Metabolic Acidosis Infographic Set 2022

EPIDEMIOLOGY + PATHOGENESIS of Metabolic Acidosis in Chronic Kidney Disease INTRODUCTION MECHANISM Kidney acid excretion is decreased in chronic kidney disease due to reduced nephron mass Prevalence Affects ~15% of all CKD patients with prevalence increasing in later stages of CKD Definition A condition in which the body has an acid content that is too high to support good health, defined as a serum bicarbonate <22 mEq/L in a patient ACID-BASE BALANCE Input Acid load from diet and protein metabolism Output Lungs (CO₂) Kidneys (NH, and titratable acids) Proximal Tubule ~80% of filtered bicarbonate reabsorbed Glutamine metabolism yields NH and HCO, NH, enters urinary space by NHE3 (sodium-hydrogen exchanger 3) or H/ATPase (proton pump) REFERENCES Along the Nephron HPO binds to secreted H When urine PH $5.5, virtually all phosphate is protonated and buffers like uric acid and creatinine contribute to titratable acid excretion Thick Ascending Limb 15% of filtered bicarbonate reabsorbed NH' enters cells by NKCC2 (Na-K-Cl cotransporter 2) NH, enters interstitium by NHEA (sodium-hydrogen exchanger 4) and generates interstitial NH concentration gradient Collecting Duct NH, and H recombine to form NH which is secreted into urine KIDNEY DISE ISTASE DIGO GLOBAL OUMES AMMONIUM (NH₂+) Produced mainly in proximal tubule. from glutamine metabolism Glutamine is mainly from diet and muscle protein degradation Excreted in urine as major adaptive kidney response to acid load ATITRATABLE ACIDS Urinary buffers derived from the systemic circulation The principal titratable buffer is HPO (90% of titratable acid excretion as H₃PO₄) Developed with support from Tricida Content compiled by Dr Michelle Lim @whatsthegfr CONSEQUENCES (1) of Metabolic Acidosis in Chronic Kidney Disease INTRODUCTION C PROGRESSION OF CKD Prevalence Affects -15% of all CKD patients with prevalence increasing in later stages of CKD Currently Undertreated Only 2.7% of patients with CKD and serum bicarbonate ≤22 mEq/L receive oral alkali Why Should We Treat? Metabolic acidosis is associated with faster progression of CKD and increased mortality. Multiple studies have shown that treatment can slow the decline in kidney function. Metabolic Acidosis Increase in mediators in response to H' stress Angiotensin II Endothelin-1 & Aldosterone Intrakidney ammonium Complement Activation Tubulointerstitial injury and fibrosis Progression of CKD KIDNEY DISEASE DIGO GLOBAL OUTCOM Angiotensin II Can trigger interstitial inflammation, fibrosis, tubular atrophy, and proteinuria that progressively reduces kidney function Enhances ammoniagenesis and kidney production of endothelin-1 and aldosterone, therefore possibly accelerates progression of kidney dysfunction This can be reduced by alkali supplementation and consumption of base-producing foods, which can then slow the rate of eGFR decline in patients with CKD Endothelin-1 (ET-1) and Aldosterone Sustained elevated ET-1 Levels are associated with increased tubulointerstitial damage, inflammation and fibrosis, leading to increased glomerular permeability and overall GFR decline Aldosterone generation (in response to stimulation of intrakidney renin-angiotensin-aldosterone system) increases distal nephron acidification and causes hemodynamic and profibrotic effects that promote kidney damage Alkali supplementation was shown to ameliorate kidney Injury due to ET-1 and reduced kidney cortical aldosterone production (in a rat remnant kidney model) Ammoniagenesis Ammonia reacts with complement C3 to form a convertase that activates the alternative complement pathway, increases inflammation and tubulointerstitial damage CONSEQUENCES (2) of Metabolic Acidosis in Chronic Kidney Disease INTRODUCTION PROTEIN CATABOLISM Prevalence Affects -15% of all CKD patients with prevalence increasing in later stages of CKD Currently Undertreated Only 2.7% of patients with CKD and serum bicarbonate ≤22 mEq/L receive oral alkali Why Should We Treat? Metabolic acidosis is associated with faster progression of CKD and increased mortality. Multiple studies have shown that treatment can slow the decline in kidney function. Metabolic Acidosis ↑Pro-inflammatory cytokines ↓ Activation of ubiquitin-proteasome pathway Muscle pH 个 Glucocorticoids Caspase-3 proteolysis ↓ Insulin/IGF-1 signalling Muscle Protein Degradation + Wasting Muscle Wasting Characterized by increased muscle turnover rate and atrophy of type II muscle fibers Associated with increased muscle protein. degradation without a change in muscie protein synthesis Administration of alkali supplementation to patients with CKD not yet on dialysis or those on maintenance dialysis increased lean body mass, improved muscle strength and dietary dietary protein intake, reduced protein catabolic rate, increased serum albumin levels, and improved physical functioning KIDNEY DISEAS GO NG GLOBAL Qures BONE DISEASE pH of interstitial fluid of bone. systemic pH intracellular pH of osteoclasts and osteoblasts Increased dissolution of bone mineral Decreased bone formation Increased cell-mediated bone resorption Osteomalacia Osteitis fibrosa cystica CONSEQUENCES (3) of Metabolic Acidosis in Chronic Kidney Disease INTRODUCTION POENDOCRINE ABNORMALITIES Prevalence Affects -15% of all CKD patients with prevalence increasing in later stages of CKD Currently Undertreated Only 2.7% of patients with CKD and serum bicarbonate ≤22 mEq/L receive oral alkali Why Should We Treat? Metabolic acidosis is associated with faster progression of CKD and increased mortality. Multiple studies have shown that treatment can slow the decline in kidney function. Metabolic Acidosis Decreased binding of insulin to its cognate receptor due to acidic environment Interference with insulin-induced intracellular signalling by suppression of PIK (phosphoinositide 3-kinasest activity in muscle Decreased Insulin Sensitivity Insulin resistance correlated with severity of metabolic acidosis in patients with CKD without diabetes Insulin-like Growth Factor-1 (IGF-1) Lower levels in metabolic acidosis Blunted response to administration of pharmacologic deses of growth hormone (GH) Correction of metabolic acidosis improved IGF-1 responsiveness to GH administration Thyroid Function Induction of metabolic acidosis in humans with normal kidney function showed signs of hypothyroidism Patients with CKD demonstrated reduced plasma 13 and 14 levels with normal thyroid stimulating hormone and a blunted response to thyrotropin Correction of metabolic acidosis in hemodialysie patients restored plasma 13 levels LASE PROVING DIGO GLOBAL OUTCO COGNITION A lower serum bicarbonate level is independently associated with lower performance in tests evaluating global cognitive / executive function Proposed mechanisms of acidosis-induced neuronal dysfunction include: Inhibition of NMDA (N-methyl-D-aspartate)-activated currents by acidosis leading to overexcitation of neural networks Acidosis induced by a Western diet (irrespective of eGFR) promoting neural excitotoxicity and subsequent cognitive impairment DIETARY MODIFICATIONS in Metabolic Acidosis and Chronic Kidney Disease INTRODUCTION Current Guidelines To aim for a normal serum bicarbonate level (22-29 mEq/L) How Can We Achieve This? Reduce endogenous acid production by promoting a base-producing diet and minimizing intake of animal protein EVIDENCE A base-producing diet increased serum bicarbonate levels, reduced urine angiotensinogen and preserved eGFR compared to usual diet MECHANISM Decreased GFR Base-producing diet HHydrogen ion accumulation Release of mediators of the adaptive response to H' stress (kidney ammonia, Ang II, ET-1, aldosterone) Short-term effect of metabolic acidosis H Increased urine H' excretion per remaining nephron GFR Further reduction of GFR Long-term effects. of metabolic acidosis + Increased kidney interstitial inflammation and fibrosis SEASE LOIGO GLOBAL OUTco BASE-PRODUCING DIETS This includes most fruit and vegetables A Exercise caution regarding potassium content CONCLUSION A base-producing diet of mostly fruit & vegetables can be an effective option for correcting metabolic acidosis and preserving kidney function TREATMENT: BICARBONATE SUPPLEMENTATION for Metabolic Acidosis in Chronic Kidney Disease INTRODUCTION MAIN SIDE EFFECTS When Should Treatment Be Started? This depends on the severity of acidosis, blood pressure, volume status and presence of hyperkalemia Treatment is reasonable with metabolic acidosis (HCO, <22 mEq/L) if no reversible causes found BICARBONATE Reacts with hydrochloric acid in gastric lumen Produces CO, Common to both Poor Palatability O OVIN GLOBAL CATION Does the accompanying cation matter? This is usually sodium. Bloating and belching The amount of sodium can be substantial (~500 mg sodium/day from 600 mg of sodium bicarbonate three times daily). This can lead to weight gain and hypertension from fluid retention. CITRATE What Are Our Options? Supplements like sodium bicarbonate and sodium citrate are the only currently available options for management of metabolic acidosis Binds readily with aluminium Release in circulation and enhance aluminum absorption in gut Acute aluminium encephalopathy High sodium intake affects the efficacy of renin-angiotensin-aldosterone system inhibition in slowing CKD progression. Potassium salts are an option but is associated with a risk of life-threatening hyperkalemia.