Disorders in Kidney Disease

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

Acute kidney injury (AKI)Chronic kidney disease (CKD)Net acid excretion (NAE)Sodium citrateHemodialysis (HD)Peritoneal dialysis (PD)Kidney transplantation

This chapter reviews acid–base disorders in acute kidney injury (AKI), chronic kidney disease (CKD), hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation. Most of these conditions are associated with high anion gap (AG) acidosis. Depending on the etiology of AKI, however, other acid–base disorders such as hyperchloremic (non-AG) acidosis, metabolic alkalosis, respiratory alkalosis, or respiratory acidosis may coexist with AG metabolic acidosis. The coexistence of lactic acidosis, ketoacidosis, and toxin ingestion in AKI patients may increase AG even further. Thus, mixed acid–base disorders are not uncommon in patients with kidney disease.

Acute Kidney Injury (AKI)

As discussed in Chap. 2, a normal subject generates 1 mEq/L/kg of fixed acid which has to be excreted. In AKI, this acid excretion is impaired. Therefore, metabolic acidosis develops with high AG. This is the most common acid–base disorder in AKI. Other acid–base disorders that complicate AKI are shown in Table 10.1.

Table 10.1

Acid–base disorders in AKI

Acid–base disorder	Mechanism	Comment
High AG metabolic acid	Accumulation of endogenous acids such as sulfate and phosphates	Most common disorder
Very high AG metabolic acidosis	Accumulations of lactic acid (sepsis, hypoxia, etc.), ketoacids, and toxins	Rather common in critically ill patients
High AG and non-AG metabolic acid	Accumulation of sulfates and phosphates with HCO₃ ⁻ loss due to diarrhea or renal tubular acidosis. ⧍AG/⧍HCO₃ ⁻ < 1 is usually seen in patients with diarrhea	Infrequent acid–base disorder
High AG metabolic acidosis and metabolic alkalosis	Removal of acid with vomiting and nasogastric suction in the presence of sulfates and phosphates. Patients receiving blood transfusions with citrated blood	Rather common in AKI patients following intubation
High AG metabolic acidosis and respiratory alkalosis	Patient with AKI and pneumonia, sepsis, or central nervous system infections	Rather common acid–base disorder
High AG metabolic acidosis and respiratory acidosis	AKI in patients with COPD or other conditions of CO₂ retention	Uncommon acid–base disorder in AKI
Low AG metabolic acidosis	AKI due to IgG myeloma	Infrequent acid–base disorder

Treating etiology of metabolic and respiratory acid–base disorders is an important aspect in the management of AKI. Use of NaHCO₃ and at times renal replacement therapies improve not only acidosis but renal function as well.

Chronic Kidney Disease (CKD)

As stated in AKI, acid–base balance is disturbed when daily acid production is not excreted. Elimination of acid load is achieved by appropriate excretion of titratable acid and NH₄ ⁺ (net acid excretion; see Chap. 2). With development of CKD, the number of functioning nephrons decreases, and the patients retain acid load because of decreased NH₄ ⁺ excretion. Most of the studies analyzed acid–base status in CKD based on serum bicarbonate concentration ([HCO₃ ⁻]) measured by an autoanalyzer or by ABG machine as calculated [HCO₃ ⁻]. Based on these measurements, the prevalence of metabolic acidosis, which is the major acid–base disturbance in CKD, has been estimated at different stages of CKD. Acidosis or low bicarbonate was usually defined as serum [HCO₃ ⁻] <22 mEq/L. A few studies document the prevalence of acidosis in predialysis CKD patients, as reviewed by Abramowitz [1] and Chen and Abramovitz [2]. According to the Nephro Test Cohort Study from France [2], the overall prevalence of metabolic acidosis in patients with CKD stages 1–4 was found to be 8%, and the severity of acidosis increases with decreases in eGFR (i.e., progression of kidney disease). In the Chronic Renal Insufficiency Cohort (CRIC) study, the prevalence of low [HCO₃ ⁻] (<22 mEq/L) in patients with eGFR 20–70 mL/min was 17.3% [2], and the decline in [HCO₃ ⁻] increased with decline in eGFR (7% in CKD 2, 13% in CKD 3, and 37% in CKD 4) [2]. In the African American Study of Kidney Disease and Hypertension (AASK) study, the measured GFR in participants was between 20 and 65 mL/min. Their mean serum [HCO₃ ⁻] was 25.1 mEq/L; however, the distribution was <20 mEq/L in 4.3%, 20–24.9 mEq/L in 35.5%, and ≥30 mEq/L in 5.5% of participants. Similar to other studies, serum [HCO₃ ⁻] decreased with lower GFR levels. These three important studies suggest that metabolic acidosis is associated with decreased kidney function [2]. It should be noted that serum [HCO₃ ⁻] does not fall <16 mEq/L in most of the CKD patients because of buffering of the acid load by bone. However, there are several factors that may lower serum [HCO₃ ⁻], including high protein intake, albuminuria, smoking, and converting enzyme inhibitors. Both the decrease in HCO₃ ⁻ and increase in AG were found to be associated with all-cause mortality and morbidity.

Net Acid Excretion in CKD (NAE)

NAE represents the amount of urinary buffers that are responsible for the excretion of H⁺ in the urine. These urinary buffers are titratable acidity (TA) in the form of H₂PO₄ ⁻ and NH₄ ⁺ (see Chap. 2). Acidosis enhances NAE to maintain normal acid–base balance. In CKD, the functioning mass decreases; however, the remaining nephrons get hypertrophied and increase their GFR.

The rate of TA excretion depends on phosphate filtration and its excretion. In CKD, filtration of phosphate increases, but its reabsorption in the proximal tubule is decreased. This reduced phosphate reabsorption is due to an increase in fibroblast growth factor-23 and parathyroid hormone. As a result, more phosphate is delivered to the distal tubule, and the formation of TA is slightly increased or normal. Thus, the rate of TA in CKD is maintained usually at normal levels.

In comparison to TA, the excretion of NH₄ ⁺ is decreased. In CKD, the functioning hypertrophied nephrons generate and excrete more NH₄ ⁺. When acid load increases, the excretion of NH₄ ⁺ is decreased, and H⁺ is retained with development of metabolic acidosis. This suggests that NH₄ ⁺ is the major urinary buffer in normal individuals and CKD patients.

Thus, TA is preserved or slightly elevated, but NH₄ ⁺ excretion decreases in CKD. Despite these changes, the urine pH remains <5.5. Although this is an acidic pH, it is slightly high when compared to that of a normal individual at comparable serum HCO₃ ^-.level.

Pattern of Acid–Base Disorders

In early stages of CKD, a non-AG (hyperchloremic) metabolic acidosis develops because of impaired HCO₃ ⁻ reabsorption and its excretion, as shown by early studies. This is followed by the development of a mixed non-AG and high AG metabolic acidosis in some patients. With progression to nondialysis-dependent CKD 5, a high AG metabolic acidosis develops in the majority of the patients. Thus, CKD patients go through these two types of acid–base disorders prior to renal replacement therapies.

Some patients with hyporeninemic hypoaldosteronism may develop non-AG metabolic acidosis at higher GFRs. These patients have hyperkalemia that is disproportionate to their GFR, and their acidosis is more severe than other patients with similar GFRs. Hyperkalemia inhibits NH₃ genesis, causing decreased NH₄ ⁺ formation.

Pathophysiology of Metabolic Acidosis

There are several mechanisms that are involved in the development of both non-AG and high AG metabolic acidosis in CKD. The major mechanism is a decrease in NH₄ ⁺ excretion. These are presented in Table 10.2.

Table 10.2

Mechanisms of metabolic acidosis in CKD

1. Decreased NH₄ ⁺ excretion and production by the failing kidney (GFR <15 mL/min) with positive H⁺ balance

2. Decreased synthesis of NH₃ (NH₄ ⁺) by hyperkalemia

3. Decreased conservation of HCO₃ ⁻ by the failing kidney

4. Insufficient titratable acid (phosphate) excretion compared to acid load

5. Increased production of anions (sulfate, phosphate) due to high protein intake

6. Increased catabolism in some malnourished patients generating sulfate and phosphate

7. Relative hypoaldosteronism due to diabetes, hypertension, interstitial disease, or drugs, such as ACE-Is, angiotensin receptor blockers, K⁺-sparing diuretics, and NSAIDs, may aggravate metabolic acidosis by lowering GFR even further

Adverse Effects of Metabolic Acidosis

In general, chronic metabolic acidosis has several adverse effects irrespective of its etiology. In CKD, however, uremic toxins may aggravate these adverse effects. For detailed discussion of adverse effects of metabolic acidosis, the reader is referred to Wesson [3]. Table 10.3 shows the most commonly observed effects of metabolic acidosis:

Table 10.3

Adverse effects of metabolic acidosis

Adverse effect	Mechanism
Muscle wasting	Due to muscle protein degradation mediated by upregulation of ubiquitin-proteasome pathway and caspase-3 protease. Acidosis activates glucocorticoid effect on protein degradation. However, total protein synthesis is not affected. Administration of base improves lean body mass
Hypoalbuminemia	Chronic acidosis was found to decrease albumin synthesis as opposed to muscle total protein synthesis. Hypoalbuminemia has been reported in CKD patients with low GFR and HCO₃ ⁻ levels. Administration of base to CKD patients improves albumin levels
Progression of kidney disease	Several studies have shown progression of kidney disease in patients with lower serum HCO₃ ⁻ levels. Potential mechanisms include an increase in AII, aldosterone, and endothelin levels, which promote renal fibrosis. Increased NH₄ ⁺ genesis by the surviving nephrons activates complement and inflammation with resultant fibrosis. Chronic acidosis may activate growth factors, cytokines, and chemokines that promote renal fibrosis. It should be noted that renal tubular acidosis may not be associated with progression of kidney disease
Bone disease	Not only abnormal vitamin D metabolism but also chronic acidosis cause bone disease in CKD. Kidney disease alone increases PTH and decreases calcitriol levels. Both cause release of Ca²⁺ salts from bone with resultant development of osteomalacia and renal osteodystrophy. Acidosis also stimulates PTH secretion. Bone buffers H⁺ in CKD with resultant decrease in bone minerals. Thus, chronic metabolic acidosis contributes to bone disease
Insulin resistance	Insulin action is decreased in metabolic acidosis because of decreased insulin binding to its receptor. Thus, glucose intolerance is common in CKD
Growth hormone, IGF-1, and thyroid hormones	Chronic acidosis lowers levels of these hormones in CKD. Blunted IGF-1 response to growth hormone has been reported
Increased inflammation	Acidosis stimulates the release of pro-inflammatory cytokines from macrophages
Cardiac contractility	Severe acidosis impairs cardiac contractility via less Ca²⁺ binding to troponin and disturbed interaction between actin and myosin