Phenotypic spectrum and antialbuminuric response to angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy in pediatric Dent disease

Abstract

Background To characterize the phenotypic spectrum and assess the antialbuminuric response to angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy in a cohort of children with Dent disease. Methods The patients’ clinical findings, renal biopsy results, genetic and follow‐up data were analyzed retrospectively. Mutations in CLCN5 or OCRL were detected by next‐generation sequencing or Sanger sequencing. Results Of 31 Dent disease boys, 24 carried CLCN5 and 7 carried OCRL mutations. Low molecular weight proteinuria and albuminuria were detected in all cases. Nephrotic‐range proteinuria and severe albuminuria were identified in 52% and 62% of cases, respectively; by 7 years of age, 6 patients had hematuria and nephrotic‐range proteinuria, and 7 patients had hematuria and moderate to severe albuminuria. In addition to disease‐related renal features, patients with Dent‐1 disease also presented with congenital cataract (1/9) and developmental delay (2/7). Seventeen of 31 patients underwent renal biopsy. Glomerular changes included mild glomerular lesions, mesangial proliferative glomerulonephritis and focal segmental glomerular sclerosis. Thirteen of the 31 patients had follow‐up records and received ACE inhibitor and/or ARB treatment for more than 3 months. After a median 1.7 (range 0.3–8.5) years of treatment, a reduction in the urinary microalbumin‐to‐creatinine ratio was observed in 54% of children. Conclusions Hematuria with nephrotic‐range proteinuria or moderate to severe albuminuria was common in Dent disease patients. Extrarenal manifestations were observed in Dent‐1 patients, which extends the phenotypic spectrum. In addition, ACE inhibitors and ARBs are well tolerated, and they are partially effective in controlling albuminuria.

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

“…The reduction in albuminuria levels seen in some DD1 and DD2 patients may be due to the action of RAAS blockers on the proteinuria originating from glomerular damage. This is the picture that emerged in a study by Deng et al on children with Dent disease, despite a decrease in albuminuria levels being reported in only half of those with confirmed glomerular disease (Deng et al 2020). ACEi/ARBs are generally well tolerated by children with Dent disease.…”

“…These extrarenal clinical signs are to be expected, but are not always seen in patients with DD2 (Table 2). On the other hand, congenital cataract and intellectual disability were also described in children with DD1 in whom next-generation sequencing (NGS) studies revealed no OCRL mutations (Deng et al 2020;Sakakibara et al 2020). Dent disease patients are also usually referred to a nephrologist rather than a neurologist (unlike Lowe syndrome patients), so cognitive defects might go unreported, leading to an incomplete description of the clinical phenotype (Bökenkamp et al 2009).…”

“…ACEi/ARBs are generally well tolerated by children with Dent disease. One patient reportedly developed hypotension, which was solved by administrating the drug in the morning (Deng et al 2020). This retrospective study only examined the short-term effects (3 months), however; no studies on the long-term effects of ACEi/ARBs in DD1 and DD2 patients have been reported to date.…”

A novel CLCN5 frame shift mutation responsible for Dent disease 1: Case report

“…The proteinuria was not relieved after the treatment, which was consistent with previous reports ( 21 ). It has been reported that angiotensin converting enzyme inhibitors (ACEI) drugs could reduce the urinary protein excretion in patients with type 1 Dent disease ( 6 , 22 ). On the other hand, Vaisbich et al did not find benefit from ACEI therapy in patients with type 1 Dent disease ( 20 ).…”

Lentiviral vector mediated gene therapy for type I Dent disease ameliorates Dent disease-like phenotypes for three months in ClC-5 null mice

“…Thiazide diuretics can decrease urinary calcium excretion in males with DD1, but side effects are common. 2 Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapies have been tried to ameliorate proteinuria, 13 but do not target the molecular etiology of DD1 and cannot stop its progression. A therapy that targets the molecular etiology is needed for better therapeutic effects.…”