Dialysis for Inborn Errors of Metabolism

Inherited dysfunction of amino and organic acid metabolism usually manifests in the early neonatal period by neurologic abnormalities such as irritability, somnolence, and, eventually, coma. In urea cycle defects or organic acidemias, these symptoms are mainly due to excessive hyperammonemia, which may cause irreversible neuronal damage. In disorders of branched-chain amino acid metabolism such as maple syrup urine disease (MSUD), prolonged accumulation of leucine and/or its metabolites (2-ketoisocaproic acid) may lead to severe permanent neurotoxicity.

During the past 3 decades, the prognosis of these previously lethal disorders has been considerably improved by the introduction of several therapeutic principles.

• 1.

  The de novo synthesis of toxic metabolites can be suppressed by a high caloric supply inducing a state of anabolism and reduced proteolysis.

• 2.

  In hyperammonemic disorders, new medications utilize alternative metabolic pathways to reduce neurologic effects. These include sodium benzoate, sodium phenylbutyrate, carbaglutamate, and various vitamins and cofactors.

• 3.

  Specific dietary modifications such as a diet low in branched-chain amino acids in MSUD.

• 4.

  Finally and most importantly, the accumulation of the small, water-soluble neurotoxic metabolites can be rapidly reversed by dialytic removal.

Because the brain damage induced by neurotoxic metabolites is directly correlated with the duration of exposure to the neurotoxic metabolites, neonatal metabolic crises are considered emergency dialysis indications requiring use of the most readily available and effective dialysis modality.

Currently available dialytic regimens include

• Peritoneal dialysis (PD)

• Intermittent hemodialysis or hemodiafiltration (IHD/IHDF)

• Continuous renal replacement therapy (CRRT) (including continuous arteriovenous hemofiltration [CAVH], continuous venovenous hemofiltration [CVVH], continuous arteriovenous hemodialysis [CAVHD], continuous venovenous hemodialysis [CVVHD])

A large body of experimental and clinical evidence suggests that the clearance achievable by PD is much less than that obtained by HD. Historically, HD machines were not created for patients weighing less than 15 kg, which meant that for this unique population group, machines were often difficult to use, required large-bore central venous access, and were operated solely off-label. Because technological advances have improved the suitability of extracorporeal blood purification techniques for neonates, they are now the therapy of choice in appropriately equipped and experienced centers. In 2012, the Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM) was designed and had successfully performed CRRT for infants less than 3 kg. It offers the advantage of extracorporeal dialysis, as well as additional advantages of smaller venous access down to 4 Fr, without sacrificing clearance or causing hemolysis. In addition, the accurate flow monitoring provides benefits to patient safety, although large-scale randomized controlled trials are not available to demonstrate advantages in survival neurological sequelae.

Although extracorporeal dialysis remains the treatment of choice, PD remains an alternative in cases where extracorporeal dialysis is contraindicated. Continuous-flow PD has been introduced as a method to improve clearance rates in PD and to more effectively dialyze neonates, although it is still not a mainstream technique used.

Techniques of Metabolite Removal

In patients with MSUD, the low endogenous clearance of leucine and other branched-chain keto and amino acids (BCAAs) is insufficient to reverse the accumulation of BCAA that occurs during catabolic states. BCAA clearances several times above the endogenous disposal rate are achieved with PD, and continuous extracorporeal blood purification techniques yield two- to threefold greater metabolite removal rates than PD. Although CVVH, CVVHD, and continuous venovenous hemodiafiltration [CVVHDF] have all been shown to be feasible, only HD has demonstrated a significant reduction of dialysis time requirements in comparison to PD.

In hyperammonemic metabolic crises, experimental evidence suggests that ammonium is more efficiently removed by extracorporeal techniques than by PD. Clinical studies have shown that normalization of blood ammonium levels usually cannot be achieved in less than 24 hours by PD, and dialysis is typically required for 2–5 days. CVVH usually reduces blood ammonium concentrations by 90% within 10–12 hours. The most efficient toxin removal method is clearly achieved by CVVHD. The superiority of CVVHD over CVVH is evident from the fact that ammonium clearance with CVVH cannot be greater and is usually considerably less than the plasma flow rate through the dialyzer. In contrast, an ammonium clearance close to dialyzer blood flow can be achieved by CVVHD, as shown in Fig. 78.1 . IHD reliably decreases blood ammonium concentrations by 75% within 3–4 hours. However, repeated sessions are frequently required because of residual or rebound hyperammonemia. Moreover, the use of IHD in neonates and young infants is usually limited by the size of the extracorporeal volume and the rapid depletion of other small solutes such as phosphate. Hence, CVVHD until complete normalization of blood ammonium levels should be considered the treatment of choice when very high dialysate flow rates can be ensured. When not possible, a combination of first IHD followed by CVVHD as maintenance therapy is recommended.