Glucosuria Is Not Always Due to Diabetes

Familial renal glucosuria is an uncommon, rarely documented condition wherein the absence of other renal or endocrine conditions and with a normal serum glucose level, glucosuria persists due to an isolated defect in the nephron’s proximal tubule. Seemingly, in these patients, the body’s physiologic function mimics that of sodiumglucose cotransporter-2 (SGLT2)-inhibiting medications with the glucose cotransporter being selectively targeted for promoting renal excretion of glucose. This has implications for the patient’s prospective development of hyperglycemic diseases, urinary tract infections (UTIs), and potentially even cardiovascular disease. Though it is a generally asymptomatic condition, it is one that seasoned clinicians should investigate given the future impacts and considerations required for their patients.

Case Presentation

Mr. A was a 28-year-old male with no medical history nor prescription medication use who presented to the nephrology clinic at Eglin Air Force Base, Florida, in June 2019 for a workup of asymptomatic glucosuria. The condition was discovered on a routine urinalysis in October 2015 at the initial presentation at Eglin Air Force Base, when the patient was being evaluated by his primary care physician for acute, benign headache with fever and chills. Urinalysis testing was performed in October 2015 and resulted in a urine glucose of 500 mg/dL (2+). He was directed to the emergency department for further evaluation, reciprocating the results.

On further laboratory testing in October 2015, his blood glucose was normal at 75 mg/dL; hemoglobin A1c was 5.5%. On repeat urinalysis 2 weeks later, his urinary glucose was found to be 500 mg/dL (2+). Each time, the elevated urinary glucose was the only abnormal finding: There was no concurrent hematuria, proteinuria, or ketonuria. The patient reported he had no associated symptoms, including nausea, vomiting, abdominal pain, dysuria, polyuria, and increased thirst. He was not taking any prescription medications, including SGLT2 inhibitors. His presenting headache and fever resolved with supportive care and was considered unrelated to his additional workup.

A diagnostic evaluation ensued from 2015 to 2020, including follow-up urinalyses, metabolic panels, complete blood counts, urine protein electrophoresis (UPEP), urine creatinine, urine electrolytes, 25-OH vitamin D level, κ/λ light chain panel, and serum protein electrophoresis (SPEP). The results of all diagnostic workup throughout the entirety of his evaluation were found to be normal. In 2020, his 25-OH vitamin D level was borderline low at 29.4 ng/mL. His κ/λ ratio was normal at 1.65, and his serum albumin protein electrophoresis was 4.74 g/dL, marginally elevated, but his SPEP and UPEP were normal, as were urine protein levels, total gamma globulin, and no monoclonal gamma spike noted on pathology review. Serum uric acid, and urine phosphorous were both normal. His serum creatinine and electrolytes were all within normal limits. Over the 5 years of intermittent monitoring, the maximum amount of glucosuria was 1,000 mg/dL (3+) and the minimum was 250 mg/dL (1+). There was a gap of monitoring from March 2016 until June 2019 due to the patient receiving care from offsite health care providers without shared documentation of specific laboratory values, but notes documenting persistent glucosuria (Table).

Analysis

Building the initial differential diagnosis for this patient began with confirming that he had isolated glucosuria, and not glucosuria secondary to elevated serum glucose. Additionally, conditions related to generalized proximal tubule dysfunction, acute or chronic impaired renal function, and neoplasms, including multiple myeloma (MM), were eliminated because this patient did not have the other specific findings associated with these conditions.

Proximal tubulopathies, including proximal renal tubular acidosis (type 2) and Fanconi syndrome, was initially a leading diagnosis in this patient. Isolated proximal renal tubular acidosis (RTA) (type 2) is uncommon and pathophysiologically involves reduced proximal tubular reabsorption of bicarbonate, resulting in low serum bicarbonate and metabolic acidosis. Patients with isolated proximal RTA (type 2) typically present in infancy with failure to thrive, tachypnea, recurrent vomiting, and feeding difficulties. These symptoms do not meet our patient’s clinical presentation. Fanconi syndrome involves a specific disruption in the proximal tubular apical sodium uptake mechanism affecting the transmembrane sodium gradient and the sodium-potassium- ATPase pump. Fanconi syndrome, therefore, would not only present with glucosuria, but also classically with proteinuria, hypophosphatemia, hypokalemia, and a hyperchloremic metabolic acidosis.

Chronic or acute renal disease may present with glucosuria, but one would expect additional findings including elevated serum creatinine, elevated urinary creatinine, 25-OH vitamin D deficiency, or anemia of chronic disease. Other potential diagnoses included MM and similar neoplasms. MM also would present with glucosuria with proteinuria, an elevated κ/λ light chain ratio, and an elevated SPEP and concern for bone lytic lesions, which were not present. A related disorder, monoclonal gammopathy of renal significance (MGRS), akin to monoclonal gammopathy of unknown significance (MGUS), presents with proteinuria with evidence of renal injury. While this patient had a marginally elevated κ/λ light chain ratio, the remainder of his SPEP and UPEP were normal, and evaluation by a hematologist/ oncologist and pathology review of laboratory findings confirmed no additional evidence for MM, including no monoclonal γ spike. With no evidence of renal injury with a normal serum creatinine and glomerular filtration rate, MGRS was eliminated from the differential as it did not meet the International Myeloma Working Group diagnostic criteria.¹ The elevated κ/λ ratio with normal renal function is attributed to polyclonal immunoglobulin elevation, which may occur more commonly with uncomplicated acute viral illnesses.