CASE SERIES OF HYPOKALEMIA SECONDARY TO RENAL TUBULAR ACIDOSIS TYPE II WITH VITAMIN D DEFICIENCY

Abstract Chronic vitamin D deficiency (VDD) can impair proximal tubular function but is an underrecognized cause of proximal renal tubular acidosis (RTA) with resultant potassium (K) wasting. We report a case series of three adults with prolonged VDD who presented with severe symptomatic hypokalemia and other proximal tubular electrolyte abnormalities (hypocalcemia and hypophosphatemia). In each patient 25-hydroxyvitamin D (25-OH D) was markedly low and intact parathyroid (PTH) was inappropriately normal. Hypokalemia proved refractory to prolonged K replacement until vitamin D status was addressed. Initiation of cholecalciferol repletion (25,000 IU weekly for 8 weeks) led to progressive normalization of serum K and other electrolytes, and resolution of symptoms without need for prolonged K supplementation.

Introduction 

Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1 alpha, 25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. VDD affects persons of all ages. Chronic VDD, though common in the elderly, is often under diagnosed and when progressing to proximal RTA can cause several simultaneous electrolyte imbalances that may present with weakness and pain as chief symptoms. Common manifestations of VDD are symmetric low back pain, proximal muscle weakness, muscle aches, and throbbing bone pain. A 25-OH D level should be obtained in patients with suspected VDD. Deficiency is defined as a serum 25-OH D level of less than 20 ng/mL (50 nmol/L), and insufficiency is defined as a serum 25-OH D level of 20 to 30 ng/mL (50 to 75 nmol/L). The goal of treatment is to normalize vitamin D levels to relieve symptoms and other adverse health outcomes. The National Kidney Foundation in the Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease encourages maintaining a value of vitamin D above 30 ng/mL (75 nmol/L). In persons with VDD, treatment may include oral ergocalciferol (vitamin D) at 50,000 IU/week for eight weeks. After vitamin D levels normalize, experts recommend maintenance dosages of cholecalciferol (vitamin D3) at 800 to 1,000 IU/day from dietary supplemental sources.

Case Presentation This clinical case series describes three adults with VDD. The clinical and laboratory findings (Table 1, 2, 3), treatment and outcomes for the described patients are listed below. 

Case 1

A 21-year-old Filipino male college student was admitted in 2022 due to difficulty with ambulation. He reported markedly reduced sun exposure during the COVID-19 pandemic. On presentation he had bilateral lower extremity weakness and laboratory abnormalities including severe hypokalemia , mild hypocalcemia, and hypophosphatemia. Nephrology evaluation initially considered proximal RTA, and the patient was empirically treated with intravenous (IV) and oral potassium chloride (KCl) and neutral sodium phosphate (Na3PO4), without clinical and biochemical improvement. Re-evaluation revealed a low 25-OH D concentration and a persistently low, progressively declining ionized calcium (iCa), while intact parathyroid hormone (iPTH) remained within the normal range. He was treated with IV calcium (Ca) gluconate followed by oral calcium carbonate (CaCO3) and started on oral cholecalciferol 25,000 IU weekly for 8 weeks. The patient experienced gradual resolution of symptoms and correction of electrolyte abnormalities. Following his recovery, the patient was discharged on weekly cholecalciferol and advise for daily sun exposure and remained asymptomatic on outpatient  (OPD) follow-up. The sustained normalization of electrolytes with vitamin D repletion supported VDD as the primary etiology.

Table 1.

Case 2

A 28-year-old Filipino woman with obesity, hypertension (HTN), type 2 diabetes mellitus, and polycystic ovary syndrome presented with bilateral lower extremity weakness. She reported prolonged reduced sunlight exposure related to remote work during the COVID-19 pandemic and subsequent night shift employment. Prior to the pandemic her serum K had been normal. In 2024 she was admitted for severe hypokalemia that proved refractory to prolonged OPD oral K replacement. Nephrology evaluation identified additional electrolyte abnormalities (hypocalcemia and hypophosphatemia) and she was started on oral CaCO3 and neutral Na3PO4. Serum 25-OH D was markedly reduced while iPTH was within normal range, ruling out secondary hyperparathyroidism as primary cause of her electrolyte disturbances and differing from the typical pattern of VDD in which iPTH is usually elevated. With the above findings, proximal RTA secondary to VDD was considered. She was initiated on oral cholecalciferol 25,000 IU weekly for 8 weeks and to continue once a week thereafter, along with instruction to increase sunlight exposure.

Table 2.

Case 3

A 54-year-old Filipino woman with hypertension was readmitted two months after a cerebellar hemorrhage for persistent dizziness, reduced mobility, and poor oral intake. Because of these conditions, she became bedbound and had minimal sun exposure. She developed progressive gastrointestinal (GI) symptoms, including abdominal pain, nausea, vomiting and constipation two days prior to admission; abdominal radiographs demonstrated ileus. Initial laboratory studies showed marked electrolyte disturbances, including hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia. The patient had a known history of hypokalemia from her prior admission.Her GI symptoms and electrolyte derangements worsened after an enema, resulting in severe hypokalemia that required aggressive IV electrolyte repletion with KCl, magnesium sulfate, and Ca gluconate, as well as oral neutral Na3PO4. Abdominal computed tomography scan incidentally identified a left adrenal mass; biochemical evaluation for a functioning adrenal tumor (aldosterone, renin, and cortisol) was normal, and the lesion was characterized as a nonfunctioning adrenal incidentaloma. Despite aggressive IV repletion and resolution of her GI symptoms, the hypokalemia and other electrolyte abnormalities persisted, prompting nephrology evaluation. Further testing revealed a markedly low 25-OH D level with a normal iPTH level. Given the pattern of hypokalemia, hypocalcemia, and hypophosphatemia in the context of a profound VDD with an inappropriately normal iPTH, proximal RTA secondary to VDD was considered. Cholecalciferol supplementation was initiated. Following vitamin D repletion, her serum K and other electrolytes gradually normalized, and the refractory hypokalemia resolved, supporting VDD as the primary etiology.  

Table 3.

Discussion Individuals with inadequate sun exposure are at risk of low vitamin D production. Vitamin D is obtained primarily from adequate exposure to sunlight, the main source for most people, and can be supplied by diet and nutritional supplements. Anything that diminishes the transmission of ultraviolet B radiation to the skin will affect the cutaneous synthesis of Vitamin D3. A low vitamin D level can be diagnosed with a blood test called 25-OH D. Three patients presented with generalized weakness due to hypokalemia and were diagnosed with proximal RTA, which in each case was attributed to VDD (markedly low 25‑OH D) related to reduced sun exposure. The VDD was associated with hypocalcemia and hypophosphatemia, findings consistent with impaired intestinal calcium and phosphate absorption. Vitamin D repletion produced clinical improvement and correction of the electrolyte abnormalities. In VDD, hypocalcemia ordinarily elicits a compensatory rise in PTH (secondary hyperparathyroidism). Low serum iCa is sensed by the calcium‑sensing receptors on parathyroid chief cells, which increases PTH secretion. PTH acts to restore calcium by increasing renal calcium reabsorption, mobilizing calcium from bone, and stimulating renal 1 alpha‑hydroxylase to raise 1,25‑(OH)2 vitamin D and thereby enhance intestinal calcium absorption. When vitamin D is deficient, intestinal Ca absorption is impaired, which sustains hypocalcemia and perpetuates PTH secretion. Prolonged stimulation may lead to parathyroid hyperplasia and gland enlargement.

The clinical syndrome is most consistent with proximal RTA in the setting of VDD causing hypocalcemia, hypophosphatemia, and hypokalemic weakness. While existing literature on this connection is limited, based on the significant clinical improvement observed in our three patients following cholecalciferol therapy, we propose that 25-OH D levels should be considered for routine assessment in patients with unexplained proximal RTA. However, the inappropriately normal PTH response merits targeted investigation to exclude an additional disorder impairing parathyroid function.