Chronic Kidney Disease Trial Research Articles

AST-120 for the management of progression of chronic kidney disease

Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD. A Medline search was performed to identify data supporting clinical experience with AST-120 for managing CKD. Prospective open-label and double-blind trials as well as retrospective analyses were included. In prospective trials and retrospective analyses, AST-120 has been shown to prolong the time to initiation of hemodialysis, and slow decline in glomerular filtration rate and the increase serum creatinine. In an initial randomized, double-blind, placebo-controlled trial in the United States, AST-120 was associated with a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise. The Evaluating Prevention of Progression in CKD (EPPIC) trials, two double-blind, placebo-controlled trials undertaken in North America/Latin America and Europe, are evaluating the efficacy of AST-120 for preventing the progression of CKD. The results of the EPPIC trials will further define the role of AST-120 in this debilitating condition.

Audit-based education lowers systolic blood pressure in chronic kidney disease: the Quality Improvement in CKD (QICKD) trial results

Strict control of systolic blood pressure is known to slow progression of chronic kidney disease (CKD). Here we compared audit-based education (ABE) to guidelines and prompts or usual practice in lowering systolic blood pressure in people with CKD. This 2-year cluster randomized trial included 93 volunteer general practices randomized into three arms with 30 ABE practices, 32 with guidelines and prompts, and 31 usual practices. An intervention effect on the primary outcome, systolic blood pressure, was calculated using a multilevel model to predict changes after the intervention. The prevalence of CKD was 7.29% (41,183 of 565,016 patients) with all cardiovascular comorbidities more common in those with CKD. Our models showed that the systolic blood pressure was significantly lowered by 2.41 mm Hg (CI 0.59–4.29 mm Hg), in the ABE practices with an odds ratio of achieving at least a 5 mm Hg reduction in systolic blood pressure of 1.24 (CI 1.05–1.45). Practices exposed to guidelines and prompts produced no significant change compared to usual practice. Male gender, ABE, ischemic heart disease, and congestive heart failure were independently associated with a greater lowering of systolic blood pressure but the converse applied to hypertension and age over 75 years. There were no reports of harm. Thus, individuals receiving ABE are more likely to achieve a lower blood pressure than those receiving only usual practice. The findings should be interpreted with caution due to the wide confidence intervals.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD

In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.

Predicting the prevalence of chronic kidney disease in the English population: a cross-sectional study

BackgroundThere is concern that not all cases of chronic kidney disease (CKD) are known to general practitioners, leading to an underestimate of its true prevalence. We carried out this study to develop a model to predict the prevalence of CKD using a large English primary care dataset which includes previously undiagnosed cases of CKD.MethodsCross-sectional analysis of data from the Quality Improvement in CKD trial, a representative sample of 743 935 adults in England aged 18 and over. We created multivariable logistic regression models to identify important predictive factors.ResultsA prevalence of 6.76% was recorded in our sample, compared to a national prevalence of 4.3%. Increasing age, female gender and cardiovascular disease were associated with a significantly increased prevalence of CKD (p < 0.001 for all). Age had a complex association with CKD. Cardiovascular disease was a stronger predictive factor in younger than in older patients. For example, hypertension has an odds ratio of 2.02 amongst patients above average and an odds ratio of 3.91 amongst patients below average age.ConclusionIn England many cases of CKD remain undiagnosed. It is possible to use the results of this study to identify areas with high levels of undiagnosed CKD and groups at particular risk of having CKD.Trial registrationCurrent Controlled Trials ISRCTN: ISRCTN56023731. Note that this study reports the results of a cross-sectional analysis of data from this trial.

Is the lower blood pressure target for patients with chronic kidney disease supported by evidence?

Major guidelines recommend a blood pressure (BP) target of less than 130/80 mmHg for patients with chronic kidney disease (CKD) even though the optimal BP target in this population is unclear. This review summarizes the evidence on BP target in CKD and highlights recent pertinent publications. Clinical trials in CKD have not definitively shown that setting a BP target that is lower than the standard target of less than 140/90 mmHg provides additional benefit for important clinical outcomes. However, subgroup analyses from the recently published posttrial cohort of the African-American Study of kidney disease and a systematic review of BP target trials in CKD suggest that lower than the standard BP target may be beneficial in patients with proteinuria level of more than 300 or 1000 mg/day. Evidence supports a BP target of less than 140/90 mmHg in most patients with CKD. A lower target may be chosen in CKD patients with proteinuria after individualized risk-benefit assessment. Treatment to a lower target may require greater vigilance to monitor for and avoid possible symptoms and adverse events from hypotension.

Blood Pressure Targets for Patients with Diabetes or Kidney Disease

The most recent scientific guideline statements from foundations and societies dealing with diabetes and kidney disease argue for blood pressure (BP) goals lower than 130/80mmHg, but whether the evidence from properly done clinical trials supports this BP level remains questionable. A review of all the evidence suggests that almost all of the data come from retrospective data analyses of randomized cardiovascular and chronic kidney disease (CKD) trials. Meta-analyses of all clinical trials to date demonstrate that reducing BP reduces risk for stroke and coronary heart disease, but none have achieved a mean BP goal of less than 130/80mmHg. In fact, only two prospective trials achieved a BP lower than 130/80mmHg in people with type 2 diabetes, as did three trials in advanced proteinuric CKD. Of these, one of the two diabetes trials showed a benefit for overall cardiovascular risk reduction, and two of the three kidney disease trials showed a benefit on slowing of advanced CKD. Of note, however, these two trials in CKD had baseline average proteinuria rates of more than 500mg/day. No benefit of a lower BP was seen in microalbuminuric CKD. Therefore, the totality of the prospective randomized trial evidence indicates that a BP less than 130/80mmHg is not defensible to slow nephropathy progression unless proteinuria levels are at least 500mg/day, and it does not reduce overall cardiovascular events in diabetes. Stroke benefit was uniformly seen at BP levels less than 130/80mmHg, however. Therefore, newer guidelines are emerging that state that the BP goal for most people is lower than 140/90mmHg with level IA or IB evidence, and that levels lower than 130/80mmHg are defensible only if advanced proteinuric CKD is present or stroke risk is very high (i.e., history of prior stroke or several risk factors for stroke, including hypertension, smoking, diabetes mellitus, dyslipidemia).

Early change in proteinuria as a surrogate outcome in kidney disease progression: a systematic review of previous analyses and creation of a patient-level pooled dataset

Proteinuria is a candidate surrogate end point for randomized controlled trials (RCTs) in chronic kidney disease (CKD). There is a reasonably sound biological basis for this hypothesis, but only preliminary empirical evidence currently exists. A systematic review and creation of a patient-level dataset of randomized controlled trials (RCTs) in CKD that reported changes in proteinuria and assessed progression of kidney disease as defined by dialysis, transplantation, death, or changes in GFR or creatinine were performed. Systematic review. Seventy RCTs met the eligibility criteria; 17 eligible RCTs contained analyses of proteinuria as a predictor of outcomes; 15 RCTs concluded that greater proteinuria was associated with adverse outcomes. A majority were studies of diabetic or hypertensive kidney disease and tested renin-angiotensin system blockade. Definitions of predictor and outcome variables were too variable to conduct a meta-analysis of group data. Database creation. Over 4 years was required to create the patient-level dataset. The final dataset included 34 studies and > 9000 patients with a variety of CKD types and interventions. There are a relatively small number of RCTs designed to rigorously test therapies for kidney disease progression. Current analyses of change in proteinuria as a predictor of CKD progression are heterogeneous and incomplete, indicating further evaluation in a pooled individual patient-level database is necessary to advance knowledge in this field.

Prevention of Cardiovascular Disease in Chronic Kidney Disease Patients

Therapeutic strategies to prevent cardiovascular disease are based on the ability of the intervention to reduce specific risk factors and subsequent end-organ damage, implying that these factors are causally involved in the pathogenesis of the disease. In subjects with normal kidney function, the control of classic, Framingham-type, risk factors (blood pressure, glycemia, lipids, smoking) reduces impressively the burden of cardiovascular disease. In chronic kidney disease (CKD), prevention is based on similar strategies in general and on reduction of proteinuria (blockade of the renin-angiotensin-aldosterone system [RAAS], salt restriction) in particular. Although several nontraditional risk factors are recognized already in early stages of CKD (stages 1 and 2), they become more prominent in stages 3 to 5, most likely responsible for a different pathology. In fact, cardiovascular and all-cause mortality increase dramatically from CKD stage 3b (glomerular filtration rate < 45 mL/min/1.72 m2) to stage 5, and the pattern of cardiac and vascular damage changes profoundly. It appears that arteriosclerosis is recognized more often than atherosclerosis, and left ventricular hypertrophy or cardiac fibrosis is prominent. Randomized controlled trials in advanced CKD and stage 5D using strategies targeting classic risk factors indicate that treatments are not as effective as in subjects with normal kidney function. Whether late stages of CKD or a risk pattern dominated by nonclassic risk factors need a different or an additional approach or whether we can use biomarkers to detect the turning point is currently a matter of intense discussion among nephrologists and clinical scientists.

HEMATOLOGY: ISSUES IN THE DIALYSIS PATIENT: Anemia Management in Chronic Kidney Disease: What Have We Learned after 17 Years?

ABSTRACTAnemia management remains controversial in patients with chronic kidney disease (CKD). The overwhelming conclusion from retrospective data analyses show a strong correlation between higher hemoglobin values and improved outcomes, including mortality, hospitalization, left ventricular hypertrophy, and quality of life. However, the evidence available from two large prospective trials in CKD comparing hemoglobin values near the current target of 11–12 g/dl with normalization or near normalization were stopped, as there was a trend toward worsening outcomes in the higher hemoglobin groups. This disparity suggests that patients who have or achieve high hemoglobin values on low doses or no erythropoietin may be inherently different from the general CKD population. Therefore targeting to a hemoglobin value above the current recommendation with intermittent erythropoietin seems unwarranted until randomized prospective trials demonstrate both safety and efficacy.