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Still Learning from Our Patients: Hypokalemia in Patients with Lupus Nephritis.

Parkland Memorial Hospital is a county hospital in Dallas, Texas, that provides care to a medically underserved population. Lupus nephritis is a common diagnosis, as I learned during my time there as a renal fellow and junior faculty member. In 2012, Dr. Kamalanathan Sambandam established a GN clinic at Parkland. Since inception, the clinic has cared for 435 patients with lupus nephritis, and an additional 464 patients with other glomerular diseases (K. Sambandam, personal communication). In this issue of Kidney360, Adomako and colleagues (1) draw on their clinical experience caring for this large population of patients to describe a new entity, idiopathic hypokalemia in lupus nephritis. They identify 20 patients with this disorder, who do not have evidence of other suspected or known causes of hypokalemia, for a prevalence of 5%. Renal potassium wasting is demonstrated in a subset of patients by measurement of the urine potassium/creatinine ratio, transtubular potassium gradient, or measurement of 24-hour urinary potassium excretion. What is the etiology of hypokalemia in these patients? Hypokalemia can occur in renal tubular acidosis (RTA), which has been previously described in patients with lupus nephritis. The authors therefore study ten patients from their clinic with lupus nephritis and RTA (prevalence, 3%). Not surprisingly, compared with control patients with lupus nephritis but without evidence of tubulopathy, the patients with RTA had a lower serum bicarbonate and higher urine pH, and four of ten patients had evidence of nephrocalcinosis or nephrolitihiasis. Although serum potassium was slightly lower in patients with RTA (3.75 mmol/L) compared with controls (4.00 mmol/L), this difference did not reach statistical significance. In contrast, the patients with idiopathic hypokalemia had lower serum potassium (3.26 mmol/L), normal serum bicarbonate and urine pH, and none had nephrocalcinosis or nephrolitihiasis. As described below, the patients with hypokalemia also had a distinct profile of serological markers. Although the diagnosis of incomplete distal RTA was not ruled out in the patients who were hypokalemic using provocative testing, the tubulopathy in these patients appears to be distinct from RTA. The authors exclude other possible causes of hypokalemia by history and laboratory evaluation. Chronic diarrhea was excluded by history, and, as noted above, many of the hypokalemic patients had demonstrated renal potassium wasting. Primary hyperaldosteronism was excluded in a subset of patients by measurement of renin activity and aldosterone concentrations. In most patients, plasma aldosterone was below the limit of detection or low, as expected given hypokalemia. Corticosteroid exposure was lower in the patients who were hypokalemic compared with controls with lupus nephritis, so mineralocorticoid effects of steroids are unlikely. Data were censored when patients were exposed to diuretics or alkali therapy; thus, these were not contributors. Data were also censored for patients with conditions or treatments that can increase serum potassium, including eGFR ,60 ml/min per 1.73 m or during periods of acute kidney injury, and when patients were exposed to potassium supplements or calcineurin inhibitors. Because most patients were on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, including 85% of the patients with hypokalemia, data were not censored on the basis of use of these medications, and, in any case, hypokalemia persisted despite their use. In fact, all patients with hypokalemia required either potassium supplementation or mineralocorticoid antagonist therapy to maintain normal serum potassium concentrations. In the aldosterone-sensitive distal nephron, sodium reabsorption through the epithelial sodium channel generates the lumen-negative charge that contributes to a favorable electrochemical gradient for potassium secretion in the connecting tubule and collecting duct. Nephrotic proteinuria has been proposed to increase activation of the epithelial sodium channel, due to increased presence of urinary proteases that can activate the channel by cleavage (2). However, the patients described by Adomako et al. with hypokalemia had, on average, subnephrotic proteinuria (0.73 g/g protein/creatinine) that was similar to controls,