Lithium-induced nephrogenic diabetes insipidus following improved medication compliance: a case report

Abstract

Background

Nephrogenic diabetes insipidus is a rare, often underrecognized complication of long-term lithium therapy. Lithium-induced nephrogenic diabetes insipidus results from chronic renal exposure, leading to significant polyuria, dehydration, and hypernatremia.

Case presentation

We describe a case of a 55-year-old White caucasian male with a schizoaffective disorder managed with lithium who presented with altered mental status and electrolyte abnormalities following a recent stroke. Evaluation revealed nephrogenic diabetes insipidus as the primary etiology, likely exacerbated by recent changes in medication adherence. The patient responded well to fluid resuscitation, reduced lithium dosage, and targeted electrolyte management.

Conclusion

This case underscores the need for vigilance in monitoring patients with nephrogenic diabetes insipidus on chronic lithium therapy, as early recognition and treatment are essential in preventing renal impairment and improving clinical outcomes.

Introduction

Diabetes insipidus (DI) is a rare condition, with a reported prevalence of 1 in 25,000 [1]. Of all DI cases, central or neurogenic cases tend to be more common than nephrogenic cases [2]. Nephrogenic cases may be congenital because of genetic mutation or acquired, typically as a side effect of pharmaceuticals, most commonly lithium [2]. Lithium is a commonly used mood stabilizer for bipolar affective disorder [3]. There are many documented side effects of chronic lithium use, with nephrogenic diabetes insipidus being the most common manifestation, occurring in up to 40% of patients [4].

Patients may undergo years of lithium therapy prior to the onset of the disease, and thus, diagnosis may often be missed. Continued lithium treatment in the setting of undiagnosed nephrogenic DI may lead to worsening dehydration and potential renal damage [4]. Several case reports have documented lithium-induced nephrogenic diabetes insipidus [5, 6]. However, there is a lack of studies directly linking improved medication adherence in a previously non-compliant patient to the development of nephrogenic DI. Here, we present a unique case of nephrogenic diabetes insipidus in a patient on chronic lithium therapy, potentially triggered by a shift in medication compliance following a transfer to a nursing facility after a recent stroke.

Case description

Clinical presentation

A 55-year-old White caucasian male with a history of schizoaffective disorder (managed with lithium for the past 10 years), hyperlipidemia, and a stroke 3 months prior (right-sided residual deficits) presented to the emergency department from his nursing home with altered mental status and syncope. Physical examination revealed signs of dehydration, evident by dry oral mucous membranes, and reduced skin turgor. He was somnolent and not oriented to time, place, or person. The cardiorespiratory exam was unremarkable. However, he exhibited weakness in the right upper and lower extremities, consistent with the residual effects of a prior stroke.

Diagnostic findings

Initial laboratory results showed hypernatremia (Na 157 mmol/L), hyperchloremia (Cl 119 mmol/L), hypercalcemia (Ca 14.3 mg/dL) with elevated ionized calcium (1.71 mmol/L), and elevated creatinine (2.25 mg/dL). Leukocytosis (15.85) and elevated creatine kinase (203 U/L) were also noted. Urinalysis revealed white blood cell (WBC) esterase, 6–10 WBCs, and hyaline casts. Although his serum lithium level was within the therapeutic range, previous levels had been subtherapeutic, making this his first therapeutic level within 8 years. A renal ultrasound ruled out hydronephrosis, and head computed tomography (CT) showed no intracranial abnormalities. Serum protein electrophoresis and urine protein electrophoresis were also unremarkable. Table 1 summarizes the trend of key laboratory results throughout hospitalization.

Table 1 Trend of key laboratory results throughout hospitalization

Management

Parathyroid hormone, parathyroid-hormone-related protein, and protein electrophoresis levels were within normal limits. Creatinine improved to baseline (0.88 mg/dL) following fluid resuscitation. The patient was started on calcitonin and zoledronic acid for hypercalcemia. However, hypernatremia worsened, peaking at 157 mmol/L, prompting initiation of intravenous fluids with 5% dextrose.

The patient exhibited significant polyuria (4–6 L/day) both before and during fluid administration in the setting of poor oral intake and an estimated free water deficit of 6 L. After several days of fluid therapy, a water deprivation test followed by desmopressin administration was performed. Urine osmolality decreased slightly from 175 mOsm/kg to 154 mOsm/kg in response to the desmopressin challenge, indicating an impaired ability to concentrate urine, consistent with nephrogenic diabetes insipidus.

Nephrology recommended continued hydration and initiated chlorthalidone 25 mg daily to enhance sodium excretion. The lithium dosage was reduced from 300 mg twice daily to 150 mg twice daily. Sodium levels normalized by day 7, and urine output decreased significantly from approximately 4–6 L/day to about 0.3 L/day with the addition of chlorthalidone.

By discharge, the patient had returned to baseline and was maintained on 150 mg lithium twice daily. A follow-up was scheduled with psychiatry to evaluate alternative mood stabilizers.

Discussion

Our case exemplifies multiple key points that should be considered by all clinicians when assessing patients in the hospital with a history of lithium use. Nephrogenic DI should be included in the differential for all patients on lithium presenting with signs of dehydration and electrolyte abnormalities. While not a common diagnosis, the potential consequences of the subsequent renal damage, as well as the multitude of complications that may result from the electrolyte abnormalities, pose life-altering and -threatening risks. Repeated episodes of dehydration and abrupt changes in sodium levels may also lead to potential psychological and neurological damage [7].

The compounding biological effects of lithium over time lead to nephrogenic DI [4]. Studies on chronic lithium therapy have shown evidence of renal remodeling, especially of the collecting ducts and principal cells [8, 9]. The mechanism behind how lithium induces remodeling is poorly understood; however, it is speculated that epithelial sodium channels (ENaCs) play a role in providing access to lithium ions to these cells [8, 9]. Thus, ENaC channel inhibitors, such as amiloride, mask polyuria and increase urine osmolality in patients with lithium-induced nephrogenic DI [8, 9]. The number of aquaporin channels has also been noted to decrease with chronic lithium use [8, 9]. Lithium-induced nephrogenic DI is also notably dose-dependent, with higher doses associated with increased risk; however, the condition has been reported even within the therapeutic or sub-therapeutic ranges [10]. In this case, improved compliance owing to supervised care led to the patient’s lithium reaching therapeutic levels, resulting in the development of nephrogenic DI.

The most reported electrolyte abnormality seen in nephrogenic diabetes insipidus is hypernatremia, as was the case in our patient’s presentation [11]. In congenital nephrogenic DI cases, the degree of electrolyte abnormalities may vary on the basis of the genetic mutation present [12]. Nephrogenic DI is also more common in patients who are acutely ill, so one should maintain a high level of suspicion when patients on lithium therapy present to the emergency department with hypernatremia [13].

Hypercalcemia is another electrolyte abnormality noted in lithium-induced nephrogenic DI and has been reported as a side effect of long-term lithium treatment [14]. It should be noted that hypercalcemia can be seen in patients on lithium therapy without concomitant nephrogenic diabetes insipidus [15]. The pathophysiology behind lithium-induced hypercalcemia is not entirely understood, but it is postulated that lithium directly stimulates parathyroid hormone (PTH) production or interacts with calcium-sensing receptors, resulting in alterations of PTH and calcium levels [16]. In these scenarios, however, PTH tends to be elevated, whereas, in our patient, the PTH level was on the lower end of the normal range. Our patient saw a reduction in serum calcium levels after treatment with fluids, calcitonin, and zoledronic acid by day 6 of admission, suggesting our patient’s hypercalcemia may have been more attributed to volume depletion than to direct lithium renal toxicity. Nevertheless, it is essential to closely monitor the calcium levels of all patients on lithium therapy, given the frequency with which abnormalities can occur.

Proper differentiation between central and nephrogenic DI is also essential for guiding management. While central DI is typically associated with trauma, idiopathic cases have been reported [17]. Additionally, cases of central DI after ischemic neurologic events have also been reported, which was essential to evaluate in our patient with a recent history of stroke [18]. The key to differentiation relies on assessing renal ability to concentrate urine in response to desmopressin. Continued high urine output following a water deprivation test and desmopressin administration indicate nephrogenic DI [14].

Thiazide diuretics are utilized in the management of nephrogenic diabetes insipidus owing to their ability to promote renal sodium excretion, which enhances diuresis and results in extracellular volume contraction [19]. This, in turn, reduces the glomerular filtration rate (GFR)[19]. The lowered GFR increases water and sodium reabsorption in the proximal tubules, thereby decreasing the delivery of solutes and water to the distal tubule and collecting duct [19]. As a result, there is a reduction in solute and water loss distally, ultimately improving the symptoms of nephrogenic diabetes insipidus [19]. Chlorthalidone, a thiazide diuretic, was very effective in this case and resulted in urine output reduction from approximately 4–6 L/day to about 0.3 L/day. Desmopressin, a synthetic vasopressin analog, is more effective in treating central DI [20]. However, there have been some studies that have reported lithium-induced nephrogenic DI that has been responsive to desmopressin [21]. Desmopressin therapy, however, did not affect our patient’s urine output or osmolality.

Additionally, evaluating recent medication and diet changes is essential in the management of nephrogenic DI. Socioeconomic factors surrounding patients, including changes in living situation, should also be assessed. In our case, it was noted that the patient had years of subtherapeutic lithium levels prior to beginning his residence at a skilled nursing facility. Lithium level on admission was in the therapeutic range, indicating a possible change in compliance with medications once the patient began living with supervised care and subsequent development of DI. Additionally, studies have shown that low-sodium diets induce increased lithium reabsorption, especially in the distal tubules [17, 22]. Our patient had significant dietary changes after his stroke, which may have led to increased lithium reabsorption [23].

Conclusion

This case underscores the importance of a thorough evaluation of patients on chronic lithium therapy, particularly those presenting with dehydration, electrolyte imbalances, or altered mental status, such as our patient. Lithium-induced nephrogenic diabetes insipidus (DI) remains a significant yet underdiagnosed complication of long-term lithium use, with hypernatremia being a hallmark feature. Timely differentiation between central and nephrogenic DI is critical for appropriate management.

Our patient’s presentation illustrates the diagnostic challenges posed by nephrogenic DI, especially when lithium levels are therapeutic, and changes in medication adherence or environmental factors play a contributory role. This case also highlights the potential impact of lithium on calcium homeostasis and the importance of addressing hypercalcemia promptly to mitigate associated complications.

The successful use of thiazide diuretics such as chlorthalidone to manage nephrogenic DI demonstrates a practical approach to reducing urine output and correcting electrolyte imbalances. Clinicians must maintain a high index of suspicion for nephrogenic DI in patients on chronic lithium therapy, ensuring regular monitoring of renal function, electrolyte levels, and lithium levels to mitigate long-term complications and improve outcomes.