The TTKG estimates the potassium concentration gradient across the cortical collecting duct, reflecting the kidney's ability to secrete or conserve potassium under aldosterone influence. In hyperkalemia, a TTKG below 7 suggests that the kidney is not appropriately excreting potassium, pointing to a renal cause such as hypoaldosteronism, aldosterone resistance, or collecting duct dysfunction. A TTKG above 7 in hyperkalemia suggests the kidney is responding appropriately and the cause is likely extrarenal (e.g., cell lysis, rhabdomyolysis, massive intake).

In hypokalemia, a TTKG above 3 indicates inappropriate renal potassium wasting, which may be due to hyperaldosteronism, diuretic use, or renal tubular disorders such as Bartter or Gitelman syndrome. A TTKG below 2 in hypokalemia suggests the kidney is conserving potassium appropriately, and losses are extrarenal (GI losses, inadequate intake, transcellular shift).

Use the TTKG when evaluating the etiology of unexplained hypokalemia or hyperkalemia. It is most valuable when the clinical picture does not clearly point to a renal versus extrarenal cause. For example, in a patient with hyperkalemia but no obvious cause (no renal failure, no potassium load, no cell lysis), the TTKG can help determine whether aldosterone deficiency or resistance is contributing.

The TTKG is valid only when certain prerequisites are met: the urine osmolality must exceed the serum osmolality (indicating ADH activity and water reabsorption in the collecting duct), and the urine sodium should be above 25 mEq/L (ensuring adequate sodium delivery to the collecting duct for potassium secretion). If these conditions are not met, the TTKG result is unreliable.

The theoretical basis of the TTKG has been questioned in recent years. The formula assumes that urea and water are the only substances reabsorbed in the medullary collecting duct and that potassium is neither secreted nor reabsorbed there. Studies have shown that these assumptions are not entirely valid, and some nephrology experts have moved away from routine TTKG use.

The TTKG cannot distinguish between specific causes within the renal or extrarenal categories. For example, a low TTKG in hyperkalemia does not differentiate between type 4 RTA, ACE inhibitor effect, or primary hypoaldosteronism. Additional testing (aldosterone levels, renin activity, urine electrolytes) is needed for a definitive diagnosis. Despite its limitations, the TTKG remains a useful bedside tool for initial assessment when interpreted cautiously alongside clinical context.