Summary: One hundred and ninety individuals on chronic in-centre haemodialysis with depressive symptoms were cluster-randomized to either an internet-based self-help therapy or usual care. The intervention therapy was a problem-solving therapy that forms part of cognitive behavioural therapy. Screening for inclusion and assessment for the primary outcome was done using the Beck Depression Inventory – second edition (BDI-II); the mean of depression severity scale was 19 out of a possible 63 in both groups (with a score of 14-19 equating to mild depression). Only 67% of participants completed the study and just over half of the intervention group completed at least three of the 10 intervention modules (54%). Those lost to follow-up were more likely to be of non-Dutch origin, married or on the wait list for a renal transplant. The most common reasons reported for not completing the intervention were health problems, lack of motivation, or death. Also, 18% who started the therapy needed help with tablet computer usage and 45% also needed help with filling out the exercises. There was no significant difference in the depression scores found (mean difference -0.1, 95% CI -3.0 to 2.7, p=0.94) for either the intention to treat or per protocol analyses.
Comment: :Mood disorders such as depression are well-recognised comorbidities for individuals with chronic diseases with high treatment and symptom burdens such as those on chronic haemodialysis. Despite this, there is little evidence for what constitutes an effective therapy for these patients. Some early non-randomised studies into the use of cognitive behavioural therapies (CBT) have shown promise in this population, with varied levels of efficacy depending on method of delivery. Disappointingly, this Dutch study was unable to demonstrate a benefit for a web-based selfdirected intervention using CBT strategies. This may be related to difficulties with powering and loss to follow-up but, given the challenges in achieving acceptance and uptake of this tool, it is likely that alternative strategies that are more “user friendly” to a dialysis cohort are required rather than further trials testing this intervention.
ISN Academy: Transplant
When enough is enough: immunoguided prevention for CMV in kidney transplant recipients is non-inferior with standard care after antithymocyte globulin induction.
Immunoguided discontinuation of prophylaxis for cytomegalovirus disease in kidney transplant recipients treated with antithymocyte globulin: a randomized clinical trial.
Paez-Vega et al. Clin Infect Dis. 2022.
Summary: In this single-center, double-blind, placebo-controlled crossover study 110 individuals with hypertension and average BP of < 150/95 mmHg were randomized to receive acetaminophen (paracetamol) 1 g four times daily or placebo for two weeks followed by a two-week washout period before crossing over to the alternate treatment. No participants had a history of regular acetaminophen use or chronic pain. Compared to placebo, acetaminophen treatment was associated with a significant increase in mean daytime systolic ambulatory BP (4.7 mmHg, 95% confidence interval [CI] 2.9-6.6, p<0.0001), mean 24-hour systolic BP (4.2 mmHg, 95% CI 2.4-6.0, p<0.0001), mean daytime diastolic BP (1.6 mmHg, 95% CI 0.5–2.7; p=0.005), and mean 24-hour diastolic BP (1.4 mm Hg, 95% CI, 0.3– 2.5; P=0.017). This effect was similar in patients with both treated and untreated hypertension at baseline. Two serious adverse events occurred during the study period that were considered not to be related to acetaminophen use. There was a reversible rise in serum ALT levels associated with acetaminophen therapy.
Comment: Acetaminophen is one the most commonly prescribed medications for the management of chronic pain worldwide. For a long period of time, it has been widely considered as a safe alternative to NSAIDs for people at high cardiovascular risk. The PATH-BP trial demonstrated a significant increase in BP associated with regular use of acetaminophen at therapeutic doses. These findings raise the possibility that acetaminophen may therefore contribute to an increase in the risk of cardiovascular events in people with hypertension by way of blood pressure elevation, and its prescription in this category of patients requires caution, especially given the limited evidence of efficacy in chronic pain. Further evaluation of the effects of acetaminophen on blood pressure in individuals with chronic pain, and of diverse ethnic backgrounds, will help extend the clinical applicability of this study’s findings.
ISN Academy: Hemodialysis
Higher ergocalciferol dosage may better treat vitamin D deficiency in haemodialysis patients, but the effect on inflammatory status remains unclear
Efficacy of high versus conventional dose of ergocalciferol supplementation on serum 25-hydroxyvitamin D and interleukin-6 levels among hemodialysis patients with vitamin D deficiency: A multicenter, randomized, controlled study
Nata et al. Ther Apher Dial. 2022.
Summary: : Seventy patients on long-term hemodialysis with serum 25-hydroxyvitamin D (25[OH]D) level <30 ng/ml were randomized to receive high- or conventional-dose of ergocalciferol for 8 weeks. The conventional regimen consisted of 50,000 units monthly or weekly, while the high-dose regimen involved 100,000 units monthly or weekly depending on the baseline vitamin D level. As expected at the end of 8 weeks the experimental group had a higher achievement of vitamin D sufficiency compared with the conventional-dose group (97.4% vs. 76.4%, p=0.012). A
significant reduction of the mean parathyroid hormone (PTH) level was observed in the high-dose group compared with the conventional-dose group. A significant decline in interleukin 6 (IL-6) level was only observed in the subgroup with very low baseline 25[OH]D level (<20ng/mL) receiving high dosage of ergocalciferol. The most frequent adverse event was constipation (45.7%) with equivalent frequency between the two groups.
Comment: High dose ergocalciferol appears to be an effective and safe strategy to achieve target vitamin D levels. Earlier studies have suggested that treatment of vitamin D replacement may also help to improve the chronic inflammation seen in end-stage kidney disease, including reductions in IL-6 levels. Such a finding may have been present in the subgroup with very low vitamin D levels at baseline, although whether this is associated with overall reductions in inflammation, and whether it translates into improved inflammation-associated clinical outcomes, remains to be seen.
ISN Academy: Glomerulonephritis
Tacrolimus is non-inferior to intravenous cyclophosphamide for the treatment of lupus nephritis in a Chinese population.
Effect of tacrolimus vs intravenous cyclophosphamide on complete or partial response in patients with lupus nephritis: a randomized clinical trial.
Zheng et al. JAMA Network Open. 2022.
Summary: In this open-label noninferiority clinical trial 314 patients with lupus nephritis class III, IV, V, III+V, or IV+V, proteinuria of 1.5g/24h or higher, and serum creatinine of <260mcmol/L were randomized to receive either tacrolimus (target levels 4-10ng/mL) or intravenous cyclophosphamide 0.5-1.0 g/m2 . All patients received IV methylprednisolone 0.5g/d for three days, followed by oral prednisolone 0.8 mg/kg/d for 4 weeks, gradually tapered to 10 mg/d. Complete response was defined as proteinuria of less than 0.5 g per 24 hours, serum albumin of 3.5 g/dL or greater, and stable kidney function (creatinine level in the reference range or an increase of <15% from baseline). Partial response was defined as proteinuria of less than 3.5 g per 24 hours and decreased by more than 50% from baseline, serum albumin of 3.0 g/dL or greater, and stable kidney function. The primary endpoint of partial or complete response at week 24 was achieved by 83% of patients in the tacrolimus group and by 75% of patients in the cyclophosphamide group (difference between groups, 7.1%; 2-sided 95%CI, −2.7% to 16.9%). Tacrolimus treatment was associated with a significantly more prominent reduction in daily proteinuria compared to cyclophosphamide. Serious treatmentemergent adverse events were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the cyclophosphamide group (24.6%). Two deaths, one in each group, were registered, both considered as immunosuppression related.
Comment: The standard of care for proliferative LN includes cyclophosphamide or mycophenolate mofetil in combination with glucocorticoids, while CNI is reserved as an alternative treatment. This trial demonstrated that tacrolimus is noninferior to IV cyclophosphamide for the treatment of LN class III, IV, and V in Chinese patients, and potentially has a more favourable safety profile. However, the study has several important limitations including openlabel design, short duration of follow-up, and the lack of comparison to steroid-sparing treatment strategies and to lower dosages of cyclophosphamide. Nevertheless, the results justify further study of tacrolimus for the treatment of proliferative LN in more diverse populations.
Summary: In this double-blind placebo-controlled crossover trial, 40 patients on intermittent haemodialysis were randomized to omega-3 (540 mg of EPA and 360 mg of DHA daily) or placebo. Exclusion criteria included a history of skin disease, phosphorus level >7mg/dl, PTH>300 mcg/l, or hepatic cholestasis. The pruritus severity score was assessed by a patient-reported score on a visual analogue scale. Additionally, the level of the pro-inflammatory prostaglandin E2 was evaluated as a marker of essential fatty acids imbalance in CKD-associated pruritus. There was a significant difference between the means of the pruritis severity score changes in the omega-3 vs placebo group at the end of first treatment period (- 3.41 ± 2.62 vs 0.06 ± 2.54, p < 0.001) and after cross-over (-1.00 ± 1.84 vs 0.13 ± 0.34, p=0.04). In the experimental group the level of the prostaglandin E2 was significantly reduced after treatment (-128.8, p = 0.04), while in placebo without significant changes. Mild gastrointestinal adverse events such as nausea and diarrhea were observed in 9% of those receiving the experimental arm.
Comment: Uremic pruritus is a very common and debilitating symptom for patients with CKD. Despite this, current evidence for the treatment is very weak, and treatment options such as pregabalin post the risk of neurological side effects. Treatment with omega-3 is very appealing as it is commonly available and generally safe, and at least three prior studies have reported beneficial effects in pruritus. Unfortunately, all studies had different methodology, which precluded meta-analysis. The current study provides further evidence of the potential efficacy of this strategy. Further studies may be needed to determine the optimum dosing, whether the assessment of prostaglandin E2 levels could guide treatment decisions, and how effectively treatment combines with evening primrose oil, which is another fatty acid commonly used in this condition.
Summary: Fifty-five CKD clinics were randomised in clusters to continue usual care, or to implement a program aimed at increasing the proportion of patients who commenced home-based dialysis (haemodialysis or peritoneal dialysis) rather than in-centre dialysis. The four components of the intervention were 1) a phone call to participating clinics to introduce the objectives, 2) providing clinics with a 1-year centre-specific audit report identifying the rates of home dialysis selection, 3) provision of educational reading materials, posters and a video to improve patient and clinician awareness of home dialysis as a treatment option and 4) a visit from a local nephrology key opinion leader to discuss home dialysis with clinicians, with ongoing follow-up to support the implementation of the written resources. Over the 12-month intervention, 5312 patients across the clinics-initiated dialysis. Unfortunately, there was no significant difference in the proportion established on home dialysis 180 days after commencing dialysis, seen in 28% of the intervention group and 24% of the control group (absolute risk difference 4%, 95%CI −2% to 10%).
Comment: Home dialysis is clearly associated with improved patient outcomes, reduced healthcare system costs and enhanced healthcare system capacity, and yet is commonly underutilised. This study proposes a logical and evidencebased intervention to help address this situation, but unfortunately was not able to demonstrate improved outcomes. The rollout of the program at the same time as an intensive program to improve the appropriate timing of dialysis initiation could have presented a burden to participants which may have affected engagement; only 45% of clinics randomised to the intervention reported high ongoing use of the educational materials. There may also have been imbalances between clinics, with those randomised to the intervention having higher baseline rates of home dialysis use, which may have reduced the relative benefit of the intervention. Furthermore, there are likely additional barriers to home dialysis such as cost, family support, and training logistics that the intervention was not designed to address. There remains a major need for ongoing research in this area.