Metabolic Acidosis in a Patient with CKD

Question 1

Which of the following regarding acid-base regulation in CKD is correct?

• A. Net endogenous acid production (NEAP) is minimally modifiable by diet change.

• B. Dietary salt can be a source of acid, contributing to acidosis.

• C. Guanylin and uroguanylin (UGN), through pendrin, play a role in Cl⁻ retention and acidosis.

• D. Plant proteins and animal proteins show a similar degree of acidogenesis.

Discussion of Question 1

The correct answer is B.

Dietary intake of acid and base precursors, metabolized to nonvolatile acidic and alkali products, is the major determinant of NEAP (net sum of acids-alkali); NEAP can thus be modified by varying diet (1). A is incorrect. Western diet generates approximately 0.7–1.0 mEq/kg body wt per day of net noncarbonic (nonvolatile) acids (approximately 50–100 mEq of daily NEAP) that rely on kidneys to excrete, chiefly in the form of ammonium and phosphoric salts. Kidney dysfunction impairs acid excretion capacity; without modifying NEAP, H⁺ surplus will predictably emerge and herald metabolic acidosis, which progressively worsens with CKD progression. Dietary modifications (i.e., adding base-generating fruits/vegetables and avoiding overconsumption of acidogenic meats and processed grains) can reduce NEAP, thereby minimizing H⁺ buildup.

The Western diet contains high levels of salt (sodium chloride), mostly 10 to >12 g/d. Given the equimolar Na⁺ and Cl⁻ in salt and approximately 140:100 Na⁺/Cl⁻ ratio in plasma, salt ingestion adds disproportionately more Cl⁻ into the body, and if unadjusted, it can cause hyperchloremia. The Cl⁻ increase leads to a reduction in OH⁻ (body fluid electroneutrality); the OH⁻ reduction obligates H⁺ elevation (ionic product constant of water: K_w = [H⁺] × [OH⁻]). Sodium chloride addition also dilutes serum HCO₃⁻. The composite outcome of these equilibrium shifts is acidosis, analogous to the much simpler low pH (5.4) for 0.9% saline (2).

Despite dietary salt loading, however, only minute (subclinical) acid-base deviations are observed in healthy adults (3). Such apparent tolerance is due to the presence of efficient homeostatic regulatory machinery, residing primarily in the gut and kidney (Figure 1). In the gut, guanolyn peptides (guanylin/UGN [4,5]) deter Na⁺ and Cl⁻ absorption by blocking Na⁺/H⁺ exchanger and stimulating cystic fibrosis transmembrane conductance regulator. In the kidney proximal tubules, through suppressing Na⁺/H⁺ exchanger and modulating membrane potential, UGN reduces net absorption of Na⁺, Cl⁻, and K⁺. In the distal tubules, in addition to blunting Na⁺ and K⁺ absorption, UGN inhibits the expression of pendrin (a Cl⁻/HCO₃⁻ exchanger) in the (non-α) intercalated cells, preventing Cl⁻ absorption in exchange for HCO₃⁻. Lower tubular fluid HCO₃⁻ also blunts HCO₃⁻-stimulated epithelial Na⁺ channel activity, further tempering Na⁺ absorption. C is incorrect. In patients with CKD, loss of functional kidney mass diminishes such a tight regulation, contributing to Na⁺ and Cl⁻ retention, volume expansion, and acidosis.

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Figure 1.

Salt absorption is regulated by guanolyn peptides in the gut and kidney. Intake of salt (sodium chloride [NaCl])-containing meals is associated with the genesis and secretion of guanolyn peptides (guanolyn [GN] and uroguanolyn [UGN]) in the gut. The guanylate cyclase-C (GC-C) receptors, when activated by GN/UGN, increase intracellular cyclic guanosine monophosphate (cGMP), which in turn, activates protein kinases (protein kinase G [PKG] and protein kinase A [PKA; via phosphodiesterase inhibition]) and ion channels, including cystic fibrosis transmembrane conductance regulator (CFTR), stimulating secretion of NaCl-containing fluids. In the kidney, UGN activates G protein–coupled receptor (GPCR), modulates membrane potential in the proximal tubular cells, and inhibits renal outer medullary potassium channel (ROMK) in the distal tubular cells (mainly the principle cells). Through a yet to be identified mechanism, UGN inhibits pendrin expression in the non–α-intercalated cells. Note that the figure is an abbreviated illustration of GN/UGN regulations related to NaCl. ENaC, epithelial sodium channel; GTP, guanosine triphosphate; NHE, Na⁺/H⁺ exchanger; PDE, phosphodiesterase.

Dietary proteins are metabolized to amino acids, which can be further broken down to yield acidic and alkaline products. Metabolizing animal proteins generates net acidic products (hydrogen chloride, sulfuric acid, and phosphoric acid). Vegetable proteins, especially soy protein, contain less acid-producing methionine, cysteine, lysine, and phosphorous and elicit minimal adaptive glomerular hyperfiltration as do animal proteins (6). Diets richer in plant foods are, in general, less acidogenic, and they are associated with better kidney function (7), whereas diets heavy in animal foods can be deleterious (8). D is incorrect.

Question 2

What should be the next step in the management of this patient?

• A. No change in the current management

• B. Dietary consultation to increase intake of fruits and vegetables

• C. Add sodium bicarbonate (NaHCO₃)

• D. Add NaHCO₃ and avoid fruits and vegetables to prevent hyperkalemia

Discussion of Question 2

The correct answer is B.

Despite frequent occurrence of acid surplus in patients with CKD on an acidogenic diet, large drops in serum HCO₃⁻ (or total CO₂) are minimized by augmenting multiple intrarenal and systemic compensatory mechanisms. These mechanisms include (1) enhanced kidney acid excretion in the form of NH₃/NH₄⁺ (high capacity) and titratable acids (low capacity) and (2) titration of excess acids by non-HCO₃⁻ buffers, including intra- and extracellular proteins and skeletal sources of bases (calcium carbonate and dibasic phosphate). The parallel release of calcium from bones can cause vascular and soft tissue calcification accompanied by bone demineralization. Acidosis has also been shown to elevate plasma fibroblast growth factor 23, a phosphatonin that, when elevated, is associated with an increased risk of cardiovascular disease. Collectively, sustained acid surplus and its induced compensatory reactions are proportionally associated with intrarenal accumulation of inflammatory and fibrogenic mediators (endothelin-1, angiotensin II, and aldosterone), systemic inflammation, muscle catabolism/wasting, osteodystrophy, CKD progression, cardiovascular complications, and all-cause mortality.

The importance of acid surplus in these deleterious outcomes is substantiated by consistent observations that, after eliminating or reducing acidic intakes in CKD animal models and patients with CKD, the deleterious sequelae can be dramatically curtailed. More relevant to our patient, Goraya et al. (9) showed that, in nondiabetic patients with CKD stage 3 (n=108) without overt acidosis (serum HCO₃⁻≥22 mEq/L), reducing NEAP by supplanting alkali (NaHCO₃) or fruits and vegetables reduces urine angiotensinogen and slows CKD progression. Additionally, compared with NaHCO₃, supplementing fruits/vegetables resulted in a small but significant reduction in body weight and BP. Plant foods also contain less bioavailable phosphorous. In a crossover study of nine patients with a mean eGFR of 32 ml/min, a 1-week vegetarian diet lowered serum phosphorus and fibroblast growth factor 23 compared with a meat-containing diet with equivalent amounts of phosphorous (10). Dietary modification, therefore, should be an integral part of CKD care. A is incorrect. Dietary information from the National Kidney Foundation can be obtained at https://www.kidney.org/nutrition/Kidney-Disease-Stages-1-4.

Although NaHCO₃ administration could be beneficial for patients with subclinical acidosis (plasma total CO₂ of 22–24 mmol/L), the current recommendation is to initiate alkaline therapy when serum HCO₃⁻ falls below 22 mEq/L. C is incorrect. Fruit/vegetable supplementation (equivalent to 50% of dietary acid load) for nondiabetic patients with moderate CKD seems well tolerated and does not have added risk of hyperkalemia. D is incorrect. In practice, however, it would be prudent to monitor serum K⁺ after modifying diet and take into account other confounding intakes, such as K⁺-sparing diuretics and salt substitutes. In circumstances of fruit/vegetable intolerance, oral alkali may be considered. Conversely, hypokalemia (K⁺<4 mEq/L), common (approximately 25%–50%) in CKD, is also detrimental. It stimulates kidney ammonia genesis and is linked to systemic inflammation, oxidative stress, hypertension, CKD progression, and cardiovascular mortality. NaHCO₃ notably augments urinary K⁺ loss, whereas dietary enrichment of fruits and vegetables can prevent K⁺ deficit; it has the added benefits of a rich fiber supply, fostering healthier bowel microbiota, intestinal mucosa, and gut transit, thereby limiting uremic toxin generation. Thus, fruits and vegetables, when tolerated, are comparatively more advantageous than NaHCO₃.

Disclosures

Dr. Qian has nothing to disclose.