Traditions and innovations in assessment of glomerular filtration rate using creatinine to cystatin C.

PURPOSE OF REVIEW: Glomerular filtration rate (GFR) is the best index for kidney function and estimated GFR (eGFR) calculated from endogenous filtration markers like serum creatinine and cystatin C is widely used in clinical practice for chronic kidney disease diagnosis and prognostication. We sought to review the evolution of GFR estimating equations, nuances of eGFR interpretation, and utility of eGFR in drug dosing. RECENT FINDINGS: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) serum creatinine eGFR equation was recently updated to exclude the race variable and the CKD-EPI creatinine-cystatin C equation demonstrated the highest reliability. Although calculated creatinine clearance by Cockcroft Gault has been traditionally used for drug dosing, the use of eGFR is slowly being adapted by the Food and Drug Administration for pharmacokinetic studies. However, the individual-level accuracy of eGFR using the CKD-EPI 2021 equations remained low, with the distribution of measured GFR at a given eGFR value spanning several CKD stages. SUMMARY: Although current methods of estimating GFR have improved in population measures of reliability, all have significant individual-level inaccuracies that can be an issue when clinical decision-making is contingent on the actual level of GFR. Modern methods of GFR measurements should be made widely available to enhance individualized patient decision-making.

Quantifying Individual-Level Inaccuracy in Glomerular Filtration Rate Estimation : A Cross-Sectional Study.

BACKGROUND: Although the population-level differences between estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) are well recognized, the magnitude and potential clinical implications of individual-level differences are unknown. OBJECTIVE: To quantify the magnitude and consequences of the individual-level differences between mGFRs and eGFRs. DESIGN: Cross-sectional study. SETTING: Four U.S. community-based epidemiologic cohort studies with mGFR. PATIENTS: 3223 participants in 4 studies. MEASUREMENTS: The GFRs were measured using urinary iothalamate and plasma iohexol clearance; the eGFR was calculated from serum creatinine concentration alone (eGFRCR) and with cystatin C. All GFR results are presented as mL/min/1.73 m2. RESULTS: The participants' mean age was 59 years; 32% were Black, 55% were women, and the mean mGFR was 68. The population-level differences between mGFR and eGFRCR were small; the median difference (mGFR - eGFR) was -0.6 (95% CI, -1.2 to -0.2); however, the individual-level differences were large. At an eGFRCR of 60, 50% of mGFRs ranged from 52 to 67, 80% from 45 to 76, and 95% from 36 to 87. At an eGFRCR of 30, 50% of mGFRs ranged from 27 to 38, 80% from 23 to 44, and 95% from 17 to 54. Substantial disagreement in chronic kidney disease staging by mGFR and eGFRCR was present. Among those with eGFRCR of 45 to 59, 36% had mGFR greater than 60 whereas 20% had mGFR less than 45; among those with eGFRCR of 15 to 29, 30% had mGFR greater than 30 and 5% had mGFR less than 15. The eGFR based on cystatin C did not provide substantial improvement. LIMITATION: Single measurement of mGFR and serum markers without short-term replicates. CONCLUSION: A substantial individual-level discrepancy exists between the mGFR and the eGFR. Laboratories reporting eGFR should consider including the extent of this uncertainty to avoid misinterpretation of eGFR as an mGFR replacement. PRIMARY FUNDING SOURCE: National Institutes of Health.

High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients.

BACKGROUND: The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. METHODS: To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. RESULTS: A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. CONCLUSIONS: Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.

Association of Monocyte Chemoattractant Protein-1 with Death and Atherosclerotic Events in Chronic Kidney Disease.

BACKGROUND: Monocyte chemoattractant protein-1 -(MCP-1), a marker of inflammation and monocyte recruitment to atherosclerotic plaques, is associated with cardiovascular (CV) outcomes in patients with acute coronary syndrome. Although plasma levels are elevated in chronic kidney disease (CKD), associations with reduced kidney function or outcomes in CKD have not been explored. METHODS: In this population-based, probability-sampled, longitudinal cohort of 3,257 participants, including 286 (8.8%) patients with CKD, we studied the association of plasma MCP-1 with estimated glomerular filtration rate (eGFR), albuminuria, death, and intermediate and hard CV outcomes in CKD and non-CKD individuals. Cox proportional hazards regression assessed associations of baseline MCP-1 with all-cause death and atherosclerotic events. RESULTS: MCP-1 was higher in CKD than non-CKD participants (p < 0.001), and negatively associated with eGFR (r = -0.23, p < 0.0001) but not albuminuria in CKD. MCP-1 was associated with pulse wave velocity and coronary artery calcification in non-CKD but not CKD individuals. At 13.5 years, there were 230 (7.7%) deaths and 168 (6.4%) atherosclerotic events in the non-CKD vs. 97 (34.0%) deaths and 62 (27.9%) events in the CKD group (p < 0.001 for each). MCP-1 was associated with death (hazards ratio [HR] 2.0 [1.4-2.9] per log-unit increase) and atherosclerotic events (1.7 [1.0-2.9]) in CKD individuals. The HR for death in CKD remained significant (1.6 [1.1-2.3]) after adjusting for CV risk factors. CONCLUSIONS: Although plasma MCP-1 increased with decreased eGFR, it remained an independent risk factor for death in CKD. MCP-1 did not correlate with intermediate CV outcomes, implicating pathways other than atherosclerosis in the association of MCP-1 with death in CKD.

Oxalate homeostasis.

Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.

Determinants and Outcomes Associated With Urinary Calcium Excretion in Chronic Kidney Disease.

CONTEXT: Abnormalities in calcium metabolism are common in chronic kidney disease (CKD). Diminished urinary calcium excretion may promote vascular calcification and increased urinary calcium excretion may lead to nephrolithiasis and nephrocalcinosis, conditions associated with CKD. OBJECTIVE: To study predictors of urinary calcium excretion and its association with adverse clinical outcomes in CKD. DESIGN, SETTING AND PATIENTS: This study assessed 3768 nondialysis participants in the Chronic Renal Insufficiency Cohort study from April 2003 to September 2008. Participants were followed up to October 2018. EXPOSURE: Clinically plausible predictors of urinary calcium excretion and 24-h urinary calcium excretion at baseline. MAIN OUTCOME MEASURES: Urinary calcium excretion; incident end stage kidney disease (ESKD), CKD progression [50% estimated glomerular filtration rate (eGFR) decline or incident ESKD], all-cause mortality, and atherosclerotic cardiovascular disease events. RESULTS: eGFR was positive correlated with 24-h urinary calcium excretion. The variables most strongly associated with 24-h urinary calcium excretion in males and females were 24-h urinary sodium (ß = 0.19 and 0.28, respectively), serum parathyroid hormone (ß = -0.22 and -0.20, respectively), loop diuretics (ß = 0.36 and 0.26, respectively), thiazide diuretics (ß = -0.49 and -0.53, respectively), and self-identified black race (ß = -0.23 and -0.27, respectively). Lower urinary calcium excretion was associated with greater risks of adverse outcomes, but these associations were greatly attenuated or nullified after adjustment for baseline eGFR. CONCLUSION: Urinary calcium excretion is markedly lower in individuals with CKD compared to the general population. Determinants of urinary calcium excretion differed between sexes and levels of CKD. Associations between urinary calcium excretion and adverse clinical events were substantially confounded by eGFR.

International Medical Graduates in Nephrology: A Guide for Trainees and Programs.

A significant portion of the nephrology workforce has traditionally consisted of non-United States (US) citizen international medical graduates and international research trainees. Although international medical graduates are offered opportunities for training and professional growth that are beyond those available in their countries of origin, they typically encounter barriers to transition from training to practice and early-stage career development. In this article, we describe the exchange visitor and temporary worker visas granted to foreign trainees in the United States, focusing on the transition from training to nephrology practice and/or research. While we provide general recommendations on how to navigate this tedious and unpredictable process for both programs and trainees, consultation with immigration attorneys is indispensable for a successful outcome. Trainees are therefore encouraged to seek continuous support from their programs/sponsors and assistance from immigration representatives at their training institutions. We provide a positive message to emphasize that there are many pathways to arrive at the desired post-training destination.

Caring for Dialysis Patients in a Time of COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic and a public health emergency. The overwhelming rise in the number of cases has brought significant challenges to healthcare systems worldwide. Patients with end-stage kidney disease (ESKD) are highly vulnerable with the multiple comorbidities that make them susceptible to adverse outcomes with COVID-19. Over 2 million people worldwide receive maintenance hemodialysis (HD) at outpatient centers. Effectively preventing the spread of infection among HD centers, healthcare personnel, and patients is essential to ensure the continued delivery of dialysis to ESKD patients. This article discusses dialysis patients' care during COVID-19, addressing measures for patient and health care personnel protection and care of dialysis patients with suspected or confirmed COVID-19.

Dietary Oxalate Intake and Kidney Outcomes.

Oxalate is both a plant-derived molecule and a terminal toxic metabolite with no known physiological function in humans. It is predominantly eliminated by the kidneys through glomerular filtration and tubular secretion. Regardless of the cause, the increased load of dietary oxalate presented to the kidneys has been linked to different kidney-related conditions and injuries, including calcium oxalate nephrolithiasis, acute and chronic kidney disease. In this paper, we review the current literature on the association between dietary oxalate intake and kidney outcomes.

Plasma Endothelin-1 and Risk of Death and Hospitalization in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND AND OBJECTIVES: Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide implicated in the pathogenesis of hypertension, congestive heart failure, and inflammation, all of which are critical pathophysiologic features of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To test the hypothesis that plasma endothelin-1 levels are associated with increased risks of mortality and hospitalization in patients with chronic kidney failure, we measured plasma endothelin-1 levels in a prospective cohort of 794 individuals receiving maintenance hemodialysis. The primary outcomes were time to death and time to hospitalization. RESULTS: The median plasma endothelin-1 level was 2.02 (interquartile range, 1.57-2.71) pg/ml. During a median follow-up period of 28 (interquartile range, 21-29) months, 253 individuals (32%) died and 643 individuals (81%) were hospitalized at least once. In multivariable models adjusted for demographic, clinical, and laboratory variables, individuals in the highest quartile of plasma endothelin-1 had a 2.44-fold higher risk of death (hazard ratio, 2.44; 95% confidence interval, 1.61 to 3.70) and a 1.54-fold higher risk of hospitalization (hazard ratio, 1.54; 95% confidence interval, 1.19 to 1.99) compared with individuals in the lowest quartile. The Harrell C-statistic of the fully adjusted model increased from 0.73 to 0.74 after addition of natural log-transformed plasma endothelin-1 (P<0.001) for all-cause mortality, and increased from 0.608 to 0.614 after addition of natural log-transformed plasma endothelin-1 (P=0.002) for hospitalization. CONCLUSIONS: Higher plasma endothelin-1 is associated with adverse clinical events in patients receiving hemodialysis independent of previously described risk factors. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_05_15_CJN11130919.mp3.

Incidence of Hyponatremia in Patients With Indwelling Peritoneal Catheters for Drainage of Malignant Ascites.

Importance: Indwelling peritoneal catheters (IPCs) are frequently used to drain tense, symptomatic, malignant ascites. Large-volume drainage may lead to hyponatremia owing to massive salt depletion. To date, no studies have examined the epidemiology of hyponatremia after placement of an IPC. Objective: To evaluate the incidence of hyponatremia after IPC placement, the risk factors associated with its development, and how it is managed. Design, Setting, and Participants: This cohort study retrospectively reviewed the medical records of 461 patients who had IPCs placed during the period between 2006 and 2016 at a tertiary care hospital in Boston, Massachusetts, of whom 309 patients met the inclusion criteria. Data analysis was performed from June to November 2019. Main Outcomes and Measures: Main outcomes were the incidence of hyponatremia (with a serum sodium level <135 mEq/L) after IPC placement, the risk factors for its development, and how it was managed. We also examined the clinical course of a subset of 21 patients with hypovolemic hyponatremia. Results: Of the 309 eligible patients with laboratory results both before IPC placement and 2 days or more after IPC placement, 189 (72.1%) were female, and the mean (SD) age was 59 (12) years. The overall incidence of hyponatremia after IPC placement was 84.8% (n = 262), of whom 21 patients (8.0%) had severe hyponatremia. The mean (SD) decrease in serum sodium level before vs after IPC placement was 5 (5.1) mEq/L and decreased by 10 mEq/L or more among 52 patients (16.8%). Patients with hyponatremia prior to IPC placement had an 8-fold higher adjusted odds of having persistent hyponatremia after IPC placement (odds ratio, 7.9; 95% CI, 2.9-21.7). Patients with hepatopancreatobiliary malignant neoplasms were more likely to develop hyponatremia (78 of 262 patients with hyponatremia [29.8%] vs 7 of 47 patients without hyponatremia [14.9%]). Hyponatremia was either unrecognized or untreated in 189 patients (72.1%). Conclusions and Relevance: Although the placement of an IPC is often a palliative measure, hyponatremia is common and is often untreated or unrecognized. Patients at highest risk, such as those with hyponatremia at baseline and those with hepatopancreatobiliary malignant neoplams, should be evaluated carefully prior to IPC placement and may warrant closer monitoring after placement. In all cases, hyponatremia should be evaluated and managed within the context of a patient's overall goals of care.