Urine concentrating defect as presenting sign of progressive renal failure in Bardet–Biedl syndrome patients

Abstract

Background Urine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet–Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression. Methods The estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls. Results At baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60–90 and <60 mL/min/1.73 m2, respectively; 27.3% showed an ACR >30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P < 0.005), suggesting that urine concentrating defect may predict disease progression. uAQP2 excretion and Na+ and Cl− fractional excretion after furosemide did not differ between hyposthenuric patients and controls, suggesting that specific collecting duct and thick ascending limb dysfunctions are unlikely to play a central role in the pathogenesis of hyposthenuria. Conclusions Hyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function.

Kidney failure in Bardet–Biedl syndrome

“…The prevalence of severe CKD in adults with BBS is reported in 8%–16%, 1,11–13 while the presence of mild or moderate CKD (CKD2‐3) is similar to that in children. Hyposthenuria, reduced urine solute concentrating capacity, resulting in polyuria and polydipsia is observed in all stages of CKD, and its presence may be a warning sign for poor renal outcome 12,14,15 . Renal biopsy is infrequently performed, but renal dysplasia and chronic tubulointerstitial nephropathy are typically identified in individuals with CKD 10,12 .…”

“…The genotype:phenotype correlation of the other BBS genes and KF risk is largely unexplored in BBS 24–26 . The severity of hyposthenuria correlates with both truncating genetic variants and reduced eGFR, suggesting opportunities to explore unknown genetic and pathogenic mechanisms for KF 14,15 …”

“…Hyposthenuria, reduced urine solute concentrating capacity, resulting in polyuria and polydipsia is observed in all stages of CKD, and its presence may be a warning sign for poor renal outcome. 12,14,15 Renal biopsy is infrequently performed, but renal dysplasia and chronic tubulointerstitial nephropathy are typically identified in individuals with CKD. 10,12 Structural genitourinary anomalies are common in BBS and include persistent fetal lobulation, parenchymal and calyceal cysts, hydronephrosis, renal agenesis, horseshoe kidney, vesicoureteral reflux, vaginal atresia, and urogenital sinus.…”

“…[24][25][26] The severity of hyposthenuria correlates with both truncating genetic variants and reduced eGFR, suggesting opportunities to explore unknown genetic and pathogenic mechanisms for KF. 14,15 Furthermore, the genetic correlations of genitourinary anomalies in BBS and KF have not been systematically examined.…”

Diffusion tensor imaging for the study of early renal dysfunction in patients affected by bardet-biedl syndrome

“…BBS patients are prone to develop renal failure 2 . Abnormal renal and urinary tract structures have been reported 3 , 4 ; accordingly, chronic kidney disease (CKD) is considered the most common cause of morbidity and mortality. The renal phenotypes of both patients and mouse models are variable, although a tubulointerstitial defect is postulated to be a common substrate 5 because of the low incidence of proteinuria and the high rate of urine concentration defects 6 , 7 .…”