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1.
Am J Kidney Dis ; 75(1): 84-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473020

RESUMO

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

2.
Endocr Rev ; 41(2)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633153

RESUMO

Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.

3.
Kidney Int ; 96(6): 1381-1388, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31679767

RESUMO

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.

4.
J Am Soc Nephrol ; 30(11): 2229-2242, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530577

RESUMO

BACKGROUND: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. METHODS: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. RESULTS: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004). CONCLUSIONS: The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

5.
Stat Med ; 38(22): 4218-4239, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31338848

RESUMO

In March of 2018, the National Kidney Foundation, in collaboration with the US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented.

6.
Diabetes Obes Metab ; 21(5): 1237-1250, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30697905

RESUMO

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals. RESULTS: Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (-0.29%; 95% CI, -0.39 to -0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70-0.94) and heart failure (RR, 0.61; 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86; 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73 m2 /y; 95% CI, 0.78-1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes. CONCLUSION: Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.

7.
Diab Vasc Dis Res ; 16(1): 47-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30238781

RESUMO

BACKGROUND: The number of patients with type 2 diabetes mellitus and diabetes mellitus-associated chronic kidney disease varies considerably between countries. Next to differences in genetic as well as life style risk factors, varying practices in medical care delivery might cause this diversity. METHOD: The PROVALID study recruited 4000 patients with type 2 diabetes mellitus at the primary level of healthcare in five European countries (Austria, Hungary, The Netherlands, Poland and Scotland). Baseline data were used to describe patient characteristics and compare the adherence to ADA (American Diabetes Association) and KDIGO (Kidney Disease: Improving Global Outcomes) guidelines with respect to metabolic and blood pressure control, use of renin-angiotensin system-blocking agents, statins and acetylsalicylic acid between the countries. RESULTS: About 34.8% of the population had evidence of diabetes mellitus-associated chronic kidney disease. The median HbA1c level of the cohort was 6.8% (ranging from 6.5 in Poland to 7.0% in Scotland). Mean blood pressure was 136/79 (±17/10) and significantly higher in subjects with elevated albuminuria. These individuals also were more often treated with renin-angiotensin system-blocking agents (74.1% vs 84.6%), whereas the use of statins was driven by cardiovascular comorbidity. Acetylsalicylic acid was used in only 28.9% subjects. Despite similar cardiovascular comorbidities and renal function, the use of renin-angiotensin system-blocking agents varied significantly between the countries from 66.7% to 87.4%. An even higher variability was observed for patients >40 years of age using statins (39.8%-82.7%) and administration of acetylsalicylic acid in patients older than 50 years (5.2%-43.8%). CONCLUSION: Our study shows that medical practice in type 2 diabetes mellitus patients with and without renal disease is different in European countries. Longitudinal follow-up will reveal if this diversity affects clinical endpoints.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fidelidade a Diretrizes/tendências , Disparidades em Assistência à Saúde/tendências , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/tendências , Atenção Primária à Saúde/tendências , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Europa (Continente)/epidemiologia , Feminino , Hemoglobina A Glicada/metabolismo , Nível de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento
8.
J Ren Nutr ; 29(4): 276-284, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30591358

RESUMO

OBJECTIVES: The objective of the study was to assess the impact of sustained dietary salt reduction on albuminuria in nearly 2000 community-dwelling adults. DESIGN AND METHODS: The present study is a prespecified secondary analysis of the China Rural Health Initiative Salt Reduction Study cluster randomized trial undertaken in 120 villages in rural China. Villages were randomized to a sodium reduction program of education and access to reduced-sodium salt substitute or control. Urinary albumin-to-creatinine ratio (uACR) and albuminuria (uACR ≥22.1 or 31.0 mg/g for men and women, respectively) were assessed at 18 months in a stratified random sample of predominantly older individuals living in participating rural villages. RESULTS: A total of 2,566 participants from 119 villages provided 1,903 eligible urine samples. The sodium reduction program reduced sodium intake by an equivalent of 0.82g of salt/day (0.06-1.68 g) (322 [24-661] mg sodium/day). The mean uACR was 8.85 (8.05-9.82) mg/g (1.00 [0.91-1.11] mg/mmol) in intervention participants compared with 10.53 (9.73-11.33) mg/g (1.19 [1.10-1.28] mg/mmol) in control participants (p=0.008). The corresponding odds ratio for albuminuria was 0.67 (0.46-0.99). CONCLUSIONS: Dietary sodium reduction was associated with significantly lower uACR and less albuminuria after 18 months. Whether CKD progression can be slowed by dietary sodium reduction should be a global research priority. CLINICALTRIALS.GOV: NCT01259700.

10.
Diabetes Care ; 41(9): 1947-1954, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29980527

RESUMO

OBJECTIVE: The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost-effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors. RESEARCH DESIGN AND METHODS: We studied participants in PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a follow-up of more than 24 months (n = 2,560; baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling. RESULTS: In univariable analyses, 9 of the 17 markers showed significant differences in median concentration between stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% was due to 5 markers. The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%. CONCLUSIONS: In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Taxa de Filtração Glomerular , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Testes de Função Renal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Eur Heart J ; 39(17): 1535-1542, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29554312

RESUMO

Aims: Both hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium. Methods and results: We performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts. Conclusions: Outpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.


Assuntos
Doenças Cardiovasculares/mortalidade , Hiperpotassemia/epidemiologia , Hipopotassemia/epidemiologia , Falência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Albuminúria , Causas de Morte , Comorbidade , Taxa de Filtração Glomerular , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
12.
Kidney Blood Press Res ; 43(1): 181-190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29466797

RESUMO

BACKGROUND/AIMS: The prevalence of diabetes mellitus type 2 and kidney disease in these patients varies widely between European countries. METHODS: In addition to store bio-samples the "Prospective cohort study in patients with type 2 diabetes mellitus for validation of biomarkers" collects information on history, physical status, laboratory measurements and medication in 4000 patients with diabetes mellitus type 2, being taken care of at the primary level of healthcare in 5 European countries (Austria, Hungary, Netherlands, Poland and Scotland). Next to comparing the rate of loss of eGFR between the countries, a further objective of the PROVALID study is to determine the 5-year cumulative incidence of renal and cardiovascular outcomes. RESULTS: The mean age of the population recruited is 62.9±10 years, 54.6% are male and the mean BMI is 30.9±5.4 kg/m2. Metabolic control (median HBA1c 6.8 % (6.2; 7.5)) is achieved via administration of metformin in 67.4% of the patients and insulin in 30.3%. Median systolic and diastolic blood pressure at recruitment is 135 (125; 146) and 80 (72; 85) mmHg, 65.4% of subjects received RAAS blocking agents. Mean eGFR is 80.7±29.2 ml/min/1.73m2 and median baseline albumin/creatinine ratio 8.3 mg (IQR: 3.8 and 25.1). CONCLUSION: PROVALID will provide information on incidence and progression of renal and cardiovascular disease and therapy in patients with type 2 diabetes mellitus in different European countries. Thus, in contrast to many other cohort studies we will be able to associate national clinical practise pattern with outcome in this highly vulnerable patient population.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Idoso , Doenças Cardiovasculares/etiologia , Protocolos Clínicos , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Europa (Continente) , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/etiologia , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos
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