Topical Brinzolamide-induced renal tubular acidosis in a patient with chronic kidney disease: a case report and review of the diagnostic blind spot

Topical Brinzolamide-induced renal tubular acidosis in a patient with chronic kidney disease: a case report and review of the diagnostic blind spot | 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 Case Report Topical Brinzolamide-induced renal tubular acidosis in a patient with chronic kidney disease: a case report and review of the diagnostic blind spot Ming-Yuan Victor Chao, Yi-chun Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8899942/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Metabolic acidosis is a common complication of advanced chronic kidney disease (CKD). However, when the severity of acidosis outweighs the degree of renal dysfunction, exogenous causes must be excluded. Carbonic anhydrase inhibitors (CAIs) are known to cause hyperchloremic metabolic acidosis, but the systemic toxicity of topical ophthalmic formulations is frequently overlooked. We report a case of severe distal renal tubular acidosis (RTA) precipitating acute-on-chronic kidney injury, caused by the systemic absorption of topical brinzolamide. Case presentation: A 73-year-old Asian male with stage 3 CKD and glaucoma presented with progressive dyspnea, anorexia, and weight loss one month after initiating brinzolamide/timolol eye drops. Laboratory evaluation revealed severe metabolic acidosis (pH 7.29, HCO3 - 8.9 mEq/L) and acute kidney injury. While the serum anion gap was elevated, the delta-delta ratio of 0.55 and a positive urine anion gap (+ 33.4 mEq/L) indicated a concomitant normal anion gap metabolic acidosis consistent with RTA. Discontinuation of the ophthalmic solution and alkali therapy resulted in the resolution of acidosis and recovery of renal function to baseline. Conclusions Topical CAIs can undergo significant systemic absorption, bypassing first-pass metabolism, and precipitate life-threatening acidosis in patients with reduced renal reserve. Clinicians must maintain a high index of suspicion for ophthalmic medications as hidden causes of mixed acid-base disorders in patients with CKD. Renal tubular acidosis Carbonic anhydrase inhibitors Brinzolamide Metabolic acidosis Chronic kidney disease Urine anion gap Glaucoma 1. Background Metabolic acidosis is a pervasive complication of advanced chronic kidney disease (CKD), typically resulting from the retention of unmeasured anions or impaired ammoniagenesis. However, when the severity of acidosis is disproportionate to the degree of renal dysfunction, clinicians must investigate exogenous etiologies. Carbonic anhydrase inhibitors (CAIs) are well-established causes of hyperchloremic metabolic acidosis when administered orally. While these agents are frequently used in topical ophthalmic formulations for glaucoma, their systemic toxicity is often overlooked. These topical agents can bypass hepatic first-pass metabolism via nasolacrimal absorption, potentially leading to significant systemic levels. Existing literature indicates that while rare, this systemic absorption can precipitate severe acid-base disturbances, particularly in the elderly or those with compromised renal reserve [1]. The aim of this case report is to illustrate a critical diagnostic blind spot in medication reconciliation. We describe a case of severe, symptomatic distal renal tubular acidosis (RTA) precipitating acute-on-chronic kidney injury, caused by the systemic absorption of topical brinzolamide in a patient with pre-existing CKD. This report emphasizes the necessity of utilizing stepwise acid-base interpretation, specifically the delta-delta ratio and urine anion gap, to uncover hidden causes of acidosis. 2. Case presentation A 73-year-old Asian man with a history of stage 3 CKD (baseline serum creatinine ~ 2.0 mg/dL), chronic bronchiectasis, and glaucoma presented to the outpatient clinic with a one-month history of progressive dyspnea, anorexia, and generalized weakness. He also reported a mild diffuse abdominal pain and a 3-kilograms weight loss (38 kilograms to 35 kilograms) over the preceding month but denied fever, cough, diarrhea, or melena. His medication history was notable for the initiation of a fixed-combination ophthalmic solution containing brinzolamide 1% and timolol 0.5% (Azarga) one month prior to presentation. On examination, the patient appeared clinically stable with a blood pressure of 136/92 mmHg and regular heart rate. Pulmonary auscultation revealed bilateral coarse breath sounds. The abdominal was soft and non-tender, and there was no costovertebral angle tenderness or peripheral edema. Laboratory evaluations revealed severe metabolic acidosis with a pH of 7.29, serum bicarbonate of 8.9 mEq/L, and partial pressure of carbon dioxide (P a CO2) of 18.8 mmHg. Serum creatinine was elevated at 3.9 mg/dL, and serum potassium was 3.3 mEq/L. The serum anion gap (AG) was elevated at 15.1 mEq/L. Given the patient’s hypoalbuminemia (2.7 g/dL), the expected anion gap was adjusted downward. Consequently, the delta-delta ratio was calculated at 0.55. Additional blood tests, including a complete blood count, demonstrated no anemia, thrombocytopenia, or leukocytosis suggestive of infection or inflammation. Liver function tests, including alanine aminotransferase, aspartate aminotransferase, bilirubin, and ammonia, were all normal. Laboratory tests for lactate, ketone, and autoimmune titers (including ANA, anti-dsDNA, anti-SSA, and anti-SSB) were also negative. Electrocardiogram showed left ventricular hypertrophy. Chest and abdominal imaging reported bilateral hilar bronchiectasis but otherwise non-significant. To differentiate the cause of the non-anion gap component, a urine anion gap(UAG) was obtained, which was positive (+ 33.4 mEq/L). The fractional excretion of bicarbonate (FeHCO 3 ) was 4.3%. Combined with hypokalemia and positive UAG, these findings supported a diagnosis of Renal Tubular Acidosis. The laboratory status was summarized in Table 1 . Given the temporal relationship between the initiation of eye drops and symptom onset, brinzolamide-induced RTA was suspected. The ophthalmic solution was discontinued and replaced with a non-CAI alternative. The patient was treated with intravenous hydration and sodium bicarbonate, followed by oral sodium bicarbonate and dietary modifications emphasizing increased fruit and vegetable intake. One week later, the acidosis had been resolved (pH 7.41, HCO 3 - 25.7 mEq/L), and renal function improved to near baseline (Creatinine 1.8 mg/dL). At the one-year follow-up, the patient remained asymptomatic with stable renal function. 3. Discussion and Conclusions This case highlights that topical ophthalmic agents can be a potent source of systemic toxicity. Brinzolamide is a sulfonamide derivative that inhibits carbonic anhydrase (CA) isozyme II. Although intended for local effect, the solution drains through the nasolacrimal duct into the highly vascularized nasopharyngeal mucosa, allowing direct entry into systemic circulation and bypassing hepatic first-pass metabolism [1]. In the renal tubule, the cytosolic enzyme Carbonic Anhydrase II (CA-II) is essential for acid-base transport in multiple segments. In the proximal tubule, CA-II generates the intracellular protons required for apical secretion and the bicarbonate for basolateral reabsorption [2]. In the distal nephron, specifically within alpha-intercalated cells, CA-II provides the substrate protons for the apical H + -ATPase pump, a critical step for urinary acidification and ammonium trapping [2,3]. Consequently, pharmacological inhibition of CA-II can mimic features of both proximal (Type 2) and distal (Type 1) RTA. In our case, the finding of a positive urine anion gap confirms a functional defect in distal hydrogen ion secretion (NH4 + excretion), supporting a mixed or distal-predominant RTA phenotype driven by this mechanism [4]. While acid-base homeostasis is typically maintained in patients with normal renal function despite significant acid loads, patients with CKD are uniquely vulnerable. As detailed by Kraut and Madias, while residual nephrons in CKD adapt via increased per-nephron ammoniagenesis, the critical reduction in total nephron mass eventually limits the overall capacity [5]. Consequently, the net renal acid excretion becomes insufficient to match endogenous or exogenous acid loads, predisposing these patients to severe metabolic acidosis. The diagnostic key in this case was the stepwise interpretation of the acid-base status. A cursory review might have attributed acidosis solely to uremia (High AG). However, the Delta-Delta ratio revealed a significant hyperchloremic component, and the positive urine anion gap confirmed a renal tubular defect. Management involves prompt discontinuation of the offending agent and alkali replacement. Only two case reports have documented similar toxicity with both brinzolamide and dorzolamide, demonstrating the unique yet significant risk in patients with renal impairment [6,7]. Furthermore, large-scale population studies suggest that topical CAIs are correlated with an increased risk of metabolic acidosis and adverse renal outcomes, including the need for dialysis, in patients with advanced CKD [8]. Interestingly, this case also highlights the utility of dietary interventions. Evidence suggests that increasing dietary alkali through fruits and vegetables can be as effective as oral sodium bicarbonate in correcting metabolic acidosis in CKD, with potential cardiovascular benefits [9]. In conclusion, topical carbonic anhydrase inhibitors can precipitate life-threatening metabolic acidosis in patients with compromised renal function. Clinicians must maintain a high index of suspicion for these agents in elderly patients with glaucoma and CKD. Furthermore, this case supports the utility of dietary interventions, such as increasing fruit and vegetable intake, as an effective strategy to manage metabolic acidosis in this population (Table 2 ). Abbreviations The following abbreviations are used in this manuscript: AG Anion gap ANA Anti-Nuclear antibody CAIs Carbonic anhydrase inhibitors CKD Chronic kidney disease dsDNA Double-Stranded Deoxyribonucleic Acid RTA Renal tubular acidosis SSA Sjögren's-syndrome-related antigen A SSB Sjögren's-syndrome-related antigen B UAG Urine anion gap Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare that they have no competing interests. Funding: The authors received no specific funding for this work. Author Contribution MYVC and YCW contributed to the writing of the manuscript. Both the authors reviewed and approved the final version of the manuscript. Acknowledgements: Not applicable. Data Availability All data generated or analyzed during this study are included in this published article. References Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol Auckl N Z. 2016;10:2433–41. https://doi.org/10.2147/OPTH.S118409 . Purkerson JM, Schwartz GJ. The role of carbonic anhydrases in renal physiology. Kidney Int. 2007;71:103–15. https://doi.org/10.1038/sj.ki.5002020 . Hamm LL, Nakhoul N, Hering-Smith KS. Acid-Base Homeostasis. Clin J Am Soc Nephrol. 2015;10:2232–42. https://doi.org/10.2215/CJN.07400715 . Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol. 2002;13:2160–70. https://doi.org/10.1097/01.asn.0000023430.92674.e5 . Kraut JA, Madias NE. Metabolic Acidosis of CKD: An Update. Am J Kidney Dis. 2016;67:307–17. https://doi.org/10.1053/j.ajkd.2015.08.028 . Menon GJ, Vernon SA. Topical brinzolamide and metabolic acidosis. Br J Ophthalmol. 2006;90:247–8. https://doi.org/10.1136/bjo.2005.075622 . Hoffmanová I, Sánchez D. Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function. Br J Clin Pharmacol. 2018;84:796–9. https://doi.org/10.1111/bcp.13499 . Wang Y-C, Ling XC, Tsai W-H, Liu J-S, Kuo K-L. Risks of Topical Carbonic Anhydrase Inhibitors in Glaucoma Patients With Chronic Kidney Disease: A Nationwide Population-Based Study. Am J Ophthalmol. 2023;253:49–55. https://doi.org/10.1016/j.ajo.2023.05.007 . Goraya N, Munoz-Maldonado Y, Simoni J, Wesson DE. Fruit and Vegetable Treatment of Chronic Kidney Disease-Related Metabolic Acidosis Reduces Cardiovascular Risk Better than Sodium Bicarbonate. Am J Nephrol. 2019;49:438–48. https://doi.org/10.1159/000500042 . Tables Table 1 Initial Laboratory Data on Presentation Parameter Value Reference Range Serum Sodium, mEq/L 131 135–145 Potassium, mEq/L 3.3 3.6–5.2 Chloride, mEq/L 107 95–105 Albumin, g/dL 2.7 3.5-5.0 Creatinine, mg/dL 3.9 0.6–1.1 BUN, mg/dL 46 6–21 Arterial blood gas PH 7.29 7.35–7.45 PaO 2, mmHg 124 > 80 PaCO 2 , mmHg 18.8 35.0–45.0 Bicarbonate, mEq/L 8.9 22–26 Urine Urine PH 5.5 5.0–8.0 Urine Sodium, mEq/L 72 N/A Urine Potassium, mEq/L 15.4 N/A Urine Chloride, mEq/L 54 N/A Note: Unit conversion factors: serum urea nitrogen in mg/dL to mmol/L, \(\:\times\:\) 0.357; creatinine in mg/dL to mmol/L, \(\:\times\:\) 88.4. Table 2 Summary of notable key points 1. Systemic Absorption Matters: Topical ophthalmic medications, such as brinzolamide and dorzolamide, can be absorbed systemically and reach therapeutic levels sufficient to cause systemic toxicity, including severe metabolic acidosis. 2. CKD is a Major Risk Factor: Patients with chronic kidney disease are at high risk for CAI-induced acidosis due to impaired drug excretion and reduced capacity for acid-base compensation. 3. Diagnostic Rigor: In complex acid-base disorders, calculating the Delta-Delta ratio is essential. It helps identify mixed disorders (e.g., concomitant RTA) that might be masked by a high anion gap metabolic acidosis associated with AKI. 4. Dietary Management: In addition to pharmacological alkali therapy, increasing fruit and vegetable intake is an evidence-based strategy to manage metabolic acidosis in CKD patients, helping to preserve renal function and improve outcomes. Abbreviations The following abbreviations are used in this manuscript: Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Apr, 2026 Reviews received at journal 19 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviews received at journal 16 Mar, 2026 Reviewers agreed at journal 06 Mar, 2026 Reviewers invited by journal 06 Mar, 2026 Editor invited by journal 20 Feb, 2026 Editor assigned by journal 18 Feb, 2026 Submission checks completed at journal 18 Feb, 2026 First submitted to journal 17 Feb, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8899942","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":601865913,"identity":"e885dc2c-81ab-4449-bf2a-31bc6d77fc65","order_by":0,"name":"Ming-Yuan Victor Chao","email":"","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming-Yuan","middleName":"Victor","lastName":"Chao","suffix":""},{"id":601865914,"identity":"6e5ac9a3-0610-4914-8505-1081e4969d90","order_by":1,"name":"Yi-chun Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYDAC9uYDzCCaH0QkFBCjhedYAliLZANIiwExWiRyDMBaDA6ASSJ06M5IMPxc2HbHbvP51YkfHhgwyPOLHcCvxezMg2TpmW3PkrfdeLtZAugww5mzEwhoOZ5wjJm37XCy2Y2zG0BaEgxuE9JyILENrMV4xtnNP4jTciKZDaTFzoC/dxuRtpw5xizNc+5wgsQN3m0WCQYSxPil/+NnnrLD9vz9Zzff/FFhI88vTUALDCQ2SIBVShCnHATsGfgPEK96FIyCUTAKRhYAABuMSLKdkUfcAAAAAElFTkSuQmCC","orcid":"","institution":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","correspondingAuthor":true,"prefix":"","firstName":"Yi-chun","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-02-17 10:09:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8899942/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8899942/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104432806,"identity":"9e19d27b-bc61-42ca-9cc2-ffc0869bbb98","added_by":"auto","created_at":"2026-03-11 15:59:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":521843,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8899942/v1/ce80dd04-f9ff-4aec-8f62-495175557a1c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Topical Brinzolamide-induced renal tubular acidosis in a patient with chronic kidney disease: a case report and review of the diagnostic blind spot","fulltext":[{"header":"1. Background","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMetabolic acidosis is a pervasive complication of advanced chronic kidney disease (CKD), typically resulting from the retention of unmeasured anions or impaired ammoniagenesis. However, when the severity of acidosis is disproportionate to the degree of renal dysfunction, clinicians must investigate exogenous etiologies.\u003c/p\u003e \u003cp\u003eCarbonic anhydrase inhibitors (CAIs) are well-established causes of hyperchloremic metabolic acidosis when administered orally. While these agents are frequently used in topical ophthalmic formulations for glaucoma, their systemic toxicity is often overlooked. These topical agents can bypass hepatic first-pass metabolism via nasolacrimal absorption, potentially leading to significant systemic levels. Existing literature indicates that while rare, this systemic absorption can precipitate severe acid-base disturbances, particularly in the elderly or those with compromised renal reserve [1].\u003c/p\u003e \u003cp\u003eThe aim of this case report is to illustrate a critical diagnostic blind spot in medication reconciliation. We describe a case of severe, symptomatic distal renal tubular acidosis (RTA) precipitating acute-on-chronic kidney injury, caused by the systemic absorption of topical brinzolamide in a patient with pre-existing CKD. This report emphasizes the necessity of utilizing stepwise acid-base interpretation, specifically the delta-delta ratio and urine anion gap, to uncover hidden causes of acidosis.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"2. Case presentation","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA 73-year-old Asian man with a history of stage 3 CKD (baseline serum creatinine\u0026thinsp;~\u0026thinsp;2.0 mg/dL), chronic bronchiectasis, and glaucoma presented to the outpatient clinic with a one-month history of progressive dyspnea, anorexia, and generalized weakness. He also reported a mild diffuse abdominal pain and a 3-kilograms weight loss (38 kilograms to 35 kilograms) over the preceding month but denied fever, cough, diarrhea, or melena. His medication history was notable for the initiation of a fixed-combination ophthalmic solution containing brinzolamide 1% and timolol 0.5% (Azarga) one month prior to presentation. On examination, the patient appeared clinically stable with a blood pressure of 136/92 mmHg and regular heart rate. Pulmonary auscultation revealed bilateral coarse breath sounds. The abdominal was soft and non-tender, and there was no costovertebral angle tenderness or peripheral edema. Laboratory evaluations revealed severe metabolic acidosis with a pH of 7.29, serum bicarbonate of 8.9 mEq/L, and partial pressure of carbon dioxide (P\u003csub\u003ea\u003c/sub\u003eCO2) of 18.8 mmHg. Serum creatinine was elevated at 3.9 mg/dL, and serum potassium was 3.3 mEq/L. The serum anion gap (AG) was elevated at 15.1 mEq/L. Given the patient\u0026rsquo;s hypoalbuminemia (2.7 g/dL), the expected anion gap was adjusted downward. Consequently, the delta-delta ratio was calculated at 0.55. Additional blood tests, including a complete blood count, demonstrated no anemia, thrombocytopenia, or leukocytosis suggestive of infection or inflammation. Liver function tests, including alanine aminotransferase, aspartate aminotransferase, bilirubin, and ammonia, were all normal. Laboratory tests for lactate, ketone, and autoimmune titers (including ANA, anti-dsDNA, anti-SSA, and anti-SSB) were also negative.\u003c/p\u003e \u003cp\u003eElectrocardiogram showed left ventricular hypertrophy. Chest and abdominal imaging reported bilateral hilar bronchiectasis but otherwise non-significant. To differentiate the cause of the non-anion gap component, a urine anion gap(UAG) was obtained, which was positive (+\u0026thinsp;33.4 mEq/L). The fractional excretion of bicarbonate (FeHCO\u003csub\u003e3\u003c/sub\u003e) was 4.3%. Combined with hypokalemia and positive UAG, these findings supported a diagnosis of Renal Tubular Acidosis. The laboratory status was summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eGiven the temporal relationship between the initiation of eye drops and symptom onset, brinzolamide-induced RTA was suspected. The ophthalmic solution was discontinued and replaced with a non-CAI alternative. The patient was treated with intravenous hydration and sodium bicarbonate, followed by oral sodium bicarbonate and dietary modifications emphasizing increased fruit and vegetable intake. One week later, the acidosis had been resolved (pH 7.41, HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e 25.7 mEq/L), and renal function improved to near baseline (Creatinine 1.8 mg/dL). At the one-year follow-up, the patient remained asymptomatic with stable renal function.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"3. Discussion and Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis case highlights that topical ophthalmic agents can be a potent source of systemic toxicity. Brinzolamide is a sulfonamide derivative that inhibits carbonic anhydrase (CA) isozyme II. Although intended for local effect, the solution drains through the nasolacrimal duct into the highly vascularized nasopharyngeal mucosa, allowing direct entry into systemic circulation and bypassing hepatic first-pass metabolism [1].\u003c/p\u003e \u003cp\u003eIn the renal tubule, the cytosolic enzyme Carbonic Anhydrase II (CA-II) is essential for acid-base transport in multiple segments. In the proximal tubule, CA-II generates the intracellular protons required for apical secretion and the bicarbonate for basolateral reabsorption [2]. In the distal nephron, specifically within alpha-intercalated cells, CA-II provides the substrate protons for the apical H\u003csup\u003e+\u003c/sup\u003e-ATPase pump, a critical step for urinary acidification and ammonium trapping [2,3]. Consequently, pharmacological inhibition of CA-II can mimic features of both proximal (Type 2) and distal (Type 1) RTA. In our case, the finding of a positive urine anion gap confirms a functional defect in distal hydrogen ion secretion (NH4\u003csup\u003e+\u003c/sup\u003e excretion), supporting a mixed or distal-predominant RTA phenotype driven by this mechanism [4].\u003c/p\u003e \u003cp\u003eWhile acid-base homeostasis is typically maintained in patients with normal renal function despite significant acid loads, patients with CKD are uniquely vulnerable. As detailed by Kraut and Madias, while residual nephrons in CKD adapt via increased per-nephron ammoniagenesis, the critical reduction in total nephron mass eventually limits the overall capacity [5]. Consequently, the net renal acid excretion becomes insufficient to match endogenous or exogenous acid loads, predisposing these patients to severe metabolic acidosis.\u003c/p\u003e \u003cp\u003eThe diagnostic key in this case was the stepwise interpretation of the acid-base status. A cursory review might have attributed acidosis solely to uremia (High AG). However, the Delta-Delta ratio revealed a significant hyperchloremic component, and the positive urine anion gap confirmed a renal tubular defect. Management involves prompt discontinuation of the offending agent and alkali replacement. Only two case reports have documented similar toxicity with both brinzolamide and dorzolamide, demonstrating the unique yet significant risk in patients with renal impairment [6,7]. Furthermore, large-scale population studies suggest that topical CAIs are correlated with an increased risk of metabolic acidosis and adverse renal outcomes, including the need for dialysis, in patients with advanced CKD [8]. Interestingly, this case also highlights the utility of dietary interventions. Evidence suggests that increasing dietary alkali through fruits and vegetables can be as effective as oral sodium bicarbonate in correcting metabolic acidosis in CKD, with potential cardiovascular benefits [9].\u003c/p\u003e \u003cp\u003eIn conclusion, topical carbonic anhydrase inhibitors can precipitate life-threatening metabolic acidosis in patients with compromised renal function. Clinicians must maintain a high index of suspicion for these agents in elderly patients with glaucoma and CKD. Furthermore, this case supports the utility of dietary interventions, such as increasing fruit and vegetable intake, as an effective strategy to manage metabolic acidosis in this population (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eThe following abbreviations are used in this manuscript:\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"524\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAnion gap\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eANA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAnti-Nuclear antibody\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCAIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCarbonic anhydrase inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCKD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eChronic kidney disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003edsDNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDouble-Stranded Deoxyribonucleic Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRTA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRenal tubular acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSjögren's-syndrome-related antigen A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSSB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSjögren's-syndrome-related antigen B\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUrine anion gap\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests:\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMYVC and YCW contributed to the writing of the manuscript. Both the authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFarkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol Auckl N Z. 2016;10:2433\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/OPTH.S118409\u003c/span\u003e\u003cspan address=\"10.2147/OPTH.S118409\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePurkerson JM, Schwartz GJ. The role of carbonic anhydrases in renal physiology. Kidney Int. 2007;71:103\u0026ndash;15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/sj.ki.5002020\u003c/span\u003e\u003cspan address=\"10.1038/sj.ki.5002020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamm LL, Nakhoul N, Hering-Smith KS. Acid-Base Homeostasis. 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Am J Kidney Dis. 2016;67:307\u0026ndash;17. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/j.ajkd.2015.08.028\u003c/span\u003e\u003cspan address=\"10.1053/j.ajkd.2015.08.028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMenon GJ, Vernon SA. Topical brinzolamide and metabolic acidosis. Br J Ophthalmol. 2006;90:247\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bjo.2005.075622\u003c/span\u003e\u003cspan address=\"10.1136/bjo.2005.075622\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffmanov\u0026aacute; I, S\u0026aacute;nchez D. Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function. Br J Clin Pharmacol. 2018;84:796\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/bcp.13499\u003c/span\u003e\u003cspan address=\"10.1111/bcp.13499\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y-C, Ling XC, Tsai W-H, Liu J-S, Kuo K-L. Risks of Topical Carbonic Anhydrase Inhibitors in Glaucoma Patients With Chronic Kidney Disease: A Nationwide Population-Based Study. Am J Ophthalmol. 2023;253:49\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ajo.2023.05.007\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2023.05.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoraya N, Munoz-Maldonado Y, Simoni J, Wesson DE. Fruit and Vegetable Treatment of Chronic Kidney Disease-Related Metabolic Acidosis Reduces Cardiovascular Risk Better than Sodium Bicarbonate. Am J Nephrol. 2019;49:438\u0026ndash;48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000500042\u003c/span\u003e\u003cspan address=\"10.1159/000500042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eInitial Laboratory Data on Presentation\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eValue\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003cp\u003eRange\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSerum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSodium, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135\u0026ndash;145\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePotassium, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.6\u0026ndash;5.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChloride, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95\u0026ndash;105\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlbumin, g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5-5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine, mg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6\u0026ndash;1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBUN, mg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u0026ndash;21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArterial blood gas\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.35\u0026ndash;7.45\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePaO\u003csub\u003e2,\u003c/sub\u003e mmHg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e124\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;80\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35.0\u0026ndash;45.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBicarbonate, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u0026ndash;26\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine PH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.0\u0026ndash;8.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine Sodium, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine Potassium, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine Chloride, mEq/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003eNote: Unit conversion factors: serum urea nitrogen in mg/dL to mmol/L, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\times\\:\\)\u003c/span\u003e\u003c/span\u003e0.357; creatinine in mg/dL to mmol/L, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\times\\:\\)\u003c/span\u003e\u003c/span\u003e88.4.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSummary of notable key points\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e1. Systemic Absorption Matters: Topical ophthalmic medications, such as brinzolamide and dorzolamide, can be absorbed systemically and reach therapeutic levels sufficient to cause systemic toxicity, including severe metabolic acidosis.\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2. CKD is a Major Risk Factor: Patients with chronic kidney disease are at high risk for CAI-induced acidosis due to impaired drug excretion and reduced capacity for acid-base compensation.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3. Diagnostic Rigor: In complex acid-base disorders, calculating the Delta-Delta ratio is essential. It helps identify mixed disorders (e.g., concomitant RTA) that might be masked by a high anion gap metabolic acidosis associated with AKI.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4. Dietary Management: In addition to pharmacological alkali therapy, increasing fruit and vegetable intake is an evidence-based strategy to manage metabolic acidosis in CKD patients, helping to preserve renal function and improve outcomes.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"1\"\u003eAbbreviations\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"1\"\u003eThe following abbreviations are used in this manuscript:\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Renal tubular acidosis, Carbonic anhydrase inhibitors, Brinzolamide, Metabolic acidosis, Chronic kidney disease, Urine anion gap, Glaucoma","lastPublishedDoi":"10.21203/rs.3.rs-8899942/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8899942/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMetabolic acidosis is a common complication of advanced chronic kidney disease (CKD). However, when the severity of acidosis outweighs the degree of renal dysfunction, exogenous causes must be excluded. Carbonic anhydrase inhibitors (CAIs) are known to cause hyperchloremic metabolic acidosis, but the systemic toxicity of \u003cem\u003etopical\u003c/em\u003e ophthalmic formulations is frequently overlooked. We report a case of severe distal renal tubular acidosis (RTA) precipitating acute-on-chronic kidney injury, caused by the systemic absorption of topical brinzolamide.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 73-year-old Asian male with stage 3 CKD and glaucoma presented with progressive dyspnea, anorexia, and weight loss one month after initiating brinzolamide/timolol eye drops. Laboratory evaluation revealed severe metabolic acidosis (pH 7.29, HCO3\u003csup\u003e-\u003c/sup\u003e 8.9 mEq/L) and acute kidney injury. While the serum anion gap was elevated, the delta-delta ratio of 0.55 and a positive urine anion gap (+\u0026thinsp;33.4 mEq/L) indicated a concomitant normal anion gap metabolic acidosis consistent with RTA. Discontinuation of the ophthalmic solution and alkali therapy resulted in the resolution of acidosis and recovery of renal function to baseline.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTopical CAIs can undergo significant systemic absorption, bypassing first-pass metabolism, and precipitate life-threatening acidosis in patients with reduced renal reserve. Clinicians must maintain a high index of suspicion for ophthalmic medications as hidden causes of mixed acid-base disorders in patients with CKD.\u003c/p\u003e","manuscriptTitle":"Topical Brinzolamide-induced renal tubular acidosis in a patient with chronic kidney disease: a case report and review of the diagnostic blind spot","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-11 15:59:37","doi":"10.21203/rs.3.rs-8899942/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-23T06:01:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-19T18:41:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195506050333854833927951488714797956317","date":"2026-04-03T13:28:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T08:52:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"95723494935038673815192568923151044639","date":"2026-03-16T07:50:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-16T04:22:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306326914163067467555999020700905911304","date":"2026-03-06T12:03:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T08:40:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-20T14:00:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T11:18:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-18T11:17:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2026-02-17T10:01:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90b90e7d-a126-4ea0-b89c-c800dbc6c07a","owner":[],"postedDate":"March 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T07:53:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-11 15:59:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8899942","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8899942","identity":"rs-8899942","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}