The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

Abstract

Background: The ciliopathies are a growing number of disorders caused by mutations in genes involved in the function of the primary cilium. Bardet-Biedl syndrome (BBS) belongs to this group of disorders. In this setting, kidney dysfunction is highly variable, and urine concentrating defect, a common feature of multiple ciliopathies, has been described as the most frequent defect. Here we review the mechanism of urine concentration and describe the possible mechanism underling this defect in ciliopathies and especially BBS, based on the current body of literature. Summary: Active Na⁺ absorption along the thick ascending limb of the loop of Henle (TAL) is critical for generating the corticomedullary osmotic gradient, and the countercurrent anatomical arrangement of the 2 branches of the loop of Henle enhances this gradient. The vasa recta, paralleling the loop of Henle, operate into the countercurrent mechanism, minimizing washout of solutes from the interstitium. Final water reabsorption is mediated by the aquaporin 2 (AQP2) water channels along the distal nephron, and it is under hormonal control. Several studies demonstrated that hyposthenuria in BBS patients relies on kidney resistance to desmopressin, suggesting a renal origin. We recently showed that the majority of hyposthenuric BBS patients have also a defect regarding maximal urine dilution. Independent studies showed that BBS10 deficiency caused AQP2 mistrafficking in vitro; accordingly, we demonstrated impaired urinary AQP2 excretion in BBS patients with combined concentrating and diluting defect. Whether receptor signaling pathways or downstream events cause AQP2 deregulation is still unclear. In addition, reduced urinary uromodulin excretion in BBS patients opens the possibility that TAL dysfunction may also play a pathogenic role. Key Message: Impaired water handling in BBS is associated with AQP2 mistrafficking. The potential role of additional factors, such as the dissipation of the medullary osmotic gradient due to TAL dysfunction and/or structural anomalies, remains to be elucidated.

Exploring Key Challenges of Understanding the Pathogenesis of Kidney Disease in Bardet–Biedl Syndrome

“… 60 Kidney-specific Bbs10 KO mice did not exhibit structural and/or functional kidney defects, suggesting that systemic rather than local factors affect kidney function. 95 Finally, Loktev et al. 56 described the phenotype of BBPI10/BBS18 null mice; obesity, hyperphagia, retinal degeneration, and male sterility recapitulated most human findings.…”

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

“…Urine Aquaporin 2 (u-AQP2) excretion has been used as marker of its abundance on the apical membrane of principal collecting duct cells [24]. Interestingly, our study indicated that after long term water restriction, in hyposthenuric BBS patients u-AQP2 excretion was not different compared with healthy volunteers, indicating that the inability to reach the maximum urine osmolality in BBS patients is not the consequence of impaired AQP2 trafficking [10, 25]. However, after acute stimuli, namely acute water loading and dDAVP infusion, BBS patients showed a blunted response of u-AQP2 excretion.…”

Urate-Lowering Agents in Asymptomatic Hyperuricemia: Role of Urine Sediment Analysis and Musculoskeletal Ultrasound

“…Moreover, the increased levels of uric acid in humans might counterbalance the loss of ascorbate. Indeed, uric acid has ‘protective’ properties such as (i) anti-oxidant activity (possibly replacing the loss of ascorbate synthesis) [5, 7], (ii) antinatriuretic and vascular effects mediating blood pressure homeostasis in low-salt environments [4], (iii) neuroprotection, particularly on dopaminergic neurons [8], (iv) modulator of the gut microbiome, whose composition is therefore different in humans from other animals [9, 10] a marker of effective blood volume and antidiuretic hormone levels [11, 12] and an accurate and reliable marker of kidney function [13]. …”