Survey of prescriptions for triple whammy drug combinations with vitamin D as a possible fourth whammy.

BACKGROUND: Improper prescriptions can cause adverse reactions in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Hospital pharmacists investigated improper prescriptions, prerenal acute kidney injury (AKI) prescriptions, and adverse effects in AKI in 199 CKD patients at Kouseikai Hospital from July 2020 to June 2021, as well as combinations of "triple whammy" drugs (renin-angiotensin-system inhibitors, diuretics, and non-steroidal anti-inflammatory drugs) plus active vitamin D preparations. All participants (average age, 73.6 ± 16.2 years) were residents of Nagasaki City or its suburbs. RESULTS: Adverse reactions occurred in 38 of the 199 patients (19.1%). 13 patients had AKI, and 9 of these cases developed during the summer. A comparison of the 38 patients in the adverse reaction group and the 161 patients in the non-occurrence group showed that the former group was significantly older and had a lower body weight. In terms of renal function, estimated glomerular filtration rate (mL/min/1.73m2) was significantly lower, blood urea nitrogen/serum creatinine (BUN/S-Cr) was higher, dehydration was involved, and active vitamin D preparations were significantly more common in the adverse reaction group. CONCLUSION: Our findings suggest that concomitant prescription of active vitamin D in combination with the drugs that constitute the triple whammy should be avoided. The absence of hypercalcemia should be confirmed and adequate fluid intake should be encouraged to prevent prerenal nephropathy.

Chapter 4: CKD treatment in cancer survivors, from Clinical Practice Guidelines for the Management of Kidney Injury During Anticancer Drug Therapy 2022.

Chronic kidney disease (CKD) is one of the most disabling disorders with significant comorbidity and mortality. Incidence and prevalence of CKD in cancer survivors are remarkably high in both adults and pediatric patients. The reasons for this high incidence/prevalence are multifold but kidney damage by cancer itself and cancer treatment (pharmacotherapy/surgery/radiation) are the main reasons. Since cancer survivors commonly have significant comorbidities, risk of cancer recurrence, limited physical function or life expectancy, special attentions should be paid when considering the treatment of CKD and its complications. Especially, shared decision-making should be considered when selecting the renal replacement therapies with as much information/facts/evidence as possible.

[Management of Chronic Kidney Disease in Cancer Survivors].

Chronic kidney disease(CKD)associated with cancer and its treatment affects life after cancer treatment. There is inconclusive opinion on whether CKD treatment in survivors after cancer treatment needs special care differently than in the general population with CKD. Several topics were discussed by nephrologists, urologists and medical oncologists, pediatricians, pharmaceutical specialists, and others based on the results of a literature search, and the consensus was documented in the "Clinical Practice Guidelines for the Management for Kidney Injury During Anticancer Drug Therapy, 2022". The prevalence of CKD among adult cancer survivors is reported to be 4-7%. The characteristics include(1)elderly and physically impaired patients(, 2)a high risk of cancer recurrence, and(3)frequently cancer treatment-related CKD. Although there are no cancer survivor-specific indications or contraindications in the selection of renal replacement therapy, renal transplantation is often preferred in pediatric cancer survivors. It was determined that it is not appropriate to recommend or not recommend the administration of erythropoietin stimulating agents for renal anemia in cancer survivors based on a systematic review and discussion between panelists. When used in individual cases, its application should be well examined and consideration should be given to avoiding high hemoglobin level and to monitoring for cancer development.

Improved Formula for Predicting Hemodialyzability of Intravenous and Oral Drugs.

BACKGROUND: The rate of drug removal by hemodialysis needs to be considered when designing drug dosage regimens for patients on hemodialysis. We previously developed a simplified equation to predict the removal rates of intravenously administered drugs by hemodialysis. Here, we addressed shortcomings of this equation and developed a more accurate equation that can also predict the removal rates of orally administered drugs. METHODS: A total of 70 drugs with known pharmacokinetic and physical parameters and drug removal rates that were measured during hemodialysis in clinical cases were randomly assigned at a 4:1 ratio to a training data group or a test data group. A prediction equation was developed by performing stepwise multiple regression analyses using the training data (i.e., the removal rate by hemodialysis) as the objective variable and pharmacokinetic parameters as the explanatory variables. The equation was validated using the test data. RESULTS: Multiple regression analyses revealed that molecular weight (MW), protein binding rate, and fraction excreted unchanged in urine relative to the volume of distribution (Vd) were independently correlated with the drug clearance rate (adjusted coefficient of determination, 0.83; p = 2.2e-16). The following equation was obtained: drug removal rate by hemodialysis (%) = -17.32 × [log (MW)] - 0.39 × [protein binding rate (%)] + 0.06 × [fraction excreted unchanged in urine (%)/Vd (L/kg)] + 83.34. Validation of the equation using the test data showed a very high correlation between predicted and measured reduction rate (R = 0.93, p = 1.87e-6). Mean error was -3.34 (95% confidence interval: -10.03, 3.35), mean absolute error was 9.59, and root mean square error was 16.48. CONCLUSION: The modified equation derived in this study using pharmacokinetic and physical parameters as variables precisely predicted the removal rates of both intravenous and oral drugs by hemodialysis.

Investigation of methods for more accurate estimation of kidney function in people with high muscle mass
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Serum creatinine (SCr) levels depend on muscle mass and are therefore elevated in people with high muscle mass, potentially leading to underestimation of kidney function in this population. Although recent therapeutic guidelines have shown measurement of serum cystatin C (ScysC) to be useful, this method has not been validated in people with high muscle mass. We conducted this study to investigate methods for more accurately estimating kidney function in people with high muscle mass. Linear regression analysis was used to assess the correlation of endogenous creatinine clearance (24-hour CLcr) and 24-hour CLcr × 0.715 (i.e., modified glomerular filtration rate (GFR)); with estimated kidney function from SCr and ScysC in 15 healthy young adult men with high muscle mass. A significant but weak positive correlation was observed between 24-hour CLcr and estimated CLcr by the Cockcroft and Gault formula (CG CLcr; R2 = 0.371, p = 0.016). The estimated GFR calculated from ScysC (eGFRcys) was significantly higher than CLcr × 0.715, but the two were not correlated (R2 = 0.125, p = 0.197). However, when CG CLcr and eGFRcr were adjusted by muscle mass parameters, the correlation between measured and estimated values improved. Further improvement was seen when participants with a fat mass greater than 25% were excluded (R2 = 0.623, p = 0.004; R2 = 0.510, p = 0.014; n = 11 for both). The results of our study suggest that currently used formulas for estimating kidney function, including eGFRcys, may not be appropriate for people with high muscle mass, but use of muscle mass parameters may improve predictivity.
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Comparative Study of Constipation Exacerbation by Potassium Binders Using a Loperamide-Induced Constipation Model.

Patients on dialysis are frequently administered high doses of potassium binders such as calcium polystyrene sulfonate (CPS) and sodium polystyrene sulfonate (SPS), which exacerbate constipation. Here, we compare the degree of constipation induced by CPS and SPS using a loperamide-induced constipation model to identify the safer potassium binder. Constipation model was created by twice-daily intraperitoneal administration (ip) of loperamide hydrochloride (Lop; 1 mg/kg body weight) in rats for 3 days. Rats were assigned to a control group, Lop group, Lop + CPS group or Lop + SPS group, and a crossover comparative study was performed. Defecation status (number of feces, feces wet weight, fecal water content and gastrointestinal transit time (GTT)) was evaluated. In the Lop + CPS group, GTT was significantly longer, and fecal water content was reduced. In the Lop + SPS group-although the fecal water content and GTT were unaffected-the number of fecal pellets and the fecal wet weight improved. Thus, SPS was less likely to cause constipation exacerbation than CPS. Considering the high frequency of constipation in dialysis patients with hyperkalemia, preferentially administering SPS over CPS may prevent constipation exacerbation.

Coefficient of Determination between Estimated and Measured Renal Function in Japanese Patients with Sarcopenia May Be Improved by Adjusting for Muscle Mass and Sex: A Prospective Study.

Creatinine (Cr) levels are strongly affected by muscle mass, and the estimated glomerular filtration rate (eGFR), a measure based on serum creatinine (SCr), is often overestimated in patients with sarcopenia. To evaluate the coefficient of determination (R2) between eGFR and the actual measured value, we performed a linear regression analysis of a modified GFR (mGFR: measured Cr clearance × 0.715) and various renal function estimates adjusted for muscle mass in 19 patients with sarcopenia. The eGFR values based on SCr (eGFRcr) were higher than those based on mGFR, although a high R2 (0.704; p < 0.001) was found between these values. There was no deviation between eGFR based on serum cystatin C (eGFRcys) and mGFR, although the R2 value 0.691 was equivalent to that of eGFRcr. In the equation used to calculate eGFRcr not adjusted for body surface area (mL/min), muscle mass parameters obtained from bioelectrical impedance analysis were used instead of actual body weight to recalculate the eGFRcr. The R2 between this eGFRcr and mGFR did not improve, although there was less deviation. However, assuming that all patients were female by using female coefficients for all patients, the R2 between eGFRcr-fcc (eGFRcr with female coefficient correction) and mGFR improved and was the highest (0.808) on substitution of appendicular skeletal muscle mass. The correlation between eGFRcr-fcc and mGFR improved over eGFRcys when muscle mass was substituted for body weight in the equation used to estimate eGFR in patients with sarcopenia and sex differences were removed.

Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats.

BACKGROUND: Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. METHODS: Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. RESULTS: The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. CONCLUSION: Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production.

Modified serum creatinine-derived equations with muscle mass-adjusted estimation of renal function and serum cystatin C-derived estimated glomerular filtration rate in elderly individuals
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AIMS: Serum creatinine (Cr)-derived estimated renal function indices are overestimated in elderly patients with reduced muscle mass (MM). We sought to identify equations correlated with measured glomerular filtration rate (mGFR) and assess the effect of bioelectrical impedance analysis (BIA)- or arm muscle circumference (AMC)-determined MM on performance. MATERIALS AND METHODS: This study involved 20 elderly patients aged 76.0 ± 6.8 (65 - 85) years, including 5 bedridden patients. Serum Cr, Cr clearance (CCr), and cystatin C (CysC) were measured, and correlations with estimated renal indices were investigated. We also assessed if BIA- or AMC-determined MM in such equations improved performance. RESULTS: Measured CCr (mCCr) × 0.715 was regarded as mGFR, which was correlated with estimated GFR (eGFRcr), more strongly after excluding bedridden patients (R = 0.393, n = 20; R = 0.925, respectively, when n = 15). Correlation between mGFR and eGFRcys in 20 cases (R = 0.894, p < 0.0001) was the most accurately quantified renal function in bedridden patients. In ambulatory cases, correlation was strong between mGFR and eGFR with use of BIA-determined MM in the eGFRcr equation (R = 0.904, p < 0.0001; n = 15). CONCLUSION: eGFR derived from equations with MM-for-body-weight substitution, and eGFRcys independent of MM, may be a more exact measure of renal function than conventional serum Cr-derived estimates in elderly bedridden patients.
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Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity.

The interplay between oxidative stress, inflammation, and tissue fibrosis leads to the progression of chronic kidney disease (CKD). Edoxaban, an activated blood coagulation factor Xa (FXa) inhibitor, ameliorates kidney disease by suppressing inflammation and tissue fibrosis in animal models. Interestingly, rivaroxaban, another FXa inhibitor, suppresses oxidative stress induced by FXa. Thus, FXa inhibitors could be multitargeted drugs for the three aforementioned risk factors for the progression of CKD. However, the exact mechanism responsible for eliciting the antioxidant effect of FXa inhibitors remains unclear. In this study, the antioxidant effect of edoxaban was evaluated. First, the intracellular antioxidant properties of edoxaban were evaluated using human proximal tubular cells (HK-2 cells). Next, direct radical scavenging activity was measured using the electron spin resonance and fluorescence analysis methods. Results show that edoxaban exhibited antioxidant effects on oxidative stress induced by FXa, indoxyl sulfate, and angiotensin II in HK-2 cells, as well as the FXa inhibitory activity, was involved in part of the antioxidant mechanism. Moreover, edoxaban exerted its antioxidative effect through its structure-specific direct radical scavenging activity. Edoxaban exerts antioxidant effects by inhibiting FXa and through direct radical-scavenging activity, and thus, may serve as multitargeted drugs for the three primary risk factors associated with progression of CKD.

Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.

We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

Direct radical scavenging activity of benzbromarone provides beneficial antioxidant properties for hyperuricemia treatment.

Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin-angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.

Olmesartan protects endothelial cells against oxidative stress-mediated cellular injury.

BACKGROUND: The primary cause of death of hemodialysis (HD) patients is cardiovascular disease, and increased oxidative stress has been proposed to be involved in the disease pathogenesis. In this study, we examined the effect of olmesartan on oxidative stress induced by angiotensin II, lipopolysaccharide, indoxyl sulfate, advanced oxidation protein products (AOPP) or hydrogen peroxide (H2O2), which are known to be present at higher concentrations in the blood of HD patients, using human umbilical vein endothelial cells (HUVECs). METHODS: Oxidative stress was evaluated by measuring the mean fluorescence intensity of CM-H2DCFCA, an ROS-sensitive fluorescent dye, in HUVECs. HUVECs were incubated with each of the above compounds in the presence or absence of olmesartan. Moreover, these oxidant-stimulated cells were also treated with the reactive oxygen species (ROS) inhibitor N-acetyl-cysteine (NAC), NADPH oxidase inhibitor diphenylene iodonium (DPI) or PKC inhibitor calphostin C. In addition, we investigated the effects of olmesartan on cytotoxicity and vascular endothelial growth factor (VEGF) secretion, which is involved in vascular inflammation in HUVECs induced by AOPP or H2O2. RESULTS: The treatment of these oxidant-stimulated cells with olmesartan resulted in a significant reduction in intracellular ROS production to an extent that was nearly equivalent to that of NAC, DPI or calphostin C. Furthermore, olmesartan reduced the cytotoxicity and VEGF secretion induced by AOPP or H2O2. CONCLUSIONS: These results demonstrated that the antioxidant activity of olmesartan might contribute to both its vasculoprotective and anti-hypertensive effects.

Possible false-negative results on therapeutic drug monitoring of phenytoin using a particle enhanced turbidimetric inhibition immunoassay in a patient with a high level of IgM.

: In this report, the authors described the unusual case of a patient in whom the plasma phenytoin concentration was unexpectedly not detected on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique, a typical immunoassay for phenytoin. The plasma concentration was measured using PETINIA and high-performance liquid chromatography in a 69-year-old male patient treated with fosphenytoin intravenously at the standard dose for 7 days. Although the plasma concentration of phenytoin was below the limit of detection (<0.5 mcg/mL) on PETINIA after the administration of fosphenytoin, the trough plasma concentration was estimated to be between 5 and 10 mg/L on high-performance liquid chromatography. When the plasma concentrations of IgM and IgG were measured using an enzyme-linked immunosorbent assay, the plasma IgG level was within the reference range, whereas the plasma IgM level was 2-3 times higher than the upper limit of the reference range. We concluded that the PETINIA method yielded a possible false-negative result regarding the phenytoin level in this patient, perhaps because of some hindrance to the measurement process by IgM. This case suggests that false-negative results should be considered when therapeutic drug monitoring reveals abnormally low values using PETINIA and that it is necessary to evaluate the plasma IgM level.

Awareness and current implementation of drug dosage adjustment by pharmacists in patients with chronic kidney disease in Japan: a web-based survey.

BACKGROUND: The aims of this study were to evaluate the current awareness of and implementation by pharmacists in Japan of adjustment of drug dosage according to renal function (ADDR) in patients with chronic kidney disease (CKD) and to clarify the factors influencing implementation of ADDR by community pharmacists. METHODS: We conducted a web-based questionnaire of Japanese community and hospital pharmacists. Responders were compared by characteristics, rate of implementation of ADDR, experience with adverse drug events, pharmacist awareness of implementation of ADDR, and obstacles to ADDR implementation experienced by pharmacists. Additionally, the factors influencing the implementation of ADDR by community pharmacists were investigated by logistic regression analysis. RESULTS: Fewer community pharmacists had implemented ADDR than hospital pharmacists. The community pharmacists had less experience with adverse drug events caused by an inappropriate dosage than the hospital pharmacists, while the hospital pharmacists had encountered more severe adverse drug events than the community pharmacists. The community pharmacists had less awareness of ADDR implementation, and believed that problems in implementing ADDR were caused by a lack of information on the renal function of patients. In the logistic regression analysis, the factors influencing implementation of ADDR were "Routinely receiving prescriptions from nephrologists", "Experience with adverse drug events caused by inappropriate dosage for CKD patients", and "Awareness of the need for pharmacists to check the dosage of renally excreted drugs"; they did not include "Lack of information on patient renal function". CONCLUSIONS: This study indicates that fewer Japanese community pharmacists than hospital pharmacists implement ADDR and that implementation of ADDR by community pharmacists is hindered by their limited awareness of the importance of patient renal function. We advocate that many countermeasures be introduced to prevent CKD patients from experiencing adverse drug events caused by inappropriate dosage. Such countermeasures would include a training program to educate pharmacists about the impact of impaired renal function on dosage of drugs that are excreted by the kidneys.

Evaluation of a creatinine clearance correction equation based on body fat mass in older Japanese patients with diabetes.

Background: The estimation of creatinine clearance (CCr) in older adult patients with diabetes is subject to deviations from the results of actual measurements because of changes in body composition. In the present study, we aimed to create a correction for the equation used for the estimation of CCr in older adult Asian patients with diabetes using body composition parameters. Methods: We enrolled 50 older Japanese patients with diabetes in whom the measured values of CCr were compared with values estimated using the Cockcroft-Gault equation. The relationships between the error in the estimated CCr and body composition parameters were investigated, and the Cockcroft-Gault equation was corrected using the appropriate parameters. To evaluate the generalizability of the corrected equation, the utility of the Cockcroft-Gault equation, which was corrected on the basis of body composition measured using a household body composition meter, was also investigated. Results: Body fat mass (BFM) was closely correlated with the error in the estimated CCr. The BFM-corrected Cockcroft-Gault equation was more accurate than the original equation. Similarly, the error became smaller using BFM measured with a household body composition meter. Conclusion: The BFM-corrected Cockcroft-Gault equation may provide an accurate method of estimating CCr that can be used in general practice.