Short Timeframe Prediction of Kidney Failure among Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Development of a short timeframe (6-12 months) kidney failure risk prediction model may serve to improve transitions from advanced chronic kidney disease (CKD) to kidney failure and reduce rates of unplanned dialysis. The optimal model for short timeframe kidney failure risk prediction remains unknown. METHODS: This retrospective study included 1757 consecutive patients with advanced CKD (mean age 66 years, estimated glomerular filtration rate 18 mL/min/1.73 m2). We compared the performance of Cox regression models using (a) baseline variables alone, (b) time-varying variables and machine learning models, (c) random survival forest, (d) random forest classifier in the prediction of kidney failure over 6/12/24 months. Performance metrics included area under the receiver operating characteristic curve (AUC-ROC) and maximum precision at 70% recall (PrRe70). Top-performing models were applied to 2 independent external cohorts. RESULTS: Compared to the baseline Cox model, the machine learning and time-varying Cox models demonstrated higher 6-month performance [Cox baseline: AUC-ROC 0.85 (95% CI 0.84-0.86), PrRe70 0.53 (95% CI 0.51-0.55); Cox time-varying: AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.60-0.64); random survival forest: AUC-ROC 0.87 (95% CI 0.86-0.88), PrRe70 0.61 (95% CI 0.57-0.64); random forest classifier AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.59-0.65)]. These trends persisted, but were less pronounced, at 12 months. The random forest classifier was the highest performing model at 6 and 12 months. At 24 months, all models performed similarly. Model performance did not significantly degrade upon external validation. CONCLUSIONS: When predicting kidney failure over short timeframes among patients with advanced CKD, machine learning incorporating time-updated data provides enhanced performance compared with traditional Cox models.

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED: The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Simultaneous glomerular filtration rate determination using inulin, iohexol, and 99mTc-DTPA demonstrates the need for customized measurement protocols.

Urinary inulin clearance is considered the gold standard of glomerular filtration rate (GFR) measurement but plasma clearance of less expensive and more accessible tracers is more commonly performed. Many plasma sampling protocols exist but little is known about their accuracy. Here, the study objectives were to compare plasma iohexol and 99mTc-DTPA GFR with varying sampling strategies to the GFR measured by urinary inulin and to identify protocols with the greatest accuracy according to clinical characteristics. GFR was measured simultaneously using urinary inulin, plasma iohexol, and plasma 99mTc DTPA clearance. Blood was sampled from 2 to 10 hours after injection. For each method, bias, precision, and accuracy (P30 and mean absolute error) were calculated for the entire cohort and for eGFR-EPI creatinine subgroups (<30, 30-59, and ≥60 ml/min/1.73m2) and the edema stage using urinary inulin clearance as the gold standard. The mean inulin GFR of the 77 participants was 33 ml/min/1.73m2. Delay of both the initial and the final samples in plasma iohexol protocols yielded the highest accuracy in the setting of low GFR (<30 ml/min/1.73m2). Early initial and final samples yielded the highest accuracy in the setting of high GFRs (≥60 ml/min/1.73m2). No sampling strategy was accurate in edematous patients. Thus, our study demonstrates that customization of GFR protocols according to the anticipated level of GFR are required to optimize protocol accuracy.

Secreted Phosphoprotein 24 is a Biomarker of Mineral Metabolism.

The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin-mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m2) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m2. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4-633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m2 (range 8-122 mL/min/1.73 m2). There was a strong inverse correlation between SPP-24 and eGFR (R = - 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = - 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = - 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study.

Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels.

BACKGROUND: The Wnt/ß-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/ß-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). METHODS: GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. RESULTS: The median [IQR] age was 64 years [53.0-71.0], and the median [IQR] mGFR was 32.6 [21.7-60.6] mL/min. DKK1 decreased (r = 0.6, p < 0.001) and sclerostin increased (r = -0.4, p < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D3 in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. CONCLUSION: The results of this study demonstrate opposing trends in Wnt/ß-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

Relationship of coronary artery calcification with renal function decline and mortality in predialysis chronic kidney disease patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have higher levels of coronary artery calcification (CAC) compared with the general population. The role of CAC in renal function decline is not well understood. METHODS: In this prospective cohort study of Stages 3-5 CKD patients with CAC scores kidney function decline, development of end-stage kidney disease (ESKD) and all-cause mortality were determined at 5 and 10 years. Baseline variables included markers of CKD and chronic kidney disease mineral and bone disorder (CKD-MBD), demographics and comorbidities. Multivariable analyses identified predictors of outcomes, and survival curves demonstrated the association of CAC score with ESKD and mortality. RESULTS: One hundred and seventy-eight patients were enrolled between 2005 and 2007. Independent predictors of ESKD at 5 years were estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR); at 10 years, eGFR was no longer a predictor, but CAC was now significant. Those who developed ESKD at the fastest rate either had the highest CAC score (≥400 AU) or were youngest and had the lowest calcidiol, and highest serum phosphate, UACR and percentage change in CAC per year. Predictors of eGFR decline over 5 years were UACR, parathyroid hormone and CAC score. Predictors of mortality at 5 years were age, diabetes and eGFR and at 10 years also included CAC score. CONCLUSIONS: In Stages 3-5 CKD patients, CAC is an independent predictor of both ESKD and mortality at 10 years. Those who developed ESKD at the fastest rate either had the highest CAC score or the worst CKD-MBD derangements.

Serum BTP concentrations are not affected by hepatic dysfunction.

BACKGROUND: Beta Trace Protein (BTP) is a promising marker of glomerular filtration rate (GFR). Equations to estimate GFR using BTP have been proposed. Very little is known about BTP's production and metabolism. It has been hypothesized that the liver metabolizes certain BTP isoforms. As such, hepatic dysfunction may influence serum levels independently of GFR. This would impact on the accuracy and precision of GFR estimates using BTP. The purpose of this study was to assess the impact of cirrhosis on serum BTP concentrations. METHODS: BTP, cystatin C (cysC) and creatinine (Cr) were measured in 99 cirrhotic subjects and in matched controls. BTP/cysC and Cr/cysC ratios were compared between cases and controls. This was repeated after stratification by Child Pugh category. Comparisons of ratios between Child Pugh category A and combined B and C case subjects were also performed. RESULTS: There were no differences in BTP/cysC ratios between cases and controls for the entire cohort (0.80 vs 0.79) or for any of the Child Pugh categories (p > 0.10). There were significant differences between cases (1.09) and controls (0.73) for the BTP/Cr ratios (p < 0.001). The BTP/Cr ratio was higher in those with more advanced cirrhosis as compared to those with less severe cirrhosis (1.20 vs 1.03, p < 0.01). There were no differences in BTP/cysC ratios between those with less severe and more advanced cirrhosis (p = 0.25). CONCLUSIONS: This study suggests that hepatic dysfunction does not influence serum BTP levels and argues against a significant role for the liver in BTP metabolism. Confirmation in a larger group of patients with advanced cirrhosis is required.

ß-Trace protein: a marker of GFR and other biological pathways.

ß-Trace protein (BTP), also known as lipocalin prostaglandin D2 synthase (L-PGDS; encoded by the PTGDS gene), is a low-molecular-weight glycoprotein and an emerging novel marker of glomerular filtration rate. BTP is an important constituent of cerebral spinal fluid and is found in much lower concentrations in blood. Its serum origin and renal handling remain poorly understood. Unlike serum creatinine, BTP is not physiologically inert. It possesses both ligand-binding and enzymatic properties. BTP catalyzes the conversion of prostaglandin H2 (PGH2) to PGD2. PGD2 is an eicosanoid involved in a variety of important physiologic processes, including platelet aggregation, vasodilation, inflammation, adipogenesis, and bone remodeling. Several studies now have documented BTP's strong association with glomerular filtration rate, end-stage renal disease, cardiovascular disease, and death in a variety of different patient populations. This review provides an overview of the biochemistry, physiology and metabolism, biological functions, and measurement of BTP; summarizes the evidence for BTP as a marker of both kidney function and cardiovascular disease; and then considers the interplay between its biological properties, serum concentration, and patient outcomes.

Predicting kidney transplantation outcomes using proteinuria ascertained from spot urine samples versus timed urine collections.

BACKGROUND: Proteinuria has been associated with transplant loss and mortality in kidney transplant recipients. Both spot samples (albumin-creatinine ratio [ACR] and protein-creatinine ratio [PCR]) and 24-hour collections (albumin excretion rate [AER] and protein excretion rate [PER]) have been used to quantify protein excretion, but which measurement is a better predictor of outcomes in kidney transplantation remains uncertain. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Tertiary care center, 207 kidney transplant recipients who were enrolled in a prospective study to measure glomerular filtration rate. Consecutive patients who met inclusion criteria were approached. PREDICTORS: ACR and PCR in spot urine samples, AER and PER in 24-hour urine collections. OUTCOMES: Primary outcome included transplant loss, doubling of serum creatinine level, or death. MEASUREMENTS: Urine and serum creatinine were measured using a modified Jaffé reaction that had not been standardized by isotope-dilution mass spectrometry. Urine albumin was measured by immunoturbidimetry. Urine protein was measured by pyrogallol red molybdate complex formation using a timed end point method. RESULTS: Mean follow-up was 6.4 years and 22% developed the primary end point. Multivariable-adjusted areas under the receiver operating characteristic curves were similar for the different protein measurements: ACR (0.85; 95% CI, 0.79-0.89), PCR (0.84; 95% CI, 0.79-0.89), PER (0.86; 95% CI, 0.80-0.90), and AER (0.83; 95% CI, 0.78-0.88). C Index values also were similar for the different proteinuria measurements: 0.87 (95% CI, 0.79-0.95), 0.86 (95% CI, 0.79-0.94), 0.88 (95% CI, 0.82-0.94), and 0.86 (95% CI, 0.77-0.95) for log(ACR), log(PCR), log(PER), and log(AER), respectively. LIMITATIONS: Single-center study. Measurement of proteinuria was at variable times posttransplantation. CONCLUSIONS: Spot and 24-hour measurements of albumin and protein excretion are similar predictors of doubling of serum creatinine level, transplant loss, and death. Thus, spot urine samples are a suitable alternative to 24-hour urine collection for measuring protein excretion in this population.

Spot urine protein measurements in kidney transplantation: a systematic review of diagnostic accuracy.

BACKGROUND: Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported the diagnostic accuracy of PCR or ACR as compared with 24-h urine protein or albumin excretion in renal transplant recipients were included. RESULTS: The search identified 8 studies involving 1871 renal transplant recipients. The correlation of the PCR to 24-h protein ranged from 0.772 to 0.998 with a median value of 0.92. PCR sensitivity ranged from 63 to 99 (50% of sensitivities were >90%); PCR specificity varied from 73 to 99 (50% of specificities were >90%). Only one study reported the bias; percent bias ranged from 12 to 21% and accuracy (within 30% of 24 h urine protein) ranged from 47 to 56% depending on the degree of proteinuria. For the ACR, percent bias ranged from 9 to 21%, and the accuracy (within 30%) ranged from 38 to 80%. CONCLUSIONS: The data regarding diagnostic accuracy of PCR and ACR is limited. Only one report studied the absolute measures of agreement (bias and accuracy). We recommend verifying PCR and ACR measurements with a 24-h protein before making any major diagnostic (e.g. biopsy) or therapeutic (e.g. change in immunosuppressive agents) decisions in this population.

Accuracy of Shorter Iohexol Glomerular Filtration Rate Measurement Protocols in Individuals with Preserved Kidney Function.

BACKGROUND: Measuring glomerular filtration rate (mGFR) using exogenous tracers is recommended in a number of settings. Plasma one-compartment multi-sample protocols (MSP) are the most commonly used with iohexol being the dominant tracer. The accuracy of MSP protocols has mostly been evaluated in the setting of reduced GFR where delayed initial and final samples are recommended. Much less is known about MSPs when GFR is not decreased, and the default protocol tends to include initial sampling at 120 minutes (min) and final sampling at 240 min post iohexol injection. The recent KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease includes research recommendations for the development of shorter more efficient mGFR protocols. The objective of this study was to assess the performance of shorter MSPs with earlier initial (60 and 90 min) and final (150, 180, and 210 min) sampling times in individuals with preserved GFR. Reference mGFR was calculated using 5 samples collected between 120-240 min. METHODS: Four different combinations of shorter sampling strategies were investigated. Performance was evaluated using measurements of bias, precision, and accuracy (P2, P5, and mean absolute error). RESULTS: The mean reference mGFR of the 43 participants was 102.3 ± 13.7 ml/min/1.73m2. All shorter mGFRs had biases less than 1 ml/min/1.73m2 and mean absolute error less than 1.6 ml/min/1.73m2. All shorter mGFRs were within 5% of the reference mGFR, and the majority were within 2%. CONCLUSIONS: These results demonstrate that shortening the mGFR procedure in individuals with preserved GFR provides similar results to the current standard while significantly decreasing procedure time.

Serum total testosterone is associated with phosphate and calcium excretion in response to oral phosphate loading in healthy middle-aged males.

Androgen receptors are expressed in the kidney and serum testosterone is negatively associated with serum phosphate in males, suggesting a role of testosterone in renal phosphate handling. In this cross-sectional study, we examined the association of serum total and free testosterone with acute phosphate and calcium excretion in males in response to an oral phosphate challenge. Thirty-five healthy adult males with normal baseline testosterone levels consumed a 500 mg phosphorus drink and the urinary excretion of minerals, as well as levels of relevant circulating parameters, were assessed at baseline and hourly for 4 h. Serum total testosterone was positively associated with overall phosphate excretion (r = 0.35, p = 0.04) and calcium excretion (r = 0.44, p = 0.00) in response to the challenge. Serum free testosterone was positively associated with post-challenge calcium excretion (r = 0.34, p = 0.048), but significance was not reached for phosphate excretion (r = 0.31, p = 0.07). Serum total and free testosterone were not associated with parathyroid hormone, fibroblast growth factor-23, or vitamin D-key factors implicated in phosphate and calcium regulation. Overall, higher serum total testosterone levels in healthy middle-aged males are associated with a greater capacity to acutely excrete phosphate and calcium after a single oral phosphate challenge, suggesting potential ramifications of testosterone deficiency related to mineral homeostasis.

Social determinants of health and dialysis modality selection in patients with advanced chronic kidney disease: A retrospective cohort study.

BACKGROUND: Social determinants of health are non-medical factors that impact health. For patients with chronic kidney disease (CKD) progressing to kidney failure, the influence of social determinants of health on dialysis modality selection (haemodialysis vs. peritoneal dialysis (PD)) is incompletely understood. METHODS: Retrospective cohort study of 981 consecutive patients with advanced CKD referred to the Ottawa Hospital Multi-Care Kidney Clinic (Canada) who progressed to dialysis from 2010 to 2021. Multivariable logistic regression was used to measure odds ratios (OR) for the associations between social determinants of health (education, employment, marital status and residence) and modality of dialysis initiation. RESULTS: The mean age and estimated glomerular filtration rate were 64 and 18 mL/min/1.73 m2, respectively. Not having a high school degree was associated with lower odds of initiating dialysis via PD compared to having a college degree (29% vs. 48%, OR 0.55 (95% confidence interval (CI) 0.34-0.88)). Unemployment was associated with lower odds of initiating dialysis via PD compared to active employment (38% vs. 62%, OR 0.40 (95% CI 0.27-0.60)). Being single was associated with lower odds of initiating dialysis via PD compared to being married (35% vs. 48%, adjusted OR 0.52 (95% CI 0.39-0.70)). Living alone at home was associated with lower odds of initiating dialysis via PD compared to living at home with family (33% vs. 47%, adjusted OR 0.55 (95% CI 0.39-0.78)). CONCLUSIONS: Social determinants of health including education, employment, marital status and residence are associated with dialysis modality selection. Addressing these 'upstream' social factors may allow for more equitable outcomes during the transition from advanced CKD to kidney failure.

Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

BACKGROUND: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. METHODS: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. RESULTS: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. CONCLUSIONS: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

Accuracy of cystatin C-based estimates of glomerular filtration rate in kidney transplant recipients: a systematic review.

BACKGROUND: As with creatinine, cystatin C can be incorporated into a formula to estimate the glomerular filtration rate (GFR). The overall performance of cystatin C-based equations in kidney transplantation is unclear with conflicting results between studies. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported mean bias (mean difference between the measured and estimated GFRs) or accuracy of the cystatin C-based GFR estimation equation (e.g. percentage of estimates within 30% of the measured GFR) against the measured GFR using renal or plasma clearance of contrast agents, radioisotopes or inulin were included. RESULTS: The search identified 10 studies that examined 14 different cystatin C-based estimating equations (n = 5 equations evaluated in more than one study). The Le Bricon equation had the best performance with a bias that ranged from -6.4 to +2.8 mL/min/1.73 m(2); 85% (95% CI, 82-88) of estimates were within 30% of the measured GFR. For the other equations, 66-82% of estimates were within 30% of the measured GFR. For the modification of diet in renal disease (MDRD) equation, 68% (95% CI, 65-72) of estimates were within 30% of the measured GFR. CONCLUSIONS: The cystatin C-based Le Bricon equation was the most accurate, and most of the cystatin C-based equations showed improvements in 30% and 50% accuracy compared with the creatinine-based MDRD equation. Cystatin C-based equations may offer an advantage over the MDRD equation in kidney transplant recipients. Estimating equations re-expressed with standardized cystatin C have been developed and their accuracy needs to be tested in the kidney transplant population.

SOCS3 deletion in B cells alters cytokine responses and germinal center output.

B cell behavior is fine-tuned by internal regulatory mechanisms and external cues such as cytokines and chemokines. Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of STAT3-dependent cytokine responses in many cell types and has been reported to inhibit CXCL12-induced retention of immature B cells in the bone marrow. Using mice with SOCS3 exclusively deleted in the B cell lineage (Socs3(Δ/Δ)mb1cre(+)), we analyzed the role of SOCS3 in the response of these cells to CXCL12 and the STAT3-inducing cytokines IL-6 and IL-21. Our findings refute a B cell-intrinsic role for SOCS3 in B cell development, because SOCS3 deletion in the B lineage did not affect B cell populations in naive mice. SOCS3 was strongly induced in B cells stimulated with IL-21 and in plasma cells exposed to IL-6. Its deletion permitted excessive and prolonged STAT3 signaling following IL-6 stimulation of plasma cells and, in a T cell-dependent immunization model, reduced the number of germinal center B cells formed and altered the production of Ag-specific IgM and IgE. These data demonstrate a novel regulatory signal transduction circuit in plasma cells, providing, to our knowledge, the first evidence of how these long-lived, sessile cells respond to the external signals that mediate their longevity.

Varenicline induced acute interstitial nephritis in the setting of idiopathic membranous glomerulonephritis.

BACKGROUND: Varenicline is a nicotinic receptor partial agonist indicated for the cessation of smoking. It is regarded as having no or minimal renal toxicity. A single case report has linked it to acute interstitial nephritis. CASE PRESENTATION: A 56 year-old female with a long-standing history of idiopathic membranous glomerulonephritis presented on routine follow-up with an unexpected rise in her serum creatinine from a stable baseline of 225 umol/L to 319 umol/L Biopsy revealed acute interstitial nephritis. There were no preceding clinical events other than the initiation of varenicline therapy three months prior. This was discontinued with no improvement in renal function. A ten week course of prednisone was initiated and creatinine levels returned to baseline. Shortly after prednisone therapy was completed, renal function worsened but the patient declined further immunosuppressive therapy. Exposure to varenicline therapy two years prior had also resulted in a reversible decline in kidney function. CONCLUSION: This is only the second case report to document varenicline-induced acute interstitial nephritis. A careful medication history and renal biopsy were essential in identifying the etiology of the acute kidney injury in this patient with a complex renal history.

The 1,24,25(OH)3D3 metabolite in clinical and experimental CKD: Impact of calcitriol treatment.

Calcitriol, and other vitamin D receptor activators, remain a primary treatment for elevated parathyroid hormone levels in patients with end stage kidney disease. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D3 and 1,25(OH)2D3 in rats with experimental kidney disease treated with calcitriol and in a cross-sectional analysis of patients requiring hemodialysis. Methods: Animals were stratified by creatinine into a time control group or calcitriol (20 ng/kg/day) for 3 weeks following CKD induction using a dietary adenine model (0.25% adenine). Hemodialysis patients were recruited and demographic data including calcitriol prescription was obtained by chart review and participant interview. Vitamin D metabolites were assessed using LC-MS/MS. In the rat model, 1,25(OH)2D3 levels increased substantially in calcitriol-treated rats yet there was no increase in its primary metabolite: 1,24,25(OH)2D3. A lower ratio of 1,24,25(OH)2D3:1,25(OH)2D3 (1,25-VMR) was associated with increased calcium levels in calcitriol treated rats. In hemodialysis patients (N = 86), the level of 1,25(OH)2D3 was substantially higher in calcitriol-treated patients yet there was no difference between groups in 1,24,25(OH)3D3, resulting in a marked decrease in the 1,25-VMR in calcitriol treated patients. In hemodialysis patients treated with calcitriol, 1,25(OH)2D3 and a lower ratio between 1,24,25(OH)3D3 and 1,25(OH)2D3 were associated with higher serum calcium levels. Impaired metabolism of exogenous calcitriol may contribute to the adverse effects associated with this treatment. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies.

Sex Differences in Phosphate Homeostasis: Females Excrete More Phosphate and Calcium After an Oral Phosphate Challenge.

CONTEXT: Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. OBJECTIVE: To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. DESIGN: Cross-sectional. SETTING: General community. PARTICIPANTS: 78 participants (40-76 years) with measured glomerular filtration rate >60 mL/min/1.73 m2 and no clinically diagnosed CVD and 14 young healthy adults. MAIN OUTCOME MEASURES: To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. RESULTS: Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. CONCLUSIONS: Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.