Discussion On Genetic And Non-genetic Causes Of Renal Calculus/nephrocalcinosis

Part 1 Disscussion of non-genetic causes of nephrolithiasis/nephrocalcinosis-The RTA secondary to the primary Sjogren's syndromeObjective:Nephrolithiasis/nephrocalcinosis?NL/NC?is a broad category of disorders that include both genetic and non-genetic causes.Part 1 aimed to explore the influence of renal tubular acidosis?RTA?secondary to the primary Sjogren's syndrome?pSS?on the formation of NL/NC,with a view to strengthening the understanding of non-genetic causes of NL/NC.Methods:From January 1^st,2015 to December 30^th,2018,a total of 38 patients in our hospital with pSS combined with RTA or pSS combined with NL/NC or pSS combined with RTA and NL/NC were selected,including 7 patients in the pSS+RTA group,22 patients in the pSS+NL/NC group and 9 patients in the pSS+RTA+NL/NC group.Retrospective analysis of their clinical data of when diagnoses were made in each group accordingly was performed.Those data included age,gender,clinical manifestations,biochemical levels and therapeutic intervention.Biochemical levels,progression of RTA,NL/NC and renal function of the last follow-up were also collected and analysed.In addition,two pSS patients with typical formation of NC were specially reported.Results:Among the 38 patients,patients both in the pSS+RTA group?7 patients?and pSS+RTA+NL/NC group?9 patients?presented typical distal renal tubular acidosis?dRTA?,while the remaining 22 patients in the pSS+NL/NC group showed no obvious manifestations of metabolic acidosis.The gender and age of diagnosis showed no difference among patients in above three groups.Diagnosis of pSS could be earlier or later than that of the RTA or NL/NC.And sometimes the pSS,RTA and NL/NC could be identified at the same time.The interval that the pSS was diagnosed before RTA or NL/NC was 8 months to 13years,with an average interval of 5.3±1.7 years.The interval that the pSS was diagnosed later than RTA or NL/NC was 1⁷ years,with an average interval of 4.5±0.9 years.The ratio of NL/NC formation in the RTA secondary to pSS was 56.25%?9/16?.There was no significant difference in the proportion of NL or NC in pSS+NL/NC group and pSS+RTA+NL/NC group.The serum levels of pH,HCO₃^-,potassium,chlorine and phosphate differed among the three groups,while no significant difference was observed in serum levels of sodium,magnesium,calcium,creatinine,uric acid and urine pH among the three groups.Different renal involvements were observed in three groups,including hematuria,proteinuria,NL/NC formation and damage of renal function.In addition to etiological treatment,application of potassium supplementation and alkalization therapy could basically relieve acidosis.In general,the prognosis of most patients was relatively good.In two patients with typical formation of NC,who were in the pSS+RTA+NL/NC group and the pSS+NL/NC group,the diagnosis of pSS was 10 years earlier and 7 years later than NC was indentified,respectively.Conclusion:The emergence of RTA or NL/NC may occur earlier or later than the diagnosis of pSS,or at the same time.The ratio of NL/NC formation in the RTA secondary to pSS was 56.25%?9/16?.Although the pSS+NL/NC group showed no obvious metabolic acidosis,it was possible that patients in this group were associated with incomplete dRTA,and NH₄Cl test should be further carried out to get accurate diagnosis.Part 2 Disscussion of genetic causes of nephrolithiasis/nephrocalcinosisObjective:Nephrolithiasis/nephrocalcinosis?NL/NC?is a series of diseases induced by some monogenetic inherited causes.Part 2 aimed to explore the influence of genetic factors on NL/NC by exploring the characteristics of NL/NC in primary dRTA and Bartter syndrome?BS?.Methods:21 previously reported patients with primary dRTA and 9 previously reported patients with BS1 by our research team were included in this study.All of the above patients were confirmed by clinical manifestation and/or genetic testing.Clinical data like manifestations,biochemical levels and imaging information of those patients were analyzed.Results:19 patients?19/21?with dRTA were confirmed to have definite pathogenic mutations,including 7 patients?7/19?with SLC4A1 mutations,7 patients?7/19?with ATP6V0A4mutations and 5 patients?5/19?with ATP6V1B1 mutations.20 patients?20/21?showed low serum pH?7.24±0.06?.All 21 patients showed low serum HCO₃^-?13.02±4.30 mmol/L?and high urinary pH?7.64±0.59?.17 patients?17/21?were suffered from hypokalemia.A total of19 patients?19/21,90.48%?were confirmed with NL/NC by urinary ultrasound,among which,the proportion of patients with SLC4A1 mutation was 71%?5/7?,while all patients with the ATP6V0A4?7/7?or ATP6V1B1?5/5?mutation and all two patients with no definite disease causing mutation were seen obvious NL/NC formation.However,no significant difference?P>0.05?of the incidence of NL/NC was seen among patients with mutations of those above three different genes.4 patients?4/21?developed with rickets/osteomalacia.Except for 1 patient who was not treated in time and progressed to ESRD?end-stage renal disease?,the rest of the patients recovered well after treatment such as citric acid and potassium supplementation.Of the 9 patients with BS1,8 patients?8/9?presented with aBS?antenatal BS?.Except for 1 patient whose serum pH was within the normal range,all the other patients presented metabolic alkalosis?CO₂CP:31.4±3.6 mmol/L?.All 9 patients?9/9?showed hypochloremia?93.4±3.3 mmol/L?and increased renin and aldosterone levels.Hyponatremia was found in 5patients?5/9?,hypokalemia in 7 patients?7/9?,increased urinary potassium/creatinine in 7patients?7/9?,increased urinary calcium/creatinine in 4 patients?4/9?,and bilateral NC in 6patients?6/9,66.67%?confirmed by urinary ultrasound.No significant difference?P>0.05?was seen in serum levels of pH,CO₂CP,sodium,potassium,chlorine,urine calcium/urine creatinine and renin between the two groups with or without NC.Conclusion:The incidence of NC in primary dRTA patients was relatively high with the NC probability of 90.48%?19/21?in this study.However,no significant difference of the incidence of NL/NC was seen among patients with different mutations.The incidence of NC in BS1 patients was 66.7%?6/9?in this study,and the ratio of urinary calcium to urinary creatinine didn't show absolute correlation with NC formation.