The Role of the Endocrine System in the Regulation of Acid-Base Balance by the Kidney and the Progression of Chronic Kidney Disease.

Systemic acid-base status is primarily determined by the interplay of net acid production (NEAP) arising from metabolism of ingested food stuffs, buffering of NEAP in tissues, generation of bicarbonate by the kidney, and capture of any bicarbonate filtered by the kidney. In chronic kidney disease (CKD), acid retention may occur when dietary acid production is not balanced by bicarbonate generation by the diseased kidney. Hormones including aldosterone, angiotensin II, endothelin, PTH, glucocorticoids, insulin, thyroid hormone, and growth hormone can affect acid-base balance in different ways. The levels of some hormones such as aldosterone, angiotensin II and endothelin are increased with acid accumulation and contribute to an adaptive increase in renal acid excretion and bicarbonate generation. However, the persistent elevated levels of these hormones can damage the kidney and accelerate progression of CKD. Measures to slow the progression of CKD have included administration of medications which inhibit the production or action of deleterious hormones. However, since metabolic acidosis accompanying CKD stimulates the secretion of several of these hormones, treatment of CKD should also include administration of base to correct the metabolic acidosis.

Accuracy of a Glycerol Dehydrogenase Assay for Ethylene Glycol Detection.

INTRODUCTION: Ethylene glycol (EG) is a frequently considered toxicant in poisoned patients. Definitive diagnosis relies on gas chromatography (GC), but this is unavailable at most hospitals. A glycerol dehydrogenase (GDH)-based assay rapidly detects EG. A rapid turnaround time and wide availability of necessary instrumentation suggest this method could facilitate the rapid detection of EG. METHODS: This is a prospective, observational analysis of banked, remnant serum samples submitted to the laboratory of a large, multi-hospital healthcare system. Samples were submitted over a 12-month period for the explicit purpose of testing for suspected EG ingestion. All samples underwent GC and the GDH-based assay. RESULTS: Of the 118 analyzed samples, 88 had no EG detected by GC, and 30 were "positive." At the manufacturer's threshold of 6 mg/dL EG, there was 100% (95%CI; 88.7-100) positive percent agreement (PPA) and 98% (92.1-99.6) negative percent agreement (NPA). Adjusted to a threshold of 9 mg/dL, both the PPA and NPA were 100%. Deming regression of the observed concentrations revealed a slope of 1.16 (1.01 to 1.32) and intercept of -5.3 (-8.9 to -1.7). CONCLUSIONS: The GDH assay provides a sensitive and specific method for the detection and quantification of EG that is comparable to a GC-based method. More widespread use of this rapid, inexpensive assay could improve the care of patients with suspected toxic alcohol exposure. Further study is needed to evaluate the test performance in real-time patient treatment decisions.

Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS-CoV-2.

Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS-CoV-2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS-CoV-2 infection. Sodium bicarbonate, carbicarb, and THAM are buffers that can be used clinically to provide base to patients. To examine whether these bases could raise lysosomal pH and therefore be a primary or adjunctive treatment of SARS-CoV-2 infection, we measured lysosomal and intracellular pH of mammalian cells after exposure to each of these bases. Mammalian HEK293 cells expressing RpH-LAMP1-3xFLAG, a ratiometric sensor of lysosomal luminal pH, were first exposed to Hepes which was then switched to sodium bicarbonate, carbicarb, or THAM and lysosomal pH measured. In bicarbonate buffer the mean lysosomal pH was 4.3 ± 0.1 (n = 20); p = NS versus Hepes (n = 20). The mean lysosomal pH in bicarbonate/carbonate was 4.3 ± 0.1 (n = 21) versus Hepes (n = 21), p = NS. In THAM buffer the mean lysosomal pH was 4.7 ± 0.07 (n = 20) versus Hepes (4.6 ± 0.1, n = 20), p = NS. In addition, there was no statistical difference between pHi in bicarbonate, carbicarb or THAM solutions. Using the membrane permeable base NH4Cl (5 mM), lysosomal pH increased significantly to 5.9 ± 0.1 (n = 21) compared to Hepes (4.5 ± 0.07, n = 21); p < 0.0001. Similarly, exposure to 1 mM hydroxychloroquine significantly increased the lysosomal pH to (5.9 ± 0.06, n = 20) versus Hepes (4.3 ± 0.1, n = 20), p < 0.0001. Separately steady-state pHi was measured in HEK293 cells bathed in various buffers. In bicarbonate pHi was 7.29 ± 0.02 (n = 12) versus Hepes (7.45 ± 0.03, [n = 12]), p < 0.001. In cells bathed in carbicarb pHi was 7.27 ± 0.02 (n = 5) versus Hepes (7.43 ± 0.04, [n = 5]), p < 0.01. Cells bathed in THAM had a pHi of 7.25 ± 0.03 (n = 12) versus Hepes (7.44 ± 0.03 [n = 12]), p < 0.001. In addition, there was no statistical difference in pHi in bicarbonate, carbicarb or THAM solutions. The results of these studies indicate that none of the buffers designed to provide base to patients alters lysosomal pH at the concentrations used in this study and therefore would be predicted to be of no value in the treatment of SARS-CoV-2 infection. If the goal is to raise lysosomal pH to decrease the infectivity of SARS-CoV-2, utilizing lysosomal permeable buffers at the appropriate dose that is non-toxic appears to be a useful approach to explore.

Regulation of Acid-Base Balance in Patients With Chronic Kidney Disease.

Normallly the kidneys handle the daily acid load arising from net endogenous acid production from the metabolism of ingested animal protein (acid) and vegetables (base). With chronic kidney disease, reduced acid excretion by the kidneys is primarily due to reduced ammonium excretion such that when acid excertion falls below acid porduction, acid accumulation occurs. With even mild reductions in glomerular filtration rate (60 to 90 ml/min), net acid excretion may fall below net acid production resulting in acid retention which may be initially sequestered in interstitial compartments in the kidneys, bones, and muscles resulting in no fall in measured systemic bicarbonate levels (eubicarbonatemic metabolic acidosis). With greater reductions in kidney function, the greater quantities of acid retained spillover systemically resulting in low pH (overt metabolic acidosis). The evaluation of acid-base balance in patients with CKD is complicated by the heterogeneity of clinical acid-base disorders and by the eubicarbonatemic nature of the early phase of acid retention. If supported by more extensive studies, blood gas analyses to confirm the acid-base disorder and newer ways for assessing the presence of acidosis such as urinary citrate measurements may become routine tools to evaluate and treat acid-base disorders in individuals with CKD.

The Role of the Nephrologist in Management of Poisoning and Intoxication: Core Curriculum 2022.

Poisoning is a common problem in the United States. Acid-base disturbances, electrolyte derangements, or acute kidney injury result from severe poisoning from toxic alcohols, salicylates, metformin, and acetaminophen. Lithium is highly sensitive to small changes in kidney function. These poisonings and drug overdoses often require the nephrologist's expertise in diagnosis and treatment, which may require correction of acidosis, administration of selective enzyme inhibitors, or timely hemodialysis. The clinical and laboratory abnormalities associated with the poisonings and drug overdoses can develop rapidly and lead to severe cellular dysfunction and death. Understanding the pathophysiology of the disturbances and their clinical and laboratory findings is essential for the nephrologist to rapidly recognize the poisonings and establish an effective treatment plan. This installment of AJKD's Core Curriculum in Nephrology presents illustrative cases of individual poisonings and drug overdoses and summarizes up to date information on their prevalence, clinical and laboratory findings, pathophysiology, diagnosis, and treatment.

Re-Evaluation of Total CO2 Concentration in Apparently Healthy Younger Adults.

The initial assessment of acid-base status is usually based on the measurement of total CO2 concentration ([TCO2]) in venous blood, a surrogate for [HCO3-]. Previously, we posited that the reference limits of serum [TCO2] in current use are too wide. Based on studies on the acid-base composition of normal subjects, we suggested that the reference limits of serum [TCO2] at sea level be set at 23-30 mEq/L. To validate this proposal, we queried the University of California at Los Angeles (UCLA's) Integrated Clinical and Research Data Repository, a database containing information on 4.5 million patients seen at UCLA from 2006 to the present. Criteria for inclusion included adults (18-40 years of age), who were free of disorders that could affect acid-base balance, were not taking medications that could affect acid-base balance, and were seen for a routine medical examination or immunization in the outpatient setting. The number of individuals who met the inclusion criteria (52% female and 48% male) was 28,480, with a mean age of 28.9 ± 5.1 years. The mean serum [TCO2] level was slightly higher in males than females, 26.6 ± 2.16 mEq/L vs. 25.0 ± 2.11 mEq/L (p < 0.05). Ninety-one percent of patient values were within the proposed 23-30 mEq/L range and 61.7% were within the 24-27 mEq/L range. These findings validate our proposal that the reference range of serum [TCO2] in venous blood at sea level be narrowed to 23-30 mEq/L. Subjects with serum [TCO2] outside this range might require assessment with a venous blood gas to exclude the presence of clinically important acid-base disorders.

Re-Evaluation of the Normal Range of Serum Total CO2 Concentration.

A reliable determination of blood pH, PCO2, and [HCO3-] is necessary for assessing the acid-base status of a patient. However, most acid-base disorders are first recognized through abnormalities in serum total CO2 concentration ([TCO2]) in venous blood, a surrogate for [HCO3-]. In screening patients on the basis of serum [TCO2], we have been concerned about the wide limits of normal for serum [TCO2], 10-13 mEq/L, reported by many clinical laboratories. Indeed, we have encountered patients with serum [TCO2] values within the lower or upper end of the normal range of the reporting laboratory, who subsequently were shown to have a cardinal acid-base disorder.Here, we present a patient who had a serum [TCO2] within the lower end of the normal range of the clinical laboratory, which resulted in delayed diagnosis of a clinically important "hidden" acid-base disorder. To better define the appropriate limits of normal for serum [TCO2], we derived the expected normal range in peripheral venous blood in adults at sea level from carefully conducted acid-base studies. We then compared this range, 23 to 30 mEq/L, to that reported by 64 clinical laboratories, 2 large commercial clinical laboratories, and the major textbook of clinical chemistry. For the most part, the range in the laboratories we queried was substantially different than that we derived and that published in the textbook, with some laboratories reporting values as low as 18-20 mEq/L and as high as 33-35 mEq/L. We conclude that the limits of values of serum [TCO2] reported by clinical laboratories are very often inordinately wide and not consistent with the range of normal expected in healthy individuals at sea level. We suggest that the limits of normal of serum [TCO2] at sea level be tightened to 23-30 mEq/L. Such correction will ensure recognition of the majority of "hidden" acid-base disorders.

Retarding progression of chronic kidney disease: use of modalities that counter acid retention.

PURPOSE OF REVIEW: Acid retention because of chronic kidney disease (CKD) increases tissue acidity and accelerates progression of CKD, whereas reduction in acid retention slows progression of CKD. Herein, we describe the mechanisms through which increased tissue acidity worsens CKD, modalities for countering acid retention and their impact on progression of CKD, and current recommendations for therapy. RECENT FINDINGS: Studies in animals and humans show that increased tissue acidity raises the renal levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, thereby worsening renal fibrosis and causing progression of CKD. Measures that counter acid retention, such as providing alkali or modifying the quantity or type of dietary protein, reduce the levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, slowing progression of CKD. Alkali can be provided as NaHCO3, sodium citrate, or base in fruits and vegetables. A serum [HCO3] of 24-26 mEq/l is targeted, because higher values can be associated with adverse consequences. SUMMARY: Insights into the mechanisms through which increased tissue acidity mediates progression of CKD and the beneficial impact of ameliorating positive acid balance underlie our recommendation for modalities that counter acid retention in CKD.

Adverse Effects of the Metabolic Acidosis of Chronic Kidney Disease.

The kidney has the principal role in the maintenance of acid-base balance, and therefore, a fall in renal net acid excretion and positive H+ balance often leading to reduced serum [HCO3-] are observed in the course of CKD. This metabolic acidosis can be associated with muscle wasting, development or exacerbation of bone disease, hypoalbuminemia, increased inflammation, progression of CKD, protein malnutrition, alterations in insulin, leptin, and growth hormone, and increased mortality. Importantly, some of the adverse effects can be observed even in the absence of overt hypobicarbonatemia. Administration of base decreases muscle wasting, improves bone disease, restores responsiveness to insulin, slows progression of CKD, and possibly reduces mortality. Base is recommended when serum [HCO3-] is <22 mEq/L, but the target serum [HCO3-] remains unclear. Evidence that increments of serum [HCO3-] >26 mEq/L might be associated with worsening of cardiovascular disease adds complexity to treatment decisions. Further study of the mechanisms through which positive H+ balance in CKD contributes to its various adverse effects and the pathways involved in mediating the benefits and complications of base therapy is warranted.

Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation.

Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO2 accumulation-and activation of the Na+-H+ exchanger isoform-1 (NHE-1). We hypothesized that a favorable interaction may result from NHE-1 inhibition during cardiac resuscitation followed by administration of a CO2-consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 min followed by defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Rats were randomized 1:1:1 to the NHE-1 inhibitor zoniporide or vehicle during CPR and disodium carbonate/sodium bicarbonate buffer or normal saline (30 ml/kg) after ROSC. Survival at 240 min declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (P = 0.004), explained by worsening postresuscitation myocardial dysfunction. Marked alkalemia occurred after buffer administration along with lactatemia that was maximal after Vehicle/Buffer, attenuated by Zoniporide/Buffer, and minimal with Zoniporide/Saline [13.3 ± 4.8 (SD), 9.2 ± 4.6, and 2.7 ± 1.0 mmol/l; P ≤ 0.001]. We attributed the intense postresuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened postresuscitation myocardial dysfunction also to severe alkalemia intensifying Na+ entry via NHE-1 with consequent Ca2+ overload injuring mitochondria, evidenced by increased plasma cytochrome c Both buffer-induced effects were ameliorated by zoniporide. Accordingly, buffer-induced alkalemia after ROSC worsened myocardial function and survival, likely through enhancing NHE-1 activity. Zoniporide attenuated these effects and uncovered a complex postresuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along with myocardial function and survival.