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Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist

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Abstract

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.

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Fig. 1
Fig. 2

Abbreviations

MCM:

Methylmalonyl-CoA mutase

MMA:

Methylmalonic acid

MMAurias:

Methylmalonic acidurias

CKD:

Chronic kidney disease

cTIN:

Chronic tubulointerstitial nephritis

aHUS:

Atypical hemolytic syndrome

cbl:

Cobalamin

hPTEC:

Human proximal tubule cells

ROS:

Reactive oxygen species

OH-Cbl:

Hydroxycobalamin

TC II:

Transcobalamin II

MeCbl:

Methylcobalamin

AdoCbl:

Adenosylcobalamin

TCA:

Tricarboxylic acid cycle

TX:

Transplantation

PA:

Propionic aciduria

PC:

Propionyl-CoA carboxylase

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Acknowledgments

We thank Prof. Stefan Kölker for his kind revision of the manuscript.

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Marina A. Morath, Friederike Hörster & Sven W. Sauer

Authors
  1. Marina A. Morath
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  2. Friederike Hörster
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  3. Sven W. Sauer
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Corresponding author

Correspondence to Marina A. Morath.

Additional information

Answers

1. d. All of the above

2. c.

3. e. All of the above

4. b.

5. d.

Questions

Questions

  1. 1.

    Metabolic crises in methylmalonic acidurias are triggered by

    1. a.

      Diarrhea

    2. b.

      Fasting

    3. c.

      Vomiting

    4. d.

      All of the above

  2. 2.

    Which fact about renal disease in methylmalonic acidurias is correct?

    1. a.

      mostly affecting distal tubule cells

    2. b.

      occurring only in adulthood

    3. c.

      existence of a genotype–phenotype correlation

    4. d.

      correlation with cumulative urinary 2-methylcitrate excretion over time

    5. e.

      in most cases curable

  3. 3.

    Which pathomechanisms of cTIN have been proposed?

    1. a.

      mitochondrial glutathione depletion

    2. b.

      impaired mtDNA homeostasis

    3. c.

      synergism of accumulated toxic metabolites

    4. d.

      impaired function of tubule dicarboxylate transporters

    5. e.

      All of the above

  4. 4.

    Which is not a treatment strategy of methylmalonic acidurias?

    1. a.

      high caloric intake

    2. b.

      high protein intake

    3. c.

      carnitine supplementation

    4. d.

      antibiotics

    5. e.

      organ transplantation

  5. 5.

    Atypical hemolytic syndrome

    1. a.

      often results in acute kidney injury

    2. b.

      is a complication of cblC disorder

    3. c.

      is by definition associated with diarrhea

    4. d.

      a and b are correct

    5. e.

      b and c are correct.

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Morath, M.A., Hörster, F. & Sauer, S.W. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol 28, 227–235 (2013). https://doi.org/10.1007/s00467-012-2245-2

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  • DOI: https://doi.org/10.1007/s00467-012-2245-2

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