You order a metabolic panel on a patient with known CKD. Apart from the BUN and creatinine, the result may be abnormal in multiple respects. Today we’re focusing on hyperkalemia, hyperphosphatemia, and metabolic acidosis.
Mechanism in CKD
The kidney plays a vital role in potassium homeostasis through its response to aldosterone in the collecting duct, but this role is impaired in the presence of increasingly impaired glomerular filtration as CKD advances. In short, the lower the GFR, the lower the kidney’s ability to excrete potassium.
Realistically, however, the cause is most often multifactorial with multiple mechanisms at play: impaired renal perfusion (e.g., presence of HF), drug effects (e.g., ACEI/ARB, MRA, salt substitutes), hyperglycemia, hyporeninemic hypoaldosteronism, etc.
What about ACEI/ARB use?
Clinical trials have demonstrated a benefit of using ACEI/ARBs in patients with CKD, particularly in terms of progression to ESRD. As such, the risk of hyperkalemia, which occurs in the minority of patients taking ACEI/ARBs, should not stop us from prescribing these medications to patients with CKD.
- 2001 meta-analysis: ACEI therapy compared with the alternative treatments was associated with significant reductions in the rate of progression to ESRD (7.4% versus 11.6%, relative risk 0.69, 95% CI 0.51-0.94)
- 2011 meta-analysis: Therapy with ACEI resulted in a significantly lower incidence of ESRD (2.6% versus 3.8%; relative risk 0.67, 95% CI 0.54-0.84); ARB therapy also reduced the incidence of ESRD compared with other drugs (14% versus 18%; relative risk 0.78, 95% CI 0.66-0.90)
Regarding hyperkalemia specifically, a 2009 retrospective analysis found that patients with CKD treated with a RAAS blocker were slightly less likely to have both moderate and severe hyperkalemia than CKD patients who were not on this treatment.
So, perhaps the more appropriate questions is when should we stop ACEI/ARB use in patients with CKD?
A 2022 retrospective cohort study evaluated the association of discontinuing RAAS inhibitors after an episode of hyperkalemia and clinical outcomes in patients with CKD, finding that RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD:
There are a variety of treatments for hyperkalemia, some which are fast-acting but do not eliminate potassium from the body (e.g., insulin, high-dose albuterol) while others are slower but effectively remove potassium from the body (e.g., GI cation exchangers, loop/thiazide diuretics); hemodialysis is another definitive therapy, but requires nephrology consultation, appropriate access, and care coordination.
- The most commonly used GI cation exchangers are sodium zirconium cyclosilicate (SZC; Lokelma) and patiromer. SZC is generally preferred over patiromer because of its more rapid onset of action.
Mechanism in CKD
CKD leads to decreased urinary phosphate excretion and decreased production of calcitriol. The latter leads to decreased calcium absorption, stimulating PTH to increase bone turnover and compromising the bony reservoir for phosphorus.
PTH decreases reabsorption of phosphorus in the proximal tubule, leading to increased excretion of phosphorus. Thus, in early CKD, phosphorus levels are typically normal.
- Clinical pearl: For a patient with an elevated creatinine and no known baseline (i.e., unclear if AKI, CKD, or AKI/CKD), a PTH level may be helpful. Patients without CKD should have a normal PTH level even with AKI, assuming their calcium level is normal
Why It Matters
Bone turnover leads to a significant increase in fragility fractures: 15%, 20.5%, 24.2%, 31.2%, and 46.3% per 1,000 person-years for CKD stages 1, 2, 3a, 3b, and 4, respectively.
If you can’t excrete it through urine and it can’t stay in bone, then it potentially builds up in your vasculature in the form of progressive atherosclerosis and even calciphylaxis.
- Also known as calcific uremic arteriolopathy, calciphylaxis is defined by severe calcification of arterioles that lead to skin necrosis, ulceration, and severe pain. It is associated with high mortality.
In earlier CKD stages, reduction in dietary phosphorus is usually adequate. At advanced CKD stages, patients may need phosphate binders (followed by vitamin D analogs) for adequate control.
- Phosphate binders include 2 broadly defined types: calcium-based binders (e.g., calcium acetate, calcium carbonate, or calcium citrate) and noncalcium-based (e.g., sevelamer, lanthanum, ferric citrate, or sucroferric oxyhydroxide). The latter group is preferred because of its lower all-cause mortality
- Vitamin D analogs include calcitriol and cinecalcet
Metabolic acidosis & Low Bicarbonate
Mechanism in CKD
The two primary ways that the kidneys affect acid-base status are through bicarbonate reabsorption and hydrogen ion excretion (mostly as ammonia). Thus, as CKD progresses, acidosis tends to worsen as a result of increased loss of bicarbonate and decreased renal excretion of acid.
Acidosis itself leads to many issues:
- Muscle wasting and protein catabolism
- Demineralization of bone
- Increased insulin resistance
- Impaired GH secretion
- Lower performance in cognitive testing
- Increased risk of progression to ESRD
- Increased all-cause mortality
Should we treat?
Multiple RCTs show a benefit in treating patients with oral alkali in terms of improving nutritional outcomes as well as preventing progression of CKD. This finding led to KDIGO’s recommendation to treat patients with CKD and metabolic acidosis; however, only around 3% of adults with CKD and acidosis are estimated to be on such treatment.
The 2019 UBI trial, which enrolled CKD patients (including those with comorbidities, excluding heart failure) and randomized them to get sodium bicarbonate treatment, demonstrated improvements in all-cause mortality as well as time to dialysis and progression of kidney disease.
As such, oral alkali treatment (e.g., sodium bicarbonate, sodium citrate) is recommended for patients with CKD and bicarbonate levels below 22.
- The cation here is important to consider: the amount of sodium can be substantial (500 mg/day), presenting potential issues for patients at risk for fluid overload, etc.
- The major electrolyte/acid-base issues that arise in CKD are hyperkalemia, hyperphosphatemia, and metabolic acidosis. Each of these tends to worsen as CKD progresses, and all generally cause increased mortality in these patients
- Hyperkalemia can be treated with resins to promote excretion, and ACEI/ARBs should be continued as long as possible while maximizing treatments for hyperkalemia
- Hyperphosphatemia occurs in conjunction with secondary hyperparathyroidism, which can affect the bones and vascular system
- Hyperphosphatemia should be treated first with a low phosphate diet, then phosphate binders
- Metabolic acidosis should be corrected, if possible, with oral alkali agents
Blog post based on Med-Peds Forum talk by Cam Ulmer, PGY4