Disease characteristics and outcomes in patients with chronic kidney disease and type 2 diabetes: a matched cohort study of spironolactone users and non-users.

BACKGROUND: Limited evidence has indicated that addition of a steroidal mineralocorticoid receptor antagonist (MRA) to the standard of care reduces proteinuria in patients with diabetic kidney disease (DKD); however, there are limited data regarding real-world MRA use in these patients. This study aimed to describe the characteristics of spironolactone users and non-users with DKD, and to explore their clinical outcomes. METHODS: This was a non-interventional, retrospective cohort study using demographic and clinical data from a US claims database (PharMetrics Plus) and the Experian consumer data asset during 2006-2015. Baseline characteristics (e.g. comorbidities) and post-inclusion clinical outcomes were described in matched cohorts of spironolactone users and non-users (n = 5465 per group). RESULTS: Although matching aligned key demographic and clinical characteristics of the cohorts, a significantly greater proportion of spironolactone users than non-users had oedema, proteinuria, and cardiovascular disease at baseline (P < 0.0001). During the post-inclusion period, disease progression and clinical events of interest such as acute kidney injury were more commonly observed in spironolactone users than non-users. Users also had higher healthcare resource utilization and costs than non-users; however, these differences diminished at later stages of disease. CONCLUSIONS: In this study, spironolactone users had a greater comorbidity burden at baseline than matched non-users, suggesting that the presence of certain comorbidities may be contributing factors in the decision to prescribe spironolactone. High healthcare resource utilization and costs for patients at later stages of disease, irrespective of spironolactone use, highlight the need for new therapies for DKD.

Assessment of effectiveness of anakinra and canakinumab in patients with colchicine-resistant/unresponsive familial Mediterranean fever.

INTRODUCTION: Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disease characterized by recurrent fever and serosal inflammation. Anti-interleukin-1 (Anti-IL-1) treatments are recommended in colchicine resistant and/or intolerant FMF patients. This study aims to evaluate the efficacy of anakinra and canakinumab in FMF patients that are resistant/intolareted to colchicine or complicated with amyloidosis. METHODS: Between January 2014 and March 2019, 65 patients following-up at Sivas Cumhuriyet University (Medical Faculty Rheumatology-Internal Medicine Department) who were diagnosed with FMF according to the criteria of Tel-Hashomer were included in the study. The laboratory values and clinical features of patients and disease activities were recorded at least every 3 months, and these data were analyzed. RESULTS: Forty-one (63.1%) patients used anakinra (100 mg/day) and 24 (36.9%) patients used canakinumab (150 mg/8 week). The median duration of anti-IL-1 agents use was 7 months (range, 3-30). Fifteen (23.1%) cases were complicated with amyloidosis. Seven (10.8%) patients had renal transplantation. Overall, the FMF 50 score response was 96.9%. In the group that had a glomerular filtration rate (GFR) ≥ 60 ml/min/m2, the median proteinuria decreased from 2390 mg/day (range, 1400-7200) to 890 mg/day (range, 120-2750) (p = 0.008). No serious infections were detected, except in one patient. CONCLUSIONS: Anti-IL-1 agents are effective and safe in the treatment of FMF patients. These agents are particularly effective at reducing proteinuria in patients with GFR ≥ 60 ml/min/m2, but less effective in cases with FMF associated with arthritis and sacroiliitis. Large and long follow-up studies are now needed to establish the long-term effects of these treatments.

[Comparative assessment of nephroprotective properties of potassium and calcium channel modulators in experimental renal injury].

The experiments in white laboratory rats have shown that a single intragasrtric administration of the new fluorine-containing potassium channel opener flocalin in a dose of 5 mg/kg in the initial stage of sublimate nephropathy increased the glomerular filtration rate, reduced creatininemia, increased urinary creatinine excretion, and decreased proteinuria. Under similar conditions, the administration of the calcium channel blocker diltiazem in a dose of 5 mg/kg (intragasrtric) showed a less pronounced antiproteinuric effect as compared to that of flocalin. A comparative assessment of the influence of flocalin and diltiazem on the basic renal function markers demonstrated predominant nephroprotective effect of flocalin in the treatment of acute toxic nephropathy.

The "cost" of treating to target: cross-sectional analysis of patients with poorly controlled type 2 diabetes in Australian general practice.

BACKGROUND: To describe the current treatment gap in management of cardiovascular risk factors in patients with poorly controlled type 2 diabetes in general practice as well as the associated financial and therapeutic burden of pharmacological treatment. METHODS: Cross-sectional analysis of data from the Patient Engagement and Coaching for Health trial. This totalled 473 patients from 59 general practices with participants eligible if they had HbA1c > 7.5%. Main outcome measures included proportions of patients not within target risk factor levels and weighted average mean annual cost for cardiometabolic medications and factors associated with costs. Medication costs were derived from the Australian Pharmaceutical Benefits Schedule. RESULTS: Average age was 63 (range 27-89). Average HbA1c was 8.1% and average duration of diabetes was 10 years. 35% of patients had at least one micro or macrovascular complication and patients were taking a mean of 4 cardio-metabolic medications. The majority of participants on treatment for cardiovascular risk factors were not achieving clinical targets, with 74% and 75% of patients out of target range for blood pressure and lipids respectively. A significant proportion of those not meeting clinical targets were not on treatment at all. The weighted mean annual cost for cardiometabolic medications was AUD$1384.20 per patient (2006-07). Independent factors associated with cost included age, duration of diabetes, history of acute myocardial infarction, proteinuria, increased waist circumference and depression. CONCLUSIONS: Treatment rates for cardiovascular risk factors in patients with type 2 diabetes in our participants are higher than those identified in earlier studies. However, rates of achieving target levels remain low despite the large 'pill burden' and substantial associated fiscal costs to individuals and the community. The complexities of balancing the overall benefits of treatment intensification against potential disadvantages for patients and health care systems in primary care warrants further investigation.

Chronic kidney disease in type 2 diabetes patients in France: prevalence, influence of glycaemic control and implications for the pharmacological management of diabetes.

AIM: Type 2 diabetes mellitus (T2DM) is often associated with chronic kidney disease. For this reason, this article reviews the relationship between treatment of T2DM and renal disease. METHOD: The review presents the recent French data on the management of diabetes in patients with renal impairment, and discusses the implications of renal disease for the treatment of such patients. Prescribing data are presented for various antidiabetic treatments, and the use of the more commonly prescribed medications is discussed with reference to T2DM patients with renal disease. RESULTS: In France, it is estimated that 4-5% of the general population has T2DM and that almost 40% of patients with end-stage renal failure have diabetes. Diabetes and renal disease are both risk factors for cardiovascular morbidity and mortality. Glycaemic control is pivotal in T2DM patients for minimizing the risk of vascular complications and hypoglycaemic episodes, particularly in patients with renal disease who also have a higher risk of hypoglycaemia. Whereas poorly controlled glycaemia increases the risk of renal disease and its progression, the risk is diminished in patients treated intensively for diabetes and in those who achieve stable glycaemic control. Intensive multitargeted treatment can also help to decrease cardiovascular morbidity and mortality, especially if started early in patients who have not yet developed macrovascular complications. CONCLUSION: In recent years, considerable improvement has been observed in France regarding the follow-up of diabetic patients. Less extensive, but nonetheless significant, improvement has also been observed in glycaemic control. However, even though treatment decisions generally take renal function into account, some at-risk treatments are often still being used in patients with renal insufficiency.

ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: a double-blind randomized clinical trial.

OBJECTIVE: The combination of an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for the treatment of diabetic nephropathy (DN), but doubts remain about its efficacy and safety. We compared the effects of combination therapy and ACEI monotherapy on proteinuria and on three urinary inflammatory cytokines (MCP-1, TGF-beta and VEGF). DESIGN AND PATIENTS: 56 patients with macroalbuminuric DN received 40 mg/d enalapril for 4 months, followed by add-on 100 mg/day losartan or placebo for another 4 months. The primary and secondary endpoints were reduction of proteinuria and cytokine levels, respectively. RESULTS: Proteinuria did not fall in either group. Repeated measures ANOVA revealed no difference between groups. A high side effect rate was observed (28.5%). Finally, unadjusted logistic regression showed no difference between groups, but after adjustments the risk of worsening proteinuria was higher in the combination therapy group (p = 0.04). The same pattern was observed for urinary MCP- 1. CONCLUSION: These results suggest that 1) in advanced DN with severe proteinuria and poor metabolic control, angiotensin II blockade may be less effective than in other groups of CKD patients. 2) In such patients, combination therapy may not afford superior renoprotection compared to enalapril. 3) Urinary MCP-1 is a promising biomarker for the response to ACEI and/or ARB treatment and for the risk of associated unwanted effects.

Cost-effectiveness of angiotensin-converting enzyme inhibitors in nondiabetic advanced renal disease.

BACKGROUND: National and international clinical guidelines do not consistently recommend treating nondiabetic proteinuric patients with advanced renal disease with an angiotensin-converting enzyme (ACE) inhibitor. OBJECTIVE: To determine the cost-effectiveness of ACE inhibitor therapy in nondiabetic proteinuric patients with advanced renal disease in Germany. METHODS: Two strategies were compared: treating patients with advanced renal disease with an ACE inhibitor and no ACE inhibitor treatment. A lifetime Markov decision model was developed using published data on costs and health outcomes and simulated the progression of renal disease with costs and benefits discounted at 3%. A statutory health insurance perspective was adopted. RESULTS: In the base-case analysis, ACE inhibitor treatment is associated with lower costs and higher benefit and therefore dominates the no-treatment strategy. A probabilistic sensitivity analysis demonstrates that the probability of savings is 80%. CONCLUSION: ACE inhibitor treatment for nondiabetic patients with advanced renal disease is highly cost effective.

Proteinuria and clinical outcomes in hypertensive patients.

This narrative review focuses on outcomes related to proteinuria in hypertension (HT), and also examines the role of current and future therapeutic strategies. Proteinuria is an independent marker of renal and cardiovascular (CV) disease in hypertensive populations, particularly in high-risk groups such as diabetic patients. Effective blood pressure (BP) control and proteinuria management are associated with significant improvements in the risk of key adverse outcomes, although a causative relationship needs careful assessment. Available antihypertensives have varying effects on proteinuria reduction. Drugs affecting the renin system offer antiproteinuric and renoprotective effects that are probably at least partially independent of their BP effects. Economic evaluations of these interventions confirm their cost-saving benefits relative to other antihypertensives, but outcomes-based research is needed in some settings.

Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.

Changes in proteinuria have been suggested as a surrogate outcome for kidney disease progression to facilitate the conduct of clinical trials. This report summarizes a workshop sponsored by the National Kidney Foundation and US Food and Drug Administration (FDA) with the following goals: (1) to evaluate the strengths and limitations of criteria for assessment of proteinuria as a potential surrogate end point for clinical trials in chronic kidney disease (CKD), (2) to explore the strengths and limitations of available data for proteinuria as a potential surrogate end point, and (3) to delineate what more needs to be done to evaluate proteinuria as a potential surrogate end point. We review the importance of proteinuria in CKD, including the conceptual model for CKD, measurement of proteinuria and albuminuria, and epidemiological characteristics of albuminuria in the United States. We discuss surrogate end points in clinical trials of drug therapy, including criteria for drug approval, the definition of a surrogate end point, and criteria for evaluation of surrogacy based on biological plausibility, epidemiological characteristics, and clinical trials. Next, the report summarizes data for proteinuria as a potential surrogate outcome in 3 broad clinical areas: early diabetic kidney disease, nephrotic syndrome, and diseases with mild to moderate proteinuria. We conclude with a synthesis of data and recommendations for further research. At the present time, there appears to be sufficient evidence to recommend changes in proteinuria as a surrogate for kidney disease progression in only selected circumstances. Further research is needed to define additional contexts in which changes in proteinuria can be expected to predict treatment effect. We recommend collaboration among many groups, including academia, industry, the FDA, and the National Institutes of Health, to share data from past and future studies.

Remission of proteinuria in primary glomerulonephritis: we know the goal but do we know the price?

Membranous nephropathy, focal segmental glomerulosclerosis and IgA nephropathy are the most commonly recognized types of primary glomerulonephritis that progress to end-stage renal disease. Persistent proteinuria is a major determinant of such progression. Reduction of proteinuria slows progression of renal disease and improves renal survival, but many of the agents used to reduce proteinuria carry a considerable risk of toxicity. The assessment of benefit versus risk of these medications can be further complicated by the temporal disconnect between the onset of benefit and of serious adverse events. In addition, relapses are common in these disorders and there is often a need for retreatment. Such retreatment might lead to repeated and/or prolonged drug exposure and to the oversight or underestimation of the cumulative dose of these agents because of the potentially extended interval between relapses. Consequently, it is very important to constantly review each patient's status and take into account their age, comorbid conditions and cumulative drug exposure when assessing treatment options. The potentially delayed development of adverse events also emphasizes the need for long-term surveillance of patients who receive immunosuppressive treatment for glomerular disease, often well beyond their drug exposure period and even when the treatment has been successful.

Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center.

BACKGROUND/AIM: No accepted therapy has been established for progressive IgA nephropathy (IgAN). The purpose of the present study was to assess low-dose steroid therapy in the treatment of patients with IgAN. METHODS: A prospective trial of low-dose steroid therapy was performed in patients with IgAN with mild histological activities. Twenty-four patients in the steroid group and 24 patients in the control group were included in this study. The initial dose of prednisolone was 0.4 mg/kgBW/day (20-30 mg/day), gradually tapered to 5-10 mg/day over 24 months. The patients with mild active inflammatory lesions were treated with prednisolone. The patients assigned to the control group were treated with dipyridamole or zilazep hydrochloride in a dose of 150 or 300 mg/day. RESULTS: In all of the patients studied, serum creatinine levels did not significantly change over 24 months. However, daily proteinuria significantly reduced after 24 months of steroid therapy (0.97 +/- 0.75 vs. 0.31 +/- 0.51 g/day, P = 0.0012), even if did not change after 24 months of anti-platelet drugs (0.89 +/- 0.49 vs. 0.68 +/- 0.69 g/day, P = 0.2289), respectively. In addition, the grade of hematuria significantly reduced after 24 months of steroid therapy (35.6 +/- 36.3 RBC/HPF vs. 13.7 +/- 28.4 RBC/HPF, P = 0.0249) and 24 months of anti-platelet drugs (30.1 +/- 37.1 RBC/HPF vs. 12.4 +/- 20.3 RBC/HPF, P = 0.0465), respectively. Systolic and diastolic blood pressures did not significantly change during treatment with steroid or anti-platelet drugs. Vascular changes (0.63 +/- 0.73) in the steroid group were lower than those (1.08 +/- 0.88) in the control group (P = 0.008). CONCLUSION: Our data suggested that low-dose steroid therapy for IgAN patients with mild inflammatory lesions could reduce the amount of urinary protein excretion and prevent deterioration of renal function, provided the histological findings in the renal biopsies showed mild vascular lesions.

Estimating the cost effectiveness of ramipril used for specific clinical indications: comparing the outcomes in four clinical trials with a common economic model.

BACKGROUND AND OBJECTIVES: Economic analyses of drug therapies are highly dependent on the clinical indications for treatment. The cost effectiveness of ramipril has been evaluated in numerous studies, usually based on the results of one specific clinical trial. We estimated the cost effectiveness of this drug across a range of currently accepted therapeutic indications, using a single health economic model and adjusted for quality of life, to compare the different outcomes observed in four clinical trials. METHODS: The cardiovascular life expectancy model, a validated Markov model, was calibrated to accurately forecast the results of four trials including AIRE, HOPE, Micro-HOPE, and REIN. We then extrapolated these results over the remaining life expectancy of the patients enrolled in each study and adjusted for the quality of life associated with the observed outcomes. The cost per quality-adjusted life-year (QALY) was then calculated from the perspective of the Canadian healthcare system incorporating the estimated direct healthcare costs associated with treatments and outcomes. RESULTS: After discounting all costs and outcomes 3% annually, the benefits associated with ramipril ranged from 0.74 QALYs in the AIRE study to 1.22 QALYs in Micro-HOPE. Treatment was estimated to be cost-saving for some patient groups, such as those in REIN. The highest cost-effectiveness ratio was observed among individuals enrolled in HOPE ($Can20 000 per QALY in 2002). CONCLUSION: Treatment with ramipril appears to be economically attractive across a wide range of patient groups, including those with increased coronary risk and/or diabetes mellitus (HOPE and Micro-HOPE), those with congestive heart failure (AIRE), and those with non-diabetic nephropathy (REIN).

An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage renal failure in 15% to 20% of patients within 10 years of the apparent onset of disease and in 30% to 40% of individuals within 20 years. Severity of renal lesions, serum creatinine level, and severe proteinuria are adverse prognostic indicators. No specific treatment has been established, but several approaches have been experimented. METHODS: We reviewed the literature and evaluated the quality of published randomized trials using standard methods and the quality of their reporting according to the revised version of the Consolidated Standards for Reporting Trials Statement. Meta-analyses of randomized trials on the efficacy of steroid treatment, cytotoxic agents, and fish oils on the outcome of renal function and daily proteinuria in patients with IgA nephropathy were performed. RESULTS: Only 10 randomized trials were available and included in the review. Their quality was very poor, and a limited amount of data was reported. Cytotoxic agents seem beneficial on both renal function (relative risk, 0.38; 95% confidence interval [CI], 0.22 to 0.66) and daily proteinuria (weighted mean difference [WMD], -1.16; 95% CI, -2.18 to -0.14) in patients with moderate to severe renal damage, steroids act mainly on proteinuria (WMD, -0.50; 95% CI, -0.78 to -0.21), and fish oils do not imply a particular benefit. This statement is based on the very limited and poor available published evidence. CONCLUSION: Only a few randomized trials, of low quality and inadequately reported, are available relating to treatment of IgA nephropathy. More properly designed and reported trials are necessary to reach a definitive assessment of this matter.

Losartan reduces the burden and cost of ESRD: public health implications from the RENAAL study for the European Union.

Type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in most industrialized countries in Europe. The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) Study evaluated the renal protective effects of losartan versus placebo on a background of non-ACE-I/non-AIIA conventional antihypertensive therapy in 1513 patients with type 2 diabetes and nephropathy. Losartan reduced the incidence of doubling of serum creatinine, end-stage renal disease (ESRD), or death by 16% (P=0.022) and reduced the risk of progression to ESRD, defined as the initiation of dialysis or transplantation, by 29% (P=0.002). We set out to estimate the potential effect of losartan on the burden and costs associated with ESRD over 3.5 years in the European Union (EU). The risk reduction in new cases of ESRD was calculated by combining type 2 diabetes population estimates for the EU with the percent absolute risk reduction of ESRD in patients treated with losartan as observed in RENAAL. The number of days each patient experienced ESRD was defined as the length of time from onset of ESRD until the minimum of death or 3.5 years. ESRD-free person-years avoided with losartan treatment were calculated by combining the population estimate with the ESRD days avoided divided by number of days in a year. ESRD costs from Germany were used to approximate the potential cost savings from reduced time with ESRD and fewer ESRD cases on a EU wide basis. There are approximately 700,000 diagnosed type 2 diabetes patients with proteinuria (urine albumin/creatinine >or=300 mg/g) in the EU. The addition of losartan to the treatment regimen of these patients is expected to lead to a reduction of 44,100 cases of ESRD, 64,400 fewer person-years with ESRD, and reduce ESRD-related costs by euro 2.6 billion over 3.5 years based on RENAAL data. Treatment with losartan not only reduced the incidence of ESRD, but also can result in substantial cost savings in the European Union.