Metabolic Acidosis of Chronic Kidney Disease

1

Introduction

Approximately, 1 mEq/kg body weight of net endogenous acid is produced in adults and 2–3 mEq/kg body weight in normal children each day. In addition, ∼4500 mEq/day (180L × 25 mEq/L) bicarbonate is filtered by the glomerulus. This filtered bicarbonate must be reabsorbed by the renal tubules and a quantity of bicarbonate equivalent to the acid produced by metabolism must be generated by the renal tubules to maintain the blood pH and serum bicarbonate concentration at normal levels of ∼7.38 ± 0.02 and 25.4 ± 0.09 mEq/L in males and ∼7.40 ± 0.02 and 24.4 ± 1.3 mEq/L in nonpregnant females, respectively. Chronic kidney disease (CKD) may cause impairment in one or both tubular processes, leading to positive acid balance and the development of metabolic acidosis. The metabolic acidosis developing in the course of CKD has previously been termed uremic acidosis. However, because it is most frequently present in the absence of uremic signs or symptoms, it is more appropriately termed the metabolic acidosis of CKD.

Importantly, acid retention producing an increase in the acidity of the interstitial milieu without a detectable fall in serum $\left[{{\text{HCO}}_3}^{-}\right]$ has been described in animals and humans with mild to moderate CKD. These findings suggest that the criteria for the diagnosis of the metabolic acidosis of CKD can be expanded to include the presence of acid retention with and without a detectable fall in serum $\left[{{\text{HCO}}_3}^{-}\right]$ . However, further study of this issue is required.

The acidosis of CKD is the most common cause of chronic metabolic acidosis (defined temporally as that lasting weeks to years) observed in the general population, and its prevalence is expected to rise over the ensuing years. This increase largely reflects aging of the population with a predicted decline in glomerular filtration rate (GFR) that accompanies it.

This form of metabolic acidosis is associated with significant adverse clinical consequences including dysfunction of several organ systems and an increase in mortality. In the present chapter, we will review the mechanisms underlying developments of metabolic acidosis with CKD, including the important role of various hormones, the effect of metabolic acidosis on different organ systems, the impact of amelioration of the metabolic acidosis by the administration of base, current recommendations for treatment, and possible complications of therapy.

2

Regulation of Acid–Base Balance With Normal Renal Function and Chronic Kidney Disease

As indicated in Fig. 17.1 , regulation of acid–base balance in the healthy individual is the result of the interplay of several factors including net endogenous acid production (NEAP), buffering by cellular and extracellular buffers, and renal reclamation of filtered bicarbonate and generation of new bicarbonate. Alterations in one of more of these processes can contribute to the development of metabolic acidosis with CKD.

3

Acid–Base Production

A finite quantity of H ⁺ or base (bicarbonate) is produced from the hepatic metabolism of ingested food. Approximately, 210 mEq of protons are generated daily from the metabolism of the neutral sulfur-containing amino acids, methionine and cysteine, which are converted to sulfate and H ⁺ ions, and the cationic amino acids, lysine, arginine, and some histidine residues, which are converted into neutral products and H ⁺ . Approximately, 160 mEq/day bicarbonate is generated from the metabolism of the amino acids, glutamate and aspartate, and organic anions such as citrate, gluconate, malate, acetate, and lactate. An additional 25–75 mEq of organic anions (potential base), half of which are metabolizable, are excreted in the urine. Therefore, NEAP each day is ∼50 mEq. However, there is often great variability among individuals, and therefore, NEAP can vary severalfold (range 20–120 mEq/day), reflecting primary differences in dietary intake. In addition, some have suggested that differences in the individual microbiome (the bacterial population of the gastrointestinal tract) could affect the quantity of NEAP produced, and this could be a fruitful area of research.

The impact of dietary intake on acid–base balance in subjects with normal renal function is exemplified by the studies of Kurtz et al. In normal subjects fed with various diets designed to produce net acid excretion between 14 and 154 mEq/day, there was an inverse relationship between plasma $\left[{{\text{HCO}}_3}^{-}\right]$ and endogenous acid load, the higher the acid load the lower the plasma $\left[{{\text{HCO}}_3}^{-}\right]$ . This impact of dietary intake on plasma $\left[{{\text{HCO}}_3}^{-}\right]$ was confirmed by Frassetto et al. in a larger cohort of individuals. An increase in NEAP of ∼100 mEq/day caused a fall in plasma $\left[{{\text{HCO}}_3}^{-}\right]$ concentration of ∼1 mEq/L.

The impact of changes in NEAP on acid–base parameters in individuals with CKD is magnified by the reduction in the ability to excrete the acid load. The magnitude of dietary NEAP in patients with CKD has been studied by several investigators. Acid–base balance in individuals with renal failure (GFR, 11–60) and metabolic acidosis ingesting a diet consisting of a purified formula had a NEAP, which was not significantly different from healthy individuals with normal renal function. Others found NEAP in patients with CKD not yet on dialysis can vary. In patients with GFR of 15–59 mL/min per 1.73 m ² , the mean acid load was 47 mEq/day in the group as a whole, but a third had an acid load less than 39 mEq/day, a third had an acid load of 39–55 mEq/day, and a third had an acid load greater than 55 mEq/day.

Uribarri et al. measured dietary net H ⁺ production in patients (1) with chronic renal failure (GFR 19–33 mL/min) and normal or reduced plasma $\left[{{\text{HCO}}_3}^{-}\right]$ concentrations ; (2) maintained on chronic ambulatory peritoneal dialysis (CAPD) with normal plasma bicarbonate concentrations; and (3) maintained on weekly hemodialysis thrice with mild predialysis metabolic acidosis (plasma [HCO ₃ ] of 21–23 mEq/L). In CAPD patients, in whom the plasma [HCO ₃ ] was in the normal range, net H ⁺ production was lower than that of individuals with normal renal function, but was similar to that of patients with CKD. Similarly, the net H ⁺ production rate in stable chronic hemodialysis patients with mild predialysis hypobicarbonatemia was reduced by ∼50%. The reduction in net H ⁺ production with both modalities of therapy was due to a decrease in sulfuric acid generation from cysteine- and methionine-containing amino acids and the retention of metabolizable organic anions, which are potential sources of base. A fall in urinary excretion of metabolizable anions has also been described at earlier stages of CKD; whether this is due to the accompanying acidosis is not clear. NEAP can be low in patients with CKD when protein intake is reduced as a therapeutic tool.

The impact of changes in NEAP on acid–base parameters might be more profound in individuals with CKD than in those with normal renal function. For example, at entry into the Modification of Diet in Renal Disease (MDRD) study, serum $\left[{{\text{HCO}}_3}^{-}\right]$ was inversely correlated with a major determinant of NEAP, the estimated protein intake (1.0 mmol/L decrease for each gram per kilogram body weight increase in protein intake). Also, a 25% reduction in estimated dietary protein intake (from 1.01 to 0.74 g/kg body weight per day) in individuals with a mean GFR of 38 ± 9.2 mL/min per 1.73 m ² caused serum $\left[{{\text{HCO}}_3}^{-}\right]$ to rise by approximately 1 mmol/L (0.91 ± 0.25 mmol/L). A similar effect of changes in dietary protein intake on serum $\left[{{\text{HCO}}_3}^{-}\right]$ was detected in the African Americans with CKD study. In addition, in dialysis patients, often a lower serum $\left[{{\text{HCO}}_3}^{-}\right]$ is observed in individuals ingesting the highest protein intake, whereas higher values of serum $\left[{{\text{HCO}}_3}^{-}\right]$ are observed in those with low protein intake.

In summary, for the most part, NEAP in individuals with CKD, both before or after initiation of maintenance dialysis, is either normal or reduced, but values can vary substantially. These findings exclude an increment in NEAP as a major contributory factor in the development of metabolic acidosis with CKD in most patients. Because NEAP is correlated with dietary protein intake, however, any increase in protein intake over normal can contribute to the development or worsening of the metabolic acidosis; whereas, any reduction in protein intake below normal can lessen the severity of the metabolic acidosis. Finally, an increase in ingestion of fruits and vegetables, sources of base, can strikingly alter NEAP. Indeed, increased intake of fruits and vegetables has been recommended as a means of providing base to patients with CKD not on dialysis.

4

Renal Bicarbonate Generation

The kidney is responsible for replenishment of bicarbonate lost in the process of buffering endogenous H ⁺ production. Bicarbonate is generated by the kidney by three processes: (1) secretion of H ⁺ and titration of filtered ${{\text{HPO}}_4}^{-}$ ; (2) metabolism of α-ketoglutarate derived from glutamine; and (3) metabolism of filtered and reabsorbed organic anions such as lactate and citrate. The secretion of protons into the tubule lumen generates intracellular bicarbonate because the secreted protons are derived from carbonic acid. Protons secreted into the tubule lumen can bind to inorganic anions (e.g., phosphate) and organic anions (e.g., citrate) depending on their respective pKas. Excretion of these protonated substances, so-called titratable acids (TAs), in the urine results in the intracellular generation of an equimolar amount of bicarbonate. In subjects with normal renal function, ∼10–30 mEq/day of new bicarbonate are generated by this mechanism each day. The dominant source of new bicarbonate (∼60%) is derived from renal extraction and metabolism of glutamine. Metabolism of 1 mol of glutamine generates 1 mol of α-ketoglutarate, which yields 2 mol of $\left[{{\text{HCO}}_3}^{-}\right]$ when converted into glucose during gluconeogenesis or oxidized in the Krebs cycle. Bicarbonate is then transported via a basolateral kNBC1 ultimately to the renal vein. Were all the ${{\text{NH}}_4}^{+}$ produced in the proximal tubule returned to the systemic circulation, new bicarbonate generated from α-ketoglutarate would be consumed within the liver in the urea cycle $\left(2{{\text{NH}}_4}^{+}+2{{\text{HCO}}_3}^{-}\to \text{urea}\right)$ resulting in no net bicarbonate generation by the kidney. However, out of the total of an estimated 54 mmol of ${{\text{NH}}_4}^{+}$ and new bicarbonate per 1.73 M ² produced each day from glutamine, 30 mmol/1.73 M ² of ${{\text{NH}}_4}^{+}$ are excreted daily in the urine. Because ∼54 mmol/1.73 M ² of new bicarbonate derived from glutamine is delivered to the renal vein, ∼24 mmol/1.73 M ² (54–30 = 24) is converted into urea, leaving ∼ 30 mmol of bicarbonate/1.73 M ² is available to buffer the daily metabolic H ⁺ load.

In the early stages of metabolic acidosis, renal extraction of glutamine is not increased; however, by day 3–6, glutamine extraction increases substantially accounting for the vast majority of ${{\text{NH}}_4}^{+}$ , and therefore new bicarbonate is produced from α-ketoglutarate. Under these circumstances, glutamine extraction and metabolism per 100 mL GFR rise as much as sevenfold and concomitantly there is a three to fourfold increment in urinary NH ₄ excretion (30 mEq, baseline; 90–120 mEq day with acidosis). The ability of the kidney to continue to generate bicarbonate at a heightened rate is supported by the increased renal delivery of glutamine resulting from increased production in other organs and tissues. In patients with CKD, renal NH ₄ excretion can be reduced substantially even in the absence of a documented reduction in serum $\left[{{\text{HCO}}_3}^{-}\right]$ . The urinary NH ₄ excretion in patients with CKD is correlated with the level of GFR. It averaged 29 mEq/24 h when GFR was > 60 mL/min/1.73 m ² but fell to < 20 mEq/24 h when GFR fell below 30 mL/min/1.73 m ² . In other studies, with metabolic acidosis and GFR < 20 mL/min, renal ${{\text{NH}}_4}^{+}$ excretion is decreased substantially to levels <15 mEq/day, and total renal ${{\text{NH}}_4}^{+}$ production was decreased by approximately 50% from 38 μmol/min/1.73 m ² to 19 μmol/min/1.73 m ² . On the other hand, when expressed per mL of GFR (an estimate of residual nephron function), both the ${{\text{NH}}_4}^{+}$ excretion and production rates are increased to levels seen with metabolic acidosis (89 μmol/min/100 mL GFR vs. 116 μmol/min 100 mL GFR) indicating that the reduction in ${{\text{NH}}_4}^{+}$ production and new bicarbonate generation are primarily due to reduced functional renal mass.

The source of ammonia production is also altered in renal failure. Glutamine extraction is approximately one-tenth of that observed with ammonium chloride–induced metabolic acidosis in individuals with normal renal function (3 μmol/min compared with ∼ 31 μmol/min). As a result, less than 35% of ${{\text{NH}}_4}^{+}$ produced can be accounted for by glutamine metabolism. The explanation for the impairment of glutamine metabolism is unclear, but it is not due to reduced delivery of glutamine to the kidney, as arterial levels of glutamine are not reduced in individuals with CKD, and glutamine-loading does not increase ammonia production or urinary ammonium excretion in patients with kidney disease. The remainder of the ${{\text{NH}}_4}^{+}$ is produced from the metabolism of other proteins and peptides generated within the kidney. Furthermore, the partitioning of ${{\text{NH}}_4}^{+}$ between the urine and renal vein is not as enhanced as might be expected for individuals with metabolic acidosis. Nevertheless, with reduced kidney mass, the excretion of ${{\text{NH}}_4}^{+}$ per remaining nephron appears to be enhanced. In rat model of CKD due to a reduction of kidney mass, the entry of NH ₄ /NH ₃ into the tubular fluid was enhanced by increased localization of the transporter Rhcg on the basolateral and luminal membranes of the distal nephrons.

The majority of patients with CKD can acidify their urine to less than 6.0 and closer to 5.0, but the urine pH achieved is on average ∼1.5 pH units higher than that of individuals without kidney disease who have a similar degree of acidemia. Also, it has been suggested that hypobicarbonatemia and the attendant reduced distal bicarbonate delivery are essential for generation of a low urine pH. This limitation on urinary acidification, per se, however, is not a major factor in the impaired net acid excretion, because it has little impact on TA formation or ammonium excretion given their respective pKas of 6.8 and 9.0. In a minority of patients with renal failure, urine pH remains above 6.0 and bicarbonaturia can be seen even though serum $\left[{{\text{HCO}}_3}^{-}\right]$ concentration is substantially below normal. In these patients, not only TA is reduced, but the elevation of urine pH would be predicted to alter the renal vein:urine ${{\text{NH}}_4}^{+}$ partitioning, thereby reducing urinary ${{\text{NH}}_4}^{+}$ excretion while enhancing its delivery to the renal vein, similar to distal renal tubular acidosis (DRTA).

The decrease in new bicarbonate generation from α-ketoglutarate, discussed previously, leaves the kidney more dependent on bicarbonate generation from TA excretion. TA excretion remains normal or only mildly decreased until the later stages of renal failure (GFR < 15 mL/min) when it is reduced to 2 to 10 mEq/day. The preservation of TA excretion until later stages of renal failure primarily reflects the ability of most patients to reduce urine pH to less than 6.0 in association with excretion of normal quantities of phosphate, often promoted by elevated levels of parathyroid hormone (PTH) and possibly FGF23. An increase in PTH levels if present can be the consequence of hypocalcemia and hyperphosphatemia or stimulation by metabolic acidosis. Because urinary phosphate excretion is the dominant factor determining TA excretion, a decrease in TA excretion can be observed in patients prior to a significant decline in renal function if protein intake is markedly reduced, they are ingesting sufficient quantities of phosphate binders to reduce filtered phosphate load and consequently urinary phosphate excretion, or there is a shift in the nature of the diet resulting in less phosphate generation.

5

Cellular Buffering

Acid introduced in the body is neutralized by buffers in the extracellular and intracellular compartments. A large fraction of the buffering done outside the extracellular compartment occurs within muscle. Thus, the intracellular pH of muscle from nondialyzed patients with CKD was substantially lower than normal controls (6.82 vs. 7.04) ; however, it has been postulated that bone can also contribute significantly to this process. The latter organ is primed for this purpose as it contains ∼35,000 mEq of exchangeable base in the form of carbonate. Buffering of protons by bone is the result of both release of freely exchangeable base independent of cellular action and cell-dependent dissolution of bone.

Buffering of acid by bone has been postulated to begin very soon after acid is introduced into the body, but may be most important in the chronic buffering of acid. This process can be modulated by different hormones including PTH. The buffering of acid with short-term metabolic acidosis (few hours duration) has been examined by different investigators. Fraley et al. found that parathyroidectomized dogs and thyroid-parathyroidectomized (TPTX) rats had a larger fall in plasma $\left[{{\text{HCO}}_3}^{-}\right]$ in response to an acid load than animals with intact glands; results consistent with impaired buffering by nonextracellular buffers, presumably bone. By contrast, in other studies in TPTX rats, no impairment of buffering of an acute acid load was found. The reasons for the discrepant results are not clear.

Even if bone is not important for acute buffering of acid loads, studies in animals and man have suggested that it is important in the buffering of chronic acid loads. Administration of osteoclast-inhibitory drugs, thereby preventing release of base, produced a greater fall in serum $\left[{{\text{HCO}}_3}^{-}\right]$ in rats with CKD than in normal controls. Buffering of acid by bone was postulated to explain the stability of acid–base parameters in patients with CKD and metabolic acidosis. This inference was based on evidence that imposition of an acid load is associated with increased urinary calcium excretion with little change in intestinal calcium absorption implicating dissolution of bone in this process. Also, Goodman et al. studied a group of individuals with chronic renal failure (GFR 11–60 mL/min) and stable metabolic acidosis using a special diet in which hydrogen input could be determined. Over a period of several days, they demonstrated that subjects were in positive H ⁺ balance by ∼12 mEq/day, although serum $\left[{{\text{HCO}}_3}^{-}\right]$ concentration did not change. The validity of this assumption has been challenged in a carefully controlled study of a small number of patients with CKD and metabolic acidosis. These investigators found patients were essentially in neutral balance suggesting that acid retention was not present in patients with CKD and stable acid–base parameters. On the other hand, a recent study involving more than 1000 patients with CKD and GFR ranging from >15 mL/min/1.73 m/ to <60 mL/min/m ² showed that patients were in positive acid–base balance even when serum $\left[{{\text{HCO}}_3}^{-}\right]$ was within the normal range.

Studies showing decreased carbonate stores in dogs with metabolic acidosis and in patients with CKD with metabolic acidosis provide further support for an important role of bone buffering of acid loads with the chronic metabolic acidosis of CKD. Whether depletion of carbonate stores or development of various types of bone disease affects the ability of bone to buffer a chronic acid load has not been examined. However, Uribarri et al. examined the bicarbonate space in a small group of stable chronic dialysis patients, some of whom presumably had bone disease. These investigators found bicarbonate space, an index of cellular buffering, to be similar to that of those with intact renal function previously reported, i.e.,∼50% body weight. However, because the type and severity of bone disease in these patients were not examined, it is still conceivable that in patients with very severe bone disease, buffering of acid loads by bone could be impaired.

6

Renal Tubular Bicarbonate Reabsorption

Under normal conditions, 95% of filtered $\left[{{\text{HCO}}_3}^{-}\right]$ is reabsorbed by the renal tubules and the urine is virtually bicarbonate free. The bicarbonate is predominately reabsorbed in the proximal tubule via a sodium–hydrogen exchanger and proton translocating ATPase (H ⁺ -ATPase). The bulk of bicarbonate reabsorption in this segment is mediated by the sodium–hydrogen exchanger. Studies using the remnant kidney model in dogs have suggested that the sodium–hydrogen exchanger is upregulated with reduced GFR, thereby preventing substantial bicarbonate wasting.

Studies in uremic rats and humans have found absolute bicarbonate reabsorptive capacity to be either increased or decreased depending on the model utilized. Despite the failure to consistently detect impaired bicarbonate reabsorptive capacity in experimental studies and the evidence that the sodium–hydrogen exchanger might be upregulated with renal failure, a few studies involving small numbers of patients with CKD have described impaired bicarbonate absorption. Schwartz et al. demonstrated that 5 out of 12 subjects with renal failure continued to excrete bicarbonate in the urine when plasma $\left[{{\text{HCO}}_3}^{-}\right]$ fell below normal. Similarly, Lameire et al. found that 5 out of 17 patients with a GFR of 6–19 mL/min had fractional excretions of bicarbonate of 4.25%–17.65% despite serum bicarbonate concentrations as low as 17 mEq/L. Other investigators also confirmed bicarbonate wasting can be seen with chronic renal failure. However, this is not a consistent observation, and the exact prevalence of bicarbonate wasting in patients with CKD remains unclear. Defective bicarbonate absorption in renal failure could be ascribed to volume expansion, excessive PTH secretion, hyperfiltration in residual nephrons, an osmotic diuresis, or the presence of disorders that preferentially affects the proximal tubule.

In summary, NEAP in CKD is similar to or less than that observed with normal renal function, indicating this process is not a major factor in the metabolic acidosis of CKD. Limited studies of bicarbonate space reflecting cellular buffering in humans have suggested that it is not different from that noted in patients with normal renal function. Bicarbonate reclamation can be impaired in some patients contributing to bicarbonate wasting, but the prevalence of this abnormality is not clear. Therefore, the major factor producing the metabolic acidosis in the majority of patients with CKD is a reduction in renal bicarbonate synthesis causing it to fall below acid production. Fig. 17.2 depicts acid–base balance in patients with CKD with metabolic acidosis. The magnitude of renal net acid excretion will vary depending on the nature of acid excretory defect and the time in the course of CKD when this parameter is measured. Values given for net acid excretion and urinary bicarbonate excretion with CKD are estimates.

7

Hormonal Regulation of Acid–Base Balance With Normal Renal Function and CKD

The factors regulating renal acid excretion have been the subject of intense investigation. Although there is evidence that changes in pH, of the cellular and interstitial compartments, can directly modulate renal acid excretion via various extrarenal and renal mechanisms, a significant role for various hormones in modulating this process has been demonstrated. As summarized in Table 17.1 , several hormones have been shown to affect acid–base balance by modulating cellular buffering of acid and/or renal net acid excretion.

Table 17.1

Interrelationship of Acid–Base Balance and Hormone Function in Normals and With Chronic Kidney Disease (CKD)

Hormone	Effect of Acidosis on Serum Level or Response	Effect of Hormone on Acid–Base Balance	Role in Acid–Base Regulation With CKD
Aldosterone	Levels with metabolic acidosis	Collecting duct H + secretion and net acid excretion	Levels may help regulate acid–base balance Levels contribute to exacerbation of metabolic acidosis in part due to suppression of ammonia production by hyperkalemia
Angiotensin II	Levels with metabolic acidosis	Collecting duct H + secretion and net acid excretion	Levels may play a role in inducing hypoaldosteronism
Insulin	Action due to impaired receptor binding and postreceptor signal transduction	Net acid excretion no effect on acid–base parameters	Unclear
PTH	Levels in some studies; attenuates end organ response in others	May play role in cellular buffering; net acid secretion	Unknown role in acid–base regulation
Growth hormone	Blunted response to hormone	Net acid excretion	Impaired action may contribute to development of metabolic acidosis
Glucagon	unknown	Net acid excretion	Unknown
Glucocorticoids		Glutamine uptake with enhanced NH 4 production and possibly net acid excretion	Unknown
ADH	Unknown	Net acid excretion	Unknown
Endothelin	Unknown	Net acid excretion	Unknown

8

Aldosterone

One of the major hormones for modulating renal acid excretion is aldosterone. Aldosterone modulates the reabsorption of sodium by the renal collecting duct. This process sets up the lumen negative potential that favors proton transport by the electrogenic H ⁺ -ATPase residing in the specialized intercalated cell. Aldosterone may also directly affect proton pumping by this transporter. It does not appear to modulate the activity of the electroneutral renal H ⁺ -K ⁺ -ATPase, another proton transporter present in the kidney whose role in renal acid excretion remains unclear. Serum aldosterone levels rise with metabolic acidosis and this may be important in the kidney’s ability to excrete an acid load. Indeed, states such as primary adrenal insufficiency and hyporeninemic hypoaldosteronism may be characterized by the development of a nonanion gap metabolic acidosis, related in part to reduced aldosterone levels. The impairment of renal acid excretion is a consequence in part of suppression of ammonia production by the accompanying hyperkalemia as correction of the hyperkalemia alone can increase ammonium excretion and improve acid–base parameters.

Serum aldosterone levels in some studies of patients with CKD are in fact elevated. However, in a subset of patients, primarily with diabetic renal disease, abnormalities in aldosterone production can develop either alone or in response to low renin levels (hyporeninemic hypoaldosteronism) contributing to the development of metabolic acidosis. A potential side effect of the use of drugs that alter tubular response to aldosterone for the treatment of CKD is an elevation in serum potassium concentration and reduction in serum $\left[{{\text{HCO}}_3}^{-}\right]$ . Therefore, both serum potassium and bicarbonate levels should be monitored carefully during treatment of these agents. Patients with preexisting CKD might be particularly prone to develop more severe acidosis because they have a lower acid excretory reserve.

9

Angiotensin II

Angiotensin II has direct effects on acid–base transport and metabolism in the proximal tubule. It stimulates Na ⁺ -H ⁺ exchange, Na ⁺ - $\left[{{\text{HCO}}_3}^{-}\right]$ cotransport, and ammonia production and secretion. Metabolic acidosis stimulates the renin–angiotensin–aldosterone system, and this effect could be important in the adaptive response to an acid challenge. Thus, studies in mice have demonstrated that blocking the type 1 angiotensin receptor prevented the adaptive increase in ammonia excretion that occurs after an acid challenge. Receptor blockade had no effect on basal rates of urinary NH ₄ excretion or proximal tubule ammonia production or secretion in nonacid-loaded mice. In addition, in acid-loaded humans, Henger et al. demonstrated that angiotensin-receptor blockade can reduce the renal response to an acid load by reducing ammonium and net acid excretion rates.

Exacerbation of metabolic acidosis caused by treatment with angiotensin converting enzyme inhibitors and/or receptor blockers in patients with CKD is a potential risk of this therapy. Indeed, studies of individuals with CKD revealed that one of the factors associated with a lower serum $\left[{{\text{HCO}}_3}^{-}\right]$ was treatment with converting enzyme inhibitors and/or receptor blockers. The administration of a reduced protein intake, thereby reducing the endogenous acid load, and administration of base early in the course of CKD will modify the occurrence of metabolic acidosis.

10

Parathyroid Hormone

PTH may not only modulate the release of bone buffers as described above, but can also affect acid–base balance by altering bicarbonate reabsorption and renal net acid excretion. Although some studies had indicated that PTH administration inhibited bicarbonate reabsorption in the proximal tubule thus inducing bicarbonaturia, other studies showed that PTH-induced bicarbonaturia was largely due to changes in the filtered load of bicarbonate. Studies by Bichara et al. not only showed that acute HCl infusion increased PTH levels, but it also enhances urinary phosphate, TA, ammonium, and net acid excretion. Moreover, PTX rats had lower net acid excretion than intact rats both in the presence and absence of an acid load. Net acid excretion was restored to appropriate levels by administration of PTH. These data suggest that PTH contributes to renal regulation of acid–base balance under normal physiologic conditions and in response to acid loads. Chronic PTH administration induces sustained elevations in serum $\left[{{\text{HCO}}_3}^{-}\right]$ in several different species due to its effect on bones and kidney. Theoretically, elevated PTH levels observed in many patients with CKD may also participate in the regulation of acid–base balance by its effect on bone buffering and renal acid excretion; however, the precise role of PTH in modulation of acid–base balance in CKD is unclear.

11

Glucocorticoids

Metabolic acidosis is associated with increased levels of adrenal corticosteroids. The resultant increase in corticosteroid levels stimulates both tubular bicarbonate reabsorption and generation, thereby reducing the severity of the acidosis. As a consequence, adrenalectomy is associated with reduced net acid excretion rates due to reduction in both TA and ammonium excretion. The augmentation by metabolic acidosis of glutamine delivery from peripheral tissues to the kidney and its extraction, and Na ⁺ -H ⁺ exchange activity in the renal brush border are blunted in the absence of glucocorticoids. Further, glutaminase activity, a key ammonia generating enzyme, is enhanced in kidney cells exposed to dexamethasone, possibly as a result of increased number of glucocorticoid receptors. Taken as a whole, these data demonstrate that glucocorticoids, independent of aldosterone, contribute to renal acid excretion when the organism is stressed by an acid load.

As mentioned previously, glutamine extraction is markedly blunted in individuals with CKD, and this contributes to the reduced rates of ammonia production and excretion observed in patients with CKD. Whether changes in glucocorticoids levels or in the tubular response to glucocorticoids contribute to altered glutamine uptake and metabolism found with CKD is unclear. In individuals with CKD, existing data suggest that except for a reduced degree of diurnal variation (lack of full morning suppression), cortisol levels are similar to normal individuals. Therefore, the reduced renal extraction of glutamine in individuals with CKD cannot be attributed solely to a reduction in glucocorticoid levels.

Studies in peripheral blood lymphocytes from individuals with CKD indicate resistance to the effects of glucocorticoids does occur. This resistance is not mediated by changes in receptor number or affinity, but occurs postreceptor and has been attributed to impaired signal transduction. Therefore, it is possible that cellular resistance in other organs such as the kidney could be present, but this remains to be confirmed.