ISN Academy: End of Life Care
“I planned each charted course, each careful step along the byway”: MY WAY coaching program can enhance Advance Care Planning in CKD patients
Advance care planning coaching in CKD clinics: a pragmatic randomized clinical trial
Lupu et al. Am J Kidney Dis. 2022; 79 (5):699-708
Summary: In this pragmatic non-blinded trial 264 patients aged 55 years or older with stage 3-5 CKD were randomized into an Advance Care Planning (ACP) coaching group, or to an enhanced usual care group where patients received educational materials to review on their own. The intervention was named Make Your Wishes About You (MY WAY) and included inperson sessions of up to 60 minutes with a coach, including patient-centered motivational interviewing and custom-made patient education materials. Patients were encouraged to bring a family member or friend. The three site coaches were a nurse experienced in hospice care, a CKD nurse practitioner, and a palliative care social worker, and were instructed by attending 3 hours of videoconferences. The intervention group had a marginally higher ACP patient engagement score at 14 weeks compared with the control group (38.01±7.53, out of a possible 45 points vs 37.25±7.46, p=0.03) but a markedly higher rate for having a documented Advanced Directive (AD; 32.8% vs 17.8%, p=0.004). One of the three sites had an AD completion rate of 72.1% with the intervention. The majority of intervention participants said they would recommend the program (96%), would like to see the resources disseminated (94%) and were prompted to seek more information about ACP as a result (78%). Emotional difficulties were observed in some patients in the coaching sessions, with 3.7% experiencing moderate distress.
Comment: Advance Care Planning reflects a patient-oriented approach to goals and preferences for future care, including end-of-life care. In earlier studies, ACP has been seen to increase patients’ and relatives’ satisfaction with medical care and decrease their distress when significant deteriorations in health arise. ACP may also reduce rates of hospitalisations when hospital care is against a patient’s documented wishes. Despite this, only a minority of CKD and dialysis patients have an AD. The present study demonstrates the value of a structured coaching program in facilitating patients to complete an AD. There were significant difficulties recruiting, including patients not being interested, being too busy, or having already completed an AD, as well as due to scheduling difficulties, which led to a smaller sample size than intended and may have introduced participation bias. Older patients had a higher rate of declining participation. The ACP discussion itself can be very delicate and may be influenced by local culture, traditions and legislation, and may require multiple follow-up conversations. Variation in success between centres also suggests an influence of the skill and experience of the coach. Further research is needed to determine the best staff training for ACP discussions, the appropriate resources for different cultural and language groups, and the best strategies to integrate coaching into usual care.
ISN Academy: Chronic Kidney Disease
The combination of an SGLT2 inhibitor and MRA significantly decreased residual albuminuria in diabetic and non-diabetic CKD patients
Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized cross-over clinical trial
Provenzano M* et al. JASN 2022.
Summary: In the open-label ‘ROTATE-3’ trial, 46 patients with CKD stage 3b or higher and albuminuria >100mg/d were randomized to receive dapagliflozin 10mg/d, eplerenone 50mg/d or their combination for a period of 4 weeks, before crossover to each of the other two treatments for 4-week blocks, with a four-week washout period between each treatment phase. All patients were on a stable maximum tolerated dosage of RAAS inhibitor for 4 weeks before the trial. Each of the three treatment strategies resulted in a decrease in the urine albumin-to-creatinine ratio (UACR) after 4 weeks of treatment, with a reduction of 19.6% from baseline with dapagliflozin, 33.7% with eplerenone and 53% with combined treatment. There was also a higher rate of achieving a ≥30% and ≥50% reduction in UACR in the dapagliflozin-eplerenone group (72% and 56%, respectively), compared with dapagliflozin (36% and 20%) and eplerenone monotherapy (43% and 26%). Changes in albuminuria with monotherapy did not correlate with the success of combination therapy. The most common adverse events were hyperkalemia (the highest rate was in the eplerenone group, 17.4%, compared to 4.3% with combination therapy) and urinary infection (the highest rate was in the dapagliflozin group, 21.7%, although only 2.2% of those receiving dapagliflozin had a symptomatic urinary infection). Rates of hypotension were 6.2% with combined therapy.
Comment: Persistent albuminuria remains a difficult clinical challenge despite the albuminuria-lowering benefits seen in recent large CKD trials like the use of dapagliflozin in DAPA-CKD and finerenone in FIDELIO. ROTATE-3 is the first trial comparing MRA and SGLT2i and their combination in patients with CKD. Despite large variability in albuminuria responses, the combination of dapagliflozin-eplerenone appeared to have a significant synergistic effect. The lack of correlation between the response to monotherapy and the response to combination therapy suggests that rotation of therapy or dual therapy may be a viable option among those who fail to respond to a single agent. In addition, the known kaliuretic effect of SGLT2 inhibitors could help mitigate the hyperkalemia associated with MRA usage when the two are prescribed in combination. Although this is a small, open-label trial without a placebo group, it lends impetus to conducting large confirmatory clinical trials to demonstrate long-term efficacy and safety of combined therapy. *Disclosure: M Provenzano is a member of the ISN GTF editorial team
ISN Academy: Glomerular Diseases
TESTING demonstrates that methylprednisolone slows down the progression of IgA nephropathy
Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial
Lv et al. JAMA. 2022;327(19):1888-1898.
Summary: The TESTING double-blind clinical trial enrolled patients with IgA nephropathy, proteinuria of 1g/24 h or higher, and estimated GFR of 20-120mL/min/1.73m2 after at least three months of standardized nephroprotective therapy. Five hundred and three participants were randomized to receive oral methylprednisolone 0.6-0.8mg/kg/24h (maximum 48mg/24h, tapered down by 8mg/24h each month, for a total of 6-9 months) or placebo. An excess of serious infections in the treatment group resulted in a change to the clinical protocol and a subsequent dose reduction of steroids to 0.4mg/kg/24h, tapered down by 4 mg/kg/mo) after 262 patients had been randomized; a review of the intermediary results was presented in the September 2017 volume of the GTF. Over a mean of 4.2 years follow-up, the primary composite endpoint of 40% decline in eGFR, kidney failure (dialysis or transplant), or death due to kidney failure occurred significantly less often in the treatment group than in the placebo group (28.8% vs 43.1%; HR 0.53, 95%CI 0.39-0.72, P<0.001). The absolute annual event rate was 4.8% lower per year in the treatment arm (95%CI, 1.6 to 8.0% lower). Steroid therapy was associated with lower rates of kidney failure (HR 0.59 [95%CI, 0.40-0.87]; P=0.008), annual loss of kidney function (2.5mL/min/1.73m2 vs 4.97mL/min/1.73m2 ), and time-averaged mean 24-hour urine protein excretion (1.70g/24h vs 2.39g/24h). The high and lower dose regimens showed similar benefits for these outcomes. Severe adverse events, including excess hospitalizations and serious infections, were significantly more Page 3 of 4 common in the methylprednisolone group (10.9%) than in the placebo group (2.8%). Comparing the two steroids regimens, the frequency of serious adverse effects was markedly higher in the full-dose regimen (22 cases, including 3 fatal) in contrast to the lower dose regimen (6, including 1 fatal).
Comment: Up to 25% of patients with IgA nephropathy (IgAN) develop kidney failure within 10 years. Corticosteroids have been used to treat IgAN for decades, however, the evidence of their efficacy and safety has remained controversial. The results of the TESTING trial clearly demonstrate significant benefits of corticosteroid therapy, both in higher and lower doses, in patients with IgAN who received standardized background therapy. Unfortunately, but not unexpectedly, this treatment is also associated with a higher risk of severe adverse events. The majority of trial participants were of Chinese origin, which may limit its generalizability. Nevertheless, as the largest IgAN clinical trial completed to date, TESTING provides robust support for the use of corticosteroids to improve the outcomes of patients with IgAN, provided that the treatment would be individually optimized on the basis of careful risk assessment in each patient.
ISN Academy: Haemodialysis
Proactive prescription of potassium in peritoneal dialysis possibly prevents peritonitis
Efficacy of potassium supplementation in hypokalemic patients receiving peritoneal dialysis: a randomized controlled trial
Pichitporn et al. Am J Kidney Dis. 2022; 79 (5):699-708
Summary: In this multicentre open-label trial, 167 peritoneal dialysis patients with hypokalaemia (K<3.5mEq/L) were randomised to receive potassium supplementation or conventional treatment during 52 weeks. Participants from the treatment group received active supplementation to maintain a serum potassium level between 4-5mEq/L. The conventional treatment arm received reactive supplementation when potassium levels fell below 3.5mEq/L. At study conclusion, the mean level of serum potassium was successfully higher in the active supplementation group compared to the control group (mean difference 0.66, 95%CI 0.53 to 0.79 mEq/L, p<0.001). The median time to first peritonitis event was significantly longer in the treatment group (223 vs. 113 days, p=0.03). The proportion of peritonitis-free patients was also lower in the experimental arm (15% vs 29%, p=0.03). Despite this, the overall rate of peritonitis was similar (0.24 vs. 0.42 episodes/patient-year at risk, p=0.1). No significant differences were noted in any of the secondary outcomes of all-cause mortality, cardiovascular death, hospitalisation, or change in modality to haemodialysis. Asymptomatic hyperkalemia (>6 mEq/L) without changes on ECG occurred only in the active supplementation group (4%).
Comment: Several prior studies have demonstrated an association between hypokalaemia and increased peritonitis risk. Hypokalaemia may contribute to constipation and intestinal bacterial overgrowth, which can facilitate transmural bacterial migration into the peritoneal space. This study evaluating the effects of potassium supplementation in hypokalemic patients on peritoneal dialysis suggests a potential benefit of a proactive potassium replacement strategy on reducing peritonitis risk. Some factors limit its generalisability, including the unblinded study design, single country recruitment, and relatively few primary outcome events. Further studies are needed to clarify this association and the potential benefit of active potassium supplementation in this group of patients.
ISN Academy: Nutrition and Hydration
Does prescribing very low-protein diet in patients with advanced chronic kidney disease give no additional advantage?
No additional benefit of prescribing a very low-protein diet in patients with advanced chronic kidney disease under regular nephrology care: a pragmatic, randomized, controlled trial
Bellizzi et al., Am J Clin Nutr 2022;115:1404–1417.
Summary: The study randomised 223 patients with CKD stage 4-5 to receive a very low-protein diet supplemented with ketoanalogues (sVLPD) or standard low-protein diet (LPD) over at least 36 months. The treatments required vigorous dietitian involvement; the protocol included 20 different diet plans for sVLPD (0.3g proteins/kg of ideal bodyweight/day) and LPD (0.6 g proteins/kg of ideal bodyweight/day) to account for energy requirements and diabetes status, and each plan was personalized after assignment. Adherence to the prescribed diet was assessed Page 4 of 4 during discussions with the nephrologist every 3 months, and with a 3-day dietary diary every 6 months, with ondemand review by a dietitian. At baseline in both groups median protein intake (PI) was around 0.8 g/kg IBW/d and at month 36, it had decreased to 0.60 g/kg IBW/d in the sVLPD group and 0.83g/kg IBW/d in the LPD group. After a median follow-up of 74.2 months, there was no significant difference in the primary outcome of “renal death” defined as end-stage kidney disease or all-cause mortality, or in the rate of eGFR decline. There was no significant difference in nutritional status between the two treatment arms and no other safety concerns raised.
Comment: Prior studies, such as the MDRD trial, have demonstrated a modest reduction in the progression of CKD with a low protein diet. Long-term follow-up of the MDRD trial suggested that those patients with a very low protein diet may have a higher risk of mortality, including after commencing dialysis. A study by Garneata and colleagues (JASN 2016) showed benefits of a very low protein diet in preventing renal death but restricted the intervention to a minority of patients most likely to maintain strict adherence. The present trial evaluated the long-term effects of sVLPD in a more representative range of patients. The lack of demonstrated efficacy and the difficulty in implementation (reflected in low recruitment rates and above-target protein intake levels) argue against widespread use of a very low protein diet in CKD.
ISN Academy: Transplant
Treatment with everolimus prevents CMV DNAemia in seropositive recipients in the absence of antiviral prophylaxis
Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial
Kaminski et al. Am J Transplant. 2022;22:1430–1441.
Summary: This open-label phase 4 multicenter trial randomised CMV-seropositive kidney transplant recipients to one of two immunosuppressive regimes to compare the incidence of CMV-infection, without the use of universal antiviral prophylaxis, over 12 months. One hundred and seventy-four patients were included to receive everolimus 1.5mg twice daily (adjusted to a 5-8ng/ml target blood concentration) or mycophenolic acid 720 mg twice daily. All patients received basiliximab induction, with steroids and cyclosporine as background immunosuppressive treatment. Weekly CMV PCR was performed for the first 3 months, then every 2 weeks from months 3-4, then monthly at months 5 and 6, then according to local policy. The proportion of patients who experienced the composite primary outcome of CMV DNAemia, CMV treatment, graft loss, death or discontinuation of the study at 6 months posttransplant was lower in the everolimus group (48.3% vs 80.5%, p<0.0001). Patients in the everolimus group showed a lower incidence of CMV DNAemia (39.2% vs 77.8%, p<0.0001), and fewer received treatment for CMV compared to the control group (21.8% vs 47.1%, p=0.0007). There were only 11 instances of CMV disease (syndrome or tissue-invasive disease) across the trial, occurring less often with everolimus but not meeting statistical significance (5.0% vs 11.2%, p=0.2). There were similar rates of rejection, graft loss, death, and withdrawal from the study between the two groups.
Comment: Multiple studies have suggested that mammalian target of rapamycin inhibitors such as everolimus have anti-CMV properties that support its use as an immunosuppressive treatment in CMV-seropositive patients. Such studies did not assess this effect as a prospective primary outcome, and the use of validated CMV PCR testing at guidelines-endorsed intervals is variable. The present study provides some evidence that this strategy may be effective without the need for additional anti-viral prophylaxis, although rates of the primary outcome were high in both treatment groups, raising some concern about this approach. A dedicated study involving everolimus with or without additional anti-viral prophylaxis may be helpful, as everolimus may be more appropriate for an additive anti-CMV effect rather than replacing the need for an antiviral agent. Larger and longer-term studies would also provide further support for the safety and efficacy of everolimus of CMV-seropositive patients.