Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist

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.

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

“…All individuals with isolated MMA, even those who are mildly affected, are thought to be at risk of developing renal insufficiency [252]. Chronic kidney disease (CKD) occurred in 47% of patients with a median age of onset at 6.5y [48] and was found most frequently in mut° (61%) and cblB (66%), less frequently in cblA (21%) and mut − (0%) patients [25].…”

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

“…HUS may cause hypertension, intravascular haemolysis, microscopic haematuria, proteinuria and renal function deterioration, occasionally proceeding to renal failure (Van Hove et al 2002; Guigonis et al 2005; Sharma et al 2007; Geraghty et al 1992; Morath et al 2013). A case of focal segmental glomerulosclerosis and atypical glomerulopathy (Brunelli et al 2002) has been reported.…”

Kidney disease and organ transplantation in methylmalonic acidaemia

“…CVVHDF was very effective at reducing ammonia in one case (Figure S1A). Daily PD may even be more successful at reducing MMA levels as compared with thrice‐weekly HD . In centers lacking the expertise for HD or CRRT while awaiting transfer or if HD cannot be performed because patient is to unstable, peritoneal dialysis should be initiated .…”

“…Furthermore, carnitine may be cleared by hemodialysis . Recent preclinical/experimental evidence suggests that the secondary mitochondrial dysfunction may be instrumental in kidney disease progression in MMA . Multiple deficiencies of OXPHOS and respiratory chain enzyme deficiencies have been demonstrated in the kidney of children with MMA who presented a more severe phenotype .…”