated with outcomes, as well as assess the strength of association of continuous infusion with each outcome. RESULTS: Four-hundred ninety-two patients were included: 118 treated with continuous and 374 with intermittent vancomycin infusion. Continuous infusion was not associated with lower rates of nephrotoxicity compared to intermittent infusion (adjusted hazard ratio (aHR) 0.72, 95% CI: 0.35-1.50). There were no advantages of continuous over intermittent infusion in the rates of any adverse event (aHR 0.93, 95% CI: 0.56-1.53), 60-day death or readmission (aHR 1.04, 95% CI: 0.68-1.61), or 60-day emergency department encounter (aHR 1.17, 95% CI: 0.68-1.99). Vancomycin area under the concentration-time curve (AUC) at discharge was the only modifiable factor identified that was independently associated with patient safety outcomes. CONCLUSION: There was no appreciable benefit of continuous infusion vancomycin on outpatient safety outcomes. AUC-centered dosing approaches warrant further investigation as strategies to improve vancomycin safety in OPAT programs.

Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.