The present study tested the hypotheses that nephrotic syndrome (NS) leads to renal K + loss because of augmented epithelial Na + channel (ENaC) activity followed by downregulation of renal K + secretory pathways by suppressed aldosterone. The hypotheses were addressed by determining K + balance and kidney abundance of K + and Na + transporter proteins in puromycin aminonucleoside (PAN)-induced rat nephrosis. The effects of amiloride and angiotensin II type 1 receptor and mineralocorticoid receptor (MR) antagonists were tested. Glucocorticoid-dependent MR activation was tested by suppression of endogenous glucocorticoid with dexamethasone. Urine and plasma samples were obtained from pediatric patients with NS in acute and remission phases. PAN-induced nephrotic rats had ENaC-dependent Na + retention and displayed lower renal K + excretion but elevated intestinal K + secretion that resulted in less cumulated K + in NS. Aldosterone was suppressed at day 8. The NS-associated changes in intestinal, but not renal, K + handling responded to suppression of corticosterone, whereas angiotensin II type 1 receptor and MR blockers and amiloride had no effect on urine K + excretion during NS. In PAN-induced nephrosis, kidney protein abundance of the renal outer medullary K + channel and γ-ENaC were unchanged, whereas the Na +-Cl - cotransporter was suppressed and Na +-K +-ATPase increased. Pediatric patients with acute NS displayed suppressed urine Na +-to-K + ratios compared with remission and elevated plasma K + concentration, whereas fractional K + excretion did not differ. Acute NS is associated with less cumulated K + in a rat model, whereas patients with acute NS have elevated plasma K + and normal renal fractional K + excretion. In NS rats, K + balance is not coupled to ENaC activity but results from opposite changes in renal and fecal K + excretion with a contribution from corticosteroid MR-driven colonic secretion.