Rule, Andrew D.

Study Objective Serum creatinine ( S c r ) concentration is used to calculate estimated glomerular filtration rate (e GFR ) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to S cr . This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections. Design Retrospective analysis of prospectively collected data. Setting Large academic tertiary care medical center. Patients A total of 308 adults with suspected or documented infections and stable kidney function who were hospitalized between 2012 and 2015. Measurements and Main Results Standardized S c r and CysC measured at the time of antibiotic dosing were used to estimate GFR from the three Chronic Kidney Disease Epidemiology Collaborative ( CKD ‐ EPI ) equations using S c r (eGFR Cr ), CysC( eGFR CysC ), or a combination of S c r and CysC (eGFR Cr‐CysC ), and these values were compared with estimated creatinine clearance (eCl cr ) from the Cockcroft‐Gault equation (standard of care for drug dosage adjustments). The eGFR s were categorized into five common dosage adjustment strata (lower than 20, 20–49, 50–79, 80–130, and higher than 130 ml/min), and agreement between equations was tested with the weighted κ statistic. Recommended drug doses varied considerably between the eC l cr and the CKD ‐ EPI equations (weighted κ [95% confidence interval]: eGFR Cr 0.73 [0.68–0.79], eGFR CysC 0.42 [0.35–0.5], eGFR Cr‐CysC 0.65 [0.6–0.71]). If eGFR Cr, eGFR CysC , or eGFR Cr‐CysC were used instead of eC l cr to dose drugs, 11%, 12%, and 8% of doses, respectively, would be higher, and 12%, 38%, and 24% of doses, respectively, would be lower. Conclusion Significant discordance in drug doses was observed when the CKD ‐ EPI equations were used in place of eCl cr . When CysC was included in eGFR equations, recommended doses were often lower. Further study is needed to develop and test drug‐specific dosing guidelines that incorporate alternate renal biomarkers and/or more contemporary eGFR equations.

AbstractBackgroundThe relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood.MethodsUltrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18–100 years). We then identified the subset of 2256 ‘healthy’ subjects to define age- and sex-specific reference ranges (2.5–97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys.ResultsIn the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight.ConclusionsOverall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.

Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase‐2·insulin‐like growth factor‐binding protein 7 ([TIMP‐2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP‐2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug‐dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP‐2]·[IGFBP7] for risk prediction in acute kidney injury and drug‐induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.

Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities. Methods We studied kidney biopsy specimens from living kidney donors ( n =2453) and patients who underwent radical nephrectomy for a renal tumor ( n =780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel–Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen. Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli ( P <0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume. Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity.

High-dose methotrexate (MTX; ≥1 g/m2) is a renally eliminated and nephrotoxic first-line therapy for central nervous system (CNS) lymphoma. Creatinine-based estimation of renal function is the recommended approach to dosing MTX in these cases, but nonrenal determinants of creatinine production and elimination in cancer patients such as malnutrition and cachexia lead to overestimation of glomerular filtration rate (GFR) by this method and a heightened risk for drug toxicity. Serum cystatin C is one of the first readily available, relatively inexpensive, endogenous biomarkers to emerge as a practical adjunct to creatinine for estimation of renal function for drug dosing. In this report, we describe two cases where cystatin C was used in conjunction with creatinine to inform MTX dosing for CNS lymphoma. In both cases, the estimated GFR was nearly 40% lower with the combination of the two biomarkers compared to creatinine-only estimates. Empiric MTX dose reductions as a product of these results likely spared the patients sustained exposure to toxic drug concentrations and facilitated earlier administration of supportive care interventions. Further prospective investigations with validated dosing regimens including cystatin C are warranted for high-dose MTX.

Aging is associated with significant changes in structure and function of the kidney, even in the absence of age-related comorbidities. On the macrostructural level, kidney cortical volume decreases, surface roughness increases, and the number and size of simple renal cysts increase with age. On the microstructural level, the histologic signs of nephrosclerosis (arteriosclerosis/arteriolosclerosis, global glomerulosclerosis, interstitial fibrosis, and tubular atrophy) all increase with age. The decline of nephron number is accompanied by a comparable reduction in measured whole-kidney GFR. However, single-nephron GFR remains relatively constant with healthy aging as does glomerular volume. Only when glomerulosclerosis and arteriosclerosis exceed that expected for age is there an increase in single-nephron GFR. In the absence of albuminuria, age-related reduction in GFR with the corresponding increase in CKD (defined by an eGFR<60 ml/min per 1.73 m 2 ) has been shown to associate with a very modest to no increase in age-standardized mortality risk or ESRD. These findings raise the question of whether disease labeling of an age-related decline in GFR is appropriate. These findings also emphasize the need for a different management approach for many elderly individuals considered to have CKD by current criteria.

Background and objectives Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. Design, setting, participants, & measurements In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. Results Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone formers and 110 controls developed hypertension. Median follow-up time was 7.8 years in stone formers and 9.6 years in controls. Stone formers were found to have a higher risk of hypertension compared with controls (hazard ratio, 1.50; 95% confidence interval, 1.18 to 1.92), even after adjusting for age, sex, body mass index, serum creatinine, CKD, diabetes, gout, coronary artery disease, dyslipidemia, tobacco use, and alcohol abuse (hazard ratio, 1.58; 95% confidence interval, 1.12 to 2.21). Results were similar after excluding patients who were ever on a thiazide diuretic (hazard ratio, 1.65; 95% confidence interval, 1.16 to 2.38). Stone composition, radiographic stone burden, number of subsequent stone events, and stone removal surgeries were not associated with hypertension ( P >0.05 for all). Conclusions The risk of hypertension was higher after the first symptomatic kidney stone event. However, kidney stone severity, type, and treatment did not associate with hypertension.