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

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.

Observations of a large Dent disease cohort.

Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.

Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports.

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia. AIMS: To review the long-term treatment of NSIAD. METHODS: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports. RESULTS: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient. CONCLUSIONS: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion.

Vasopressin type 2 receptor V88M mutation: molecular basis of partial and complete nephrogenic diabetes insipidus.

BACKGROUND/AIMS: Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis. METHODS: Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors. RESULTS: Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression. CONCLUSION: The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation.

Day-to-Day variation of the urine protein: creatinine ratio in female dogs with stable glomerular proteinuria caused by X-linked hereditary nephropathy.

BACKGROUND: Interpretation of serial urine protein:creatinine (UPC) values is confounded by a lack of data regarding random biologic variation of UPC values in dogs with stable glomerular proteinuria. HYPOTHESIS: That there is minimal day-to-day variability in the UPC of dogs with unchanging proteinuria and the number of measurements needed to reliably estimate UPC varies with the magnitude of proteinuria. ANIMALS: Forty-eight heterozygous (carrier) female dogs with X-linked hereditary nephropathy (XLHN) causing stable proteinuria. METHODS: Urine samples were obtained daily by cystocentesis for 3 consecutive days on 183 occasions (549 samples). The UPC was measured for each sample with a single dry-film chemistry auto-analyzer. Data were analyzed retrospectively by a power of the mean model because the variance of UPC values within the 3-day evaluation periods increased as the magnitude of proteinuria increased. RESULTS: To demonstrate a significant difference (P < .05) between serial values in these proteinuric dogs, the UPC must change by at least 35% at high UPC values (near 12) and 80% at low UPC values (near 0.5). One measurement is adequate to reliably estimate the UPC when UPC <4, but 2-5 determinations are necessary at higher UPC values. CONCLUSIONS AND CLINICAL IMPORTANCE: These guidelines for interpretation of serial UPC values in female dogs with XLHN may also be helpful for interpretation of UPC values in dogs with other glomerulopathies.

Urinary biomarkers of renal disease in dogs with X-linked hereditary nephropathy.

BACKGROUND: Sensitive and specific biomarkers for early tubulointerstitial injury are lacking. HYPOTHESIS: The excretion of certain urinary proteins will correlate with the state of renal injury in dogs with chronic kidney disease. ANIMALS: Twenty-five male colony dogs affected with X-linked hereditary nephropathy (XLHN) and 19 unaffected male littermates were evaluated. METHODS: Retrospective analysis of urine samples collected every 2-4 weeks was performed. Urine proteins evaluated were retinol binding protein (uRBP/c), ß2-microglobulin (uB2M), N-acetyl-ß-D-glucosaminidase (uNAG/c), neutrophil gelatinase-associated lipocalin (uNGAL/c), and immunoglobulin G (uIgG/c). Results were correlated with serum creatinine concentration (sCr), glomerular filtration rate (GFR), urine protein : creatinine ratio, and histopathologic analysis of serial renal biopsies. Analytical validation was performed for all assays; uNAG stability was evaluated. RESULTS: All urinary biomarkers distinguished affected dogs from unaffected dogs early in their disease process, increasing during early and midstages of disease. uRBP/c correlated most strongly with conventional measures of disease severity, including increasing sCr (r = 0.89), decreasing GFR (r = -0.77), and interstitial fibrosis (r = 0.80), P < .001. However, multivariate analysis revealed age, sCr, uIgG/c, and uB2M, but not uRBP/c, as significant independent predictors of GFR (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: All urinary biomarkers were elevated before sCr increased, but typically after proteinuria developed in dogs with progressive glomerular disease because of XLHN. uRBP/c measurement might be promising as a noninvasive tool for diagnosis and monitoring of tubular injury and dysfunction in dogs.

Novel techniques and newer markers for the evaluation of "proximal tubular dysfunction".

Renal Fanconi syndromes are both clinically challenging and physiologically fascinating. The diagnosis requires a certain index of suspicion to correctly identify the clinical symptomatology and pursue the appropriate laboratory evaluations. The renal Fanconi syndrome (FS) is a defect of proximal tubular function attributable to different rare inherited diseases or acquired disorders caused by a multitude of exogenous agents. It can manifest as complete or incomplete FS, characterized by low molecular weight proteinuria, glucosuria, aminoaciduria, and loss of electrolytes, bicarbonate and lactate. Implementation of new methods and recent findings from urinary proteome pattern in patients with renal FS has led to the identification of new markers for proximal tubular dysfunction. Future combined proteomic and metabonomic studies will provide additional potential biomarkers and may help to gain novel insights in the diagnosis and differentiation of the various forms of FS. Moreover, the observation of poor renal uptake of 99 mTc-DMSA in patients with tubular proteinuria, which is not fully understood yet, may also help to elucidate the individual basis of FS in early stages. This review focuses on the new advances in the evaluation of proximal tubular dysfunction in various forms of Fanconi syndrome.