Principles of Kidney Pharmacotherapy for the Nephrologist: Core Curriculum 2021.

Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents.

Evaluation of Systemic Corticosteroids in Patients With an Acute Exacerbation of COPD and a Diagnosis of Pneumonia.

Background: Chronic obstructive pulmonary disease (COPD) and pneumonia are leading causes of morbidity and mortality and are frequently comorbid. Studies of systemic corticosteroids in pneumonia have shown conflicting outcomes, whereas studies in acute exacerbations of COPD (AECOPD) have shown significant benefits. No studies have evaluated systemic corticosteroids in patients with both an AECOPD and pneumonia. Purpose: To evaluate the use of systemic corticosteroids in patients with both an AECOPD and pneumonia. Patients and Methods: Patients with a diagnosis of both COPD or obstructive chronic bronchitis with exacerbation and pneumonia admitted to the University of Colorado Hospital between July 1, 2012 and May 20, 2016 were retrospectively evaluated. Patients who received systemic corticosteroids were compared to those that did not. The primary outcome was length of hospital stay (LOHS). Secondary outcomes were in-hospital treatment failure, a composite of intensive care unit (ICU) admission, ventilation, and escalation of steroid therapy, 30-day AECOPD or pneumonia readmission, and 30-day mortality. Results: A total of 138 patients were included-- 89 in the steroid group and 49 in the non-steroid group. No significant differences in baseline characteristic were noted. No difference was seen in mean LOHS (4.7±3.2 versus 4.2±2.1 days, p=0.27), in-hospital treatment failure (7% versus 4%, p=0.72), 30-day readmission or 30-day mortality between the steroid and non-steroid groups, respectively. There was a difference in mean LOHS for patients with severe pneumonia between the steroid and non-steroid groups (6.0±4.0 versus 4.3±1.8; p=0.03). Conclusions: This study suggests that systemic corticosteroids may not provide a clinical benefit to patients with an AECOPD and pneumonia.

Body composition and bone mineral density after ovarian hormone suppression with or without estradiol treatment.

OBJECTIVE: Suppression of ovarian hormones in premenopausal women on gonadotropin-releasing hormone agonist (GnRH(AG)) therapy can cause fat mass (FM) gain and fat-free mass (FFM) loss. Whether this is specifically caused by a decline in serum estradiol (E2) is unknown. This study aims to evaluate the effects of GnRH(AG) with placebo (PL) or E2 add-back therapy on FM, FFM, and bone mineral density (BMD). Our exploratory aim was to evaluate the effects of resistance exercise training on body composition during the drug intervention. METHODS: Seventy healthy premenopausal women underwent 5 months of GnRH(AG) therapy and were randomized to receive transdermal E2 (GnRH(AG) + E2, n = 35) or PL (GnRH(AG) + PL, n = 35) add-back therapy. As part of our exploratory aim to evaluate whether exercise can minimize the effects of hormone suppression, some women within each drug arm were randomized to undergo a resistance exercise program (GnRH(AG) + E2 + Ex, n = 12; GnRH(AG) + PL + Ex, n = 12). RESULTS: The groups did not differ in mean (SD) age (36 [8] and 35 [9] y) or mean (SD) body mass index (both 28 [6] kg/m). FFM declined in response to GnRH(AG) + PL (mean, -0.6 kg; 95% CI, -1.0 to -0.3) but not in response to GnRH(AG) + E2 (mean, 0.3 kg; 95% CI, -0.2 to 0.8) or GnRH(AG) + PL + Ex (mean, 0.1 kg; 95% CI, -0.6 to 0.7). Although FM did not change in either group, visceral fat area increased in response to GnRH(AG) + PL but not in response to GnRH(AG) + E2. GnRH(AG) + PL induced a decrease in BMD at the lumbar spine and proximal femur that was prevented by E2. Preliminary data suggest that exercise may have favorable effects on FM, FFM, and hip BMD. CONCLUSIONS: Suppression of ovarian E2 results in loss of bone and FFM and expansion of abdominal adipose depots. Failure of hormone suppression to increase total FM conflicts with previous studies of the effects of GnRH(AG). Further research is necessary to understand the role of estrogen in energy balance regulation and fat distribution.

Prescription ergocalciferol dosing for vitamin D repletion: a retrospective evaluation.

STUDY OBJECTIVES: To determine the efficacy and safety of vitamin D repletion with prescription ergocalciferol and to determine patient-specific factors that may influence the amount of ergocalciferol needed to attain vitamin D sufficiency. DESIGN: Retrospective medical record review. SETTING: University-affiliated outpatient health system. PATIENTS: A total of 1446 patients aged 18-89 years who had a prescription for ergocalciferol 50,000 IU between January 1, 2007, and December 31, 2008, were identified; of these patients, 582 patients had a vitamin D concentration measured 120 days before their first prescription (baseline) and had another concentration measured 60-180 days after this prescription (follow-up) and were deemed "first-time users" of ergocalciferol. MEASUREMENTS AND MAIN RESULTS: Vitamin D sufficiency was defined as a 25-hydroxyvitamin D (vitamin D) concentration of 30 ng/ml or higher. Twenty-nine different ergocalciferol prescribing regimens were identified in the 1446 patients. For the 582 first-time users of ergocalciferol, vitamin D concentrations increased from a mean ± SE of 17.7 ± 0.32 ng/ml at baseline to 32.9 ± 0.73 ng/ml at first follow-up concentration, with a mean ± SE prescribed ergocalciferol dose of 63,876 ± 1973 IU given over an average of 17 weeks. Overall, 326 (56%) of the 582 first-time users attained sufficiency with their prescribed regimen. With use of a logistic regression model to control for variables that could influence a patient's response to vitamin D, patients prescribed 50,000-100,000 IU/week were significantly more likely to attain vitamin D sufficiency compared with those prescribed less than 50,000 IU/week (OR 2.61, 95% CI 1.37-4.99). Body mass index of 30 kg/m(2) or higher decreased the odds of attaining vitamin D sufficiency, whereas use of a loading dose did not increase the odds of attaining sufficiency. CONCLUSION: Many different ergocalciferol regimens were used to replace vitamin D, and overall attainment of vitamin D sufficiency appeared to be moderate. Based on our findings, an ergocalciferol regimen of 50,000-100,000 IU/week with no loading dose could be considered as a starting point for vitamin D repletion.

Combination vitamin D therapy in stage 5 chronic kidney disease.

OBJECTIVE: To review the data supporting combination therapy with vitamin D and vitamin D receptor activators (VDRAs) in patients with stage 5 chronic kidney disease (CKD). DATA SOURCES: Literature was searched using PubMed and EMBASE using the terms kidney disease, kidney failure-chronic, and vitamin D. Limits applied included humans, adults (19 years or older), and clinical trials (and related), with publication dates between January 1, 1980, and May 16, 2011. STUDY SELECTION AND DATA EXTRACTION: All English-language publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 3 prospective observational studies, 1 prospective cohort study, and 1 retrospective study. DATA SYNTHESIS: To our knowledge, there have been no randomized controlled trials evaluating the safety and efficacy of vitamin D supplementation in combination with VDRA therapy in patients with stage 5 CKD. Relatively small observational studies have demonstrated improvements in 25-hydroxyvitamin D (25-OHD) concentrations and markers of mineral and bone metabolism as well as reduced VDRA use in patients with stage 5 CKD. Not all patients in these studies were receiving VDRA therapy. Therapy was safe, with no patients exceeding the recommended upper limit for 25-OHD concentrations and only a small percentage experiencing transient/correctable hypercalcemia. CONCLUSIONS: Vitamin D supplementation to maintain 25-OHD concentrations at 20-30 ng/mL or higher with or without VDRA therapy is inexpensive, appears safe, and may have additional health benefits in patients with stage 5 CKD. Well-designed, randomized controlled trials are needed to determine the efficacy and safety of combination vitamin D therapy in patients with stage 5 CKD.

Managing osteoporosis in postmenopausal women.

PURPOSE: To describe strategies used in managing postmenopausal osteoporosis, including a bone-healthy lifestyle, adequate calcium and vitamin D intake, and drug therapy options; considerations in selecting osteoporosis drug therapy; and the role of health-system pharmacists in managing osteoporosis in postmenopausal women. SUMMARY: Postmenopausal women are at risk for osteoporosis and fractures. Weight-bearing and resistance exercise, limiting alcohol and caffeine intake, smoking cessation, and fall prevention strategies are part of a bone-healthy lifestyle used to manage postmenopausal osteoporosis. Supplements containing calcium and vitamin D are needed by many postmenopausal women because of an inadequate intake and other factors. The choice of osteoporosis drug therapy should take into consideration patient characteristics and preference and drug efficacy, safety, route of administration, dosing frequency, convenience, cost, and potential for nonadherence. Bisphosphonates generally are preferred for the prevention and treatment of osteoporosis in postmenopausal women, with raloxifene, teriparatide, and calcitonin salmon as alternatives. Denosumab, a fully human monoclonal immunoglobulin G(2) antibody, may become available soon for prevention and treatment of postmenopausal osteoporosis. Health-system pharmacists can improve the management of osteoporosis in postmenopausal women by counseling them on a bone-healthy lifestyle and making recommendations for calcium and vitamin D supplements and osteoporosis medications to prevent or treat the disease. CONCLUSION: A variety of approaches are available to promote bone health in postmenopausal women. Health-system pharmacists can promote interventions to optimize patient outcomes.

The relationship between adipokines, body composition, and bone density in men with chronic obstructive pulmonary disease.

Osteoporosis is common in patients with chronic obstructive pulmonary disease (COPD). Data regarding the relationship between adipokines and bone mineral density (BMD) in this population is lacking. The purpose of this pilot study was to determine associations between the adipokines tumor necrosis factor-alpha (TNF-alpha), leptin, adiponectin and resistin, body composition, and BMD in men with severe COPD. This was a cross-sectional study of men with severe COPD who visited the University of Colorado Hospital COPD Center. Bone density and parameters of body composition were measured by dual-energy X-ray absorptiometry. Twenty-three men were included (mean age = 66 years, mean percent predicted forced expiratory volume in one second = 32%). On bivariate analysis, there was no association between TNF-alpha and BMD. Parameters of body composition and serum concentrations of leptin and adiponectin were significantly associated with total hip and spine bone density. However, with partial correlation analysis, total body mass was the only independent predictor of total hip BMD, explaining approximately 50% of the variability. Overall, 18 out of 23 men enrolled (78%) had low bone density by T-score, and nine (39%) were classified as having osteoporosis. The men with osteoporosis had lower parameters of body composition, lower mean serum leptin concentrations, and a greater impairment in measures of lung function compared to the men without osteoporosis. We conclude that the effect of adipokines on BMD does not appear to be independent of body mass. However, larger studies are needed to further evaluate the relationship between adipokines, body weight, and BMD in patients with COPD.

Diagnosis and management of osteoporosis in the older senior.

The older senior is at high risk for osteoporosis. It is important for healthcare providers to be fully aware of the potential risks and benefits of diagnosing and treating osteoporosis in the older senior population. Data indicate that bone mineral density testing is under-utilized and drug therapy is often not initiated when indicated in this population. Bone mineral density testing with central dual energy x-ray absorptiometry is essential and cost-effective in this population. All older seniors should be educated on a bone-healthy lifestyle including age-appropriate weight-bearing exercise and smoking cessation if necessary. It is important to remember that falls play a very important role in the risk for osteoporotic fractures, especially in the older senior. All older seniors should be evaluated annually for falls and strategies should be implemented to reduce fall risk in this population. The risk for vitamin D insufficiency and deficiency is high in the older senior and can contribute to falls and fractures. Adequate intakes of calcium and vitamin D are important and deficiencies need to be treated. Data on osteoporosis drug therapy in the older senior are lacking. Based on data from subgroup analyses of large osteoporosis trials in postmenopausal women, current osteoporosis therapies appear safe and efficacious in the older senior and most will live long enough to derive a benefit from these therapies. Further studies are needed in older seniors, especially men, to better understand the risks and benefits of pharmacologic therapy for the management of osteoporosis.

Osteoporosis risk in premenopausal women.

Although clinically significant bone loss and fractures in healthy premenopausal women are rare, more women are seeking evaluation for osteoporosis from their health care providers. As pharmacists are in an ideal position to influence the management of premenopausal women with osteoporosis, it is important that pharmacists understand the available data on bone loss, fractures, and risk factors and secondary causes for osteoporosis, as well as when to recommend testing and treatment in premenopausal women. Limited data are available; therefore, we conducted a MEDLINE search of the literature from January 1993-August 2008. Studies evaluating bone loss, fractures, and fracture risk in healthy premenopausal women were targeted and summarized; most recommendations are based on expert opinion. A small but statistically significant loss in bone mineral density of 0.25-1%/year by dual-energy x-ray absorptiometry is seen healthy premenopausal women; the clinical significance of this is unknown. Whereas absolute fracture risk is low, premenopausal fractures appear to increase postmenopausal fracture risk by 1.5-3-fold. Risk factors for low bone density appear to be similar between pre- and postmenopausal women. Bone density screening in healthy premenopausal women is not recommended, but bone mineral density testing is advisable for those who have conditions or who receive drug therapy that may cause secondary bone loss. Lifestyle modification emphasizing bone-healthy habits such as adequate calcium and vitamin D nutrition, regular exercise, limitation of caffeine and alcohol consumption, and avoidance of tobacco are essential to the management of osteoporosis risk. The efficacy and safety of osteoporosis drugs have not been adequately demonstrated in premenopausal women. Therefore, pharmacologic interventions cannot be recommended in young women with low bone mass but may be considered in those having a more significant fracture risk, such as those with a previous low-trauma fracture or an identified secondary cause for bone loss.

Clinical challenges in the management of osteoporosis.

While knowledge regarding the diagnosis and treatment of osteoporosis has expanded dramatically over the last few years, gaps in knowledge still exist with guidance lacking on the appropriate management of several common clinical scenarios. This article uses fictional clinical scenarios to help answer three challenging questions commonly encountered in clinical practice. The first clinical challenge is when to initiate drug therapy in a patient with low bone density. It is estimated that 34 million America have low bone density and are at a higher risk for low trauma fractures. Limitations of using bone mineral density alone for drug therapy decisions, absolute risk assessment and evidence for the cost-effectiveness of therapy in this population are presented. The second clinical challenge is the prevention and treatment of vitamin D deficiency. Appropriate definitions for vitamin D insufficiency and deficiency, the populations at risk for low vitamin, potential consequences of low vitamin D, and how to manage a patient with low vitamin D are reviewed. The third clinical challenge is how to manage a patient receiving drug therapy for osteoporosis who has been deemed a potential treatment failure. How to define treatment failure, common causes of treatment failure, and the approach to the management of a patient who is not responding to appropriate osteoporosis therapy are discussed.

Vitamin D intervention by pharmacists in geriatric outpatients.

OBJECTIVES: To develop a pharmacist-provided educational intervention that instructs participants to consume 1,200 IU vitamin D daily and to evaluate its effect on serum 25-hydroxyvitamin D (vitamin D) concentrations and self-reported daily vitamin D intake in geriatric outpatients with insufficient vitamin D. DESIGN: Randomized controlled trial. SETTING: University-affiliated geriatric clinic, December 2005 to May 2006. PATIENTS: 80 participants aged 65 to 89 years. INTERVENTION: Participants with insufficient vitamin D (12-31 ng/mL) were randomized to receive either the educational intervention (n = 23) or no intervention (n = 22). MAIN OUTCOME MEASURES: Difference in change from baseline to 12 weeks in vitamin D concentrations and self-reported daily vitamin D intake between groups. RESULTS: At 12 weeks, vitamin D concentrations in the educational intervention group (n = 22) increased from a mean (+/- SD) of 23.5 +/- 5.0 to 30.4 +/- 6.3 ng/mL. Vitamin D concentrations in the nonintervention group (n = 21) increased from 22.8 +/- 5.4 to 26.9 +/- 6.2 ng/mL. The difference between the groups at 12 weeks did not reach statistical significance (P = 0.07). However, 12 participants (55%) in the educational intervention group achieved sufficient vitamin D concentrations compared with only 5 participants (24%) in the nonintervention group (P = 0.04). Self-reported daily vitamin D intake increased by a mean of 647 IU/day in the educational intervention group and 67 IU/day in the nonintervention group. The difference in self-reported intake between groups at 12 weeks, controlling for baseline, was significant (P < 0.0001). Serum parathyroid hormone concentrations decreased significantly among those in the intervention group (P = 0.04). CONCLUSION: A pharmacist-developed and -administered vitamin D educational intervention increased the proportion of participants achieving sufficient vitamin D concentrations, increased the self-reported daily vitamin D intake, and lowered serum parathyroid hormone concentrations. However, it did not significantly increase the overall mean serum vitamin D concentration, compared with the control group. A daily recommendation of more than 1,200 IU vitamin D daily is likely necessary to ensure that all geriatric outpatients with insufficient vitamin D concentrations achieve the target of at least 32 ng/mL.

Prevalence of vitamin D insufficiency in elderly ambulatory outpatients in Denver, Colorado.

BACKGROUND: Vitamin D insufficiency is common in the elderly. However, previous studies have utilized 25-hydroxvvitamin D (25[OH]D) concentrations as low as <16 ng/mL for defining vitamin D insufficiency. Moreover, most of the studies have been conducted in European patients, in certain geographic areas of the United States, or in institutionalized elderly. OBJECTIVE: The goal of this study was to characterize vitamin D concentrations in ambulatory elderly living in metropolitan Denver, Colorado, utilizing 25(OH)D concentrations <32 ng/mL as the definition for vitamin D insufficiency. METHODS: Ambulatory older adults (aged 65-89 years) with clinic visits during December 2005 and January 2006 were enrolled. Serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, phosphorus, creatinine, and albumin were measured; height and weight were also measured. Data regarding dietary and over-the-counter vitamin D intake were collected, as well as information on body mass index, history of osteoporosis, osteoporosis treatment, and history of falls and fractures. RESULTS: Eighty patients (mean [SD] age, 77.8 [5.3] years; age range, 66-89 years) completed the study; there were no dropouts. The majority of patients were white (88%) and female (68%). Fifty-nine (74%) were found to have vitamin D insufficiency. Mean total and over-the-counter vitamin D intake was significantly higher in sufficient (P < 0.01) and insufficient (P < 0.05) patients compared with deficient patients, but dietary intake did not differ significantly between groups. The majority of patients who were vitamin D insufficient consumed more than the recommended 400 to 600 IU/d of vitamin D. Obese patients were found to have significantly lower 25(OH)D concentrations (P < 0.001) and higher PTH concentrations (P = 0.04) than nonobese patients. CONCLUSIONS: Vitamin D insufficiency is prevalent in ambulatory, and especially obese, elderly living in Denver, Colorado, despite vitamin D intake consistent with national recommendations. Dietary intake of vitamin D appeared to be unreliable to prevent insufficiency. Based on our results, along with other published data, we feel that national recommendations for vitamin D intake in the elderly should be increased to at least 800 to 1000 IU/d of over-the-counter supplemental cholecalciferol.

Is there an optimal corticosteroid regimen for the management of an acute exacerbation of chronic obstructive pulmonary disease?

Systemic corticosteroids are standard of care for the management of an acute exacerbation of chronic obstructive pulmonary disease (COPD). Several prospective, randomized trials demonstrated modest improvements in patient outcomes when short courses of systemic corticosteroids were used. However, the most appropriate dosage regimen remains controversial, as the corticosteroid regimens used in these trials differed greatly, and no studies have directly compared medium-, high-, and low-dose regimens. In addition, data are lacking on the safety, efficacy, and appropriate dosing of systemic corticosteroids in women and in patients with an acute exacerbation of COPD and concomitant pneumonia or severe respiratory failure. Systemic corticosteroid use is associated with several adverse effects that are dose and/or duration dependent. Evidence suggests that higher dose corticosteroid regimens may place patients at increased short-term and long-term risk, without additional clinical benefit. Tapering of systemic corticosteroid regimens, although a common practice, is unnecessary in most circumstances. The risk for hypothalamic-pituitary-adrenal-axis suppression is negligible when low-dose, short-course corticosteroid regimens are used, and no evidence exists to suggest that abruptly stopping a low-dose steroid regimen will increase the risk of disease relapse. Still, no studies have directly compared tapered and non-tapered regimens in patients with an acute exacerbation of COPD. Consistent with clinical guideline recommendations, safety and efficacy data support the use of low-dose corticosteroid regimens such as prednisone 40 mg orally once/day for 10-14 days in most patients with an acute exacerbation of COPD. Further studies are needed to clarify the optimal systemic corticosteroid regimen for an acute exacerbation of COPD.

Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease.

PURPOSE: The use of systemic corticosteroids for the management of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) was studied. METHODS: Medical charts of patients admitted to the hospital between July 2002 and November 2003 with a primary diagnosis of AECOPD were retrospectively reviewed. The primary objective was to characterize the drug, dosage, route, frequency, and duration of systemic corticosteroids prescribed for the management of AECOPD. The secondary objective was to compare the mean length of stay (LOS) and 30-day relapse rate between patients who received lower and higher dosages of corticosteroids. RESULTS: One hundred forty-five admissions (123 patients) for AECOPD (mean +/- S.D. age, 65 +/- 11 years) were evaluated. Higher dosages of systemic corticosteroids (>80 mg of prednisone equivalent [PE] per day) were prescribed for 51% and i.v. therapy for 56% of admissions. The mean +/- S.D. total systemic corticosteroid exposure during hospitalization for all admissions was 759 +/- 971 mg of PE (mean +/- S.D. daily exposure = 134 +/- 111 mg of PE per day). The mean LOS was significantly longer for the higher-dosage group than for the lower-dosage group (6.1 versus 4.2 days, p = 0.0004). A tapered regimen was prescribed for 79% of discharges. Twenty-seven percent of the discharges with routine follow-up care had a relapse of disease within 30 days. CONCLUSION: This retrospective observational study confirmed a wide variability in the dosages of systemic corticosteroids for the inpatient management of AECOPD, including the use of higher dosages and tapered regimens. Prospective randomized studies are needed to determine the most effective regimen of systemic corticosteroids in patients with AECOPD.