Direct Renin

Plasma Direct Renin (DR) and eDR* definitions

1. For patients not taking an ACEI or ARB or DRI (aliskiren/tekturna/rasilez):
Direct Renin (μU/mL)
Low renin: < 6.5
Medium renin: 6.5 – 45
High renin: > 45
2. For patients taking an ACEI of ARB or DRI (aliskiren/tekturna/rasilez)
Direct Renin (μU/mL) eDR
Low renin: < 45 < 6.5
Medium renin: 65 -350 65-45
High renin: > 350 > 45

* eDR (effective renin) = 0.13 x DR. It reflects the fact that the effectiveness of plasma renin is reduced by about 90% in patients taking an ACEI or ARB or aliskiren

Relationship of plasma renin activity (PRA) to direct plasma renin (DR) levels

Plasma renin activity (PRA) is used to estimate the capacity of the circulation to generate angiotensin II, the active hormone of the renin-angiotensin system. In fact PRA usually changes in relation to the circulating concentration of renin. However, PRA sometimes reflects changes in renin substrate (plasma angiotensinogen). This difference is usually not important since, unlike renin, plasma angiotensinogen rarely changes; moreover, when angiotensinogen does change it changes slowly (over days).

In contrast, the direct plasma renin test (DR) detects only the circulating concentration of the enzyme renin. If plasma angiotensinogen falls, DR usually rises to compensate for the reduced capacity of plasma to generate angiotensin; if plasma angiotensinogen rises, DR usually falls thereby maintaining a constant rate of angiotensin generation.

Under most circumstances, PRA and DR change together and in proportion to each other. Thus, for must purposes the two tests can be used interchangeably, as long as the difference in units is taken into account.

Situations in which PRA and plasma DR do not change proportionally.

  1. Patients taking direct renin inhibitors (e.g. aliskiren – i.e., tekturna/rasilez): In such patients DR is proportionally much higher than PRA because PRA falls whereas DR rises. This directional difference in the two measurements occurs because aliskiren induces an increase in the plasma renin concentration while simultaneously reducing the activity of circulating renin by about 90%. Since angiotensin is generated only by the 10% of renin that remains unbound to aliskiren, but DR measures both the inactive aliskiren-bound renin and the active free renin, PRA falls in patients taking aliskiren whereas DR rises.Because aliskiren increases the circulating renin concentration by 2 to 10 fold, PRA levels usually fall by considerably less than 90% in patients taking aliskiren.
  2. Patients with PRA levels over 40 ng/ml/hr: In such patients DR is proportionally higher than PRA. In patients taking an ACEI and/or ARB and/or a natriuretic drug, PRA levels sometimes rise to very high levels. When PRA reaches around 40 ng/ml/hr the liver can no longer synthesize angiotensinogen fast enough to keep up with its utilization by renin. This leads to a positive feedback loop: as angiotensinogen levels fall the kidneys secrete more renin to produce sufficient levels of angiotensin II. The higher renin levels in turn cause even greater depletion of plasma angiotensinogen thereby inducing even higher rates of renin secretion. Thus, when PRA levels exceed 40 ng/ml/hr, DR levels can rise to incredibly high levels – out of proportion to the rise in PRA.To make matters worse, a methodological issue may result in underestimation of the PRA level in patients with very high plasma renin concentrations because plasma angiotensinogen is used up during the PRA assay. Under usual circumstances less than 10% of the usual plasma angiotensinogen level is depleted during 3 hours at 37C. But when plasma angiotensinogen is abnormally low, and PRA is over 40 ng/ml/hr, as much as 50% of plasma angiotensinogen may be depleted during the assay. When that happens the measured PRA level is falsely low. To get around this problem our laboratory used a very short Ang I generation time for samples with high PRA levels. However, few commercial laboratories take the time to repeat the assay with the shorter Ang I generation time.
  3. Pregnancy and high estrogen levels: In such patients  DR is proportionally lower than PRA. Angiotensinogen levels increase markedly during pregnancy and whenever plasma estrogen is elevated. In such patients renin secretion falls to compensate for the higher rate of angiotensin generation. That results in a fall in DR levels.
  4. Congestive heart failure:  In such patients plasma DR is proportionally higher than the PRA because plasma angiotensinogen levels are usually subnormal.