Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis

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Organic acidurias, such as glutaric aciduria type 1 (GA1), methylmalonic (MMA), and propionic aciduria (PA) are a prominent group of inherited metabolic diseases involving accumulation of eponymous metabolites causing endogenous intoxication. For all three conditions, guidelines for diagnosis and management have been developed and revised over the last years, resulting in three revisions for GA1 and one revision for MMA/PA. The process of clinical guideline development in rare metabolic disorders is challenged by the scarcity and limited quality of evidence available. The body of literature is often fragmentary and where information is present, it is usually derived from small sample sizes. Therefore, the development of guidelines for GA1 and MMA/PA was initially confronted with a poor evidence foundation that hindered formulation of concrete recommendations in certain contexts, triggering specific research projects and initiation of longitudinal, prospective observational studies using patient registries. Reversely, these observational studies contributed to evaluate the value of newborn screening, phenotypic diversities, and treatment effects, thus significantly improving the quality of evidence and directly influencing formulation and evidence levels of guideline recommendations. Here, we present insights into interactions between guideline development and (pre)clinical research for GA1 and MMA/PA, and demonstrate how guidelines gradually improved from revision to revision. We describe how clinical studies help to unravel the relative impact of therapeutic interventions on outcome and conclude that despite new and better quality of research data over the last decades, significant shortcomings of evidence regarding prognosis and treatment remain. It appears that development of clinical guidelines can directly help to guide research, and vice versa.

Section: How Development In Guideline Methodology Has Shaped Formulat...mentioning

confidence: 99%

How guideline development has informed clinical research for organic acidurias (et vice versa)

Forny

Hörster

Baumgartner

et al. 2023

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“…The ability for therapeutic interventions to lower sMMA concentrations can be limited by decreased clearance by the kidneys, unless the kidneys are specifically targeted by the treatment. This has been clearly illustrated in the transplant literature, with maximum MMA reduction documented in combined liver–kidney transplant recipients, but not in isolated liver or kidney‐only transplant cohorts 17–19,22,26 . Even in liver and kidney transplant recipients, sMMA remains in the 150–500 μmol/L range due to generation of MMA in extrahepatic organs, mainly in the skeletal muscle 89 .…”

Section: Circulating and Urine Biomarkersmentioning

confidence: 97%

“…This has been clearly illustrated in the transplant literature, with maximum MMA reduction documented in combined liver-kidney transplant recipients, but not in isolated liver or kidney-only transplant cohorts. [17][18][19]22,26 Even in liver and kidney transplant recipients, sMMA remains in the 150-500 μmol/L range due to generation of MMA in extrahepatic organs, mainly in the skeletal muscle. 89 Mean concentrations of sMMA in patients with the mut 0 subgroup, per transplant type, and before/after transplantation in patients enrolled in the NIH natural history study are provided in Figures 4A and 5A, while data from the OPBG patient series are depicted in Figure 5G-I.…”

Section: Methylmalonic Acid: Serum Csf and Urinementioning

confidence: 99%

“…On the other hand, kidney or liver–kidney transplantation is offered to patients with advanced kidney disease in need of renal replacement therapy depending on the degree of associated metabolic instability and disease severity. Isolated kidney transplant as an elective surgery does not provide sufficient enzymatic activity to alleviate disease burden and avoid progression for patients at the severe end of the disease spectrum 24–26 . Reports from large transplant centers on the outcomes of isolated liver or kidney and combined organ transplantations have been invaluable in providing benchmarks for the development of new therapeutics, especially liver‐targeted approaches.…”

Section: Introductionmentioning

confidence: 99%

“…Isolated kidney transplant as an elective surgery does not provide sufficient enzymatic activity to alleviate disease burden and avoid progression for patients at the severe end of the disease spectrum. [24][25][26] Reports from large transplant centers on the outcomes of isolated liver or kidney and combined organ transplantations have been invaluable in providing benchmarks for the development of new therapeutics, especially liver-targeted approaches.…”

Section: Introductionmentioning

confidence: 99%

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Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

Manoli

Gebremariam

McCoy

et al. 2023

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Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin‐2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

Safety, efficacy, and timing of transplantation(s) in propionic and methylmalonic aciduria

Chakrapani

Stojanović

Vara

et al. 2023

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Propionic (PA) and methylmalonic aciduria (MMA) share many clinical similarities, which include the risk of acute metabolic encephalopathies, and some long-term complications, such as optic neuropathy, pancreatic involvement, developmental disability, and similar management approaches, but they also represent distinct clinical and biochemical entities. In the severe forms of PA and MMA, most long-term complications cannot be prevented with conventional clinical management. Organ transplantation represents a form of partial enzyme replacement to improve the long-term outlook for these disorders. There is evidence that early liver transplant in both disorders greatly improves metabolic stability and reduces the risk of long-term complications. For MMA, early liver transplant reduces methylmalonic acid levels which in turns reduces its effects on kidneys, and therefore slows progression of chronic kidney disease. However, established organ damage cannot be reversed. For patients with MMA who present with chronic kidney disease, consideration should be given for combined liver and kidney transplants. Transplantation in PA and MMA carries a high risk of complications and requires highly specialised pre-operative and peri-operative management. Involvement of a multidisciplinary team is essential and should include metabolic team, nephrologist, hepatologist, hepatobiliary and renal transplant surgeons, anaesthesiologists, cardiologists, intensive care team, dieticians and specialist nurses. These patients require life-long multidisciplinary follow-up. There is increasing evidence in the literature on excellent short to medium-term patient and allograft survival following transplantation when patients are managed by a multidisciplinary team in a specialist centre. Improved early diagnosis and reductions in transplant-related mortality and morbidity have allowed early transplantation to be used electively to further improve the outcome.