Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial

Background

In the primary analysis of the PREDICT trial, a higher hemoglobin target (11–13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9–11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes.

Methods

Patients with an estimated glomerular filtration rate (eGFR) 8–20 ml/min/1.73 m² without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model.

Results

In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43–0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m²/year; 95% confidence interval: 0.38–1.63), while the proteinuria slope did not differ between the groups.

Conclusions

In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes.

Clinical trial registration

Clinicaltrials.gov (identifier: NCT01581073).

     

Rationale and study design of a clinical trial to assess the effects of LDL apheresis on proteinuria in diabetic patients with severe proteinuria and dyslipidemia

Background

Diabetic nephropathy is a leading cause of end-stage kidney disease in the world. Although various types of treatment for diabetes, hypertension and dyslipidemia have improved prognosis and quality of life in patients with diabetic nephropathy, there still exist some diabetic patients with severe proteinuria showing poor prognosis. This clinical trial, LICENSE, aims to confirm the impact of LDL apheresis on proteinuria exhibiting hyporesponsiveness to treatment.

Methods

This ongoing trial is a multicenter, prospective study of diabetic patients with severe proteinuria. The objective is to examine the impact of LDL apheresis on proteinuria in patients with diabetic nephropathy. The other subject is to investigate safety of LDL apheresis in these patients.

Results

The subjects consist of diabetic patients with serum creatinine (Cr) levels below 2 mg/dL who present severe proteinuria above 3 g/g Cr or 3 g/day and LDL cholesterol above 120 mg/dL. The target number of registered patients will be 35 patients. Urinary protein excretion and renal function will be observed for 24 weeks after the treatment of LDL apheresis.

Conclusion

This study will determine the effectiveness and safety of LDL apheresis for diabetic nephropathy patients with severe proteinuria and dyslipidemia.

     

Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents,darbepoetiN alfa (BRIGHTEN Trial)

Background

Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified.

Methods

This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index.

Results

The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated.

Conclusion

By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.

     

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: Rationale and design of the ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial

Background

Since dyslipidemia has been shown to be an independent risk factor for the progression of chronic kidney disease (CKD), low-density lipoprotein cholesterol (LDL-C)-lowering therapy can be potentially associated with inhibition of CKD progression. The ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial was designed to determine whether atorvastatin has protective effects on renal function in patients with dyslipidemia and CKD.

Methods

We decided to carry out a prospective multi-center, open-labeled, randomized trial to compare the reno-protective effects between diet therapy alone and atorvastatin plus diet therapy in patients with dyslipidemia (LDL-C ≥ 140 mg/dL if not treated or LDL-C ≥ 100 mg/dL if treated with lipid-lowering drugs in subjects taking dyslipidemia-treating agents other than statins) and CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²]. The primary endpoint is the change in eGFR (mL/min/1.73 m²) as calculated by the modified MDRD equation for Japanese after 2 years of treatment.

Results

Enrollment began in April 2009 and was completed in March 2011. A total of 334 patients (213 male and 121 female) were randomly assigned to either diet therapy alone or atorvastatin plus diet therapy and included in an intent-to-treat population. In the atorvastatin and control groups, the mean ages were 63.2 and 63.1 years, mean eGFRs were 55.9 and 54.0 mL/min/1.73 m², and median urinary albumin/creatinine ratios were 24.9 and 29.1 mg/g, respectively.

Conclusions

This study distinguishes itself from similar studies by increasing statistical accuracy derived from its significantly larger sample size and longitudinal magnitude. The results of this study will help to determine whether atorvastatin has reno-protective effects in patients with dyslipidemia and CKD.     

Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney disease: a randomized controlled study

Background: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD). Methods: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure. Results: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. -2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (-29 ± 2 vs. -38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (-4 ± 1 vs. -9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period. Conclusion: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection.     

Effect of aliskiren in chronic kidney disease patients with refractory hypertension undergoing hemodialysis: a randomized controlled multicenter study

Background

Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD).

Methods

The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy.

Results

A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group.

Conclusion

Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin?angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies.     

The evaluation of off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) randomized controlled trial: study design and rationale

Background

Off-loading is essential for diabetic foot management, but remains understudied. The evaluation of Off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) trial aims to evaluate the efficacy of a new removable device “Orthèse Diabète” in the healing of diabetic foot.

Methods/design

ORTHODIAB is a French multi-centre randomized, open label trial, with a blinded end points evaluation by an adjudication committee according to the Prospective Randomized Open Blinded End-point. Main endpoints are adjudicated based on the analysis of diabetic foot photographs. Orthèse Diabète is a new removable off-loading orthosis (PROTEOR, France) allowing innovative functions including real-time evaluation of off-loading and estimation of patients’ adherence. Diabetic patients with neuropathic plantar ulcer or amputation wounds (toes or transmetatarsal) are assigned to one of 2 parallel-groups: Orthèse Diabète or control group (any removable device) according to a central computer-based randomization. Study visits are scheduled for 6 months (days D7 and D14, and months M1, M2, M3, and M6). The primary endpoint is the proportion of patients whose principal ulcer is healed at M3. Secondary endpoints are: the proportion of patients whose principal ulcer is healed at M1, M2 and M6; the proportion of patients whose initial ulcers are all healed at M1, M2, M3, and M6; principal ulcer area reduction; time-related ulcer-free survival; development of new ulcers; new lower-extremity amputation; infectious complications; off-loading adherence; and patient satisfaction. The study protocol was approved by the French National Agency for Medicines and Health Products Safety, and by the ethics committee of Saint-Louis Hospital (Paris). Comprehensive study information including a Patient Information Sheet has been provided to each patient who must give written informed consent before enrolment. Monitoring, data management, and statistical analyses are providing by UMANIS Life Science (Paris), independently to the sponsor. Since 27/10/2013, 13 centres have agreed to participate in this study, 117 participants were included, and 70 have achieved the study schedules. The study completion is expected for the end of 2016, and the main results will be published in 2017.

Conclusion

ORTHODIAB trial evaluates an innovating removable off-loading device, seeking to improve diabetic foot healing (ClinicalTrials.gov identifier: NCT01956162).

     

The effectiveness and cost evaluation of pain exposure physical therapy and conventional therapy in patients with complex regional pain syndrome type 1. Rationale and design of a randomized controlled trial

ABSTRACT: BACKGROUND: Pain Exposure Physical Therapy is a new treatment option for patients with Complex Regional Pain Syndrome type 1. It has been evaluated in retrospective as well as in prospective studies and proven to be safe and possibly effective. This indicates that Pain Exposure Physical Therapy is now ready for clinical evaluation. The results of an earlier performed pilot study with an n = 1 design, in which 20 patients with Complex Regional Pain Syndrome type 1 were treated with Pain Exposure Physical Therapy, were used for the design and power calculation of the present study. After completion and evaluation of this phase III study, a multi-centre implementation study will be conducted. The aim of this study is to determine whether Pain Exposure Physical Therapy can improve functional outcomes in patients with Complex Regional Pain Syndrome type 1. Methods/design This study is designed as a single-blinded, randomized clinical trial. 62 patients will be randomized with a follow-up of 9 months to demonstrate the expected treatment effect. Complex Regional Pain Syndrome type 1 is diagnosed in accordance with the Bruehl/International Association for the Study of Pain criteria. Conventional therapy in accordance with the Dutch guideline will be compared with Pain Exposure Physical Therapy. Primary outcome measure is the Impairment level SumScore, restricted version. DISCUSSION: This is the first randomized controlled study with single blinding that has ever been planned in patients with Complex Regional Pain Syndrome type 1 and does not focus on a single aspect of the pain syndrome but compares treatment strategies based on completely different pathophysiological and cognitive theories. Trial registration Clinical trials NCT00817128; National Trial Register NTR2090.     

Effects of pre-dialysis resistance training on sarcopenia,inflammatory profile,and anemia biomarkers in older community-dwelling patients with chronic kidney disease: a randomized controlled trial

Background

Sarcopenia and chronic kidney disease (CKD) have been associated with negative outcomes in older people, including inflammatory profile and anemia biomarkers.

Aims

To investigate the effects of pre-dialysis resistance training (RT) on sarcopenia, inflammatory profile, and anemia biomarkers in older patients with CKD.

Methods

A total of 107 patients with CKD (65.4?±?3.7 years) were randomly allocated into four groups: sarcopenic RT (n?=?37), non-sarcopenic RT (n?=?20), sarcopenic control (n?=?28), and non-sarcopenic control (n?=?22). DXA and handgrip strength were used to classify sarcopenia according to EWGSOP-2. Treatment groups underwent a 24-week intervention with RT before each dialysis session, three times per week. Blood sample analysis for ferritin, hepcidin, iron availability, and inflammatory profile (TNFα, IL-6, and IL-10) was conducted. All-cause mortality was recorded over 5 years.

Results

Sarcopenic RT group increased iron availability after the intervention, while their counterparts decreased. Ferritin and hepcidin significantly decreased in sarcopenic RT group. RT elicited a reduction in both TNFα and IL-6, while increasing IL-10 in both intervention groups. The rate of sarcopenic subjects substantially decreased after the intervention period (from 37 to 17 in the RT group; p?=?0.01). The proportion of deaths was higher (P?=?0.033) for sarcopenic subjects (Controls 35.7% vs RT 29.7%) when compared to non-sarcopenic subjects (Controls 18% vs RT 10%). The proportion of deaths decreased according to the randomization group (X2?=?8.704; P?<?0.1).

Conclusions

The 24-week RT intervention elicited a better sarcopenia status, better inflammatory profile, and improved anemia biomarkers. Sarcopenia was associated with higher mortality rate in older patients with CKD.

     

Efficacy and tolerability of manidipine in the treatment of hypertension in patients with non-diabetic chronic kidney disease without glomerular disease. Prospective, randomized, double-blind study of parallel groups in comparison with enalapril

BACKGROUND: Calcium channel blockers (CCBs) are effective blood pressure lowering agents, giving rise to a prevalent dilation of the afferent arteriole. Manidipine, a long-lasting dihydropyridine CCB, demonstrates its action not only on the afferent arteriole, but also on the efferent one. This suggests theoretically a renoprotective effect in patients with chronic kidney diseases (CKD). METHODS: This was a multicenter, prospective, randomized, double-blind, parallel group study, to evaluate the efficacy and tolerability of manidipine (M; 10-20 mg/day), in comparison with enalapril (E; 10-20 mg/day) in the treatment of hypertension in 136 patients with CKD secondary to primary renoparenchymal disease. Changes in blood pressure values from baseline were considered as the primary outcome of the study. Proteinuria changes and the rate of renal function decline were also evaluated. RESULTS: During a 48-week follow-up, mean SBP decreased from 155+/-11.7 to 138.7+/-13.9 mmHg in M and from 157.3 +/-11.8 to 134.2+/-13.9 mmHg in E; mean DBP decreased from 100.3+/-4.2 to 86.1+/-6.5 mmHg in M and from 100.3+/-4.2 to 84.7+/-6.3 mmHg in E. Proteinuria remained unchanged in M (from 1.6+/-1.59 to 1.62+/-1.79 g/24h), and decreased significantly in E (from 1.37+/-1.45 g/24h to 1+/-1.55 g/24h). No significant difference was observed in the rate of renal function decline in the two groups. CONCLUSIONS: Manidipine was safe and effective, obtaining a significant reduction in SBP and DBP from baseline. Although patients treated with enalapril showed a better antiproteinuric response, the two treatments were equally effective in reducing the rate of CRF progression in patients without glomerular disease.     

Effects of correction of metabolic acidosis on blood urea and bone metabolism in patients with mild to moderate chronic kidney disease: a prospective randomized single blind controlled trial

BACKGROUND: There are no controlled trials on the efficacy of oral bicarbonate therapy in patients with mild to moderate chronic kidney disease (CKD). This prospective randomized controlled study was done to evaluate the effects of correction of metabolic acidosis on renal functions and bone metabolism in this group of patients. PATIENTS AND METHODS: Forty patients were randomized to treatment with oral bicarbonate or placebo for a period of 3 months. Investigations at baseline included venous pH, bicarbonate, renal functions, serum iPTH, and bone radiology. The treatment group (Group B) received daily oral sodium bicarbonate therapy at a dose of 1.2 mEq/kg of body weight. Their venous blood pH and bicarbonate levels were estimated weekly to keep blood pH near 7.36 and bicarbonate at 22-26 mEq/L by adjusting the dose of sodium bicarbonate. At the end of 3 months, all the tests were repeated in both groups. RESULTS: After oral bicarbonate therapy (OBT), there was a significant decline in the rise of blood urea level in Group B associated with a sense of well-being in 50% patients. The rise in parathormone (PTH) was six times the baseline value in Group A and only 1.5 times baseline value in Group B, although not statistically significant. There was no significant change in total calcium, phosphorus, alkaline phosphatase, creatinine, total protein, or albumin levels. CONCLUSION: Correction of metabolic acidosis in patients with moderate CKD attenuates the rise in blood urea and PTH, which might prevent the deleterious long-term consequences of secondary hyperparathyroidism.     

Darbepoetin alfa administered every other week maintains hemoglobin levels over 52 weeks in patients with chronic kidney disease converting from once-weekly recombinant human erythropoietin: results from simplify the treatment of anemia with Aranesp (STAAR)

BACKGROUND/AIM: Darbepoetin alfa, an effective treatment for anemia of chronic kidney disease (CKD), can be administered at extended intervals. Simplify the Treatment of Anemia with Aranesp (STAAR), a multicenter, 52-week study, was conducted to assess the efficacy of darbepoetin alfa administered subcutaneously every other week (Q2W) in maintaining hemoglobin (Hb) in CKD patients not receiving dialysis. METHODS: This is a subgroup analysis of subjects converted from once-weekly (QW) recombinant human erythropoietin (rHuEPO; US Aranesp package insert) and who received up to 52 weeks of darbepoetin alfa therapy (evaluation period 20-32 weeks). Enrolled subjects had a creatinine clearance < or = 70 ml/min or an estimated glomerular filtration rate < or = 60 ml/min and transferrin saturation > or = 20%. Darbepoetin alfa doses were titrated to maintain Hb levels < or = 12 g/dl. The primary endpoint was mean Hb during evaluation. RESULTS: There were 524 subjects enrolled in the study who were previously receiving rHuEPO QW. Mean Hb +/- standard deviation was 11.2 +/- 1.27 g/dl at baseline, and the least squares mean +/- SE was 11.4 +/- 0.04 during evaluation. The mean +/- SD Q2W darbepoetin alfa dose was 49.7 +/- 21.9 microg at baseline and 48.9 +/- 35.5 microg at evaluation. Darbepoetin alfa was well tolerated. CONCLUSIONS: Study subjects with CKD receiving QW rHuEPO were effectively converted to Q2W darbepoetin alfa, which was well tolerated. Hb levels were maintained over 52 weeks without a significant change in darbepoetin alfa dose.     

Acute effects of light emitting diodes therapy (LEDT) in muscle function during isometric exercise in patients with chronic obstructive pulmonary disease: preliminary results of a randomized controlled trial

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to early muscle fatigue. Light-emitting diodes therapy (LEDT) has been used to minimize muscle fatigue in athletes and healthy subjects. The aim of this study is to investigate the acute effects of LEDT on muscle fatigue and perception of effort in patients with COPD during isometric endurance test of the quadriceps femoris (QF). Ten patients (VEF₁ 50?±?13 % of predicted) underwent a single LEDT and sham application, 48 h apart, in a randomized crossover design. The LEDT and sham were applied in three localized areas of the QF (rectus femoris, vastus lateralis, and vastus medialis). Before and after exposure to LEDT and sham, the patients performed an isometric endurance test (60 % of the maximum voluntary isometric contraction), until the limit of tolerance concomitant to surface electromyography recording (median frequency as mean outcome). The slope obtained from linear regression analysis of the median frequency (MF) over endurance time was also used as an endurance index. Endurance time increased significantly after exposure to LEDT (from 26?±?2 to 53?±?5 s) as compared to sham (from 23?±?3 to 30?±?4 s) (F?=?64, P?=?0.0001). A greater decline in MF was observed during isometric endurance test after sham, compared to LEDT (F?=?14.6, P?=?0.004). The slope of the MF over time was lower post-LEDT compared to post-sham (?0.7?±?0.3 vs. ?1.5?±?0.8; P?=?0.004). The dyspnea score corrected for endurance time was lower post-LEDT (P?=?0.008) but similar for fatigue both post-LEDT and post-sham. A single application of LEDT minimizes muscle fatigue and increases isometric endurance time.     

Effect of repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease

BACKGROUND: AST-120 is an orally administered adsorbent used in Japan for prolonging time to initiation of hemodialysis and improving uremic symptoms in patients with chronic kidney disease (CKD). As AST-120 is suspected to reduce the progression of CKD by adsorbing renal toxins in the gastrointestinal tract, the objective of the current study was to determine whether binding of AST-120 to creatinine in the intestines could acutely alter creatinine balance, thereby limiting the utility of serum creatinine (sCr) as a measure of progression of renal function. Such information may be critical for the design of future studies to assess the efficacy of AST-120 in CKD patients. METHODS: Patients with CKD (n = 20) received oral doses of AST-120(3 g t.i.d.) and placebo in a two-way crossover study. Blood and urine were collected for determination of sCr, 24-hour urinary creatinine (UcrV), creatinine clearance (Ccr), and urea nitrogen clearance (URCL). Differences between treatments were assessed using an ANCOVA model. RESULTS: Following AST-120 and placebo treatments, mean sCr (1.73 and 1.79 mg/dl, respectively) and UcrV (1,264.73 and 1,286.05 mg) values were not significantly different. No significant differences were observed for Ccr and URCL. CONCLUSION: These results indicate that AST-120 has no acute impact on creatinine balance in patients with CKD. Consequently, sCr and other markers of renal function are acceptable measures for assessing changes in renal function following AST-120 treatment.