Proteinuria in Dent disease: a review of the literature

Abstract

BackgroundDent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review.DesignPubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein–creatinine ratio > Albustix) was used for NP classification.ResultsData were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria.ConclusionMore than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.

A role for OCRL in glomerular function and disease

“…Three other splicing predictive tools (SpliceSiteFinder-like, MaxEntScan [35] and NNSPLICE [36], which are algorithms run on the bioinformatics interface Alamut) also showed the OCRL variant abolished the splice acceptor site (data not shown). Taken together, these programs strongly suggest that the mature transcript of the OCRL variant will undergo exon skipping of exon 15 to yield the mature transcript illustrated (right) significantly benefit low molecular weight proteinuria (indicative of tubular dysfunction), yet there are reports of improvement in proteinuria after commencing enalapril therapy in a patient with Dent disease [21], supporting a therapeutic approach targeting a glomerular origin for proteinuria.…”

“…In our patient case, the pathology was caused by an exon 15 skipping mutation. This is the commonest exon for reported OCRL mutations but is not in the domain where IPIP27A binds (which is exons [21][22].…”

“…In the absence of extra-renal manifestations characteristic of Lowe syndrome, a diagnosis of Dent-2 disease was made [17]. A mutation in CLCN5, which is expressed in podocytes [18], has also been identified in Dent-1 patients presenting with nephrotic range proteinuria and FSGS on renal biopsy [19][20][21], and in a recent review by van Berkel et al, glomerulosclerosis was detected in almost two thirds of patients with Dent disease [22]. Nephrotic-range proteinuria [22] has been reported in several other studies of novel and known pathogenic OCRL mutations [15,16,22,23].…”

Personalized Intervention in Monogenic Stone Formers

“…22,43 Type 1 is caused by X-linked recessive mutations in CLCN5 , encoding an H+/Cl− exchanger. Since the disease is rare and has a variable presentation, it may escape clinical diagnosis.…”

“…Therefore, recognition by genetic screening (as reported in 1 instance 6 ) will enable avoidance of unnecessary biopsy or allow empirical immunosuppressive therapy, as well as the opportunity to plan for curative transplant. 43 However, it is noteworthy that low molecular weight proteinuria, comprising retinol binding protein and β2-microglobulin, is a hallmark of the disease and a better route to diagnosis.…”