The human microsomal 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) metabolizes active cortisol into cortisone and protects the mineralocorticoid receptor from glucocorticoid occupancy. In a congenital deficiency of 11 beta-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia. In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene. This is a 4-yr-old male with arterial hypertension. The plasma renin activity and serum aldosterone were undetectable in the presence of a high cortisol to cortisone ratio. PCR amplification and sequence analysis of HSD11B2 gene showed the homozygous mutation in exon 4 Asp223Asn (GAC-->AAC) and a single nucleotide substitution C-->T in intron 3. Using site-directed mutagenesis, we generated a mutant 11 beta HSD2 cDNA containing the Asp223Asn mutation. Wild-type and mutant cDNA was transfected into Chinese hamster ovary cells and enzymatic activities were measured using radiolabeled cortisol and thin-layer chromatography. The mRNA and 11 beta HSD2 protein were detected by RT-PCR and Western blot, respectively. Wild-type and mutant 11 beta HSD2 protein was expressed in Chinese hamster ovary cells, but the mutant enzyme had only 6% of wild-type activity. In silico 3D modeling showed that Asp223Asn changed the enzyme's surface electrostatic potential affecting the cofactor and substrate enzyme-binding capacity. The single substitution C-->T in intron 3 (IVS3 + 14 C-->T) have been previously reported that alters the normal splicing of pre-mRNA, given a nonfunctional protein. These findings may determine the full inactivation of this enzyme, explaining the biochemical profile and the early onset of hypertension seen in this patient.
Idiopathic nephrotic syndrome is the most common glomerular disease in childhood, affecting 1 to 3 per 100,000 children under the age of 16. It most commonly occurs in ages between 2 and 10. Its cause is unknown, and its histology corresponds to minimal change disease in 90% of cases, or focal segmental glomerulosclerosis. Steroid-resistant nephrotic syndrome represents 10-20% of idiopathic nephrotic syndrome in pediatrics. It has a poor prognosis, and its management is a significant therapeutic challenge. Half of patients evolve to end-stage renal disease within 5 years, and are additionally exposed to complications secondary to persistent NS and to the adverse effects of immunosuppressive therapy. The primary goal of treatment is to achieve complete remission, but even a partial remission is associated with a better renal survival than the lack of response. This paper is the result of the collaborative effort of the Nephrology Branch of the Chilean Society of Pediatrics with aims at helping pediatricians and pediatric nephrologists to treat pediatric idiopathic nephrotic syndrome. In this second part, handling of steroid-resistant nephrotic syndrome as well as nonspecific therapies are discussed.
Idiopathic nephrotic syndrome is the most common glomerular disease in childhood, affecting 1 to 3 per 100,000 children under the age of 16. It most commonly occurs in ages between 2 and 10. Its cause is unknown and its histology corresponds to minimal change disease in 90% of cases, or focal segmental glomerulosclerosis. 80 to 90% of cases respond to steroids (steroid-sensitive nephrotic syndrome) with good prognosis and long-term preservation of renal function over time. 70% of patients with SSNS have one or more relapses in their evolution, and of these, 50% behave as frequent relapsing or steroid-dependent, a group that concentrate the risk of steroid toxicity. Patients with steroid-resistant nephrotic syndrome have a poor prognosis and 50% of them evolve to end-stage renal disease. The goal of therapy is to induce and maintain remission of the disease, reducing the risk secondary to proteinuria while minimizing the adverse effects of treatments, especially with prolonged use of corticosteroids. This paper is the result of the collaborative effort of the Nephrology Branch of the Chilean Society of Pediatrics with aims at helping pediatricians and pediatric nephrologists to treat pediatric SNI. In this first part, recommendations of steroid-sensitive nephrotic syndrome are discussed.
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