Prolonged Hypokalemia Long After Causative Factor Elimination in Pseudo-Bartter/Gitelman Syndrome

Prolonged Hypokalemia Long After Causative Factor Elimination in Pseudo-Bartter/Gitelman Syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Prolonged Hypokalemia Long After Causative Factor Elimination in Pseudo-Bartter/Gitelman Syndrome Atsushi Kondo, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Yu Tanaka, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4168546/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pseudo-Bartter/Gitelman syndrome (PBS/PGS) results from medication and lifestyle factors, causing hypokalemia and potential kidney dysfunction. Treatment involves eliminating the underlying causes, typically leading to rapid improvement. However, PBS/PGS findings may persist long after the removal of causative factors, and its pathogenesis remains unclear. This study focused on 49 cases diagnosed with PBS/PGS based on apparent causes; the cases had no pathogenic variants related to hereditary kidney diseases. They were categorized into two groups: the current group (n = 39), where causative factors persisted, and the past group (n = 10), where more than one year had elapsed since the elimination of the causative factors at the time of examination. A retrospective comparative analysis was conducted between these groups. All patients were female, except for two in the current group. The median time since the elimination of causes in the past group was 7.5 years. Hypokalemia and kidney dysfunction were observed in both groups without statistically significant differences. Both groups exhibited overactivation of renin-angiotensin systems. This study is the first to reveal the possibility of persistent PBS/PGS findings even after the removal of causative factors. While swift removal of the cause of PBS/PGS is crucial, long-term post-removal monitoring is essential to improve renal prognosis. Health sciences/Nephrology Health sciences/Diseases/Kidney diseases/Acid base fluid electrolyte disorders Health sciences/Diseases/Kidney diseases/Chronic kidney disease Pseudo-Bartter/Gitelman syndrome renin-angiotensin system salt-losing tubulopathy hypokalemia hypokalemic nephropathy chronic kidney disease Figures Figure 1 Introduction Gitelman syndrome (GS) is an inherited salt-losing tubulopathy (SLT), which is caused by loss-of-function mutations in the SLC12A3 gene on chromosome 16q13.[1] This gene encodes for a thiazide-sensitive sodium chloride co-transporter located in the distal convoluted tubule of the kidney. When its function is lost or weakened, massive sodium loss in urine occurs, leading to a compensatory loss of potassium and other substances. This results in hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In general, GS has a milder clinical course compared to Bartter syndrome (BS). The onset of GS is commonly later in school age or adulthood, whereas BS is one of the SLTs that mostly occurs in the fetal to infantile period.[1,2] The symptoms of GS are nonspecific and include the following: salt cravings, muscle spasms, muscle weakness, and fatigability. Renal prognosis is usually considered to be good. However, in a large quality of life (QOL) survey in patients with GS, it was revealed that patients suffering from these symptoms had a significant reduction in their QOL.[3] Alternatively, there are some cases in which patients develop symptoms similar to those of GS, despite the absence of any pathogenic variants in SLT-related genes, which is known as pseudo-Bartter/Gitelman syndrome (PBS/PGS).[2,4] The causes of this condition may vary, including some medications that can cause hypokalemia such as diuretics or laxatives, severe hyperemesis gravidarum, alcoholism, anorexia nervosa, and excessive dieting. Among these, long-term regular use of laxatives is reported to be the most common cause.[4] An important clinical feature of PBS/PGS is that these patients are known to be more prone to renal dysfunction compared to patients with GS.[4] Additionally, there are some reports of end-stage kidney disease (ESKD) in patients with PGS due to anorexia nervosa or persistent laxative abuse.[5-7] As no fundamental treatment for PBS/PGS has been established, the main treatments are the elimination of the underlying causes and potassium supplementation. In many cases, such as pregnancy-induced PBS/PGS, electrolyte abnormalities improve immediately once the apparent cause is resolved.[8] However, in some cases, recovery of the electrolyte abnormalities may take a long time after the elimination of causative factors. We encountered several cases in which hypokalemia persisted for years after the cause was resolved, and renal function deteriorated. Although such cases are clinically significant, there have been no reports investigating cases with prolonged hypokalemia and progressive renal dysfunction long after the elimination of the underlying causes of PBS/PGS. In this study, we examined cases of patients diagnosed with PBS/PGS who underwent comprehensive genetic analysis for suspected SLTs. We compared the clinical manifestations of patients with clear and persistent causes of PBS/PGS at diagnosis with those who only had causes of PBS/PGS in the past. Results We focused on 157 cases in which no pathogenic variant was detected despite comprehensive genetic testing including targeted next-generation sequencing (NGS) for 136 genes related to inherited kidney diseases (Supplementary Table S1) for suspected SLT at our institution between April 2006 and April 2023. Additionally, we diagnosed PBS/PGS in 51 cases where a clear medical history of a causative factor of PBS/PGS (e.g., medication and lifestyle history) could be confirmed. These patients were categorized into two groups: the current group (n=39), in which the causative factors persisted at the time of examination, and the past group (n=10), in which at least one year or more had elapsed since the elimination of the causative factors (Figure 1). The characteristics and clinical manifestations of the patients in each group are shown in Table 1. The median age at the time of genetic testing was 44.0 years (range 16–60 years) in the current group and 37.5 years (range 29–58 years) in the past group. All but two patients in the current group were female. Body weight (median 39.0 vs. 51.2 kg p=0.0116) and body mass index (BMI) (median 16.7 vs. 19.4 kg/m 2 , p=0.0031) were both significantly higher in the past group. In the past group, the median time since the elimination of causes was 7.5 years (range: 1–18 years). No obvious hypertension or hypotension was observed except for one case of hypertension in the current group. Diagnostic opportunities included numerous incidental blood tests conducted during routine checkups, screening for infectious diseases, and monitoring the progress of other diseases in both groups. Very few cases were diagnosed with the main complaint of symptoms related to hypokalemia, such as numbness, tetraplegia, tetany, muscle weakness, and fatigue (Table 1). In both groups, emaciation and excessive dieting emerged as the predominant factors contributing to PBS/PGS, accounting for 74.4% in the current group and 80% in the past group, followed by laxative abuse (Table 2). Blood tests conducted before the initiation of treatment revealed evident hypokalemia in both the current and past groups, with a median of 2.4 vs. 2.55 mEq/L, respectively (p=0.5116). The median serum magnesium concentration in the current and past groups was 1.89 mg/dL vs. 1.85 mg/dL, respectively (p=0.985) (Table 3). No significant differences were observed between the two groups in terms of electrolyte parameters or venous blood gas results. Notably, overactivation of the renin–angiotensin system was observed in both groups, as evidenced by a median plasma renin activity (PRA) of 21.2 vs. 13.2 ng/mL/h (p=0.2393) and a median plasma aldosterone concentration (PAC) of 253 vs. 165 pg/mL (p=0.031), in the current and past groups, respectively. While the past group showed a statistically significant decrease in PAC, this finding may imply that causative factor elimination was accomplished. Renal dysfunction was observed in both groups, with no significant differences in renal function at the time of genetic testing. The median serum creatinine level (Cr) was 0.855 vs. 0.83 mg/dL (p=0.9113) and the median estimated glomerular filtration rate (Cr-eGFR)[9] was 57.61 vs. 60.72 mL/min/1.73 m 2 (p=0.8442) in the current and past groups, respectively (Table 3). Furthermore, we conducted another comparative analysis restricted to cases where excessive dieting or emaciation was identified as the sole cause of PBS/PGS. These cases amounted to 15 cases in the current group and 8 cases in the past group. In the past group, the cases were objectively confirmed to have complete removal of the causative agent at the time of genetic testing. As a result, the analysis findings for each item were consistent with those observed for the entire cohort as described above, except that there was no significant difference in PAC (Supplementary Table S2). Discussion To the best of our knowledge, this is the first report indicating the persistence of PBS/PGS findings long after the elimination of the underlying cause. Clinically, it is noteworthy that even in cases where the causative factor has been resolved for over a year, patients continue to manifest the same degree of hypokalemia and renal dysfunction. Incidental blood tests are the most common diagnostic opportunity, suggesting that renal dysfunction may progress without awareness. In the past group, the causes were revealed in some cases for the first time when patients were re-interviewed after negative genetic test results for SLTs were reported. These observations emphasize the importance of detailed medical interviews and the necessity for an extended follow-up period in such cases. Regarding pathogenesis, we suspect that prolonged hypokalemia may result in a low set point for serum potassium levels being fixed in the renal tubules. The details are unknown because there are no previous reports of cases such as those described in this study. However, the observed overactivation of the renin-angiotensin system in the past group, similar to that in the current group, supports this hypothesis, albeit indirectly. No patients in the past group underwent longitudinal evaluation of the renin-angiotensin system, but one case in the current group (Bartter8 in Supplementary Table S3) did. She developed PBS/PGS due to prolonged laxative abuse, and despite the correction of the laxative dosage to an appropriate level, persistent activation of the renin-angiotensin system was confirmed.[7] Chronic hypokalemia has been reported as a factor causing renal impairment, termed hypokalemic nephropathy.[10-12] The pathogenesis of this condition is considered to be renal dysfunction due to decreased renal blood flow. This is caused by increased sodium reabsorption in the proximal tubules due to hyperactivation of the renin-angiotensin system, resulting in diminished urine concentrating ability. Vacuolar degeneration of the proximal tubular epithelial cells is a well-known histological feature. In the past group of this study, renal biopsy was performed in only one case (B027 in Supplementary Table S4). Nonetheless, immunofluorescence and electron microscopy findings were not available, and the details of the light microscopy findings were unclear. It was only reported that no hyperplasia of the juxtaglomerular apparatus was observed. To validate the hypothesis mentioned above, it is necessary to periodically examine PRA and PAC and to accumulate renal pathological findings in PBS/PGS cases. This study has some limitations. First, it is a retrospective study and therefore included cases with incomplete data for some parameters. In particular, urinalysis results could not be confirmed in most cases, and potassium and calcium excretion levels could not be reviewed. Second, diseases other than PBS/PGS may have been present. We excluded other congenital renal tubular diseases by NGS analysis, such as autosomal dominant hypocalcemia, HNF1B -related nephropathy, cystic fibrosis, congenital chloride diarrhea, nephronophthisis, Dent’s disease, mitochondrial disease, and congenital anomalies of the kidney and urinary tract, which are known to present with hypokalemia. 2 However, hypokalemia due to unidentified genetic abnormalities may have been present. Recently, it was reported that some pathogenic mitochondrial DNA (mtDNA) variants in the genes encoding the transfer RNAs for phenylalanine and isoleucine can cause a Gitelman-like syndrome and progressive renal dysfunction.[13] Although we were not able to search for these mtDNA variants in the present study, it is necessary to include the investigation for these variants in comprehensive genetic testing in the future, especially in cases with a maternal inheritance pattern. Lastly, we could not determine whether the severity or duration of PBS/PGS treatment resulted in prolonged hypokalemia after elimination. To clarify these issues, it is necessary to accumulate cases with long-term follow-up after PGS/PGS diagnosis. In conclusion, this study indicates that PBS/PGS findings, including hypokalemia, persist over an extended period, even after the removal of causative factors, indicating a potential link to the development of renal dysfunction. Furthermore, sustained activation of the renin-angiotensin system may be involved in this process. Given that persistent hypokalemia due to PBS/PGS can lead to renal dysfunction and even ESKD in some patients, this prolonged manifestation is clinically significant, emphasizing the need for prompt elimination of the cause and long-term follow-up to improve renal prognosis. However, the lack of previous reports on such cases leaves uncertainty around numerous aspects. Therefore, it is imperative to systematically accumulate additional cases in the future to gain a comprehensive understanding of the intricate pathophysiological mechanisms hypothesized above. Methods A total of 692 patients underwent comprehensive genetic testing including NGS for 136 genes related to inherited kidney diseases (Supplementary Table S1) for suspected SLT at our institution between April 2006 and April 2023. Patient clinical profiles were extracted from the genetic test request forms written by attending physicians and reviewed retrospectively. All patients presented with hypokalemia, which was defined as a serum potassium level of < 3.5 mEq/L, and based on their clinical findings and a thorough examination of potential causes, the attending physician ruled out other associated conditions such as primary aldosteronism, neoplastic disease, or adrenal hyperplasia. In this study, we focused on 157 cases in which no pathogenic variant was detected despite comprehensive genetic testing. Additionally, we diagnosed PBS/PGS in 51 cases where a clear medical history of a causative factor of PBS/PGS (e.g., medication and lifestyle history) could be confirmed. These patients were categorized into two groups: the current group (n=40), in which the causative factors persisted at the time of examination, and the past group (n=11), in which at least one year or more had elapsed since the elimination of the causative factors. One patient in the current group was excluded because he was diagnosed with idiopathic granulomatous interstitial nephritis based on renal biopsy results. Additionally, one patient in the past group was excluded because of the unavailability of detailed laboratory data (Figure 1). The definition of excessive dieting was an intentional weight loss of 5% or more over a 6–12-month period. Emaciation was defined as a sustained BMI of less than 17 kg/m 2 , which corresponds to moderate anorexia nervosa in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.[14] For statistical analysis, the Mann–Whitney U test was employed using GraphPad Prism 9.5.1 for Windows (GraphPad Software, Boston, Massachusetts USA, www.graphpad.com). All analyses were two-tailed, and the significance threshold was set at p < 0.05. Declarations Ethical approval All procedures were reviewed and approved by the Institutional Review Board of the Kobe University School of Medicine. The study was performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients and/or their legal guardians. Acknowledgments We would like to thank Editage (www.editage.jp) for the English language editing. This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23K07698), and Childhood-onset, rare, and intractable kidney diseases in Japan, Research on rare and intractable diseases, Health, Labour and Welfare Sciences Research Grants (20FC1028) to Kandai Nozu. Author contributions A.K. and K.N. contributed to the conception and design of the study. T.H., Y.I., Y.I., Y.T., H.K., C.U., N.S., and C.N. performed the experiments, collected and analyzed the data, and wrote the manuscript. All authors reviewed and approved the final version of the manuscript. Competing interests The authors declare no competing interests. Data availability statement We have provided all data in the text and supplementary data file. References Simon, D. B. et al. Gitelman's variant of Bartter’s syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat. Genet . 12, 24–30 (1996). doi: 10.1038/ng0196-24. Nozu, K. et al. Inherited salt-losing tubulopathy: An old condition but a new category of tubulopathy. Pediatr. Int . 62 , 428–437 (2020). doi: 10.1111/ped.14089. Cruz, D.N., Shaer, A.J., Bia, M.J., Lifton, R.P., Simon, D.B. Gitelman’s syndrome revisited: An evaluation of symptoms and health-related quality of life. Kidney Int . 59 , 710–717 (2001). doi: 10.1046/j.1523-1755.2001.059002710.x. Matsunoshita, N. et al. Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics. Genet. Med . 18 , 180–188 (2016). Doi: 10.1038/gim.2015.56. Yasuhara, D. et al. ‘End-stage kidney’ in longstanding bulimia nervosa. Int. J. Eat. Disord . 38 , 383–385 (2005). doi: 10.1002/eat.20198. Wada, K., Shinoda, T. A case report of an anorexia nervosa patient with end-stage renal disease due to pseudo Bartter’s syndrome and Chinese herb nephropathy requiring maintenance hemodialysis. Ther. Apher. Dial . 12 , 417–420 (2008). doi: 10.1111/j.1744-9987.2008.00621.x. Kondo, A. et al. A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease. CEN Case Rep . Epub ahead of print (2024). doi: 10.1007/s13730-024-00851-9. Yoshihara, M., Sayo, A., Mayama, M., Oguchi, H. Pseudo Gitelman syndrome associated with pregnancy. Obstet. Gynecol . 126 , 877–880 (2015). doi: 10.1097/AOG.0000000000000834. Matsuo, S. et al. Revised equations for estimated GFR from serum creatinine in Japan. Am. J. Kidney Dis . 53 , 982–992 (2009). doi: 10.1053/j.ajkd.2008.12.034. Perkins, J.G., Petersen, A.B., Riley, J.A. Renal and cardiac lesions in potassium deficiency due to chronic diarrhea. Am. J. Med . 8, 115–123 (1950). doi: 10.1016/0002-9343(50)90348-2. Schwartz, W.B., Relman, A.S. Effects of electrolyte disorders on renal structure and function. N. Engl. J. Med . 276 , 383–389 (1967). doi: 10.1056/NEJM196702162760705. Yalamanchili, H.B., Calp-Inal, S., Zhou, X.J., Choudhury, D. Hypokalemic nephropathy. Kidney Int. Rep . 3, 1482–1488 (2018). doi: 10.1016/j.ekir.2018.07.014. Viering, D. et al. Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA. J. Am. Soc. Nephrol . 33, 305–325 (2022). doi:10.1681/ASN.2021050596 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders : DSM-5™ (5th ed.). Arlington, VA: American Psychiatric Publishing, Inc (2013). Tables Tables 1-3 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.xlsx SupplementaryMaterials.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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When its function is lost or weakened, massive sodium loss in urine occurs, leading to a compensatory loss of potassium and other substances. This results in hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In general, GS has a milder clinical course compared to Bartter syndrome (BS). The onset of GS is commonly later in school age or adulthood, whereas BS is one of the SLTs that mostly occurs in the fetal to infantile period.[1,2] The symptoms of GS are nonspecific and include the following: salt cravings, muscle spasms, muscle weakness, and fatigability. Renal prognosis is usually considered to be good. However, in a large quality of life (QOL) survey in patients with GS, it was revealed that patients suffering from these symptoms had a significant reduction in their QOL.[3]\u003c/p\u003e\n\u003cp\u003eAlternatively, there are some cases in which patients develop symptoms similar to those of GS, despite the absence of any pathogenic variants in SLT-related genes, which is known as pseudo-Bartter/Gitelman syndrome (PBS/PGS).[2,4] The causes of this condition may vary, including some medications that can cause hypokalemia such as diuretics or laxatives, severe hyperemesis gravidarum, alcoholism, anorexia nervosa, and excessive dieting. Among these, long-term regular use of laxatives is reported to be the most common cause.[4] An important clinical feature of PBS/PGS is that these patients are known to be more prone to renal dysfunction compared to patients with GS.[4] Additionally, there are some reports of end-stage kidney disease (ESKD) in patients with PGS due to anorexia nervosa or persistent laxative abuse.[5-7] As no fundamental treatment for PBS/PGS has been established, the main treatments are the elimination of the underlying causes and potassium supplementation. In many cases, such as pregnancy-induced PBS/PGS, electrolyte abnormalities improve immediately once the apparent cause is resolved.[8] However, in some cases, recovery of the electrolyte abnormalities may take a long time after the elimination of\u0026nbsp;causative factors. We encountered several cases in which hypokalemia persisted for years after the cause was resolved, and renal function deteriorated. Although such cases are clinically significant, there have been no reports investigating cases with prolonged hypokalemia and progressive renal dysfunction long after the elimination of the underlying causes of PBS/PGS.\u003c/p\u003e\n\u003cp\u003eIn this study, we examined cases of patients diagnosed with PBS/PGS who underwent comprehensive genetic analysis for suspected SLTs. We compared the clinical manifestations of patients with clear and persistent causes of PBS/PGS at diagnosis with those who only had causes of PBS/PGS in the past.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe focused on 157 cases in which no pathogenic variant was detected despite comprehensive genetic testing\u0026nbsp;including targeted next-generation sequencing (NGS) for 136 genes related to inherited kidney diseases (Supplementary Table S1) for suspected SLT at our institution between April 2006 and April 2023. Additionally, we diagnosed PBS/PGS in 51 cases where a clear medical history of a causative factor of PBS/PGS (e.g., medication and lifestyle history) could be confirmed.\u0026nbsp;These patients were categorized into two groups: the current group (n=39), in which the causative factors persisted at the time of examination, and the past group (n=10), in which at least one year or more had elapsed since the elimination of the causative factors\u0026nbsp;(Figure 1).\u003c/p\u003e\n\u003cp\u003eThe characteristics and clinical manifestations of the patients in each group are shown in Table 1. The median age at the time of genetic testing was 44.0 years (range 16\u0026ndash;60 years) in the current group and 37.5 years (range 29\u0026ndash;58 years) in the past group. All but two patients in the current group were female. Body weight (median 39.0 vs. 51.2 kg p=0.0116) and\u0026nbsp;body\u0026nbsp;mass\u0026nbsp;index (BMI)\u0026nbsp;(median 16.7 vs. 19.4 kg/m\u003csup\u003e2\u003c/sup\u003e, p=0.0031) were both significantly higher in the past group.\u0026nbsp;In the past group, the median time since the elimination of causes was 7.5 years (range: 1\u0026ndash;18 years). No obvious hypertension or hypotension was observed except for one case of hypertension in the current group. Diagnostic opportunities included numerous incidental blood tests conducted during routine checkups, screening for infectious diseases, and monitoring the progress of other diseases in both groups. Very few cases were diagnosed with the main complaint of symptoms related to hypokalemia, such as numbness, tetraplegia, tetany, muscle weakness, and fatigue (Table 1).\u0026nbsp;In both groups, emaciation and excessive dieting emerged as the predominant factors contributing to PBS/PGS, accounting for 74.4% in the current group and 80% in the past group, followed by laxative abuse (Table 2).\u003c/p\u003e\n\u003cp\u003eBlood tests conducted before the initiation of treatment revealed evident hypokalemia in both the current and past groups, with a median of 2.4 vs. 2.55 mEq/L, respectively (p=0.5116). The median serum magnesium concentration in the current and past groups was 1.89 mg/dL vs. 1.85 mg/dL, respectively (p=0.985) (Table 3). No significant differences were observed between the two groups in terms of electrolyte parameters or venous blood gas results. Notably, overactivation of the renin\u0026ndash;angiotensin system was observed in both groups, as evidenced by a median plasma renin activity (PRA) of 21.2 vs. 13.2 ng/mL/h (p=0.2393) and a median\u0026nbsp;plasma aldosterone concentration (PAC) of 253 vs. 165 pg/mL (p=0.031), in the current and past groups, respectively. While the past group showed a statistically significant decrease in PAC, this finding may imply that causative factor elimination was accomplished. Renal dysfunction was observed in both groups, with no significant differences in renal function at the time of genetic testing. The median serum creatinine level (Cr) was 0.855 vs. 0.83 mg/dL (p=0.9113) and the median estimated glomerular filtration rate (Cr-eGFR)[9]\u0026nbsp;was 57.61 vs. 60.72 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e (p=0.8442) in the current and past groups, respectively (Table 3).\u003c/p\u003e\n\u003cp\u003eFurthermore, we conducted another comparative analysis restricted to cases where excessive dieting or emaciation was identified as the sole cause of PBS/PGS. These cases amounted to 15 cases in the current group and 8 cases in the past group. In the past group, the cases were objectively confirmed to have complete removal of the causative agent at the time of genetic testing. As a result, the analysis findings for each item were consistent with those observed for the entire cohort as described above, except that there was no significant difference in PAC (Supplementary Table S2).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first report indicating the persistence of PBS/PGS findings long after the elimination of the underlying cause. Clinically, it is noteworthy that even in cases where the causative factor has been resolved for over a year, patients continue to manifest the same degree of hypokalemia and renal dysfunction. Incidental blood tests are the most common diagnostic opportunity, suggesting that renal dysfunction may progress without awareness. In the past group, the causes were revealed in some cases for the first time when patients were re-interviewed after negative genetic test results for SLTs were reported. These observations emphasize the importance of detailed medical interviews and the necessity for an extended follow-up period in such cases.\u003c/p\u003e\n\u003cp\u003eRegarding pathogenesis, we suspect that prolonged hypokalemia may result in a low set point for serum potassium levels being fixed in the renal tubules. The details are unknown because there are no previous reports of cases such as those described in this study. However, the observed overactivation of the renin-angiotensin system in the past group, similar to that in the current group, supports this hypothesis, albeit indirectly. No patients in the past group underwent longitudinal evaluation of the renin-angiotensin system, but one case in the current group (Bartter8 in Supplementary Table S3) did. She developed PBS/PGS due to prolonged laxative abuse, and despite the correction of the laxative dosage to an appropriate level, persistent activation of the renin-angiotensin system was confirmed.[7]\u003c/p\u003e\n\u003cp\u003eChronic hypokalemia has been reported as a factor causing renal impairment, termed hypokalemic nephropathy.[10-12]\u0026nbsp;The pathogenesis of this condition is considered to be renal dysfunction due to decreased renal blood flow. This is caused by increased sodium reabsorption in the proximal tubules due to hyperactivation of the renin-angiotensin system, resulting in diminished urine concentrating ability. Vacuolar degeneration of the proximal tubular epithelial cells is a well-known histological feature.\u0026nbsp;In the past group of this study, renal biopsy was performed in only one case (B027\u0026nbsp;in Supplementary Table S4). Nonetheless, immunofluorescence and electron microscopy findings were not available, and the details of the light microscopy findings were unclear. It was only reported that no hyperplasia of the juxtaglomerular apparatus was observed. To validate the hypothesis mentioned above, it is necessary to periodically examine PRA and PAC and to accumulate renal pathological findings in PBS/PGS cases.\u003c/p\u003e\n\u003cp\u003eThis study has some limitations. First, it is a retrospective study and therefore included cases with incomplete data for some parameters. In particular, urinalysis results could not be confirmed in most cases, and potassium and calcium excretion levels could not be reviewed. Second, diseases other than PBS/PGS may have been present. We excluded other congenital renal tubular diseases by NGS analysis, such as autosomal dominant hypocalcemia, \u003cem\u003eHNF1B\u003c/em\u003e-related nephropathy, cystic fibrosis, congenital chloride diarrhea, nephronophthisis, Dent\u0026rsquo;s disease, mitochondrial disease, and congenital anomalies of the kidney and urinary tract, which are known to present with hypokalemia.\u003csup\u003e2\u003c/sup\u003e However, hypokalemia due to unidentified genetic abnormalities may have been present. Recently, it was reported that some pathogenic mitochondrial DNA (mtDNA) variants in the genes encoding the transfer RNAs for phenylalanine and isoleucine can cause a Gitelman-like syndrome and progressive renal dysfunction.[13] Although we were not able to search for these mtDNA variants in the present study, it is necessary to include the investigation for these variants in comprehensive genetic testing in the future, especially in cases with a maternal inheritance pattern. Lastly, we could not determine whether the severity or duration of PBS/PGS treatment resulted in prolonged hypokalemia after elimination. To clarify these issues, it is necessary to accumulate cases with long-term follow-up after PGS/PGS diagnosis.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study indicates that PBS/PGS findings, including hypokalemia, persist over an extended period, even after the removal of causative factors, indicating a potential link to the development of renal dysfunction. Furthermore, sustained activation of the renin-angiotensin system may be involved in this process. Given that persistent hypokalemia due to PBS/PGS can lead to renal dysfunction and even ESKD in some patients, this prolonged manifestation is clinically significant, emphasizing the need for prompt elimination of the cause and long-term follow-up to improve renal prognosis. However, the lack of previous reports on such cases leaves uncertainty around numerous aspects. Therefore, it is imperative to systematically accumulate additional cases in the future to gain a comprehensive understanding of the intricate pathophysiological mechanisms hypothesized above.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA total of 692 patients underwent comprehensive genetic testing including NGS for 136 genes related to inherited kidney diseases (Supplementary Table S1) for suspected SLT at our institution between April 2006 and April 2023. Patient clinical profiles were extracted from the genetic test request forms written by attending physicians and reviewed retrospectively.\u0026nbsp;All patients presented with hypokalemia, which was defined as a serum potassium level of \u0026lt; 3.5 mEq/L, and based on their clinical findings and a thorough examination of potential causes, the attending physician ruled out other associated conditions such as primary aldosteronism, neoplastic disease, or adrenal hyperplasia.\u0026nbsp;In this study, we focused on 157 cases in which no pathogenic variant was detected despite comprehensive genetic testing. Additionally, we diagnosed PBS/PGS in 51 cases where a clear medical history of a causative factor of PBS/PGS (e.g., medication and lifestyle history) could be confirmed.\u0026nbsp;These patients were categorized into two groups: the current group (n=40), in which the causative factors persisted at the time of examination, and the past group (n=11), in which at least one year or more had elapsed since the elimination of the causative factors. One patient in the current group was excluded because he was diagnosed with idiopathic granulomatous interstitial nephritis based on renal biopsy results. Additionally, one patient in the past group was excluded because of the unavailability of detailed laboratory data (Figure 1).\u003c/p\u003e\n\u003cp\u003eThe definition of excessive dieting was an intentional weight loss of 5% or more over a 6\u0026ndash;12-month period. Emaciation was defined as a sustained BMI of less than 17 kg/m\u003csup\u003e2\u003c/sup\u003e, which corresponds to moderate anorexia nervosa\u0026nbsp;in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.[14]\u003c/p\u003e\n\u003cp\u003eFor statistical analysis, the Mann\u0026ndash;Whitney U test was employed using GraphPad Prism 9.5.1 for Windows (GraphPad Software, Boston, Massachusetts USA, www.graphpad.com). All analyses were two-tailed, and the significance threshold was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures were reviewed and approved by the Institutional Review Board of the Kobe University School of Medicine. The study was performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients and/or their legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for the English language editing.\u003c/p\u003e\n\u003cp\u003eThis study\u0026nbsp;was\u0026nbsp;supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23K07698),\u0026nbsp;and\u0026nbsp;Childhood-onset, rare, and intractable kidney diseases in Japan, Research on rare and intractable diseases, Health, Labour and Welfare Sciences Research Grants (20FC1028) to Kandai Nozu.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.K. and K.N. contributed to the conception and design of the study. T.H., Y.I., Y.I., Y.T., H.K., C.U., N.S., and C.N. performed the experiments, collected and analyzed the data, and wrote the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe have provided all data in the text and supplementary data file.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSimon, D. B. \u003cem\u003eet al.\u003c/em\u003e Gitelman's variant of Bartter\u0026rsquo;s syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. \u003cem\u003eNat. Genet\u003c/em\u003e. \u003cstrong\u003e12,\u003c/strong\u003e 24\u0026ndash;30 (1996). doi: 10.1038/ng0196-24.\u003c/li\u003e\n\u003cli\u003eNozu, K. \u003cem\u003eet al.\u003c/em\u003e Inherited salt-losing tubulopathy: An old condition but a new category of tubulopathy. \u003cem\u003ePediatr. Int\u003c/em\u003e. \u003cstrong\u003e62\u003c/strong\u003e, 428\u0026ndash;437 (2020). doi: 10.1111/ped.14089.\u003c/li\u003e\n\u003cli\u003eCruz, D.N., Shaer, A.J., Bia, M.J., Lifton, R.P., Simon, D.B. Gitelman\u0026rsquo;s syndrome revisited: An evaluation of symptoms and health-related quality of life. \u003cem\u003eKidney Int\u003c/em\u003e. \u003cstrong\u003e59\u003c/strong\u003e, 710\u0026ndash;717 (2001). doi: 10.1046/j.1523-1755.2001.059002710.x.\u003c/li\u003e\n\u003cli\u003eMatsunoshita, N. \u003cem\u003eet al.\u003c/em\u003e Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics. \u003cem\u003eGenet. Med\u003c/em\u003e. \u003cstrong\u003e18\u003c/strong\u003e, 180\u0026ndash;188 (2016). Doi: 10.1038/gim.2015.56.\u003c/li\u003e\n\u003cli\u003eYasuhara, D. \u003cem\u003eet al.\u003c/em\u003e \u0026lsquo;End-stage kidney\u0026rsquo; in longstanding bulimia nervosa. \u003cem\u003eInt. J. Eat. Disord\u003c/em\u003e. \u003cstrong\u003e38\u003c/strong\u003e, 383\u0026ndash;385 (2005). doi: 10.1002/eat.20198.\u003c/li\u003e\n\u003cli\u003eWada, K., Shinoda, T. A case report of an anorexia nervosa patient with end-stage renal disease due to pseudo Bartter\u0026rsquo;s syndrome and Chinese herb nephropathy requiring maintenance hemodialysis. \u003cem\u003eTher. Apher. Dial\u003c/em\u003e. \u003cstrong\u003e12\u003c/strong\u003e, 417\u0026ndash;420 (2008). doi: 10.1111/j.1744-9987.2008.00621.x.\u003c/li\u003e\n\u003cli\u003eKondo, A. \u003cem\u003eet al.\u003c/em\u003e A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease. \u003cem\u003eCEN Case Rep\u003c/em\u003e. Epub ahead of print (2024). doi: 10.1007/s13730-024-00851-9.\u003c/li\u003e\n\u003cli\u003eYoshihara, M., Sayo, A., Mayama, M., Oguchi, H. Pseudo Gitelman syndrome associated with pregnancy. \u003cem\u003eObstet. Gynecol\u003c/em\u003e. \u003cstrong\u003e126\u003c/strong\u003e, 877\u0026ndash;880 (2015). doi: 10.1097/AOG.0000000000000834.\u003c/li\u003e\n\u003cli\u003eMatsuo, S. \u003cem\u003eet al.\u003c/em\u003e Revised equations for estimated GFR from serum creatinine in Japan. \u003cem\u003eAm. J. Kidney Dis\u003c/em\u003e. \u003cstrong\u003e53\u003c/strong\u003e, 982\u0026ndash;992 (2009). doi: 10.1053/j.ajkd.2008.12.034.\u003c/li\u003e\n\u003cli\u003ePerkins, J.G., Petersen, A.B., Riley, J.A. Renal and cardiac lesions in potassium deficiency due to chronic diarrhea. \u003cem\u003eAm. J. Med\u003c/em\u003e. \u003cstrong\u003e8,\u003c/strong\u003e 115\u0026ndash;123 (1950). doi: 10.1016/0002-9343(50)90348-2.\u003c/li\u003e\n\u003cli\u003eSchwartz, W.B., Relman, A.S. Effects of electrolyte disorders on renal structure and function. \u003cem\u003eN. Engl. J. Med\u003c/em\u003e. \u003cstrong\u003e276\u003c/strong\u003e, 383\u0026ndash;389 (1967). doi: 10.1056/NEJM196702162760705.\u003c/li\u003e\n\u003cli\u003eYalamanchili, H.B., Calp-Inal, S., Zhou, X.J., Choudhury, D. Hypokalemic nephropathy. \u003cem\u003eKidney Int. Rep\u003c/em\u003e. \u003cstrong\u003e3,\u003c/strong\u003e 1482\u0026ndash;1488 (2018). doi: 10.1016/j.ekir.2018.07.014.\u003c/li\u003e\n\u003cli\u003eViering, D. \u003cem\u003eet al.\u003c/em\u003e Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA. \u003cem\u003eJ. Am. Soc. Nephrol\u003c/em\u003e. \u003cstrong\u003e33,\u003c/strong\u003e 305\u0026ndash;325 (2022). doi:10.1681/ASN.2021050596\u003c/li\u003e\n\u003cli\u003e\u003cem\u003eAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders\u003c/em\u003e: DSM-5\u0026trade; (5th ed.). Arlington, VA: American Psychiatric Publishing, Inc (2013).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-3 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pseudo-Bartter/Gitelman syndrome, renin-angiotensin system, salt-losing tubulopathy, hypokalemia, hypokalemic nephropathy, chronic kidney disease","lastPublishedDoi":"10.21203/rs.3.rs-4168546/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4168546/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePseudo-Bartter/Gitelman syndrome (PBS/PGS) results from medication and lifestyle factors, causing hypokalemia and potential kidney dysfunction. Treatment involves eliminating the underlying causes, typically leading to rapid improvement. However, PBS/PGS findings may persist long after the removal of causative factors, and its pathogenesis remains unclear. This study focused on 49 cases diagnosed with PBS/PGS based on apparent causes; the cases had no pathogenic variants related to hereditary kidney diseases. They were categorized into two groups: the current group (n\u0026thinsp;=\u0026thinsp;39), where causative factors persisted, and the past group (n\u0026thinsp;=\u0026thinsp;10), where more than one year had elapsed since the elimination of the causative factors at the time of examination. A retrospective comparative analysis was conducted between these groups. All patients were female, except for two in the current group. The median time since the elimination of causes in the past group was 7.5 years. Hypokalemia and kidney dysfunction were observed in both groups without statistically significant differences. Both groups exhibited overactivation of renin-angiotensin systems. This study is the first to reveal the possibility of persistent PBS/PGS findings even after the removal of causative factors. While swift removal of the cause of PBS/PGS is crucial, long-term post-removal monitoring is essential to improve renal prognosis.\u003c/p\u003e","manuscriptTitle":"Prolonged Hypokalemia Long After Causative Factor Elimination in Pseudo-Bartter/Gitelman Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-22 01:58:58","doi":"10.21203/rs.3.rs-4168546/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d89fc960-0aa6-4242-b171-27cdf5de3a7b","owner":[],"postedDate":"April 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30760148,"name":"Health sciences/Nephrology"},{"id":30760149,"name":"Health sciences/Diseases/Kidney diseases/Acid base fluid electrolyte disorders"},{"id":30760150,"name":"Health sciences/Diseases/Kidney diseases/Chronic kidney disease"}],"tags":[],"updatedAt":"2024-10-23T05:55:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-22 01:58:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4168546","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4168546","identity":"rs-4168546","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}