Persistent hypoglycemic attacks during hemodialysis sessions in an infant with congenital nephrotic syndrome: Answers

Uremia is typically associated with abnormal glucose metabolism. Impaired metabolism and impaired tissue sensitivity of insulin are largely responsible for the abnormal glucose metabolism and hyperglycemia in patients with end-stage kidney disease (ESKD) [1]. The development of spontaneous hypoglycemia is an unusual manifestation of disturbed glucose metabolism in chronic kidney disease (CKD) [2]. There are multiple factors that contribute to hypoglycemia in patients with CKD, including decreased caloric intake, reduced renal gluconeogenesis, impaired release of epinephrine as a counter-regulatory hormone, concurrent hepatic disease, and decreased metabolism of drugs that lead to reduction in the plasma glucose concentration [3]. Infections, low glycogen storage of infants, long hemodialysis (HD) sessions, metabolic diseases, carnitine deficiency, and deficiencies in growth hormone, cortisol, and rarely thyroid hormone may be the other reasons for hypoglycemia in patients receiving HD [4] (Table 1).

The difficulty is that clinical findings of adrenal insufficiency are similar to those of renal failure [5]. Early detection of adrenal insufficiency can be difficult due to non-specific signs and symptoms including general weakness, easy fatigability, weight loss, anorexia, nausea, vomiting, and unexplained fever [6].Unexplained sustained hypotension and persistent hypoglycemia in ESKD patients should alert the clinicians for adrenal insufficiency [5]. Hyperpigmentation, called as “bronzing,” can be the first sign of Addison’s disease. If present, this characteristic change in the skin color should arouse suspicion for the disease in uremic patients. Electrolyte disturbances, especially hyponatremia and hyperkalemia, and metabolic acidosis are other important findings particularly for primary adrenal insufficiency. However, it is not easy to distinguish these abnormalities in patients with ESKD as they may also arise from renal failure. In addition, a patient receiving dialysis with adrenal insufficiency may not show electrolyte imbalance and metabolic acidosis, which is corrected with dialysis solution [7]. This situation may make the diagnosis of adrenal insufficiency harder in patients treated with dialysis.

There are limited data about causes of adrenal insufficiency in pediatric HD patients. According to case reports of adult HD patients, the etiologies of adrenal insufficiency are tuberculosis, systemic AA-amyloidosis, usage of the drugs (like megestrol acetate) which suppress the hypothalamic-pituitary-adrenal axis, pituitary apoplexy or atrophy, isolated ACTH deficiency, history of unilateral adrenalectomy, and steroid withdrawal in rejected renal allografts [8‐13]. An adult study has shown that the rate of adrenal insufficiency was 20% in hypotensive HD patients. Primary adrenal insufficiency was caused mainly by infectious (cytomegalovirus and tuberculosis), autoimmune, and unknown disorders, and the secondary form mostly by exogenous steroid intake in this patient population [5].

In our patient with congenital nephrotic syndrome (CNS), one of the potential causes of primary adrenal insufficiency might be adrenal damage secondary to sepsis. Another potential cause might be a genetic disease that can explain both conditions. Therefore, we analyzed all coding exons of SGPL1, which has recently been shown to be associated with the NPHS14. We found a homozygous variation (c.1079G>T; p.G360V) in SGPL1 (NM_003901) with Sanger sequencing. Both healthy parents were heterozygous for the same variation. Minor allele frequency of the variation was < 0.01. In addition, in silico analyses predicted this variation as pathogenic (i.e., Sorting Intolerant From Tolerant (SIFT) (http://​sift.​jcvi.​org): damaging; MutationTaster (http://​www.​mutationtaster.​org): disease causing; Polymorphism Phenotyping v2 (PolyPhen2) (http://​genetics.​bwh.​harvard.​edu/​pph2/​index.​shtml): probably damaging). Taken together, we considered that this variation is the underlying genetic abnormality causing the phenotype observed in our patient.