Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts

Abstract

Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments.

Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC.

Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease.

Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Keywords: CLCN5; Dent disease; FSGS; Low molecular weight proteinuria; Proteinuria; α1-Microglobulin.

Conflict of interest statement

DISCLOSURE

The authors declare that they have no conflicts of interest.

Figures

Fig. 1

Relationship between Total Protein/Creatinine (mg/g) versus Albumin/Total Protein for Dent disease (DD1) (filled circles), CKiD with glomerular disease (CKiD G) (unfilled rhombs) and CKiD with tubulointerstitial disease (CKiD TI) (unfilled triangles) cohorts.

Fig. 2. ROC curves comparing the predictive performance of urinary α1-microglobulin/Creatinine (α1M/Cr), urinary α1-microglobulin/Total Protein (α1M/TP), and Albumin to Total Protein (A/TP) for distinguishing Dent disease 1 (DD1) from the total CKiD cohort.

Circles on each ROC curve represent the cutoff for each marker with the highest sensitivity and specificity.

Fig. 3. ROC curves comparing the predictive performance of α1-microglobulin/Creatinine (α1M/Cr), urinary α1-microglobulin/Total Protein (α1M/TP), and Albumin to Total Protein (A/TP) for distinguishing Dent disease 1 (DD1) and CKiD with glomerular disease (CKiD G) cohort.

Circles on each ROC curve represent the cutoff for each marker with the highest sensitivity and specificity.

Fig. 4. ROC curves comparing the predictive performance of α1-microglobulin/Creatinine (α1M/Cr), urinary α1-microglobulin/Total Protein (α1M/TP), and Albumin to Total Protein (A/TP) for distinguishing Dent disease 1 (DD1) and tubulointerstitial disease (CKiD TI) cohort.

Circles on each ROC curve represent the cutoff for each marker with the highest sensitivity and specificity.