Subclinical proximal tubulopathy in hepatitis B:The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity,such as estimated glomerular filtration rate(eGFR)and phosphatemia,are late markers of proximal tubulopathy.Multiple early markers are available,but no consensus exists on their use.AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy(SPT),as defined with early biomarkers,in treated vs untreated hepatitis B virus(HBV)-monoinfected patients.METHODS A prospective,non-randomized,multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted.The patients were separated into three groups:Naïve,starting entecavir(ETV)treatment,or starting tenofovir disoproxil(TDF)treatment.Data on the early markers of SPT,the eGFR and phosphatemia,were collected quarterly.SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%.The prevalence and cumulative incidence of SPT at month 24(M24)were calculated.Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests,whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data.Multivariate analyses were used to adjust for any potential confounding factors.RESULTS Of the 196 patients analyzed,138(84 naïve,28 starting ETV,and 26 starting TDF)had no SPT at inclusion.At M24,the prevalence of SPT was not statistically different between naïve and either treated group(21.1%vs 30.7%,P<0.42 and 50.0%vs 30.7%,P=0.32 for ETV and TDF,respectively);no patient had an eGFR lower than 50 mL/min/1.73 m²or phosphatemia less than 0.48 mmoL/L.In the multivariate analysis,no explanatory variables were identified after adjustment.The cumulative incidence of SPT over 24 mo(25.5%,13.3%,and 52.9%in the naïve,ETV,and TDF groups,respectively)tended to be higher in the TDF group vs the naïve group(hazard ratio:2.283,P=0.05).SPT-free survival at M24 was 57.6%,68.8%,and 23.5%for the naïve,ETV,and TDF groups,respectively.The median survival time without SPT,evaluated only in the TDF group,was 5.9 mo.CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients.SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

New SLC12A3 disease causative mutation of Gitelman's syndrome

Gitelman's syndrome(GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazidesensitive Na Cl cotransporter. In this study we report a new mutation of SLC12A3 found in two brothers affected by GS. Hypokalemia, hypocalciuria and hyperreninemia were present in both patients while hypomagnesemia was detected only in one. Both patients are compound heterozygotes carrying one well known GS associated mutation(c.2581 C > T) and a new one(c.283 del C) in SLC12A3 gene. The new mutation results in a possible frame-shift with a premature stopcodon(pG ln95 Argfs X19). The parents of the patients, heterozygous carriers of the mutations found in SLC12A3, have no disease associated phenotype. Therefore, the new mutation is causative of GS.

Hypokalemic Paresis Revealing a Primary Sjogren’s Syndrome

Hypokalemic acidosis can complicate a primary Sj&ouml;gren’s syndrome. The clinical feature is rarely revealed by manifestations due to hypokalemia. We report the case of a 46-year-old woman, admitted to explore a paresthesia and paresis of inferior limbs. The diagnosis of Sj&ouml;gren’s syndrome was retained since there was the association of xerophthalmia, sialadenitis at the labial biopsy and positive immunological results (anti-SSA and anti-SSB). The absence of another auto-immune or systemic illness allowed us to consider that the Sj&ouml;gren’s syndrome was primary. The biological explorations revealed a hyperchloremic and hypokalemic acidosis. The treatment was based on corticosteroid and potassium supplementation. The follow-up was marked by a clinical and biological amelioration.

Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly

Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple epithelia.Sequence variants in CLDN10 have been linked to HELIX syndrome,a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary,sweat,and lacrimal glands.Here,we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10.In addition to hypohidrosis(H),electrolyte(E)imbalance with impaired urine concentrating ability,and hypolacrimia(L),phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis(I)nor xerostomia(X).Employing cellular TJ reconstitution assays,we demonstrate perturbation of cis-and trans-interactions between mutant claudin-10 proteins.Ultrastructures of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant case.Throughout,both major isoforms,claudin-10a and claudin-10b,are differentially affected with claudin-10b showing more severe molecular alterations.However,expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity,indicating that aberrant claudin-10 is generally capable of forming functional paracellular channels.Thus,mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly.Additional ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.

Molecular pathophysiology of Bartter's and Gitelman's syndromes

Background:In the last two decades,progress in cytogenetic and genome research has enabled investigators to unravel the underlying molecular mechanisms of inherited tubulopathies such as Bartter's and Gitelman's syndromes and helped physicians to better understand not only these two pathologic entities but also renal pathophysiology and salt sensitive hypertension.Data sources:Articles collected from PubMed and open access journals included original articles,research articles,and comprehensive reviews.They were evaluated by the authors with an special emphasis on originality and up to date information about molecular pathophysiology.Results:Bartter's and Gitelman's syndromes are two different inherited salt loosing tubulopathies.They are characterized by various inability of distal nephron to reabsorb sodium chloride with resultant extarcellular volume contraction and increased activity of the renin angiotensin aldosterone system.Hypokalemic metabolic alkalosis is a common feature of these two forms of tubulopathies.Hypercalciuria characterizes the majority of Bartter's syndrome,and hypomagnesemia with hypocalciuria characterizes Gitelman's syndrome.Low blood pressure is a common feature among patients who suffered from these tubulopathies.Bartter's syndromes encompass a heterogeneous group of ion channels defects localized at the thick ascending limp of Henle's loop with resultant loss of function of sodium-potassium-2 chloride cotransporter.These defects result in the impairment of the countercurrent multiplication system of the kidney as well as calcium,potassium and acid base disturbances which in the majority of cases are proved lethal especially in the antenatal and/or immediate postnatal life period.The underlying pathology in Gitelman's syndrome is defined to the distal convoluted tubule and is related to loss of function of the sodium-chloride cotransporter.The results of this defect encompass the inability of extracellular volume homeostasis,magnesium and potassium conservation,and acid base disturbances which are generally mild and in the majority of cases are not life-threatening.Conclusions:Recent advances in molecular patho­physiology of Bartter's and Gitelman's syndromes have helped physicians to better understand the underlying mechanisms of these pathologic entities which remain obscure.Data collected from experiments among genetically manipulated animals enable us to better understand the pathophysiology of mammalian kidney and the underlying mechanisms of salt sensitive hypertension and to lay a foundation for the future development of new drugs,especially diuretics and antihypertensive drugs.