Acute Kidney Injury After Accelerated Dosing of Tirzepatide in a Patient with Multiple Comorbidities: A Case Report

Introduction

Tirzepatide is a once-weekly injectable drug that functions as a dual agonist of the gastric inhibitory polypeptide and glucagon-like peptide-1 (GLP-1) receptors. It has demonstrated strong efficacy in improving glycemic control and promoting weight reduction among individuals with type 2 diabetes and obesity [1–3].

A recent retrospective cohort study involving over 14 000 patients with type 2 diabetes showed that tirzepatide was associated with lower risks of all-cause mortality, major adverse cardiovascular events, acute kidney injury (AKI), and other kidney-related outcomes relative to GLP-1 receptor agonists. The risk of AKI was lower in the tirzepatide group, with an adjusted hazard ratio of 0.78 (95% confidence interval, 0.70–0.88), suggesting a protective effect in real-world clinical settings [4].

Pooled analyses from randomized controlled trials and post hoc analyses of the SURPASS-4 clinical trial further support tirzepatide’s renal safety, indicating no significant increase in AKI risk compared with placebo, insulin, or GLP-1 receptor agonists. The risk of AKI did not appear to be dose-dependent; tirzepatide was associated with reduced albuminuria and stable or improved estimated glomerular filtration rate in both diabetic and non-diabetic populations [5]. A recent systematic review and meta-analysis by Kamrul-Hasan et al. reinforced these findings, emphasizing tirzepatide’s renoprotective properties relative to other therapies [6].

Despite this favorable renal profile, a safety paradox exists. Large clinical trials demonstrate renoprotective effects in most patients; rare but severe cases of AKI have been identified in clinical practice, frequently associated with dehydration due to gastrointestinal adverse effects such as nausea, vomiting, or diarrhea, as described in tirzepatide’s United States Food and Drug Administration (FDA)-approved labeling [7]. Other case reports have proposed alternative mechanisms, including acute interstitial nephritis (AIN) and rhabdomyolysis-induced acute tubular necrosis (ATN) [8,9]. This discrepancy underscores a critical need to identify patient subgroups – particularly those with multimorbidity, polypharmacy, or non-standard dosing regimens – who may be predisposed to these uncommon adverse events. As tirzepatide’s use expands for weight management in non-diabetic populations, especially among patients with complex comorbid conditions, clarity concerning its renal safety in these groups is essential [6,10–12].

This case report contributes to the current discourse by documenting a rare instance of AKI in a non-diabetic, multimorbid patient after accelerated tirzepatide dose escalation for pre-bariatric surgery weight optimization. By examining the combined effects of rapid titration, polypharmacy, and comorbidities, this report seeks to identify potential risk factors for AKI in vulnerable patients, emphasizing the importance of cautious administration and vigilant monitoring.

Approval for this case report was obtained from the Institutional Review Board of Imam Abdulrahman Bin Faisal University. Written informed consent for publication was obtained from the patient. Anonymity and data confidentiality were maintained; all data were used solely for research purposes.

Case Report

A 66-year-old Saudi man, married, with a secondary school education and no history of smoking, presented to the family medicine clinic at our hospital for a routine medication refill and general evaluation. His medical history included hypertension (managed with perindopril 10 mg, bisoprolol 5 mg, and spironolactone 25 mg once daily), morbid obesity (baseline weight 186 kg, height 174 cm, body mass index 61.4 kg/m2), hypothyroidism (status post-partial thyroidectomy 20 years prior, managed with levothyroxine 125 μg daily), benign prostatic hyperplasia (managed with alfuzosin 10 mg daily), prediabetes (managed with metformin XR 750 mg daily), and dyslipidemia (managed with atorvastatin 20 mg daily). He also had a history of bilateral knee replacement. On presentation, his vital signs were stable (blood pressure: 125/60 mmHg; heart rate: 86 bpm; temperature: 36.5°C; respiratory rate: 18 breaths/min; oxygen saturation: 100% on room air). He expressed frustration with his morbid obesity due to its detrimental effects on mobility and quality of life, motivating his interest in bariatric surgery. Initial laboratory investigations showed a hemoglobin level of 13.9 g/dL, white blood cell count of 10.3×109/L, platelet count of 262×109/L, serum creatinine of 1.01 mg/dL, blood urea nitrogen of 25 mg/dL, sodium of 135 mmol/L, potassium of 4.5 mmol/L, hemoglobin A1C of 6.2%, and fasting blood glucose of 104 mg/dL. His medications were refilled, and he was referred for a bariatric surgery consultation for weight management.

Seeking earlier surgical intervention, the patient pursued care at a private hospital. The bariatric surgeon recommended a trial of tirzepatide with accelerated dosing to achieve partial weight reduction before surgery. Tirzepatide was initiated at 2.5 mg weekly via subcutaneous injection for 1 month, followed by 5 mg weekly for 1 month, 7.5 mg weekly for 1 month, and 10 mg weekly for 2 weeks. The dose was then increased to 12.5 mg weekly, resulting in a total treatment duration of approximately 4 months and weight loss of 35 kg (~19% of baseline body weight). No documentation of blood pressure or renal function monitoring was available concerning this period at the private hospital.

Before the scheduled bariatric procedure, routine preoperative laboratory evaluation at the private hospital revealed acute renal impairment with metabolic acidosis and hyperkalemia. Laboratory results showed a hemoglobin level of 12.9 g/dL, white blood cell count of 11×109/L, platelet count of 249×109/L, serum creatinine of 2.4 mg/dL, and potassium of 6.8 mmol/L. Venous blood gas analysis demonstrated a pH of 7.31 and total carbon dioxide (CO2) of 16 mmol/L. The patient reported decreased appetite but denied nausea, vomiting, diarrhea, dysuria, urinary frequency or urgency, fever, nocturia, lower limb edema, dizziness, fatigue, postural hypotension, palpitations, chest pain, orthopnea, or paroxysmal nocturnal dyspnea during the 4 months of tirzepatide therapy, as documented in follow-up visits at the private hospital. However, the accuracy of this retrospective self-report is uncertain because mild gastrointestinal symptoms may have been underreported.

The patient was admitted to the intensive care unit for management of AKI with hyperkalemia and a possible infectious etiology. Treatment included antihyperkalemic measures, intravenous fluids, intravenous sodium bicarbonate, and intravenous antibiotics. A non-contrast computed tomography scan of the abdomen and pelvis excluded urinary tract obstruction. Nephrology consultation was obtained for further management and follow-up.

One day after improvement in the intensive care unit, the patient was transferred to the medical ward. His general condition and laboratory parameters continued to improve. On the second day of ward admission, the medical team decided to discharge him with instructions to discontinue tirzepatide, spironolactone, and metformin XR. A follow-up appointment with the geriatric and internal medicine departments was scheduled. Laboratory results at discharge showed a serum creatinine of 1.18 mg/dL, blood urea nitrogen of 42 mg/dL, potassium of 5 mmol/L, sodium of 135 mmol/L, total CO2 of 19 mmol/L, white blood cell count of 9.6×109/L, hemoglobin of 12 g/dL, and platelet count of 220×109/L.

Subsequently, the patient returned to our hospital’s family medicine clinic for routine follow-up. His clinical condition had substantially improved; laboratory findings showed a hemoglobin A1C of 6.0%, fasting blood glucose of 94 mg/dL, and all other parameters within normal limits.

Discussion

This case report describes a rare instance of AKI with metabolic acidosis and hyperkalemia in a 66-year-old man with multiple comorbidities after rapid tirzepatide dose escalation for pre-bariatric surgery weight optimization. The temporal association between the accelerated dosing regimen (from 2.5 mg to 12.5 mg over 4 months, including an increase from 10 mg to 12.5 mg after only 2 weeks) and the onset of AKI suggests a relationship, although causality cannot be established due to multiple confounding factors. The following discussion systematically explores the differential diagnosis for AKI, considering the combined effects of rapid titration, polypharmacy, and underlying comorbidities in our patient.

Volume depletion secondary to gastrointestinal adverse effects is a well-documented mechanism of AKI associated with GLP-1 receptor agonists and dual gastric inhibitory polypeptide/GLP-1 agonists such as tirzepatide, as noted in the FDA-approved labeling [7]. The patient’s denial of nausea, vomiting, or diarrhea during the 4-month treatment period suggests that overt dehydration was unlikely to be the primary cause. However, he reported decreased appetite, a known gastrointestinal adverse effect of tirzepatide that may reduce oral fluid intake and result in subclinical volume depletion. In a patient taking perindopril (an angiotensin-converting enzyme inhibitor) and spironolactone (a potassium-sparing diuretic) – agents that can impair renal autoregulation and alter volume status – subclinical volume depletion could precipitate a pre-renal state. The reliance on retrospective self-reporting limits the certainty of excluding gastrointestinal symptoms because mild manifestations may have been underreported or forgotten, particularly given the patient’s focus on the positive outcome of substantial weight loss (35 kg, ~19% of initial body weight). Thus, volume depletion remains a highly probable contributor to the development of AKI [7,10,13].

A pharmacodynamic interaction between tirzepatide and the patient’s antihypertensive medications (perindopril, bisoprolol, and spironolactone) may also have contributed to reduced renal perfusion, potentially exacerbating hyperkalemia and precipitating AKI. Tirzepatide’s vasodilatory and natriuretic properties, combined with renin-angiotensin-aldosterone system (RAAS) inhibition by perindopril and the potassium-sparing effects of spironolactone, could have compromised renal perfusion, particularly in the setting of substantial weight reduction (19% of baseline body weight); this reduction may have enhanced the blood pressure-lowering effect. The absence of ambulatory or clinic-based blood pressure measurements during treatment renders this hypothesis speculative - no documentation of systemic hypotension was available. This limitation highlights the importance of regular blood pressure and renal function monitoring in patients receiving tirzepatide during concurrent use of complex antihypertensive regimens [10,11].

Although less likely, intrinsic renal injury mechanisms such as ATN or AIN should be considered. Case reports have described tirzepatide-associated AIN, an idiosyncratic hypersensitivity reaction, and rhabdomyolysis-induced ATN. The clinical presentation in the present case does not strongly support either AIN or rhabdomyolysis. However, without a renal biopsy – which was not clinically indicated – intrinsic renal injury remains a diagnosis of exclusion [8,9]. A non-contrast computed tomography scan ruled out urinary tract obstruction, effectively excluding post-renal causes.

The accelerated dose escalation, particularly the increase from 10 mg to 12.5 mg after only 2 weeks (compared with the standard 4-week titration interval), may have intensified tirzepatide’s gastrointestinal and hemodynamic effects. The standard titration schedule allows physiological adaptation to adverse effects such as nausea or vasodilation, which may challenge renal compensatory mechanisms in multimorbid patients. Rapid titration could amplify these effects, contributing to volume depletion or hemodynamic instability, especially in a patient with multiple comorbidities and concurrent medications affecting renal perfusion. Although clinical trials indicate that the risk of AKI is not dose-dependent, the non-standard dosing in this case may have increased the patient’s vulnerability to AKI by exceeding physiological compensatory capacity [5,10].

The rarity of AKI in a non-diabetic, multimorbid patient highlights the importance of identifying susceptible patient phenotypes. Similar challenges in managing polypharmacy-related AKI risk have been observed in other contexts, such as patients with sepsis receiving vancomycin and piperacillin-tazobactam, where comorbidities and complex medication regimens enhance susceptibility [14].

The combined effects of rapid dose escalation, complex medication regimens, significant weight loss, and volume depletion secondary to reduced appetite likely increased the patient’s susceptibility to AKI. This situation parallels the “triple whammy” paradigm in nephrology, in which concurrent use of a RAAS inhibitor, a diuretic, and a nonsteroidal anti-inflammatory drug (NSAID) heightens AKI risk through synergistic mechanisms involving impaired renal autoregulation and volume depletion. In the present case, tirzepatide’s potential to induce volume depletion may have produced a similar synergistic nephrotoxic effect, substituting for the NSAID component [10,15,16]. Clinicians should adhere to the recommended 4-week titration schedule and conduct baseline and periodic monitoring of renal function and electrolytes, particularly during the initial weeks after dose escalation. Regular blood pressure monitoring is essential to detect potential hemodynamic alterations, especially in patients receiving antihypertensive therapy.

Conclusions

This case report documents a rare occurrence of AKI in a non-diabetic, multimorbid patient undergoing accelerated tirzepatide dose escalation for pre-bariatric surgery weight optimization. The AKI likely resulted from a multifactorial interaction of subclinical volume depletion, pharmacodynamic effects of antihypertensive medications, and rapid dose escalation, which led to increased renal vulnerability in a patient with complex comorbidities and polypharmacy. Clinicians should strictly follow the standard 4-week titration protocol and ensure consistent monitoring of renal function, electrolytes, and blood pressure in multimorbid patients, particularly those receiving RAAS inhibitors or diuretics. Further research is warranted to establish optimal monitoring strategies and identify specific risk factors for rare renal adverse events in non-diabetic patients treated with tirzepatide, ensuring safe and effective therapeutic use.