Moderate-severe Chronic Kidney Disease Research Articles

Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review.

Hyperuricemia with consequent monosodium urate crystal deposition leads to gout, characterized by painful, incapacitating inflammatory arthritis flares that are also associated with increased cardiovascular event and related mortality risk. This narrative review focuses on emerging pharmacologic urate-lowering treatment (ULT) and management strategies in gout. Undertreated, gout can progress to palpable tophi and joint damage. In oral ULT clinical trials, target serum urate of < 6.0 mg/dL can be achieved in ~ 80-90% of subjects, with flare burden reduction by 1-2 years. However, real-world ULT results are far less successful, due to both singular patient nonadherence and prescriber undertreatment, particularly in primary care, where most patients are managed. Multiple dose titrations commonly needed to optimize first-line allopurinol ULT monotherapy, and substantial potential toxicities and other limitations of approved, marketed oral monotherapy ULT drugs, promote hyperuricemia undertreatment. Common gout comorbidities with associated increased mortality (e.g., moderate-severe chronic kidney disease [CKD], type 2 diabetes, hypertension, atherosclerosis, heart failure) heighten ULT treatment complexity and emphasize unmet needs for better and more rapid clinically significant outcomes, including attenuated gout flare burden. The gout drug armamentarium will be expanded by integrating sodium-glucose cotransporter-2 (SGLT2) inhibitors with uricosuric and anti-inflammatory properties as well as clinically indicated antidiabetic, nephroprotective, and/or cardioprotective effects. The broad ULT developmental pipeline is loaded with multiple uricosurics that selectively target uric acid transporter 1 (URAT1). Evolving ULT approaches include administering selected gut anaerobic purine degrading bacteria (PDB), modulating intestinal urate transport, and employing liver-targeted xanthine oxidoreductase mRNA knockdown. Last, emerging measures to decrease the immunogenicity of systemically administered recombinant uricases should simplify treatment regimens and further improve outcomes in managing the most severe gout phenotypes.

#3696 THE PROACT 2 PHASE 3 STUDY DESIGN: A RANDOMIZED CONTROLLED STUDY OF REACT IN PARTICIPANTS WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE

Abstract Background and Aims The global burden of chronic kidney disease (CKD) is estimated at 850 million people worldwide, with diabetic kidney disease (DKD) being the main cause. Existing medical therapies may delay the deterioration of kidney function; however, many patients continue to progress to kidney failure. REACT (Renal Autologous Cell Therapy), a cell-based advanced therapy, is being developed to decrease the risk of CKD progression. REACT is composed of selected renal cells (SRC), isolated from a participant's own kidney, which are involved in the process of kidney repair and regeneration. Preclinical studies in multiple animal models of DKD have demonstrated that SRC injected directly into the kidney cortex produced a regenerative response improving overall kidney function and histology. Encouraging early clinical results from phase 2 studies with REACT resulted in RMAT (Regenerative Medicine Advanced Therapy) designation by the Food and Drug Administration in the USA. Method Description of therapy - REACT is derived from the participant's kidney tissue obtained by percutaneous biopsy in an outpatient setting. Renal cells are culture expanded ex vivo, and SRC are isolated. SRC are cryopreserved at a concentration of 100 × 106 cells/mL and shipped to the clinical site approximately 12 weeks after the biopsy. REACT will be percutaneously reinjected by specially trained interventional proceduralists utilizing CT guidance and a non-cutting 25-gauge needle inserted into the kidney cortex. A single REACT dose will be injected into each kidney, approximately 3 months apart. Participants - The study will enroll 600 participants from approximately 250 global sites (including 38 sites in the EU)) with up to 60 months of follow-up. Patients aged 30-80 years with type 2 diabetes who have an estimated glomerular filtration rate (eGFR) of 20-50 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) 300-5000 mg/g will be eligible. Participants will be randomized 1:1 to REACT or sham biopsy/injection in a single blind manner. Standard-of care therapies including renin angiotensin system inhibitors and sodium glucose cotransporter inhibitors may be given as per local guidance. Results Study Endpoints - The primary endpoint for proact 2 is the time from first injection to the earliest of ≥40% eGFR decline, eGFR &amp;lt; 15 mL/min/1.73m2 sustained for 30 days, initiation of chronic dialysis or kidney transplantation, or cardiovascular or renal death. proact 2 is an endpoint driven trial with 80% power to detect a hazard ratio of 0.6 for the primary outcome. Key secondary outcomes will include time to these individual components as well as annualized change in eGFR and change from baseline in UACR. Conclusion proact 2 is a global Phase 3 randomized controlled trial that will evaluate the safety and efficacy of REACT on major kidney disease endpoints, among participants with type 2 diabetes and moderate-severe CKD. This trial is part of a comprehensive phase 3 development program with an estimated start date of June 2023. REACT, a novel autologous cell therapy composed of SRC, has the potential to directly improve kidney function with a goal to prevent kidney failure.

Deep learning-based electrocardiographic screening for chronic kidney disease

BackgroundUndiagnosed chronic kidney disease (CKD) is a common and usually asymptomatic disorder that causes a high burden of morbidity and early mortality worldwide. We developed a deep learning model for CKD screening from routinely acquired ECGs.MethodsWe collected data from a primary cohort with 111,370 patients which had 247,655 ECGs between 2005 and 2019. Using this data, we developed, trained, validated, and tested a deep learning model to predict whether an ECG was taken within one year of the patient receiving a CKD diagnosis. The model was additionally validated using an external cohort from another healthcare system which had 312,145 patients with 896,620 ECGs between 2005 and 2018.ResultsUsing 12-lead ECG waveforms, our deep learning algorithm achieves discrimination for CKD of any stage with an AUC of 0.767 (95% CI 0.760–0.773) in a held-out test set and an AUC of 0.709 (0.708–0.710) in the external cohort. Our 12-lead ECG-based model performance is consistent across the severity of CKD, with an AUC of 0.753 (0.735–0.770) for mild CKD, AUC of 0.759 (0.750–0.767) for moderate-severe CKD, and an AUC of 0.783 (0.773–0.793) for ESRD. In patients under 60 years old, our model achieves high performance in detecting any stage CKD with both 12-lead (AUC 0.843 [0.836–0.852]) and 1-lead ECG waveform (0.824 [0.815–0.832]).ConclusionsOur deep learning algorithm is able to detect CKD using ECG waveforms, with stronger performance in younger patients and more severe CKD stages. This ECG algorithm has the potential to augment screening for CKD.

Calculated versus measured albumin-creatinine ratio to predict kidney failure and death in people with chronic kidney disease

Albumin-to-creatinine ratio (ACR), the preferred method to quantify proteinuria, can be calculated from urine dipstick protein or protein-to-creatinine ratio (PCR). The performance of calculated vs. measured ACR in predicting kidney failure and death without kidney failure in people with chronic kidney disease (CKD) is unknown. Here, we used population-based data from Alberta, Canada, to identify adults with incident moderate-severe CKD (sustained for more than 90 days) from 2008-04-01 to 2017-03-31, who had same-day measures of ACR and urine dipstick (ACR-dipstick cohort) or PCR (ACR-PCR cohort) in the two years before cohort entry. We followed participants until 2019-03-31 and trained competing risk models of kidney failure and death without kidney failure including age, sex, estimated glomerular filtration rate, diabetes, cardiovascular disease, and either measured or calculated ACR. Model performance was tested in cohorts created using the same algorithm in Manitoba, Canada. The ACR-dipstick and ACR-PCR cohorts included 18,731 and 4,542 people (training cohorts) and 821 and 1,831 people (testing cohorts), respectively. In internal and external testing, there was closer agreement between predictions based on measured vs. PCR-calculated ACR than between those based on measured vs. dipstick-calculated ACR. The dipstick-calculated ACR had higher Brier scores than measured ACR from year three for both outcomes, indicating worsening calibration. Models including measured or calculated ACR had similar discrimination: year one-to-five area under the receiver operating characteristic curve of 83-89% for kidney failure and 69-75% for mortality. Thus, if confirmed in different ethnic groups, calculated ACR can be used for risk predictions when the measured ACR is not available. PCR-calculated ACR may have superior performance to dipstick-calculated ACR.

Impact of chronic kidney disease on case ascertainment for hospitalised acute myocardial infarction: an English cohort study.

ObjectivesAcute myocardial infarction (AMI) case ascertainment improves for the UK general population using linked health data sets. Because care pathways for people with chronic kidney disease (CKD) change based on disease severity, AMI case ascertainment for these people may differ compared with the general population. We aimed to determine the association between CKD severity and AMI case ascertainment in two secondary care data sets, and the agreement in estimated glomerular filtration rate (eGFR) between the same data sets.MethodsWe used a cohort study design. Primary care records for people with CKD or risk factors for CKD, identified using the National CKD Audit (2015–2017), were linked to the Myocardial Ischaemia National Audit Project (MINAP, 2007–2017) and Hospital Episode Statistics (HES, 2007–2017) secondary care registries. People with an AMI recorded in either MINAP, HES or both were included in the study cohort. CKD status was defined using eGFR, derived from the most recent serum creatinine value recorded in primary care. Moderate–severe CKD was defined as eGFR <60 mL/min/1.73 m2, and mild CKD or at risk of CKD was defined as eGFR ≥60 mL/min/1.73 m2 or eGFR missing. CKD stages were grouped as (1) At risk of CKD and Stages 1–2 (eGFR missing or ≥60 mL/min/1.73 m2), (2) Stage 3a (eGFR 45–59 mL/min/1.73 m2), (3) Stage 3b (eGFR 30–44 mL/min/1.73 m2) and (4) Stages 4–5 (eGFR <30 mL/min/1.73 m2).ResultsWe identified 6748 AMIs: 23% were recorded in both MINAP and HES, 66% in HES only and 11% in MINAP only. Compared with people at risk of CKD or with mild CKD, AMIs in people with moderate–severe CKD were more likely to be recorded in both MINAP and HES (42% vs 11%, respectively), or MINAP only (22% vs 5%), and less likely to be recorded in HES only (36% vs 84%). People with AMIs recorded in HES only or MINAP only had increased odds of death during hospitalisation compared with those recorded in both (adjusted OR 1.61, 95% CI 1.32 to 1.96 and OR 1.60, 95% CI 1.26 to 2.04, respectively). Agreement between eGFR at AMI admission (MINAP) and in primary care was poor (kappa (K) 0.42, SE 0.012).ConclusionsAMI case ascertainment is incomplete in both MINAP and HES, and is associated with CKD severity.

The association between modifiable perioperative parameters and renal function after nephrectomy.

To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy. We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy. Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance. Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.

Real-world comparison of direct-acting oral anticoagulants and vitamin K antagonists in chronic kidney disease: a systematic review and meta-analysis

ABSTRACT Background: No clear clinical guidelines exist on anticoagulant use for chronic kidney disease (CKD) patients. We compared the efficacy and safety of direct-acting oral anticoagulants (DOACs) vs. vitamin K antagonists (VKA) in patients with CKD by pooling data from real-world observational studies. Research design & methods: This systematic review searched PubMed, Embase, and CENTRAL databases and pooled multivariable-adjusted hazard ratios (HR) of outcomes. Results: Fifteen studies were included. Our results indicated a small but significant reduction in the risk of all-cause mortality (p = 0.01), stroke or systemic embolism (p = 0.03), and major bleeding (p = 0.01) with DOAC as compared to VKA. In subgroup analysis based on the severity of CKD, no difference in the risk of stroke or systemic embolism was noted in any subgroups. The risk of mortality was reduced only in patients with moderate-severe or severe CKD and the risk of major bleeding was reduced only in patients with moderate-severe or moderate CKD. Conclusion: DOACs are associated with only a modest reduction in stroke or systemic embolism, major bleeding, and mortality when compared to VKA in CKD patients. Reduction in mortality and major bleeding with DOAC may only be seen in moderate-to-severe CKD patients.

Variables asociadas con mortalidad en una población de pacientes mayores de 80 años y con algún grado de dependencia funcional, hospitalizados por COVID-19 en un Servicio de Geriatría

ObjectiveThe SARS-CoV-2 pandemic conditions high mortality rates in hospitalized elderly. Currently, a few studies include octogenarian patients and none of them analyze the impact of functional status on this health outcome. Our objective is to describe the characteristics of patients older than 80 years hospitalized for coronavirus disease 2019 (COVID-19), to determine the mortality rate and to identify associated factors. Material and methodsProspective observational study carried out on patients over 80 years admitted for COVID-19 in a Geriatrics Service. Sociodemographic, clinical, functional, mental, analytical, radiological, therapeutic and healthcare variables were collected. The factors associated with in-hospital lethality were analyzed by bivariate analysis. Results58 cases with laboratory-confirmed COVID-19 were included, mean age 88.3 ± 5.4 years, 69% women, 65.5% moderate-severe cognitive impairment and previous Barthel index 40.66 ± 36. The main symptoms were fever (60,3%), dyspnea (53.4%) and deterioration of functional condition (50%). The most frequent comorbidities were cardiovascular disease (75.9%), hypertension (HT) (74.1%) and chronic kidney disease (CKD) (50%). A mortality rate of 41,4% was detected and the associated factors were: severe functional dependence (OR = 3.8 [1.2-12.2]), moderate-severe cognitive impairment (OR = 4.9 [1-25.4]) and CKD (OR = 3.2 [1.1-9.7]). ConclusionHigh mortality rates are observed in older patients hospitalized for COVID-19, with a higher risk of dying in those with severe functional dependence or cognitive impairment. These findings reinforce the value of Geriatric Assessment to develop strategies to adapt diagnostic and therapeutic decision-making and to optimize care for elderly patients in the event of a new epidemic outbreak.

Alendronate use and bone mineral density gains in women with moderate-severe (stages 3B\u20135) chronic kidney disease: an open cohort multivariable and propensity score analysis from Funen, Denmark

SummaryBisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients.PurposeThis study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD).MethodsWe created a cohort of CKD stage 3B–5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD.ResultsUse of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B–5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users.ConclusionIn a real-world cohort of women with stage 3B–5 CKD, use of alendronate appears associated with a significant improvement of 2–3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.

Relationship between the Renal Function and Adverse Clinical Events in Patients with Atrial Fibrillation: A Japanese Multicenter Registry Substudy.

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist, but the real-world data after approval of direct oral anticoagulants (DOACs) are still lacking in Japan. We investigated the association of the baseline renal function and adverse clinical events and risk of adverse clinical events with DOACs compared to warfarin for each renal functional level in Japanese AF patients. Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter observational registry (median follow-up period: 39 months). The creatinine clearance (CrCl) values were estimated by the Cockcroft–Gault formula, and divided into normal renal function, and mild and moderate-severe CKD (CrCl ≥ 80, 50–79, <50 mL/min). Results: In the SAKURA AF Registry, the baseline CrCl data were available for 3242 patients (52% for DOAC and 48% for warfarin user). The relative risk of adverse clinical events was significantly higher in the patients with a CrCl < 50 mL/min as compared to those with a CrCl ≥ 80 mL/min (adjusted HRs: 2.53 for death, 2.53 for cardiovascular [CV] events, 2.13 for strokes, and 1.83 for major bleeding). Risks of all adverse clinical events were statistically even between DOAC and warfarin users for each renal function level. Conclusion: Moderate–severe CKD was associated with a higher mortality, CV events, strokes, and major bleeding than normal renal function. The safety and effectiveness of DOACs over warfarin were similar for each renal function level. By a worsening renal function, the incidence of adverse clinical events increased, especially deaths and CV events as compared to strokes and major bleeding.

Safety of Bisphosphonates in Moderate-to-Severe (Stage 3b-5) Chronic Kidney Disease: A Bi-National Cohort Analysis of 291,096 Patients from Spain and the United Kingdom

Background: Although contraindicated in patients with severe chronic kidney disease (CKD) due to a lack of safety data, bisphosphonates are commonly used to prevent or treat bone fragility in these patients. We studied the safety of bisphosphonates in patients with moderate-to-severe CKD. Methods: Patients with stage 3b+ CKD based on 2+ estimated glomerular filtration rate (eGFR) measures were identified in two primary-care records databases, the UK CPRD GOLD during 1997-2016 and the Catalan (Spain) SIDIAP during 2007-2015. New bisphosphonate users were propensity-scorematched with up to five non-users to minimise confounding, and followed until treatment discontinuation, switching, dropout, death, or 10 years. The primary outcome was CKD stage worsening (eGFR decline or renal replacement therapy). Secondary outcomes included hospitalised acute kidney injury (AKI), gastrointestinal bleeding/ulcers (GIE), and hypocalcaemia. Hazard ratios (HRs) were estimated using Cox regression for SIDIAP participants, and sub-HRs (sHRs) calculated using Fine-Gray models for CPRD. Findings: We matched 2,447 bisphosphonate users with 8,931 non-users from CPRD, and 1,399 users with 6,547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in both CPRD (HR [95% CI]: 1·14 [1·04, 1·26]) and SIDIAP (HR: 1·16 [1·04, 1·29]). No statistically significant risk differences were found for AKI, GIE, or hypocalcaemia. Interpretation: A modest (10%-15%) increased risk of CKD progression was identified in association with bisphosphonate use amongst patients with moderate-severe disease. No other safety concerns were identified. Our findings should be considered in combination with effectiveness data before prescribing bisphosphonates to patients with moderate-severe CKD. Funding Statement: Funding was provided by the National Institute of Health Research Health Technology Assessment project number 14/36/02. The project was partially funded by CIBERFES, Instituto Carlos III, Spain. JP and MJP-S are supported by PI16/00619 (Spanish Ministry of Health ISCIII FIS-FEDER) and RD16/0009/0013 (ISCIII FEDER RedinRen). Declaration of Interests: B Abrahamsen reports research grants from UCB and Novartis. NK Arden reports personal fees from Flexion, Freshfields, Janssen, Merck, and Regeneron. C Cooper reports lecture fees and honoraria from the Alliance for Better Bone Health Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB. A Judge is a subpanel member of the NIHR PGfAR, has received consultancy fees from Freshfields Bruckhaus Deringer, and has held advisory board positions (which involved receipt of fees) at Anthera Pharmaceuticals, INC. MK Javaid reports research support and speaker fees from Amgen. D Prieto-Alhambra reports research grants from UCB, Amgen, and Les Laboratoires Servier, and departmental (not personal) speaker and consultancy fees from UCB and Amgen. D Prieto-Alhambra is a member of the NIHR HTA CET panel since November 2017. DE Robinson, MS Ali, VY Strauss, L Elhussein, Y Ben-Shlomo, F Caskey, D Dedman, and A Delmestri have nothing to disclose. Ethics Approval Statement: This study was approved by the CPRD Independent Scientific Advisory Committee (protocol number 15_ 53R2A).

New Molecules for Treating Resistant Hypertension: a Clinical Perspective.

To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions. RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.

Serum concentration of homocysteine in spontaneous feline chronic kidney disease

Serum homocysteine (Hcy) increases in people and dogs with chronic kidney disease (CKD). Hyperhomocysteinemia (HHcy) has also been associated with CKD-related hypertension and proteinuria. The aims of this study were to: (1) validate an enzymatic method for quantification of Hcy in feline serum; (2) evaluate whether HHcy was associated with the presence and severity of CKD, proteinuria or hypertension; and (3) determine whether HHcy could predict disease progression.The intra- and inter-assay coefficients of variation (CVs) and the recovery rates of linearity under dilution and spiking recovery tests of the enzymatic method were 3.1–6.7%, 11.6–12.5%, 96.9±5.4% and 96.9±5.4%, respectively. Healthy cats at risk of CKD (n=17) and cats with CKD (n=19) were sampled over a 6-month period (63 samples in total). Cats with CKD had significantly higher Hcy concentrations (P=0.005) than cats at risk. The concentration of Hcy was higher (P=0.002) in moderate-severe CKD than in mild CKD and correlated moderately with serum creatinine (P<0.0001; r=0.51). The concentration of Hcy increased with the magnitude of proteinuria and correlated weakly with urinary protein to creatinine ratio (P=0.045; r=0.26). HHcy was not associated with hypertension. At the time of enrollment, Hcy concentration was significantly higher (P=0.046) in cats that developed CKD compared to cats that remained stable. The enzymatic method for Hcy measurement in feline serum was precise and accurate. HHcy was relatively common in cats with advanced CKD and seemed to predict disease progression, but further studies are warranted.

Lactic acidosis associated with metformin in patients with moderate to severe chronic kidney disease: study protocol for a multicenter population-based case-control study using health databases

BackgroundThe use of metformin in patients with type 2 diabetes mellitus has been associated with lactic acidosis. However, the information available in patients with moderate-severe chronic kidney disease is scarce.MethodsThe ALIMAR-C2 study is a case-control study to assess the association between metformin and lactic acidosis in patients with type 2 diabetes mellitus and moderate-severe chronic kidney disease. The study will be performed with computerized registered electronic health records from eight Spanish hospitals linked to their corresponding primary care health areas from 2010 to 2016, comprising approximately 22.1 million person-years of follow-up. Logistic regression will be used to assess the crude and adjusted risk of lactic acidosis associated with metformin use overall and stratifying by use and dose categories, and chronic kidney disease stage. The overall case fatality rate of lactic acidosis, as well as the case fatality rate stratified by chronic kidney disease stage, will be calculated.DiscussionThe ALIMAR-C2 study will provide useful information about the risk of lactic acidosis in type 2 diabetes mellitus patients with renal impairment using metformin.

Mesenchymal stromal cells (Cyto-MSC) are well-tolerated and associated with renal function improvement in patients with chronic kidney disease: an observational retrospective study

Background & Aim Background Microvascular disease and structural damage are hallmarks of chronic kidney disease (CKD). We have demonstrated previously that mesenchymal stromal cells (MSCs) could differentiate into mesangial cells in animal models of glomerular injury. We further demonstrated that MSCs promoted angiogenesis in diabetic patients with critical limb ischemia. Given the ability to improve vascularity and structure, MSCs may potentially improve renal function in CKD. Objective In this study, we evaluated the safety, tolerability and renal function of patients with CKD who had participated in MSC-related clinical trials. Methods, Results & Conclusion Methodology There were 4 clinical trials approved at the National University Malaysia in collaboration with Cytopeutics (Cyberjaya, Malaysia) which provided the mesenchymal stromal cells (Cyto-MSC) for treatment of acute stroke, heart failure, diabetes with critical limb ischemia and severe deforming osteoarthritis. All patients received 65-130 × 106 Cyto-MSC intravenously. Severity of chronic kidney disease is based on baseline estimated glomerular filtration rate (eGFR) and serum creatinine which are markers of renal dysfunction. These and other blood tests including fasting blood sugar (FBS) and Hba1c (marker of glycemic control) were measured at baseline and 12 months post infusion. Results 82 patients (53 men, 29 women; age 38-92 years) with different CKD stages (stage 3, n=65; stage 4, n=5; stage 5, n=12) were identified. 33 patients have type 2 diabetes. All patients tolerated the treatment well. There was significant improvement in serum creatinine (170±148 vs. 144±123 μmol/L; p=0.013) and eGFR values (37±17 vs. 41±18 mL/min/1.73m2; p=0.001). Patients with stage 3 CKD have the most significant eGFR value improvement (45±9 vs. 50±10 mL/min/1.73m2; p=0.006). Among diabetic patients, improvements were observed in creatinine (167±138 vs. 145±115 μmol/L, p=0.011), eGFR (37±15 vs. 41±16, p=0.05), HbA1c (7.4±2.1 vs. 6.2±1.4 %, p=0.011) and FBS (7.1±1.1 vs. 6.8±0.8 mmol/L %, p=0.021). There was also modest positive correlation between FBS with urea (p=0.001) and eGFR (p=0.016). Conclusion Cyto-MSC appears to be safe and well-tolerated by patients with moderate-severe CKD and associated with improvement in renal function particularly for moderate CKD patients. Further randomized prospective studies are warranted.

Evaluation of a chronic kidney disease risk assessment service in community pharmacies

Targeted 'opportunistic' screening might be a sustainable approach for the early detection of people with undiagnosed chronic kidney disease (CKD). The aim of this study was to implement and evaluate a CKD risk assessment service in the community pharmacy setting. Twenty-four pharmacies in Tasmania, Australia participated in this study. Targeted people were aged between 50 and 74 years, with at least one CKD risk factor. The QKidney risk calculator was used to estimate the participants' 5-year percentage risk of developing moderate-severe CKD. Participants identified with ≥3% risk were referred to their general practitioner (GP) and followed-up after 9 months. Laboratory data was collected from a pathology provider. The main outcome measures were rates of GP referral uptake and of participants who underwent estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (ACR) measurement. We analyzed data for 389 screened participants, of whom 203 (52.1%) had ≥3% 5-year risk of developing moderate-severe CKD and were referred to their GP. Follow-up was successful for 126 participants and showed low (27%) GP referral uptake. Analysis of the pathology data revealed suboptimal kidney testing in participants with ≥3% risk, with eGFR and ACR tests performed for only 52.7% and 25.1% of these participants, respectively. There is significant scope for improving early detection of CKD via implementation of a community pharmacy-based CKD risk assessment service. However, a healthcare system that encourages inter-professional collaboration between community pharmacists and GPs, and provides a robust referral pathway is needed to optimize the effectiveness of this service.

Predictors of new-onset chronic kidney disease in patients managed surgically for T1a renal cell carcinoma: An Australian population-based analysis.

New-onset chronic kidney disease (CKD) following surgical management of kidney tumors is common. This study evaluated risk factors for new-onset CKD after nephrectomy for T1a renal cell carcinoma (RCC) in an Australian population-based cohort. There were 551 RCC patients from the Australian states of Queensland and Victoria included in this study. The primary outcome was new-onset CKD (eGFR <60 mL/min per 1.73 m2 ) and the secondary outcome was new-onset moderate-severe CKD (<45 mL/min per 1.73 m2 ). Multivariable logistic regression was used to evaluate associations between patient, tumor and health-service characteristics and these outcomes. Forty percent (219/551) of patients developed new-onset CKD, and 12% (68/551) experienced new-onset moderate-severe CKD. Risk factors for new-onset CKD were age, lower preoperative eGFR, tumor size >20 mm, radical nephrectomy, lower hospital caseloads (<20 cases/year), and rural place of residence. The associations between rural place of residence and low center volume were a consequence of higher radical nephrectomy rates. Risk factors for CKD after nephrectomy generally relate to worse baseline health, or likelihood of undergoing radical nephrectomy. Surgeons in rural centres and hospitals with low caseloads may benefit from formalized integration with specialist centers for continued professional development and case-conferencing, to assist in management decisions.

HUGE EQUATION ACCURACY FOR SCREENING CHRONIC KIDNEY DISEASE: A PROSPECTIVE STUDY

Objectives: Chronically reduced glomerular filtration rate (GFR) in old people does not always mean that they suffer from chronic kidney disease (CKD) since their GFR can just be induced by ageing. The HUGE equation has been recently described and validated in Spain for screening CKD without taking into account the patient´s GFR value This study evaluated HUGE performance in Argentine patiens. Material &amp; Method: This was a prospective study to assess the operational characteristics of the HUGE equation for diagnosing CKD (diagnostic accuracy) in an ambulatory adult (age ≥ 18 years old) population (n: 205) assisted at the ambulatory clinical consult of Hospital Italiano de San Justo, Buenos Aires, Argentina in 2016. Results: It was documented that HUGE equation had a sensitivity of 56.7% (IC: 37.4% - 74.5%), and a specificity of 95.9% (IC: 88.6% - 99.1%) for screening CKD in elderly individuals who have an estimated GFR &lt; 45 ml/min/1.73 m². Additionally, it was found that the screening strategy of combining HUGE with estimated GFR and urinalyses, showed a very good performance for detecting CKD, not only in elderly people but also in young people. Both triple combined CKD screening strategies showed a sensitivity around 86%, and 98% in young and elderly people, respectively. Conclusion: This study documented that the HUGE equation had and acceptable performance for screening moderate-severe CKD (stages III b-V) in elderly people, and an excellent performance for screening CKD in general population in combination with estimated GFR and urinalyses.

Physical activity and metabolic health in chronic kidney disease: a cross-sectional study

BackgroundPatients with chronic kidney disease (CKD) are at high risk of progression to end stage renal disease and cardiovascular events. Physical activity may reduce these risks by improving metabolic health. We tested associations of physical activity with central components of metabolic health among people with moderate-severe non-diabetic CKD.MethodsWe performed a cross-sectional study of 47 people with CKD (estimated GFR <60 ml/min/1.73 m2) and 29 healthy control subjects. Accelerometry was used to measured physical activity over 7 days, the hyperinsulinemic-euglycemic clamp was used to measure insulin sensitivity, and DXA was used to measured fat mass. We tested associations of physical activity with insulin sensitivity, fat mass, blood pressure, serum lipid concentrations, and serum high sensitivity C-reactive protein concentration using multivariable linear regression, adjusting for possible confounding factors.ResultsParticipants with CKD were less active than participants without CKD (mean (SD) 468.1 (233.1) versus 662.3 (292.5) counts per minute) and had lower insulin sensitivity (4.1 (2.1) versus 5.2 (2.0 (mg/min)/(μU/mL)), higher fat mass (32.0 (11.4) versus 29.4 (14.8) kg), and higher triglyceride concentrations (153.2 (91.6) versus 99.6 (66.8) mg/dL). With adjustment for demographics, comorbidity, medications, and estimated GFR, each two-fold higher level of physical activity was associated with a 0.9 (mg/min)/(μU/mL) higher insulin sensitivity (95% CI 0.2, 1.5, p = 0.006), an 8.0 kg lower fat mass (−12.9, −3.1, p = 0.001), and a 37.9 mg/dL lower triglyceride concentration (−71.9, −3.9, p = 0.03). Associations of physical activity with insulin sensitivity and triglycerides did not differ significantly by CKD status (p-values for interaction >0.3).ConclusionsGreater physical activity is associated with multiple manifestations of metabolic health among people with moderate-severe CKD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0400-x) contains supplementary material, which is available to authorized users.

Worsening Renal Function and Prognosis in Pulmonary Hypertension Patients Hospitalized for Right Heart Failure

Increased central venous pressures have been associated with the development of worsening renal function (WRF), an important marker of prognosis. We sought to determine the incidence and prognostic significance of WRF in pulmonary hypertension patients (PH) with isolated right HF. A prospective study of PH clinic patients admitted to hospital for right HF. WRF was defined as a rise in creatinine of 26 μmol/L (0.3 mg/dL) within the first 48 hours of admission. A total of 32 patients were enrolled in this study, 67% of patients had moderate-severe chronic kidney disease with an eGFR ≤ 60 mL/min and 34% (n=11) developed WRF during their admission. The mean right atrial pressure was higher in patients with WRF (19 ± 7 mm Hg vs 12 ± 6 mm Hg, P=.05). A total of 36% of patients with WRF died in hospital compared to 5% in the group that did not develop WRF (OR for hospital death 13.3 ± 16, P=.03). The combined endpoint of death or readmission at 6 months was 45% in the WRF group and 43% in the group without WRF (P=.89). Significant renal dysfunction is common in patients with PH and an acute decline in renal function is an important marker of in hospital death and short term mortality in right heart failure.