Preservation of kidney function in kidney transplant recipients by alkali therapy (Preserve-Transplant Study): rationale and study protocol

Wiegand, Anna; Ritter, Alexander; Graf, Nicole; Arampatzis, Spyridon; Sidler, Daniel; Hadaya, Karine; Müller, Thomas; Wagner, Carsten A.; Wüthrich, Rudolf P.; Mohebbi, Nilufar

doi:10.1186/s12882-018-0956-8

Cited by 16 publications

(13 citation statements)

References 31 publications

(34 reference statements)

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“…The promising effects of acidosis treatment on CKD progression have been shown in small, randomized controlled clinical trials of adults (15,16,43,44). Currently, there is an ongoing multicenter, randomized trial of alkali therapy use to preserve allograft function in adult transplant participants (45). There are no trials of alkali therapy exclusively in children.…”

Section: Discussionmentioning

confidence: 99%

Low Serum Bicarbonate and CKD Progression in Children

Brown

Roem

et al. 2020

CJASN

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Background and objectivesStudies of adults have demonstrated an association between metabolic acidosis, as measured by low serum bicarbonate levels, and CKD progression. We evaluated this relationship in children using data from the Chronic Kidney Disease in Children study.Design, setting, participants, & measurementsThe relationship between serum bicarbonate and a composite end point, defined as 50% decline in eGFR or KRT, was described using parametric and semiparametric survival methods. Analyses were stratified by underlying nonglomerular and glomerular diagnoses, and adjusted for demographic characteristics, eGFR, proteinuria, anemia, phosphate, hypertension, and alkali therapy.ResultsSix hundred and three participants with nonglomerular disease contributed 2673 person-years of follow-up, and 255 with a glomerular diagnosis contributed 808 person-years of follow-up. At baseline, 39% (237 of 603) of participants with nonglomerular disease had a bicarbonate level of ≤22 meq/L and 36% (85 of 237) of those participants reported alkali therapy treatment. In participants with glomerular disease, 31% (79 of 255) had a bicarbonate of ≤22 meq/L, 18% (14 of 79) of those participants reported alkali therapy treatment. In adjusted longitudinal analyses, compared with participants with a bicarbonate level >22 meq/L, hazard ratios associated with a bicarbonate level of <18 meq/L and 19–22 meq/L were 1.28 [95% confidence interval (95% CI), 0.84 to 1.94] and 0.91 (95% CI, 0.65 to 1.26), respectively, in children with nonglomerular disease. In children with glomerular disease, adjusted hazard ratios associated with bicarbonate level ≤18 meq/L and bicarbonate 19–22 meq/L were 2.16 (95% CI, 1.05 to 4.44) and 1.74 (95% CI, 1.07 to 2.85), respectively. Resolution of low bicarbonate was associated with a lower risk of CKD progression compared with persistently low bicarbonate (≤22 meq/L).ConclusionsIn children with glomerular disease, low bicarbonate was linked to a higher risk of CKD progression. Resolution of low bicarbonate was associated with a lower risk of CKD progression. Fewer than one half of all children with low bicarbonate reported treatment with alkali therapy. Long-term studies of alkali therapy’s effect in patients with pediatric CKD are needed.

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Section: Discussionmentioning

confidence: 99%

Low Serum Bicarbonate and CKD Progression in Children

Brown

Roem

et al. 2020

CJASN

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“…13 A prospective patient-blinded multicenter randomized controlled trial to verify the effectiveness of alkaline administration in transplanted kidneys is ongoing in Switzerland. 34 Our prominent concern in this study was the true frequency and cause of HCMA in transplanted kidneys, as well as determining Two important findings were confirmed by the changes between the two time points of 3 months and 1 year post-KT. The first finding was that HCMA became more apparent under low-Hb conditions and reduced with the increase in the Hb level.…”

Section: Discussionmentioning

confidence: 63%

“…Moreover, unlike the relatively optimistic tone so far 1–4,6 an observational study of a large Korean cohort indicated that the presence of acidosis (total CO 2 < 22 mM) at 3 months after KT had an effect on long‐term graft prognosis 13 . A prospective patient‐blinded multicenter randomized controlled trial to verify the effectiveness of alkaline administration in transplanted kidneys is ongoing in Switzerland 34 …”

Section: Discussionmentioning

confidence: 98%

Increased intrarenal post‐glomerular blood flow is a key condition for the development of calcineurin inhibitor‐induced renal tubular acidosis in kidney transplant recipients

Kaneko

Usui

Takahashi

et al. 2022

Clinical Transplantation

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Background: Hyperchloremic metabolic acidosis (HCMA) from renal tubular acidosis (RTA) is common in kidney transplant (KT) recipients. Calcineurin inhibitors (CNIs) are a potential cause of RTA, and whether HCMA is a determinant of poor graft prognosis is controversial. Methods: The subjects were living‐donor KT recipients (LDKTRs, n = 47) and matched donors (n = 43). All cases of rejection, extrarenal causes, and respiratory disorders were excluded. HCMA was defined as having a [Na+]–[Cl−] value of ≤34 or starting alkalization. We determined the potential causes of HCMA in LDKTRs at 3 months (m) and 1 year (y) post‐KT. We examined renal hemodynamic parameters in 26 LDKTRs at 1 y post‐KT: namely, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF; GFR/RPF) and pre‐/post‐glomerular vascular resistance (pre‐/postVR). Results: The HCMA incidence in the 3‐m post‐KT LDKTR group was higher than that of the donors (51.0% vs. 6.9%, p < 0.001, adjusted odds ratio: 6.7–15.7). Among adjusted factors, the most dominant HCMA contributor was low hemoglobin concentration (Hb ≤ 12 g/dl). Compared to non‐HCMA cases, HCMA patients had low FF and low post‐VR (p = 0.008, 0.003, respectively) suggesting increased intrarenal post‐glomerular blood flow. The high pathological score of alternative arteriolar hyalinosis (aah) ≥2 was a significant HCMA risk. The tacrolimus trough level was not high in HCMA but was significantly high in HCMA in the low post‐VR setting (p = 0.002). Conclusion: Among LDKTRs, low hemoglobin level is an important contributor to the manifestation of HCMA in the induction period, and increased intrarenal post‐glomerular blood flow is a key condition for the development of CNI‐induced RTA.

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“…[9][10][11]25] Alkali therapies are widely available and well tolerated in the pediatric CKD population. [17] Despite the availability of tolerable treatment options, published benefits of acidosis correction in growth impaired children with RTA, and proposed benefits on overall CKD progression [16,[26][27][28][29][30], treatment rates of MA remain suboptimal with only approximately one third of children with low serum bicarbonates in CKiD (one of the largest cohorts of children with CKD) reporting treatment with alkalinizing agents. [7,16] Data from our current investigation suggests that long term use of alkali therapy may have beneficial effects on height in children with CKD.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Associations between Low Serum Bicarbonate and Linear Growth in Children with CKD

Brown

Carroll

et al. 2022

Kidney360

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Background: Poor linear growth is a consequence of chronic kidney disease (CKD) that has been linked to adverse outcomes. Metabolic acidosis (MA) has been identified as a risk factor for growth failure. We investigated the longitudinal relationship between MA and linear growth in children with CKD and examined whether treatment of MA modified linear growth. Methods: To describe longitudinal associations between MA and linear growth, we used serum bicarbonate levels, height measurements and standard deviation (z-scores) of children enrolled in the prospective cohort study, Chronic Kidney Disease in Children. Analyses were adjusted for covariates recognized as correlating with poor growth including demographic characteristics, glomerular filtration rate (GFR), proteinuria, calcium, phosphate, parathyroid hormone, and CKD duration. CKD diagnoses were analyzed by disease categories, non-glomerular or glomerular. Results: The study population included 1082 children with CKD: 808 with non-glomerular etiologies and 274 with glomerular etiologies. Baseline serum bicarbonate levels {less than/equal to}22mEq/L were associated with worse height z-scores in all children. Longitudinally, serum bicarbonate levels {less than/equal to}18mEq/L and 19-22mEq/L were associated with worse height z-scores in children with non-glomerular CKD causes, with adjusted mean values of -0.39, (95%CI: -0.58, -0.20) and -0.17, (95%CI: -0.28, -0.05), respectively. Children with non-glomerular disease and more severe GFR impairment had a higher risk for worse height z-score. A significant association was not found in children with glomerular diseases. We also investigated the potential effect of treatment of MA on height in children with a history of alkali therapy use finding that only persistent users had a significant positive association between their height z-score and higher serum bicarbonate levels. Conclusions: We observed a longitudinal association between MA and lower height z-score. Additionally, persistent alkali therapy use was associated with better height z-scores. Future clinical trials of alkali therapy need to prospectively evaluate this relationship.

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Preservation of kidney function in kidney transplant recipients by alkali therapy (Preserve-Transplant Study): rationale and study protocol

Cited by 16 publications

References 31 publications

Low Serum Bicarbonate and CKD Progression in Children

Low Serum Bicarbonate and CKD Progression in Children

Increased intrarenal post‐glomerular blood flow is a key condition for the development of calcineurin inhibitor‐induced renal tubular acidosis in kidney transplant recipients

Longitudinal Associations between Low Serum Bicarbonate and Linear Growth in Children with CKD

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