1 Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU)
(Visual abstract by Divya Bajpai @divyaa24 )
While the threshold for starting treatment may differ, most of us use sodium bicarbonate in acidemic patients in ICU, especially in the setting of acute kidney injury. This is one of those practices where very little evidence exists to guide decisions (in fact nearly equal basic science data exists for and against bicarbonate use).
Much-needed evidence addressing this dilemma now comes from this multicentre, open-label RCT of 389 adult patients who were admitted within 48 h to the ICU with severe acidemia (pH ≤7⋅20, PaCO2 ≤45 mm Hg, and bicarbonate concentration ≤20 mmol/L) and with a SOFA score of ≥4 OR an arterial lactate concentration of ≥2 mmol/L randomized to receive either no sodium bicarbonate (control group) or 4⋅2% of iv sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7⋅30. The primary outcome -a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7- was not different in the two arms: 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate –5⋅5%, 95% CI –15⋅2 to 4⋅2; p=0⋅24) without significant effect of the treatment group (crude OR 0⋅775, 95% CI 0⋅505–1⋅190; p=0⋅24).
In the pre-specified subgroup involving 182 (47% ) patients with AKI-AKIN stage 2 or 3, therapy offered some benefit: the primary outcome occurred in 74 (82%) of 90 patients in the control group and 64 (70%) of 92 patients in the bicarbonate group (absolute difference estimate –12⋅3%, 95% CI –26⋅0 to –0⋅1; p=0·0462)
More patients in control group underwent renal-replacement therapy during their ICU stay (52% vs 35%, absolute difference estimate –16⋅7 days, 95% CI –26⋅4 to –7⋅0; p=0⋅0009; figure 3); and when indicated, renal replacement therapy was started earlier in the control group than in the bicarbonate group (7 hours vs 19 hours). Hyperkalemia and acidosis were the main reasons for RRT in the control group and Serum creatinine and serum blood urea nitrogen were the main reasons to start renal-replacement therapy in the bicarbonate group.
Do these findings change my practice? Not really; IV bicarbonate in lactic acidosis is unlikely to offer any survival advantage where the primary treatment is the treatment of the underlying cause. But in presence of renal insufficiency, bicarbonate therapy may be useful in postponing dialysis and at least is not associated with significant harm. In this sense, the study findings support what we do. See an excellent post on PulmCrit blog here.
2 Canagliflozin and renal outcomes in type 2 diabetes
(Visual abstract by Divya Bajpai @divyaa24 )
Results of CANVAS program were published last year. We discussed the paper here. The trials concluded that patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation.
The results of a prespecified exploratory analysis of the effects of canagliflozin on a range of renal outcomes were published last month in the Lancet. CANVAS program included two comparable studies- CANVAS and CANVAS-R. Participants in CANVAS were randomized to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomized to receive canagliflozin at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. People with type 2 diabetes and an HbA1c of 7·0–10·5% who were aged at least 30 years and had a history of a symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were included in the study.
The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient- years in the placebo group; hazard ratio 0·53, 95% CI 0·33–0·84). After an initial drop in the eGFR, Canagliflozin preserved the eGFR better. New onset albuminuria (micro/macroalbuminuria) occurred less frequently in the canagliflozin group.
Rates of acute kidney injury and hyperkalemia did not differ in the two groups. The heightened risk of amputation and fractures in canagliflozin group was similar in participants with eGFR above and below 60 mL/min per 1·73 m².
Considering very few clinically relevant renal events, these results are hypothesis generating at the best and as authors admit, aren’t enough for the drug to get formally approved for renoprotection in diabetes. The number needed to treat (NNT) for the primary composite outcome in this trial was 771! If we think 40% reduction in MDRD eGFR is a clinically relevant outcome, 296.2 patients would have to receive canagliflozin (instead of control treatment) for one additional patient to NOT have 40% reduction in MDRD eGFR. For surrogate like albuminuria though, the NNT was 36.9.
3 Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients
Gabapentin and pregabalin are often prescribed for neuropathic pain in patients on hemodialysis. KDIGO suggests the use of gabapentin for pruritus and restless leg syndrome. Not surprisingly, many of these patients do not tolerate these medications dependent on renal clearance for their elimination.
From the US Renal Data System, Ishida et al identified 140,899 Medicare-covered adults receiving hemodialysis and investigated the association between gabapentin and pregabalin, and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture.
19% and 4% of patients received gabapentin and pregabalin, respectively. Not unexpectedly, gabapentin was associated with 50%, 55%, and 38% higher hazards of altered mental status, fall, and fracture, respectively, in the highest dose category (>300 mg/day), but even lower dosing was associated with a higher hazard of altered mental status (31%–41%) and fall (26%–30%). Pregabalin was associated with up to 51% and 68% higher hazards of altered mental status and fall, respectively.
Finding the safer doses of these drugs or the safer alternatives to improve the quality of life of these patients is the need of the hour.
4 Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome (RITURNS)
Vitamin R is rocking again!
In an RCT from Kolkata, Basu et al randomized 176 children aged 3 to 16 years with the corticosteroid-dependent nephrotic syndrome to receive either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375mg/m2). Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95%CI, 1.93-14.07). Among the patients who experienced relapse, the median time to the first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Rituximab group had lower cumulative corticosteroid dose (25.8 ±27.8 vs 86.3 ± 58.0 mg/kg) and better catch-up growth.
Mild to moderate infections were twice as common in the tacrolimus group.
Authors conclude that in children with the corticosteroid-dependent nephrotic syndrome, rituximab is more effective than tacrolimus in maintaining disease remission.
A significant number of children with this disease suffer morbidity and mortality that can be associated with immunosuppression and until long-term safety data become available, we need to involve patient families in shared decision making before resorting to the vitamin R.
5 Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones
(Visual abstarct by Aakash Shingada @aakashshingada)
Meltzer et al randomized 512 adults presenting to the emergency department with symptomatic ureteric stones <9 mm in diameter on CT to receive either Tamsulosin or placebo. The primary outcome was the passage of a ureteral stone within 28 days after randomization, as determined by the participant’s visualization or physical capture of the stone. At the end of the 28-day treatment period, the urinary stone passage rate of 49.6% among participants assigned to Tamsulosin did not differ significantly from the placebo passage rate of 47.3%(relative risk, 1.05; 95.8%CI,0.87-1.27;P = .60)
In a large study done in China, tamsulosin arm had a higher stone expulsion rate compared to the placebo (86% vs 79%; p<0.001) for distal ureteral stones of size 4-7 mm. In the subgroup analysis, stones larger than 5 mm had higher odds of expulsion.
It is possible that Tamsulosin does not facilitate expulsion of small stones or the stones in the upper ureter. In the case of larger stones, will this study change the current practice?
6 Belimumab in kidney transplantation
While T-cell mediated rejections are largely treatable, antibody-mediated rejections pose a significant threat to the renal allografts. B cells also have a regulatory role and thus could play both a positive and negative role. Strategies targeting B cells with preservation of their regulatory functions would be a boon to transplantation.
B lymphocyte stimulator (BLyS) is a cytokine that promotes B cell proliferation. High serum concentrations of BLyS are associated with the development of de-novo donor specific antibodies.
We know belimumab as an FDA-approved therapy for non-severe auto-antibody positive SLE. Belimumab is a monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human BLyS to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity.
In a double-blind, randomised, placebo-controlled phase 2 trial sponsored by GSK (manufacturer of belimumab), 28 kidney transplant recipients were randomly assigned to receive iv belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions, in addition to the standard immunosuppression (Basiliximab, tacrolimus, MMF, prednisolone).
Belimumab effectively removed circulating free BLyS. However, the co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. There was no major safety concern observed. There was a nonsignificant trend towards reduction in naive B cells and kidney specific IgG, with significant reductions in activated memory B cells and circulating plasmablasts. In authors’ words, ‘the reduction in activated memory B cells and preformed IgG indicates the drug’s potential in sensitized kidney transplant recipients.’
In larger studies, it will be interesting to see the long-term safety and efficacy of belimumab.
7) Analysis of Luminex-based algorithms to define unacceptable HLA antibodies in CDC-crossmatch negative kidney transplant recipients
With the solid phase assays for identifying anti-HLA antibodies, we now can hope to improve transplant outcomes by avoiding transplantation if anti-HLA antibodies are present. However, this approach will result in a smaller donor pool available for a growing waiting list. CDC cross match may be negative even when anti-HLA antibodies are present. However, relevance of a positive single antigen bead assay in presence of negative CDC cross match is less clear.
In a study from Germany, transplant-day sera of CDC cross-match negative kidney transplant patients were screened retrospectively for the presence of anti-HLA class I and class II IgG antibodies using solid-phase microsphere-based assay. If pretransplant sera revealed the presence of anti-HLA IgG antibodies, the corresponding HLA were classified as unacceptable HLA-antigen mismatches.
Among the 211 patients studied, 115 (54.5%) had anti-HLA-specific IgG antibodies retrospectively detected by the Luminex assay using day of transplant sera. 67/211 patients (31.8%) had donor-specific anti-HLA-antibodies. Among the 67 DSA-positive patients, 16 (23.9%) experienced AMR during a median follow up of 4.9 years, majority occurring within the first year.
Of these 16 patients with AMR, 11 could be identified if the threshold of positive DSA test was kept at MFI value 3000 SAB assay [according to the German Society of Immunogenetics (DGI) consensus, algorithm I]. Authors also tested two more algorithms.
- Algorithm II (ME algorithms): all antibodies against HLA A, B or DR with MFI above 5000 or antibodies against HLA DQ with MFI above 10,000.
- Algorithm III (MFI_10,000): all anti-HLA antibodies with MFI above 10.000.
Algorithms (I) and (II) had comparable efficacy but were superior to (III) in identifying at-risk patients.
To calculate the extent of the Eurotransplant donor pool that would be excluded during organ allocation due to the presence of this kind of unacceptable antigen match due to donor specific antibody, the virtual panel-reactive antibody (vPRA) level was calculated. Median vPRA was between 69.2 and 79.1%, translating into a potential prolongation of waiting time between 1.5 and 1.8 years, respectively.
Donor specific antibodies in absence of CDC cross match positivity reflect a high immunologic risk. At the expense of a better match, this will shrink the donor pool and prolong waiting time.
In order to minimize this impact, we need to understand how to identify those who had DSAs but did not develop rejection.