The number of drugs which are being used in medical practice which can cause hyperkalemia has increased, specially since it was realised that captopril could protect renal function even without reducing the blood pressure. These drugs affect the RAAS (renin angiotensin aldosterone system). This system helps regulate renal, cardiac, and vascular physiology, and its activation is central to many common pathologic conditions including hypertension, heart failure, and renal disease. Hyperkalemia is a natural outcome of the use of these drugs.
The classical (historical) view of the RAS pathway begins with renin cleaving its substrate, angiotensinogen (AGT), to produce the inactive peptide, angiotensin I, which is then converted to angiotensin II by endothelial angiotensin-converting enzyme (ACE). ACE activation of angiotensin II occurs most extensively in the lung. Angiotensin II mediates vasoconstriction as well as aldosterone release from the adrenal gland, resulting in sodium retention and increased blood pressure.
There are also several tissue (local) renin-angiotensin systems that function independently of each other and of the circulating RAAS. In particular, angiotensin II generation at the tissue level by these local systems appears to have physiologic effects that are as important as circulating angiotensin II and, under some circumstances, more important than circulating angiotensin II.
What stimulates renin secretion?
- Baroreceptors (or stretch receptors) in the wall of the afferent arteriole of the glomerulus.
- Cardiac and arterial baroreceptors, both of which enhance renin secretion via the beta-1-adrenergic receptors
- The cells of the macula densa in the early distal tubule, which appear to be stimulated by a reduction in chloride delivery, particularly to this site.
Since normally we do not ingest chloride by itself it is sodium intake clinically which appears to regulate the RAAS. A low sodium intake (or sodium and water losses from any site) leads to a reduction in extracellular fluid volume and stimulation of renin secretion. Acute increases in renin secretion, such as those occurring with hypovolemia, primarily reflect the release of preformed renin from intracellular secretory granules. Chronic, persistent stimuli to renin release lead to increased synthesis of new prorenin and renin.
Measurement of renin
- The plasma renin activity (PRA) is an indirect measure of renin that employs an enzyme-kinetic bioassay, which measures its capacity to generate angiotensin I. The rate of angiotensin I production, and therefore PRA, is critically dependent upon the concentration of substrate in plasma (ie, angiotensinogen).
- The plasma renin concentration (PRC) employs a direct immunosorbent assay that detects both prorenin and renin
In pregnant women and in women taking oral contraceptive the PRA level may be higher than PRC levels. Measurements were made in hypertension in an attempt to define groups with high renin activity and low renin activity in order to better regulate therapy but the variations in the measurements did not yield accurate results. Hence measuring these values does not add much to the evaluation of essential hypertension and are more useful if primary aldosteronism is suspected.
The drugs used to inhibit the RAAS are: angiotensin converting enzyme inhibitors ACE-I like captopril, enalapril, lisinopril etc, angiotensin receptor blocking agents or ARBs like losartan, irbesartan, valsartan etc and mineralocorticoid receptor antagonists or MRAs like spironolactone. Aliskiren (the sole available renin inhibitor) is effective and safe as a single antihypertensive agent, it should not be combined with an ACE inhibitor or ARB
Whether or not to block the RAS is no longer the appropriate question in the clinical scenarios of diabetic nephropathy, chronic kidney disease, and heart failure. Efforts are dedicated to answering how best to optimize blockade. Discoveries of new peptides, enzymes, receptors, and cell-signaling targets of the system are changing our understanding of physiology and providing potential new therapeutic targets.
How often are you likely to encounter hyperkalemia?
- General population: 2-3%
- All hospitalised patients: 1-10%
- Patients with CKD (chronic kidney disease) up to 50%.
When should you worry or take action? A cardiologist will start decremental reduction in ACE-I, ARBs and MRAs at levels above 5 Eq/l. A nephrologist will probably push his/her luck to 5.5 or even 6, but will then stop the drugs. If you look at the slide given below i.e. the PARADIGM heart failure trial you will notice that the exclusion criteria included a serum potassium of 5.2 mEq/l at screening and 5.4 mEq/l at randomisation and an eGFR below 30ml/min/1.73 sq meter.
This should make you understand very firmly that any CKD patient in Stage 3b should not be receiving these drugs as the risk of death from hyperkalemia is too high to counter any potential benefit. Also the ACEi and ARBs reduce the GFR because they reduce the intraglomerular pressure. A drug which is being used to reduce proteinuria in order to ensure that the decline in the GFR is halted is of no use if it is causing the decline itself.
Why does hyperkalemia occur in heart failure?
As the cardiac output declines the blood flow to the kidney is also reduced, causing a decline in the GFR. Thus less K is eliminated through the kidney. Patients with HF tend to behave as if they are in the pre-renal stage of renal failure. The sodium filtered through the glomerulus is absorbed in the proximal tubule so less remains for exchange for hydrogen ion and potassium which is mediated by aldosterone. This is further complicated by the fact patients are on RAAS inhibiting drugs and on diuretics which deplete the volume. Patients on dialysis are better able to handle potassium because of remaining healthy glomeruli. Remember that in CKD the nephron in which the glomerulus is sclerosed does not function at all but the nephron with a functioning glomerulus works normally.
In diabetes there is reduced renal function because of damage to the glomerular basement membrane caused by proteinuria, the patient may be on RAAS inhibiting drugs and may also be in heart failure. The following slide provides guidelines regarding the use of RAAS inhibition based on serum potassium. It follows KDOQI, NICE (National Institute for Clinical Excellence) among others.
What can be done for hyperkalemia?
- In a hyperkalemic emergency serum potassium can be reduced quickly by helping the K to become intracellular and protecting the cell membrane. The use of intravenous insulin and glucose and intravenous calcium are recommended. Since in both diabetes and CKD acidosis is a factor in causing the hyperkalemia the use of intravenous bicarbonate is common clinical practice.
- Patients who can have the potassium lowered slowly − Most patients with hyperkalemia have chronic, mild (≤5.5 mEq/L) or moderate (5.5 to 6.5 mEq/L) elevations in serum potassium due to chronic kidney disease (CKD) or the use of medications that inhibit the renin-angiotensin-aldosterone system ([RAAS] or both).
- Such patients do not require urgent lowering of the serum potassium and can often be treated with dietary modification, use of diuretics (if otherwise appropriate), treatment of chronic metabolic acidosis, or reversal of factors that can cause hyperkalemia (eg, nonsteroidal anti-inflammatory drugs, hypovolemia).
- In some instances, drugs that inhibit the RAAS are reduced or discontinued, and drugs that remove potassium by gastrointestinal cation exchange are prescribed for chronic use.
Drugs used in chronic hyperkalemia.
SPS (sodium polystyrene sulfonate) is usually premixed in sorbitol. This sorbitol is no longer recommended as it causes a high incidence of intestinal necrosis as a side effect. SPS alone is not always available and, when available, comes as a powder that must be reconstituted. It is a cation exchange resin which exchanges Na for hydrogen ions in the stomach and then exchanges the hydrogen ion for other cation in the large intestine. it reduces the serum potassium by .82 to 1.14 mEq/l depending on the dosage. However it is a bulky drug which most patients find unpleasant to drink and causes acute bowel necrosis, diarrhea, hypernatremia and gastrointestinal disturbances.
Use SPS if;
- Patient has potentially life-threatening hyperkalemia
- Dialysis is not readily available
- Newer cation exchangers are not available
- Other therapies to remove potassium (eg, diuretics, rapid restoration of kidney function) have failed or are not possible
Patiromer and SZC are compared below in a slide you might find useful.