SGLT2 Inhibitor Induced Euglycemic DKA (EDKA) With Proximal Renal Tubular Acidosis (RTA) as a Rare Fatal Complication in a Non-Insulin Dependent Diabetic Patient: A Challenging Dilemma

Introduction: Diabetic Ketoacidosis (DKA) is characterized by a triad of hyperglycemia, acidemia, and ketonemia. Rarely, it would present with normal glucose levels making its diagnosis very challenging. The incidence of euglycemic DKA (eDKA) has increased with the introduction of the novel sodium-glucose cotransporter-2 inhibitors (SGLT2i). Currently, the reported incidence of SGLT2i induced DKA is 0.16–0.76 events per 1000 patient-years. We present a rare case of SGLT2i induced eDKA with proximal renal tubular acidosis (RTA). Case Presentation A 69 year-old male with type 2 diabetes mellitus presented to the hospital with severe respiratory distress, nausea and vomiting for 2 days. His home medications include metformin and canagliflozin. He was afebrile with respiratory rate 60 breaths/min. Arterial blood gas: pH 7.21, pCO2 9.2, pO2 223, HCO3 6. Blood glucose level was 120 mg/dl. Urinalysis was positive for large ketonuria >160 mg/dl and glycosuria >500 mg/dl. Serum anion gap and urine anion gap were elevated 29 mEq/L and 105 mEq/L respectively. Serum osmolarity and urine osmolality were elevated 296 mosm/kg and 653 mosm/kg respectively. Lactic acid was 5.3. Acetone was detected in blood. No source of infection was identified. Hemoglobin A1C was 5% and c-peptide was within normal range. Insulin and Islet cells antibodies were negative. DKA protocol was initiated until the anion gap closed. However, non-anion gap metabolic acidosis was persistent with profound hypophosphatemia. Repeat urinalysis showed glycosuria with pH ≤ 5.5, phosphaturia and generalized aminoaciduria. Ultimately, the patient elected to receive hospice care. Discussion: SGLT2i are currently recommended as second-line medications for type 2 diabetes mellitus. Their unique mechanism of action prevents glucose reabsorption from the proximal renal tubules. SGLT2i use is growing significantly, especially after recent clinical trials that demonstrated favorable protective effects. EDKA is precipitated by sepsis, acute illness, dehydration, or starvation. Once the diagnosis is suspected, SGLT2i should be stopped immediately. SGLT2i induced eDKA should be treated in a similar fashion as DKA. It is worth to note that SGLT2i half-life ranges from 11–17 hours, and despite drug discontinuation, glycosuria may persist for several days. What made our case unique and made the diagnosis challenging, was the normal blood glucose level, as well as other differentials that could have easily explained the acidosis including starvation ketosis and lactic acidosis. Also, the state of proximal RTA resembling renal Fanconi syndrome that occurred in correlation with canagliflozin therapy. To the best of our knowledge, this is the fourth reported case of proximal RTA with the use of canagliflozin resulting in life-threatening complications. The diagnosis was very challenging due to lack of awareness of this severe adverse effect.

Small Molecule Channels Harness Membrane Potential to Concentrate Potassium in trk1Δtrk2Δ Yeast

ABSTRACTMany protein ion channels harness membrane potential to move ions in opposition to their chemical gradient. Deficiencies of such proteins cause several human diseases, including cystic fibrosis, Bartter Syndrome Type II, and proximal renal tubular acidosis. Using yeast as a readily manipulated eukaryotic model system, we asked whether, in the context of a deficiency of such protein ion channel function in vivo, small molecule channels could similarly harness membrane potential to concentrate ions. In yeast, Trk potassium transporters use membrane potential to move potassium ions from a compartment of relatively low concentration outside cells (∼15mM) to one of >10 times higher concentration inside (150-500mM). trk1Δtrk2Δ yeast are missing these potassium transporters and thus cannot concentrate potassium or grow in standard media. Here we show that potassium permeable, but not potassium selective, small molecule ion channels formed by the natural product amphotericin B can harness membrane potential to concentrate potassium in trk1Δtrk2Δ cells and thereby restore growth. This finding expands the list of potential human channelopathies that might be addressed by a molecular prosthetics approach.

A Complicated Pregnancy in an Adult with HNF4A p.R63W-Associated Fanconi Syndrome

Renal Fanconi syndrome (RFS) is characterised by generalised dysfunction of the proximal renal tubules, resulting in excessive urinary loss of solutes, most notably bicarbonate, and type II (proximal) renal tubular acidosis. It is a rare condition, and literature around its management through pregnancy is limited. We present the management of a 37-year-old woman with RFS secondary to the HNF4A p.R63W mutation, through her third pregnancy. She presented at 28 + 5 weeks with dehydration, low serum bicarbonate, and profound metabolic acidosis. Daily infusions of sodium bicarbonate were necessary, and the requirements increased throughout the pregnancy. She also demonstrated both fasting hypoglycaemia and episodes of postprandial hyperglycaemia which required complex management. Due to concerns around fetal health, an elective caesarean section was performed at 34 weeks, delivering a healthy baby girl. This case highlights the potential complexity of pregnancy in patients with RFS and the need for a multidisciplinary approach to its management.