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. 2020 Dec 6;14(6):1545-1551.
doi: 10.1093/ckj/sfaa182. eCollection 2021 Jun.

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

Miriam Zacchia  1 , Francesca Del Vecchio Blanco  2 , Annalaura Torella  2 , Raffaele Raucci  1 , Giancarlo Blasio  2 , Maria Elena Onore  2 , Emanuela Marchese  3   4 , Francesco Trepiccione  1   5 , Caterina Vitagliano  1 , Valentina Di Iorio  6 , Perna Alessandra  1 , Francesca Simonelli  6 , Vincenzo Nigro  2   7 , Giovambattista Capasso  1   5 , Davide Viggiano  1   8
Affiliations

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

Miriam Zacchia et al. Clin Kidney J. .

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.

Keywords: GFR; ciliopathy; genetics; kidney disease; urine osmolality.

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Figures

FIGURE 1:
FIGURE 1:
Kidney function trajectory in BBS subjects. (A) eGFR declines with age in BBS. Inset: the rate of decrease does not significantly change with age [Pearson’s coefficient of eGFR variation (mL/min/year) versus age = −0.27, P = 0.17]. (B) Urine osmolarity changes do not follow the same trajectory of the eGFR decline as a function of age. Fitting curves are quadratic for panel A and linear for the inset and for panel B. 95% CIs are also reported.
FIGURE 2:
FIGURE 2:
uAQP2:creatinine ratio in four healthy volunteers and five hyposthenuric BBS patients. Each lane is representative of uAQP2 abundance per 0.5 mg creatinine loaded. Densitometric analysis is shown in the right panel.
FIGURE 3:
FIGURE 3:
Furosemide test showing mean FENa% and FECl% at baseline and every hour up to 4 h in five hyposthenuric BBS patients and five controls. Both BBS patients and controls showed a significant increase after furosemide administration, with no difference among the two groups.
FIGURE 4:
FIGURE 4:
Schematic representation of a proposed mechanism leading to renal disease in BBS.
See this image and copyright information in PMC

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