Missed Antimicrobial Stewardship Opportunities for Hospitalized Patients with Urinary Tract Infections Receiving Ceftriaxone.

Background: Ceftriaxone is a commonly utilized antibiotic for the treatment of urinary tract infections (UTI) despite the limited literature supporting its use. Opportunities for antimicrobial stewardship (ASP), including IV-to-PO conversions and de-escalation of therapy, are often missed in the hospital setting. Objective: The study reported here describes the utilization of ceftriaxone in patients admitted to the hospital and treated for UTIs in a large health system, focusing on opportunities for IV-to-PO conversion of antibiotic therapy. Methods: This was a multi-center, retrospective, descriptive study conducted in a large health system. Patients admitted from January 2019 to July 2019 were included for analysis if they were 18 years or older at admission, diagnosed with acute cystitis, acute pyelonephritis, or unspecified UTI, and received two or more doses of ceftriaxone. The primary outcome was to evaluate the percentage of patients who were eligible for conversion from IV ceftriaxone to oral antibiotics while admitted to the hospital based on the defined criteria for automatic pharmacist conversion in the health system. Percentage of urine cultures with susceptibility to cefazolin, the duration of antibiotic therapy in the hospital, and an evaluation of oral antibiotics prescribed at discharge were also recorded. Results: A total of 300 patients were included; 88% met the pre-specified criteria for IV-to-PO conversion, but only 12% were converted from IV-to-PO antibiotics during hospitalization. Approximately 65% of patients remained on IV ceftriaxone until discharge, at which time they were converted to a PO antibiotic, most commonly fluoroquinolones followed by third-generation cephalosporins. Conclusion: Patients admitted to the hospital and receiving treatment with ceftriaxone for UTI were infrequently converted to oral therapy prior to discharge despite meeting criteria for automatic pharmacist IV-to-PO conversion. Findings highlight opportunities to contribute to antimicrobial stewardship initiatives across the health system and the importance of tracking and reporting results to frontline providers.

Criteria Restricting Inappropriate Meropenem Empiricism (CRIME): a quasi-experimental carbapenem restriction pilot at a large academic medical centre.

The broad-spectrum activity of carbapenems makes them appealing for empirical use; however, they are associated with development of Clostridioides difficile infection (CDI) and multidrug resistance. Selective carbapenem use is vital in maintaining their effectiveness. We examined the impact of meropenem restriction criteria on utilisation and patient outcomes. This quasi-experimental study was conducted at a single academic medical centre after medication use evaluation found frequent inappropriate meropenem utilisation. Antimicrobial stewardship-led restriction criteria were developed and implemented in February 2022. Investigators aimed to determine how restriction criteria affected meropenem utilisation across 8 weeks in the pre- (February-April 2020) versus post-implementation period (February-April 2022). The primary outcome was inappropriateness of meropenem utilisation. Secondary outcomes included days of therapy per 1000 patient-days (DOT/1000 PD), hospital length of stay (LOS), CDI Standardized Infection Ratio (SIR), and acquisition cost. Across the 8-week timeframes, reductions in inappropriate meropenem use (64.5% vs. 12.8%; P < 0.001), duration of therapy [5.8 (3.2-7.3) vs. 2.4 (1.0-5.5) days; P < 0.001] and utilisation (30.5 vs. 8.3 DOT/1000 PD; P < 0.001) pre- versus post-implementation were observed. Total meropenem orders decreased by 65% (P < 0.001). Median hospital LOS also decreased between periods [11.9 (7.8-20.4) vs. 9.2 (5.4-15.2) days], although not statistically significant (P = 0.051). There was no difference in CDI SIR (0.1 vs. 0.1; P = 0.99). Projected annual cost savings were ∼US$57 300. Implementation of antimicrobial stewardship-initiated restriction criteria can reduce inappropriate meropenem utilisation, overall number of orders, and total duration of therapy.

Effects of sevelamer carbonate versus calcium acetate on vascular calcification, inflammation, and endothelial dysfunction in chronic kidney disease.

Hyperphosphatemia is present in most patients with end-stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium-based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL-cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF-23 levels and there was no change with CA treatment. The inflammatory markers IL-8, IFN-γ, and TNFα decreased with response to both treatments. The levels of IL-6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti-inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Racial differences in the relationship between high-normal 25-hydroxy vitamin d and parathyroid hormone levels in early stage chronic kidney disease / Diferenças raciais na relação entre níveis normais-elevados de 25-hidroxivitamina d e hormônio da paratireóide na doença renal crônica em estágio inicial

ABSTRACT Aim: Current guidelines do not address between-person variability in markers of bone and mineral metabolism across subgroups of patients, nor delineate treatment strategies based upon such factors. Methods: A cross sectional study was carried out to analyze data from 20,494 United States Veterans and verify the variability of Vitamin D (25(OH)D) and parathyroid hormone (PTH) levels across race and stage of chronic kidney disease. Results: PTH levels were higher in Black Americans (BA) than White Americans (WA) at all levels of 25(OH)D and across eGFR strata. There was a progressive decline in PTH levels from the lowest (25(OH)D < 20) to highest quartile (25(OH)D >=40) in both BA (134.4 v 90 pg/mL, respectively) and WA (112.5 v 71.62 pg/mL) (p<0.001 for all comparisons). Conclusion: In this analysis, higher than normal 25(OH)D levels were well tolerated and associated with lower parathyroid hormone values in both blacks and whites. Black Americans had higher PTH values at every level of eGFR and 25(OH)D levels suggesting a single PTH target is not appropriate.

RESUMO Objetivo: as diretrizes atuais não abordam a variabilidade entre as pessoas nos marcadores do metabolismo ósseo e mineral em subgrupos de pacientes, nem traçam estratégias de tratamento com base em tais fatores. Métodos: realizamos um estudo transversal para analisar dados de 20.494 veteranos de guerra dos Estados Unidos e verificar a variabilidade nos níveis de vitamina D (25 (OH) D) e hormônio da paratireóide (PTH) entre a raça e o estágio da doença renal crônica. Resultados: os níveis de PTH foram maiores em americanos negros (AN) do que em americanos brancos (AB) em todos os níveis de 25 (OH) D e em todos os estratos de TFGe. Houve um declínio progressivo nos níveis de PTH do quartil mais baixo (25 (OH) D <20) para o quartil mais alto (25 (OH) D> = 40) em AN (134,4 v 90 pg/mL, respectivamente) e AB (112,5 v 71,62 pg/mL) (p <0,001 para todas as comparações). Conclusão: Nesta análise, níveis de 25 (OH) D acima do normal foram bem tolerados e associados a valores mais baixos do hormônio da paratireóide em negros e brancos. Os americanos negros tinham valores de PTH mais altos em todos os níveis de TFGe e 25 (OH) D, sugerindo que uma única meta de PTH não é apropriado.

Racial differences in the relationship between high-normal 25-hydroxy vitamin d and parathyroid hormone levels in early stage chronic kidney disease.

AIM: Current guidelines do not address between-person variability in markers of bone and mineral metabolism across subgroups of patients, nor delineate treatment strategies based upon such factors. METHODS: A cross sectional study was carried out to analyze data from 20,494 United States Veterans and verify the variability of Vitamin D (25(OH)D) and parathyroid hormone (PTH) levels across race and stage of chronic kidney disease. RESULTS: PTH levels were higher in Black Americans (BA) than White Americans (WA) at all levels of 25(OH)D and across eGFR strata. There was a progressive decline in PTH levels from the lowest (25(OH)D < 20) to highest quartile (25(OH)D >=40) in both BA (134.4 v 90 pg/mL, respectively) and WA (112.5 v 71.62 pg/mL) (p<0.001 for all comparisons). CONCLUSION: In this analysis, higher than normal 25(OH)D levels were well tolerated and associated with lower parathyroid hormone values in both blacks and whites. Black Americans had higher PTH values at every level of eGFR and 25(OH)D levels suggesting a single PTH target is not appropriate.

An examination of multiple explanations for secondary hyperparathyroidism
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AIMS: Seven theories address the evolution of secondary hyperparathyroidism (SHPT) as chronic kidney disease (CKD) progresses. The tradeoff-in-the-nephron hypothesis states that the plasma parathyroid hormone ([PTH]) concentration rises because an increased phosphate concentration in the cortical distal nephron ([P]CDN) reduces the ionized calcium concentration in that segment. In the present study, we compared this hypothesis to its predecessors. MATERIALS AND METHODS: We studied 30 patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 (mean 29.5). To examine historic theories, we performed regressions of [PTH] on plasma concentrations of ionized calcium, phosphorus, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and fibroblast growth factor 23, and on calcium excreted per volume of filtrate (ECa/Ccr). To assess the tradeoff-in-the-nephron hypothesis, we examined regressions of [PTH] on 100/eGFR and phosphorus excreted per volume of filtrate (EP/Ccr). RESULTS: Regressions pertinent to historic theories yielded significant direct relationships between [PTH] and both ECa/Ccr and [FGF23], but neither association supported the theory to which it pertained. [PTH] varied directly with 100/eGFR and with EP/Ccr, a surrogate for [P]CDN. EP/Ccr correlated strongly with 100/eGFR. CONCLUSIONS: The only theory of SHPT that our data support is the tradeoff-in-the-nephron hypothesis. Other theories are not supported.

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption.

BACKGROUND: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]. METHODS: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1-84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations. RESULTS: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption. CONCLUSIONS: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.

Evidence that TmP/GFR can be estimated with the Walton-Bijvoet nomogram in chronic kidney disease
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BACKGROUND: The Walton-Bijvoet nomogram incorporates the assumption that GFR = creatinine clearance (Ccr). It determines phosphate tubular maximum per volume of filtrate (TmP/GFR) from serum phosphorus ([P]s) and fractional excretion of P (FEP), and equates TmP/GFR with actual reabsorption per volume of filtrate (TRP/Ccr) at FEP ≥ 20%. It has not been validated in chronic kidney disease (CKD). METHODS: We studied 28 controls and 30 patients with stages 3 - 4 CKD. From samples of serum (s) and urine (u), we calculated P excretion per volume of filtrate (EP/Ccr) as [P]u[cr]s/[cr]u, TRP/Ccr as [P]s - EP/Ccr, and FEP as [P]u[cr]s/[P]s [cr]u or 1/{1 + (TRP/Ccr)/(EP/Ccr)}. Because a plot of TRP/Ccr against EP/Ccr resembled a hyperbola, we performed a linear regression of TRP/Ccr on 1/(EP/Ccr). From the resulting equation, we derived a hyperbolic formula relating TRP/Ccr to EP/Ccr; from that formula, we calculated TRP/Ccr and FEP as functions of EP/Ccr. RESULTS: The regression of TRP/Ccr on 1/(EP/Ccr) was significant. The horizontal limb of the derived hyperbola commenced at FEP ≍ 20% and depicted stable P reabsorption at FEP > 20%. CONCLUSIONS: TRP/Ccr was a hyperbolic function of EP/Ccr over a wide range of GFR. Like the Walton-Bijvoet nomogram, this function projected a near-constant TRP/Ccr - i.e., a TmP/GFR - at FEP > 20%. The nomogram depicts TmP/GFR accurately in CKD.
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Cardiovascular Pharmacogenomics--Implications for Patients With CKD.

CKD is an independent risk factor for cardiovascular disease (CVD). Thus, patients with CKD often require treatment with cardiovascular drugs, such as antiplatelet, antihypertensive, anticoagulant, and lipid-lowering agents. There is significant interpatient variability in response to cardiovascular therapies, which contributes to risk for treatment failure or adverse drug effects. Pharmacogenomics offers the potential to optimize cardiovascular pharmacotherapy and improve outcomes in patients with CVD, although data in patients with concomitant CKD are limited. The drugs with the most pharmacogenomic evidence are warfarin, clopidogrel, and statins. There are also accumulating data for genetic contributions to ß-blocker response. Guidelines are now available to assist with applying pharmacogenetic test results to optimize warfarin dosing, selection of antiplatelet therapy after percutaneous coronary intervention, and prediction of risk for statin-induced myopathy. Clinical data, such as age, body size, and kidney function have long been used to optimize drug prescribing. An increasing number of institutions are also implementing genetic testing to be considered in the context of important clinical factors to further personalize drug therapy for patients with CVD.

Phosphate homeostasis, parathyroid hormone, and fibroblast growth factor 23 in stages 3 and 4 chronic kidney disease.

AIMS: Increased concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) often coincide with normal serum phosphorus ([P]s) in chronic kidney disease (CKD). We hypothesized that the phosphate concentration ([P]f) in the cortical distal nephron (CDN) determines [PTH] and [FGF23] in this circumstance. METHODS: We studied 29 patients with CKD at 4 visits and 28 controls at 1 visit. Assuming GFR = creatinine clearance (Ccr), we examined the following regressions: [P]s on its determinants, EP/Ccr and TRP/Ccr (P excretion and reabsorption per volume of filtrate); [PTH] and [FGF23] on [P]s and EP/Ccr; and TRP/Ccr on [PTH] and [FGF23]. We assumed that EP/Ccr is proportional to [P]f in the CDN. RESULTS: In controls, [P]s correlated with TRP/Ccr but not EP/Ccr. [PTH] and [FGF23] were unrelated to [P]s, EP/Ccr, and TRP/Ccr. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr. [PTH] correlated with [P]s at 2 visits and with EP/Ccr at 4; [FGF23] correlated with [P]s and EP/Ccr at all visits. TRP/Ccr correlated with [FGF23] and [PTH] at one visit each. CONCLUSIONS: [P]f in the CDN, not [P]s, determined [PTH] in CKD. Because [FGF23] was consistently associated with only one determinant of [P]s, EP/Ccr, we infer that [P]f also determined [FGF23]. In patients with CKD, we speculate that [P]f in the CDN regulates FGF23 synthesis at that site.

Community-acquired acute kidney injury: A challenge and opportunity for primary care in kidney health.

Community-acquired acute kidney injury (CA-AKI) has been found to be a common event in the population. Current incidence estimates are not available, but evaluations of severe elevations in serum creatinine indicate that incidence can be as high as 989 cases per million population in those older than 80 years. Data on risk factors are limited, but older age and higher comorbid illness burden, especially diabetes and cardiovascular disease, seem to be more common in patients who suffer CA-AKI. In addition to being more common than hospital-acquired AKI, the long-term sequelae of CA-AKI seem to be just as severe, including renal disease progression and mortality. Efforts to better understand the aetiology of CA-AKI and how ultimately to prevent the development of this condition will need to be taken. In the meantime, a concerted effort by general internists and nephrologists will be needed to prevent CA-AKI in the highest risk patients and thus limit the poor outcomes associated with this entity.

Role of T-regulatory cells in the response to hepatitis B vaccine in hemodialysis patients.

Human disease elicits a complex array of biological processes that results in long-term protective immunological memory to infectious agents. Chronic kidney disease is known to impair induction of sustained immunological memory to hepatitis B vaccine (HBVax) antigens. We asked the question: Does end-stage renal disease promote changes in subtypes of regulatory T (Treg) cells that correlate with diminished amnestic response to HBVax antigen compared to healthy controls? The study design and setting was a prospective observational cohort at a veterans affairs medical center. End-stage renal disease patients on hemodialysis (HD) were compared with individuals with self-reported normal kidney function. All subjects received HBVax. Peripheral blood was sampled for assessment for Treg cells pre and post vaccination. CD4+ FOXP3 Treg numbers were similar between HD and healthy subjects during a 14-day time period post vaccination. HD subjcts had lower anti-HBSag antibody than CON (control) subjects (330 ± 108.7 vs. 663.1 ± 129.7 IU/mL; P = 0.063). Hemodialysis subjects with resting Tregs higher than the median value in our cohort demonstrated a significantly lower change in HBsAB at 30 days post booster vaccination (P = 0.030). No such relationship was found for the activated Treg subset among HD subjects, or either subset among CON subsets. In our limited comparison study of 11 HD and 8 CON subjects, Treg subsets did not differ between the two groups; but differences in the suppressive Treg numbers in the HD group could explain the altered antibody response to HBVax and is worthy of further study.

Incidence and Clinical Predictors of Nonresponse to Hepatitis B Vaccination among Patients Receiving Hemodialysis: Importance of Obesity.

OBJECTIVES: The objectives of this study were to quantify the incidence of hepatitis B virus (HBV) vaccine nonresponse and identify clinical characteristics associated with vaccine nonresponse. METHODS: A retrospective cohort study was conducted among patients undergoing hemodialysis (HD) receiving the HBV vaccine. Study inclusion criteria were age 18 years and older, receipt of HD treatment for ≥ 1 month, receipt of ≥ 1 dose of HBV vaccine, availability of anti-HB surface antibody (anti-HBs) laboratory values ≥ 2 weeks after last HBV vaccine, and prevaccine anti-HBs value <10 mIU/mL. Clinical data were abstracted from patients' medical records. The outcome of interest was vaccine nonresponse, defined as anti-HBs values <10 IU/mL. Multivariate regression was used to determine variables independently associated with vaccine nonresponse. Kaplan-Meier estimates were constructed for determining HBV vaccine response retention. RESULTS: Of the 119 patients evaluated, nonresponse was observed in 58%. Mean age at first vaccination for vaccine responders and nonresponders was 58.8 ± 16.5 and 65.9 ± 14.1 (P = 0.01), respectively. Variables independently associated with nonresponse were age 58 years and older (adjusted relative risk, 95% confidence interval 1.62, 1.06-2.46; P = 0.02) and body mass index ≥ 36.4 kg/m(2) (adjusted relative risk, 95% confidence interval 1.66, 1.34-2.07; P < 0.01). Among the 50 patients who achieved an initial vaccine response, 26% were not able to maintain vaccine response upon subsequent anti-HBs measurement. The probability of retaining vaccine response over time was significantly modified by body mass index ≥ 25 kg/m(2). CONCLUSIONS: The frequency of nonresponse to the HBV vaccine was high among patients undergoing HD. The clinical covariates most predictive of vaccine nonresponse were advanced age at the time of vaccination and excess body weight.

Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial.

BACKGROUND: Diabetes mellitus (DM) and vitamin D deficiency are major health concerns around the world. Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity. OBJECTIVES: We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism, components of metabolic syndrome (MetS) and specific inflammatory biomarkers. PATIENTS AND METHODS: A double blind, randomized clinical trial was conducted in King Khalid University Hospital, Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control, MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), Interleukin (IL-6), leptin, adiponectin and vascular cell adhesion molecule-1 (VCAM-1). Twenty-two patients with type II diabetes with insulin resistance, glycated hemoglobin (HbA1c) ≥ 6 (42 mmol/mol) and serum 25(OH)D < 50 nmol/L were randomized using a computer program to receive either supplementation with cholecalciferol (5000 IU/day) or placebo for 12 weeks. The primary outcome was change in HbA1c levels from baseline. RESULTS: Median [IQR] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [48, 67.3] nmol/L (P = 0.002). There was no significant difference in the change of HbA1c between the groups (P = 0.5) with a decrease of -0.1% [-1, 0.5] in the vitamin D group and an increase of 0.15% [0.1, 0.2] in the placebo group. A significant improvement was observed in the homeostasis model of assessment of ß-cell activity (HOMA-%B) (P = 0.03) with vitamin D supplementation compared to baseline. CONCLUSIONS: Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved ß-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity.

Parameters of phosphorus homeostasis at normal and reduced GFR: theoretical considerations.

AIMS: Influx and reabsorption of phosphorus (IP and TRP) are assessed with fractional excretion and reabsorption (FEP and FTRP, nl ≤ 20% and ≥ 80%), or with excretion and reabsorption per volume of filtrate (EP/GFR and TRP/GFR, fasting nl ≈ 0.4 and 3.0 mg/dL). We analyzed these parameters at normal and reduced GFR. METHODS: We equated GFR with creatinine clearance (Ccr) to develop necessary equations. We plotted serum phosphorus ([P]s), EP/Ccr, and FEP against their determinants, and TRP/Ccr against EP/Ccr at FEP of 20% or 40%. RESULTS: Linear equations related [P]s to EP/Ccr and TRP/Ccr, and EP/Ccr to [cr]s and [P]u/[cr]u (a surrogate for IP). FEP rose in curvilinear fashion as Esub>P/Ccr rose and TRP/Ccr fell; changes in low values of EP/Ccr and TRP/Ccr induced large changes in FEP. At increased EP/Ccr (as in CKD), maintenance of FEP ≤ 20% required impossibly high TRP/Ccr; at EP/Ccr of 2.0 mg/dL, FEP and FTRP of 40% and 60% required normal TRP/Ccr. CONCLUSIONS: EP/Ccr varies with IP at normal GFR, and with IP and [cr]s at low GFR. FEP, a function of EP/Ccr and TRP/Ccr, varies primarily with the lower ratio, which is always EP/Ccr at normal GFR. At low GFR, high FEP is inevitable if IP is preserved, and TRP/Ccr may be normal despite low FTRP. Contributions of IP and TRP to [P]s should be assessed with EP/Ccr and TRP/Ccr. FEP and FTRP have limitations at any GFR.

Parameters of phosphorus homeostasis at normal and reduced GFR: empiric observations.

AIMS: Influx (IP) determines urinary excretion of phosphorus (EP). Contributions of IP and reabsorption (TRP) to serum phosphorus ([P]s) can be depicted by normalization to creatinine clearance (EP/Ccr and TRP/Ccr) or by calculation of fractional excretion and reabsorption (FEP and FTRP). We analyzed these parameters at normal and reduced GFR. METHODS: We studied 29 patients with chronic kidney disease (CKD) and 28 controls. From [cr] and [P] in serumand urine we calculated [P]u/[cr]u, EP/Ccr, TRP/Ccr, (TRP/Ccr)/(EP/Ccr), FEP, and FTRP. We compared means between groups and examined pertinent linear regressions. RESULTS: [P]s was not different in CKD and controls. [Cr]s, EP/Ccr, and FEP were higher and TRP/Ccr, (TRP/Ccr)/(EP/Ccr), and FTRP were lower in CKD. [P]u/[cr]u, a surrogate for IP, was similar in both groups. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr; EP/Ccr with [P]u/[cr]u and [cr]s; and FEP with EP/Ccr, TRP/Ccr, [P]u/[cr]u, and [cr]s. In controls, [P]s correlated with TRP/Ccr; EP/Ccr with [P]u/[cr]u; and FEP with EP/Ccr and [P]u/[cr]u. In both groups, FEP was a precise inverse function of (TRP/Ccr)/(EP/Ccr). Despite wide variation in TRP/Ccr, FEP was < 20% in 26/28 controls and > 20% in 27/29 patients with CKD. CONCLUSIONS: GFR affected determinants of [P]s, EP/Ccr, and FEP. FTRP was often dissociated from TRP/Ccr at normal or reduced GFR.

Normalized vitamin D metabolite concentrations are better correlated to pharmacological effects than measured concentrations.

BACKGROUND: Vitamin D deficiency has been associated with a multitude of diseases, ranging from fractures to cancer. Nearly 99% of vitamin D metabolites are bound to proteins, altering the relationship between concentration and activity. METHODS & RESULTS: Normalized concentrations were calculated and validated using published data regarding the correlation of 25-hydroxyvitamin D with bone mineral density. In addition, healthy and kidney disease subjects were recruited for preliminary investigations. Use of the normalizing equations resulted in statistically significant improvements in the relationship between vitamin D metabolites and several markers of health status. CONCLUSION: Normalized concentrations are similar to clinically reported values and are easier to interpret than free or bioavailable concentrations, since their values match the range of measured total concentrations.

Determination of vancomycin and gentamicin clearance in an in vitro, closed loop dialysis system.

BACKGROUND: The purpose of this study was to evaluate the feasibility of utilizing an in-vitro, closed loop hemodialysis system as a method to assess drug clearance. Secondarily, this study tested the influence of variables (blood flow rate, dialysate flow rate, and type of filter) in the hemodialysis procedure on the clearance of vancomycin and gentamicin. METHODS: An in-vitro, closed loop hemodialysis system was constructed. The vancomycin (30 mg/L) and gentamicin (25 mg/L) were added to a simulated blood system (SBS). Four conditions (C1-C4) were tested by defining the filter (Polyflux 170H or F180) and the blood and dialysate flow rates (BFR and DFR). All hemodialysis sessions were 3 hours in length and each condition was completed in duplicate. Dialysate effluent was collected in a 50 gallon polyethylene drum. Samples were collected (in duplicate) from the SBS and the dialysate effluent at baseline and at the end of the hemodialysis session. Samples were analyzed for vancomycin and gentamicin with an ultrahigh performance liquid chromatography/tandem mass spectrometry method. RESULTS: A total of eight 3-hour hemodialysis sessions were conducted. For all tested conditions (C1-C4), vancomycin was undetectable in the SBS at the end of dialysis. However, total vancomycin recovery in the dialysis effluent was 85±18%, suggesting that up to 15% may have adsorbed to the dialysis filter or tubing. Gentamicin clearance from SBS was >98% in all tested conditions. Average gentamicin recovery in the dialysate effluent was 99±15%. CONCLUSION: Both vancomycin and gentamicin were readily removed by high-flux hemodialysis under all conditions studied. No significant differences in drug clearance were observed between conditions used in this in vitro study. The clinical implications of changing these hemodialysis parameters are unknown.

Use of sevelamer to examine the role of intraluminal phosphate in the pathogenesis of secondary hyperparathyroidism.

AIMS: Parathyroid hormone (PTH) promotes calcium reabsorption in the cortical distal nephron (CDN). The phosphate concentration ([P]f) rises in that segment in chronic kidney disease (CKD); in theory, high [P]f could reduce availability of calcium for reabsorption and necessitate a compensatory rise in [PTH]. With assumptions, [P]f is proportional to phosphate excreted/volume of filtrate (EP/GFR). We therefore hypothesized that [PTH] would correlate with EP/GFR in CKD, and ΔPTH] would correlate with ΔEP/GFR after sevelamer therapy. METHODS: We conducted a 4-week, placebo-controlled trial of sevelamer carbonate in patients with CKD. [PTH]1-84 and parameters of phosphate homeostasis were measured before and after treatment. GFR was assumed to equal creatinine clearance (Ccr). Pertinent linear regressions were performed. RESULTS: Phosphate excretion fell in the sevelamer group only. Decrements in [PTH] with sevelamer differed from increments with placebo. With either treatment, [PTH] correlated with EP/Ccr and ΔPTH] correlated with ΔEP/Ccr. Changes in [PTH] were minimal in some sevelamer recipients despite reductions in EP/Ccr; calcium excreted/volume of filtrate was low in these subjects. CONCLUSIONS: Phosphate influx affected [PTH] in CKD by determining [P]f in the CDN. In some patients, low calcium influx may have blunted the effect of sevelamer on [PTH].

Tubular calcium reabsorption and other aspects of calcium homeostasis in primary and secondary hyperparathyroidism.

AIMS: Primary hyperparathyroidism (PHPT) causes hypercalcemia by increasing tubular calcium reabsorption. Because chronic kidney disease (CKD) is associated with normocalcemia, we inferred that calcium reabsorption is also normal, and hypothesized that normal reabsorption requires excessive parathyroid hormone (PTH) in CKD. METHODS: The following were obtained in controls and patients with CKD or PHPT: estimated GFR (eGFR); concentrations of PTH 1-84, 1,25-dihydroxyvitamin D, and ultrafilterable and ionized calcium ([PTH], [1,25(OH)2D], [Ca]uf, [Ca]i); and ratios of calcium excreted or reabsorbed per volume of filtrate (ECa/Ccr, TRCa/Ccr). Pertinent linear regressions were examined. RESULTS: In CKD, [PTH] was increased, but ECa/Ccr, TRCa/Ccr, [Ca]uf, and [Ca]i equaled control values. [PTH] was inversely related to eGFR but unrelated to [1,25(OH)2D]. TRCa/Ccr was constant at all [PTH]. In PHPT, [PTH] was no higher than in CKD, but TRCa/Ccr, [Ca]uf, and [Ca]i were increased. [1,25(OH)2D] correlated with [PTH]. In controls, TRCa/Ccr varied directly with [1,25(OH)2D] and inversely with [PTH]. CONCLUSIONS: In controls, calcium reabsorption rose with [1,25(OH)2D], and [PTH] fell in response. In PHPT, [PTH] determined [1,25(OH)2D]; together, the hormones increased calcium reabsorption and caused hypercalcemia. In CKD, normal calcium reabsorption required high [PTH].