Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study.

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

University of Montreal's Clinician-Investigator Program: A 10-Year Descriptive Evaluation.

PURPOSE: Clinician-investigators have an important role in the development and implantation of new therapies and treatment modalities; however, there have been several reports highlighting a pending shortage in the clinician-investigators' workforce. In Canada, the Royal College has promoted the development of clinician-investigators programs (CIP) to facilitate the training of these individuals. There is currently a paucity of data regarding the outcomes of such programs. This study aims to identify the strengths and areas of improvement of the Montreal University CIP.  Methods: An internet-based 51-question survey was distributed to all the alumni from the University of Montreal CIP. Participation was voluntary and no incentives were provided. The response rate was 64%.  Results: Among respondents, 50% (n=16) had completed their clinical residency and all CIP requirements. The majority of these individuals (63%) had become independent investigators and had secured provincial and national funding. Satisfaction of the respondents was high regarding the overall program (85%), the research skills developed during the CIP (84%) and the financial support obtained during the program (72%). The satisfaction rate regarding career planning was lower (63%).  Conclusion: This survey demonstrates that, while indicators are favorable, some areas still require improvement. Several steps to improve the CIP have been identified; notably, the transition from the CIP to early independent career has been identified as critical in the development of clinician-investigators and steps have been taken to improve this progression.

Incidence of fractures in middle-aged individuals with early chronic kidney disease: a population-based analysis of CARTaGENE.

BACKGROUND: Previous studies evaluating fractures in chronic kidney disease (CKD) have mostly focused on hip or major fractures in aged populations with moderate to advanced CKD. We aimed at evaluating the association between early CKD and fracture incidence at all sites across age and sex in middle-aged individuals. METHODS: We analyzed CARTaGENE, a prospective population-based survey of 40- to 69-year-old individuals from Quebec (Canada). Estimated glomerular filtration rate (eGFR) at baseline was evaluated categorically or continuously using restricted cubic splines. Fractures at any site (except toes, hand and craniofacial) for up to 7 years of follow-up were identified through administrative databases using a validated algorithm. Adjusted Cox models were used to evaluate the association of CKD with fracture. Interaction terms for age and sex were also added. RESULTS: A total of 19 391 individuals (756 CKD Stage 3; 9114 Stage 2; 9521 non-CKD) were included and 829 fractures occurred during a median follow-up of 70 months. Compared with the median eGFR of 90 mL/min/1.73 m2, eGFRs of ≤60 mL/min/1.73 m2 were associated with increased fracture incidence in unadjusted and adjusted models [adjusted hazard ratio (HR) = 1.25 (95% confidence interval 1.05-1.49) for 60 mL/min/1.73 m2; 1.65 (1.14-2.37) for 45 mL/min/1.73 m2]. The eGFR was linearly associated with fracture incidence <75 mL/min/1.73 m2 [HR = 1.18 (1.04-1.34) per 10 mL/min/1.73 m2 decrease] but not above [HR = 0.98 (0.91-1.06) per 10 mL/min/1.73 m2 decrease). The effect of decreased eGFR on fracture incidence was more pronounced in younger individuals [HR = 2.45 (1.28-4.67) at 45 years; 1.11 (0.73-1.67) at 65 years] and in men. CONCLUSIONS: Even early CKD increases fracture incidence, especially in younger individuals and in men.

Formulas for Calculated Osmolarity and Osmolal Gap: A Study of Diagnostic Accuracy.

BACKGROUND: The osmolal gap has been used for decades to screen for exposure to toxic alcohols. However, several issues may affect its reliability. We aimed to develop equations to calculate osmolarity with improved performance when used to screen for intoxication to toxic alcohols. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 7,525 patients undergoing simultaneous measurements of osmolality, sodium, potassium, urea, glucose, and ethanol or undergoing similar measurements performed within 30 minutes of a measurement of toxic alcohol levels at a single tertiary-care center from April 2001 to June 2016. Patients with detectable toxic alcohols were excluded. INDEX TEST: Equations to calculate osmolarity using multiple linear regression. OUTCOMES: The performance of new equations compared with published equations developed to calculate osmolarity, and to diagnose toxic alcohol intoxications more accurately. RESULTS: We obtained 7,525 measurements, including 100 with undetectable toxic alcohols. Among them, 3,875 had undetectable and 3,650 had detectable ethanol levels. In the entire cohort, the best equation to calculate osmolarity was 2.006×Na + 1.228×Urea + 1.387×Glucose + 1.207×Ethanol (values in mmol/L, R2=0.96). A simplified equation, 2.0×Na + 1.2×Urea + 1.4×Glucose + 1.2×Ethanol, had a similar R2 with 95% of osmolal gap values between -10.9 and 13.8. In patients with undetectable ethanol concentrations, the range of 95% of osmolal gap values was narrower than previous published formulas, and in patients with detectable ethanol concentrations, the range was narrower or similar. We performed a subanalysis of 138 cases for which both the toxic alcohol concentration could be measured and the osmolal gap could be calculated. Our simplified equation had superior diagnostic accuracy for toxic alcohol exposure. LIMITATIONS: Single center, no external validation, limited number of cases with detectable toxic alcohols. CONCLUSIONS: In a large cohort, coefficients from regression analyses estimating the contribution of glucose, urea, and ethanol were higher than 1.0. Our simplified formula to precisely calculate osmolarity yielded improved diagnostic accuracy for suspected toxic alcohol exposures than previously published formulas.

Central blood pressures in early chronic kidney disease: an analysis of CARTaGENE.

BACKGROUND: Vascular stiffness and advanced chronic kidney disease (CKD) are strong determinants of higher central blood pressure (BP) and are associated with high cardiovascular morbidity and mortality. Whether mild-to-moderate CKD is associated with higher central BP independently of other comorbid conditions remains uncertain. METHODS: We evaluated the central hemodynamic profile [central systolic BP, central pulse pressure (PP), augmentation index, PP amplification, augmented pressure] of Stage 3 CKD patients and compared it with participants with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m 2 in the CARTaGENE populational cohort through propensity score matching and multivariate regression analyses. RESULTS: Of the 20 004 participants, 13 114 had valid pulse wave analysis and eGFRs >30 mL/min/1.73 m 2 , of which 515 had Stage 3 CKD. These 515 patients had significantly higher peripheral systolic BP (127 ± 16 versus 125 ± 15 mmHg, P = 0.01) and central PP (43.0 ± 11.4 versus 39.7 ± 10.0 mmHg, P <0.001) than the control group (eGFR >60 mL/min/1.73 m 2 ). Propensity score matching allowed the creation of 500 pairs with similar clinical characteristics. In this matched cohort, central BPs were similar in Stage 3 CKD patients compared with controls (central PP 42.9 ± 11.3 versus 43.7 ± 11.3 mmHg, P = 0.3). Multivariate analysis using data from all patients also found that the higher central hemodynamic readings found in Stage 3 CKD patients disappeared after adjusting for comorbid conditions. In a subset of 609 participants in whom albuminuria levels were measured, urine albumin excretion was not independently associated with higher central hemodynamic indices. CONCLUSION: In this large cohort from the general population, early CKD and albuminuria was not independently associated with detrimental central hemodynamic parameters.

Diagnosis and outcomes of acute kidney injury using surrogate and imputation methods for missing preadmission creatinine values.

BACKGROUND: Missing preadmission serum creatinine (SCr) values are a common obstacle to assess acute kidney injury (AKI) diagnosis and outcomes. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest using a SCr computed from the Modification of Diet in Renal Disease (MDRD) with an estimated glomerular filtration rate of 75 ml/min/1.73 m2. We aimed to identify the best surrogate method for baseline SCr to assess AKI diagnosis and outcomes. METHODS: We compared the use of 1) first SCr at hospital admission 2) minimal SCr over 2 weeks after intensive care unit admission 3) MDRD computed SCr and 4) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) computed SCr to assess AKI diagnosis and outcomes. We then performed multilinear regression models to predict preadmission SCr and imputation strategies to assess AKI diagnosis. RESULTS: Our one-year retrospective cohort study included 1001 critically ill adults; 498 of them had preadmission SCr values. In these patients, AKI incidence was 25.1% using preadmission SCr. First SCr had the best agreement for AKI diagnosis (22.5%; kappa = 0.90) and staging (kappa = 0.81). MDRD, CKD-EPI and minimal SCr overestimated AKI diagnosis (26.7%, 27.1% and 43.2%;kappa = 0.86, 0.86 and 0.60, respectively). However, MDRD and CKD-EPI computed SCr had a better sensitivity than first SCr for AKI (93% and 94% vs. 87%). Eighty-eight percent of patients experienced renal recovery at least 3 months after hospital discharge. All methods except the first SCr significantly underestimated the percentage of renal recovery. In a multivariate model, age, male gender, hypertension, heart failure, undergoing surgery and log first SCr best predicted preadmission SCr (adjusted R2 = 0.56). Imputation methods with first SCr increased AKI incidence to 23.9% (kappa = 0.92) but not with MDRD computed SCr (26.7%;kappa = 0.89). CONCLUSION: In our cohort, first SCr performed better for AKI diagnosis and staging, as well as for renal recovery after hospital discharge than MDRD, CKD-EPI or minimal SCr. However, MDRD SCr and CKD-EPI SCr improved AKI diagnosis sensitivity. Imputation methods minimally increased agreement for AKI diagnosis.

Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 µM; interquartile range [IQR]: 12.82-32.70 µM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Plasmapheresis in cast nephropathy: yes or no?

PURPOSE OF REVIEW: Renal failure is a frequent complication of multiple myeloma and portends a poor prognosis. Plasmapheresis has been suggested as an adjunct to chemotherapy to halt or reverse renal injury associated with multiple myeloma. The purpose of this article is to review the rationale for using plasmapheresis for this indication and then provide a discussion of the evidence regarding its use. RECENT FINDINGS: The outcome of patients with multiple myeloma has improved considerably in recent years, mostly owing to the introduction of new highly effective chemotherapeutic agents. However, patients with renal failure who do not recover independent renal function continue to have very poor prognosis. Recent evidence now indicates that an early and sustained reduction in circulating free light chains (FLCs) is associated with improved renal recovery in patients with myeloma kidney. Extracorporeal removal of FLCs with plasmapheresis, or other techniques, can achieve rapid and sustained reduction in serum FLC concentration in patients with acute myeloma kidney. Unfortunately, there is currently no convincing evidence in the literature that the addition of mechanical removal of FLC to standard chemotherapy translates into clinical benefits for patients. SUMMARY: Plasmapheresis is theoretically attractive as a means of rapidly lowering serum FLC burden in the hope of reducing nephrotoxicity in patients with multiple myeloma. However, the role of plasmapheresis in improving renal prognosis and patient survival remains to be demonstrated.

Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management.

We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR), the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we thought that the highest risk category was too broad, including as it does people at disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria and D and T categories for patients on dialysis or with a functioning renal transplant. We recommend target blood pressure of 140/90mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of hemoglobin A1c targets. We do not agree with routine restriction of sodium intake to <2g/d, instead suggesting reduction of sodium intake in those with high intake (>3.3g/d). We suggest screening for anemia only when GFR is <30mL/min/1.73m(2). We recognize the absence of evidence on appropriate phosphate targets and methods of achieving them and do not agree with suggestions in this area. In drug dosing, we agree with the recommendation of using absolute clearance (ie, milliliters per minute), calculated from the patient's estimated GFR (which is normalized to 1.73m(2)) and the patient's actual anthropomorphic body surface area. We agree with referral to a nephrologist when GFR is <30mL/min/1.73m(2) (and for many other scenarios), but suggest urine albumin-creatinine ratio > 60mg/mmol or proteinuria with protein excretion > 1g/d as the referral threshold for proteinuria.

Carbamazepine poisoning treated by multiple extracorporeal treatments.

CONTEXT: Hemoperfusion (HP) or dialysis is occasionally used following carbamazepine (CBZ) toxicity but it remains unclear which is the most efficient modality. We describe a case of severe CBZ intoxication treated with different extracorporeal modalities during which CBZ toxicokinetics were compared. CASE DETAILS: A 58-year-old man was transferred to our facility 24 hours after ingesting over 14 g of sustained-release CBZ. Because of worsening neurological condition requiring mechanical ventilation and CBZ levels reaching 47.6 µg/mL, he underwent three intermittent hemodialysis (IHD), two continuous veno-venous hemofiltration (CVVH), and one IHD with HP (IHD-HP). IHD and CVVH removed 1.73 g of carbamazepine over 43 hours. Mean apparent half-life was 8.8 hours during IHD 49.1 hours during CVVH, and 5.1 hours during IHD-HP, while measured endogenous half-life after extracorporeal therapies was 81.4 hours. Mean CBZ clearances were 106.2 mL/min during IHD and 21.2 mL/ min during CVVH. His neurological status improved during extracorporeal elimination, and he was discharged without sequela after 16 days. Treatments were well tolerated aside from thrombocytopenia during IHDHP. DISCUSSION: All extracorporeal treatments facilitated CBZ elimination, although CVVH was significantly less efficient than IHD and IHD-HP. IHD-HP may be better than IHD alone but must be weighed against its risks. IHD appears sufficient to eliminate CBZ and may need to be repeated or prolonged according to the clinical context if CBZ absorption is delayed.

The risk of thromboembolic events in kidney transplant patients.

Little is known about the risk of venous thrombosis following kidney transplant. To determine this we estimated the risk of thromboembolic events (TEs) in a cohort of consecutive patients who underwent kidney transplantation at a single tertiary care center over an 11-year period and calculated standardized incidence ratios (SIRs) for a first TE in kidney transplant recipients compared with the general population. We then performed a nested case-control study and compared patients with and without TEs to identify risk factors for thrombosis. Among 913 kidney transplant recipients (KTRs), 68 patients developed these events. The SIR for TEs in KTRs compared with the general population was 7.9 over the duration of follow-up. The risk was particularly higher in the first post-transplant year (SIR 26.1) but remained elevated afterward (SIR 5.2). Hospitalization, use of sirolimus, low hemoglobin level, and use of renin-angiotensin system inhibitors were independently associated with these events. When cases of TEs that occurred during hospitalization were excluded, the risk of these events remained elevated. The risk of TEs in KTRs was eightfold higher than in the general population but not fully explained by the increased risk associated with hospitalization. Our results underscore the important risk of thrombosis in patients who received a kidney transplant, making vigilance mandatory especially during hospitalization.

The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection.

RATIONALE: Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation. OBJECTIVE: Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling. METHODS AND RESULTS: We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant patients with acute VR (n = 16) compared to ATIR (n = 16) and normal graft function (n = 32, P = 0.004). In patients with acute VR, graft loss was associated with elevated LG3 levels. Increasing LG3 serum levels in aortic allograft recipients significantly increased neointima formation. LG3 injection fostered accumulation of α-smooth muscle actin-positive cells and decreased the number of CD31 positive EC. LG3 increased the migration of VSMC through extracellular signal-regulated kinases 1/2-dependent pathways. CONCLUSION: These results indicate that LG3 is a novel regulator of obliterative vascular remodeling during rejection.

Biomarkers of inflammation, fibrosis, cardiac stretch and injury predict death but not renal replacement therapy at 1 year in a Canadian chronic kidney disease cohort.

BACKGROUND: Newer biomarkers, reflective of biological processes, such as inflammation and fibrosis, cardiac stretch or damage and vascular health may be useful in understanding clinical events in chronic kidney disease (CKD). We assessed whether these newer biomarkers, alone or as a panel, improve risk prediction for renal replacement therapy or death, over and above conventional clinical, demographic and laboratory variables. METHODS: We conducted a prospective observational Canadian cohort study in 2544 CKD patients with estimated glomerular filtration rate (eGFR) of 15-45 mL/min/1.73 m(2), under nephrology care, in urban and rural centers. We measured traditional clinical and laboratory risk factors, as well as newer biomarkers: cystatin C, high sensitivity c-reactive protein (hsCRP), interleukin 6 (IL6), transforming growth factor ß1 (TGFß1), fibroblast growth factor 23 (FGF23), N-terminal probrain natriuretic peptide (NT-proBNP), troponin I and asymmetric dimethylarginine (ADMA). Key outcomes were renal replacement therapy (RRT, dialysis or transplantation) and death, during the first year follow-up after enrollment: a time point important for clinical decision-making for patients and providers. RESULTS: Newer biomarkers do not improve the prediction of RRT, when added to conventional risk factors such as eGFR, urine albumin to creatinine ratio, hemoglobin, phosphate and albumin. However, in predicting death within 1 year, cystatin C, NT-proBNP, hsCRP and FGF23 values significantly improved model discrimination and reclassification: c statistic increased by absolute 4.3% and Net Reclassification Improvement for categories of low, intermediate and high risk at 11.2%. CONCLUSIONS: Our findings suggest that the addition of newer biomarkers may be useful in predicting death in patients with established CKD within a 1-year timeframe. This information may be useful in informing prognosis and redirect resources to serve patients at higher risk to improve outcomes and sustainability of the nephrology care system.

Plasmapheresis in myeloma cast nephropathy.

Renal failure in multiple myeloma is frequent, and portends a dismal prognosis. Precipitation of free light chains in tubules contributes to development of cast nephropathy and renal failure. Treatment with plasmapheresis is reported as an adjunct to chemotherapy in these patients, but evidence regarding its efficacy in the literature is conflicting. In this article, we report the case of a 63-year-old man who presented with severe acute renal failure due to myeloma cast nephropathy and whose kidney function improved significantly following treatment with dexamethasone and a course of 8 plasma exchanges. We then provide a review of the technical aspects of plasmapheresis, followed by an analysis of the randomized trials that have been published to date on the efficacy of plasmapheresis for myeloma cast nephropathy.

Effect of cinacalcet availability and formulary listing on parathyroidectomy rate trends.

BACKGROUND: Recent trends in parathyroidectomy rates are not known. Our objective was to investigate the trend in parathyroidectomy rates between 2001 and 2010, and to evaluate if the availability and reimbursement of cinacalcet modified that trend. METHODS: Using a provincial administrative database, we included all adult patients receiving chronic dialysis treatments between 2001 and 2010 (incident and prevalent) in a time series analysis. The effect of cinacalcet availability on parathyroidectomy bimonthly rates was modeled using an ARIMA intervention model using different cut-off dates: September 2004 (Health Canada cinacalcet approval), January 2005, June 2005, January 2006, June 2006 (date of cinacalcet provincial reimbursement), and January 2007. RESULTS: A total of 12 795 chronic dialysis patients (mean age 64 years, 39% female, 82% hemodialysis) were followed for a mean follow-up of 3.3 years. During follow-up, 267 parathyroidectomies were identified, translating to an average rate of 7.0 per 1000 person-years. The average parathyroidectomy rate before cinacalcet availability was 11.4 /1000 person-years, and 3.6 /1000 person-years after cinacalcet public formulary listing. Only January 2006 as an intervention date in the ARIMA model was associated with a change in parathyroidectomy rates (estimate: -5.58, p = 0.03). Other intervention dates were not associated with lower parathyroidectomy rates. CONCLUSIONS: A reduction in rates of parathyroidectomy was found after January 2006, corresponding to cinacalcet availability. However, decreased rates may be due to other factors occurring simultaneously with cinacalcet introduction and further studies are needed to confirm these findings.

Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).

BACKGROUND: The Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) is a large, prospective, pan-Canadian, cohort study designed to improve our understanding of determinants of renal and cardiovascular (CV) disease progression in patients with chronic kidney disease (CKD). The primary objective is to clarify the associations between traditional and newer biomarkers in the prediction of specific renal and CV events, and of death in patients with CKD managed by nephrologists. This information could then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments. METHODS/DESIGNS: Commenced in 2008, 2546 patients have been enrolled with eGFR between 15 and 45 ml/min 1.73m2 from a representative sample in 25 rural, urban, academic and non academic centres across Canada. Patients are to be followed for an initial 3 years at 6 monthly intervals, and subsequently annually. Traditional biomarkers include eGFR, urine albumin creatinine ratio (uACR), hemoglobin (Hgb), phosphate and albumin. Newer biomarkers of interest were selected on the basis of biological relevance to important processes, commercial availability and assay reproducibility. They include asymmetric dimethylarginine (ADMA), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), troponin I, cystatin C, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and transforming growth factor beta 1 (TGFß1). Blood and urine samples are collected at baseline, and every 6 monthly, and stored at -80°C. Outcomes of interest include renal replacement therapy, CV events and death, the latter two of which are adjudicated by an independent panel. DISCUSSION: The baseline distribution of newer biomarkers does not appear to track to markers of kidney function and therefore may offer some discriminatory value in predicting future outcomes. The granularity of the data presented at baseline may foster additional questions.The value of the cohort as a unique resource to understand outcomes of patients under the care of nephrologists in a single payer healthcare system cannot be overstated. Systematic collection of demographic, laboratory and event data should lead to new insights. The mean age of the cohort was 68 years, 90% were Caucasian, 62% were male, and 48% had diabetes. Forty percent of the cohort had eGFR between 30-45 mL/min/1.73m², 22% had eGFR values below 20 mL/min/1.73m²; 61% had uACR < 30. Serum albumin, hemoglobin, calcium and 25-hydroxyvitamin D (25(OH)D) levels were progressively lower in the lower eGFR strata, while parathyroid hormone (PTH) levels increased. Cystatin C, ADMA, NT-proBNP, hsCRP, troponin I and IL-6 were significantly higher in the lower GFR strata, whereas 25(OH)D and TGFß1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable.

Impact of Successive Office Blood Pressure Measurements During a Single Visit on Cardiovascular Risk Prediction: Analysis of CARTaGENE.

BACKGROUND: Multiple office blood pressure (BP) readings correlate more closely with ambulatory BP than single readings. Whether they are associated with long-term outcomes and improve cardiovascular risk prediction is unknown. Our objective was to assess the long-term impact of multiple office BP readings. METHODS: We used data from CARTaGENE, a population-based survey comprising individuals aged 40 to 70 years. Three BP readings (BP1, BP2, and BP3) at 2-minute intervals were obtained using a semiautomated device. They were averaged to generate BP1-2, BP2-3, and BP1-2-3 for systolic BP (SBP) and diastolic BP. Cardiovascular events (major adverse cardiovascular event [MACE]: cardiovascular death, stroke, and myocardial infarction) during a 10-year follow-up were recorded. Associations with MACE were obtained using adjusted Cox models. Predictive performance was assessed with 10-year atherosclerotic cardiovascular disease scores and their associated C statistics. RESULTS: In the 17 966 eligible individuals, 2378 experienced a MACE during follow-up. Crude SBP values ranged from 122.5 to 126.5 mm Hg. SBP3 had the strongest association with MACE incidence (hazard ratio, 1.10 [1.05-1.15] per SD) and SBP1 the weakest (hazard ratio, 1.06 [1.01-1.10]). All models including SBP1 (SBP1, SBP1-2, and SBP1-2-3) were underperformed. At a given SBP value, the excess MACE risk conferred by SBP3 was 2× greater than SBP1. In atherosclerotic cardiovascular disease scores, SBP3 yielded the highest C statistic, significantly higher than most other SBP measures. In contrast to SBP, all diastolic BP readings yielded similar results. CONCLUSIONS: Cardiovascular risk prediction is improved by successive office SBP values, especially when the first reading is discarded. These findings reinforce the necessity of using multiple office BP readings.

Screening for Primary Aldosteronism Among Hypertensive Adults with Obstructive Sleep Apnea: A Retrospective Population-Based Study.

BACKGROUND: Hypertension plus obstructive sleep apnea (OSA) is recommended in some guidelines as an indication to screen for primary aldosteronism (PA), yet prior data has brought the validity of this recommendation into question. Given this context, it remains unknown whether this screening recommendation is being implemented into clinical practice. METHODS: We conducted a population-based retrospective cohort study of all adult Ontario (Canada) residents with hypertension plus OSA from 2009 to 2020 with follow-up through 2021 utilizing provincial health administrative data. We measured the proportion of individuals who underwent PA screening via the aldosterone-to-renin ratio by year. We further examined screening rates among patients with hypertension plus OSA by the presence of concurrent hypokalemia and resistant hypertension. Clinical predictors associated with screening were assessed via Cox regression modeling. RESULTS: The study cohort included 53,130 adults with both hypertension and OSA, of which only 634 (1.2%) underwent PA screening. Among patients with hypertension, OSA, and hypokalemia, the proportion of eligible patients screened increased to 2.8%. Among patients ≥65 years with hypertension, OSA, and prescription of ≥4 antihypertensive medications, the proportion of eligible patients screened was 1.8%. Older age was associated with a decreased likelihood of screening while hypokalemia and subspecialty care with internal medicine, cardiology, endocrinology, or nephrology were associated with an increased likelihood of screening. No associations with screening were identified with sex, rural residence, cardiovascular disease, diabetes, or respirology subspecialty care. CONCLUSIONS: The population-level uptake of the guideline recommendation to screen all patients with hypertension plus OSA for PA is exceedingly low.

Gene polymorphisms as clinical tools in chronic glomerulopathies: a prospective study.

BACKGROUND/AIMS: Studies have proposed various polymorphisms of genes implicated in the physiopathology of chronic kidney disease as risk factors of progression and potential clinical tools. We sought to validate and simultaneously compare their predictive value in a prospective cohort of chronic glomerulopathies receiving recommended antihypertensive and antiproteinuric therapies. METHODS: Using PubMed, we identified 9 polymorphisms previously associated with progression. These were mostly of the renin-angiotensin-aldosterone and inflammation pathways: MCP-1 A2518G, TGF-ß1 T869C and C-509T, ACE I/D, AGT M235T, AT1R A1166C, TSC-22 A-396G, eNOS 4b/a and CYP11ß2 C-344T. We hypothesized that their determination would identify individuals at higher risk of progression. RESULTS: We recruited 93 predominantly male and Caucasian patients with a mean age of 63 and baseline eGFR of 33 ml/min/1.73 m(2) followed prospectively over a median of 36 months. 61% of patients had diabetic nephropathy, almost all received RAA blockade (90%) and none immunosuppressive therapy. The average blood pressure during follow-up was 140/72 mm Hg, the urinary protein to creatinine ratio 0.15 g/mmol and the rate of renal function decline -3.2 ± 4.1 ml/min/1.73 m(2)/year. Proteinuria and blood pressure strongly predicted progression. However, under recommended therapy, none of the proposed polymorphisms predicted renal function decline. In addition, none showed simple or partial correlations with the severity of proteinuria or blood pressure. Finally, summation variable of risk polymorphisms did not predict progression. CONCLUSION: This study does not validate the use of these 9 polymorphisms as individual clinical tools in patients with chronic glomerulopathies on recommended antihypertensive and antiproteinuric therapies.