Definition of Non-Gap Acidosis Non Gap Metabolic • Low Bicarbonate, low pH (vs. Resp Alk) • Normal Anion Gap (~10 mEq/L) Acidosis o Note Albumin • Use of AG assumes normal plasma Albumin • Always correct to Alb of 4

• Compensatory decrease in PCO2 Thomas DuBose, M.D., MACP, FASN o Predicting Respiratory Compensation: - ASN Board Review Course – 2014 • Winter Equation: PCO2 = 1.5 (HCO3 ) + 8 ± 2 - August 4, 2014, 8:15 – 9:00 a.m. • Add 15 to Patient’s [HCO3 ]

Causes of Non-Gap Acidoses Clinical Examples: NAG Acidosis . Diarrhea or other GI losses of alkali (e.g., tube Electrolyte Values (mEq/L) drainage) NAG-MA . Ureteral diversion (e.g., ileal loop, Serum + High ureterosigmoidostomy) Electrolytes Normal NAG-MA AG-MA . Posttreatment of ketoacidosis (dilutional) Sodium 140 140 140 . Progressive chronic kidney disease Chloride 105 115 115 . Bicarbonate 25 15 5 Toluene ingestion (excretion of hippurate) Anion gap 10 10 20 . Drugs . Carbonic anhydrase inhibitors: acetazolamide, topiramate, sulfamyalon AG 0+10 . Amphotericin B . CaCl , MgSO , Cholestyramine C   -10 -20 2 4 . Acid loads (NH4Cl, acidic amino acids –TPN) . For Hyperkalemia: amiloride, triamterenene, spironolactone, TMP . Post ‐ hypocapnic state Need pHa to R/O Chronic Respiratory Alkalosis . RTA’s –proximal, classical distal, mixed, type 4

Mnemonic for Non-Gap Acidosis UNDERSTANDING NON-GAP • HAARDUPS METABOLIC ACIDOSIS – Hyperalimentation – Acetazolamide or any CA Inhibitor – Amphotericin B 1. Overview of Renal Pathophysiology – RTA 2. Distinguishing Renal from Non‐Renal – Diarrhea Forms – Ureterosigmoidostomy ‐ Role of the Kidney in the Defense Against – Post hypocapneic state, pancreatic fistula Metabolic Acidosis – Sulfamyalon Role of Kidney in Acid-Base Balance Kidney Defends Against 1. Reabsorption of filtered bicarbonate ~ 4,000 Acidosis by Reabsorption of mEq/day Bicarbonate (Proximal Tubule) 2. Production of “new” bicarbonate via net acid excretion ~ 70 mEq/day and Excretion of Acid Both are the result of H+ secretion (Ammonium) Body Balance Equation: Net acid production = Net acid excretion NAE is highly responsive to acidosis. Upregulation of ammonium production and excretion by normal kidney is expected in non-renal acidosis.

The daily dietary response: defense against GLN Acidification of Urine: Defense metabolic acidosis by the kidney 2 Against NH + HCO - K+ • Metabolism of protein 4 3 Metabolic from a Western diet + Acidosis 1 Na o Releases acid into 1 + H+ Na extracellular space + + + + H H+ H Na H 1 o Consumes bicarbonate that must be replaced Na+ H+ - • Kidney responds by 2CI + ‐ NH4 2 1. R HCO increasing net acid + 3 + H 2. NAE = NAP excretion as NH4 to H+ K+ H O make new 2 NH3 {}+ bicarbonate ↑Net Acid + Excretion H 2 Urine pH < 5.5 Urine Am High

Urine Anion Gap to Approximate Urine Urine osmolal gap to approximate Ammonium Excretion urine ammonium • Spot Urine Electrolytes: Na+, K+, Cl‐ in a patient Urine Osmolal Gap = Measured Urine Osmolality with hyperchloremic metabolic acidosis  Calculated Urine Osmolality • Calculate Urine Anion Gap: UAG = (Na + K) − Cl u u Urine Osmolal Gap = • Interpretation: + (Na + K)u > Clu: NH4 low (Ammonium excretion Uosm [2 (Na + K)u + urea/2.8 + glucose/18 impaired)

+ Clu > (Na + K)u: NH4 adequate (non‐renal Uam = UOsm Gap ÷ 2 hyperchloremic acidosis) • Pitfalls: Unusual Anions (Drugs) Ketonuria Urine ammonium of 75 mEq/L with NAG acidosis Toluene if renal tubule function is normal Types of Renal Acidoses Renal Tubular Acidosis • Hypokalemic Forms Inability of the kidney to excrete o Proximal RTA (Type 2) sufficient acid or retain sufficient o Classical Distal RTA (Type 1) bicarbonate, resulting in a clinical • Hyperkalemic Forms syndrome characterized by non- o Aldosterone Deficiency or Resistance (Type 4) o Non-mineralocorticoid Voltage Defect gap metabolic acidosis, • Normokalemic hyperchloremia, and impaired o Progressive CKD urinary acidification. o Uremic Acidosis

NAG Acidosis of Would you recognize and/or Progressive CKD treat acidosis in this patient?

• Technically a renal tubule defect • Na 140, Cl 110, HCO3 21, K 4 + o Elevated urine NH4 excretion per functional nephron • What groups of patients might fall o Declining number of functional nephrons • Shift from Non-Gap to Gap Acidosis with advanced into this category? CKD o Elderly patients with”presbynephric RTA” (Morris) • Acidosis contributes to progression of o Some stone formers CKD o Some with osteoporosis o Stage 3b and > CKD • Mild acidosis is under recognized and • Acidosis contributes to progression of treated CKD • What is target bicarbonate level? • Therefore, treat to target of >22 mEq/L

Features of Proximal RTA Lumen Interstitial space (Type 2)

HCO ‐ • Non-gap acidosis in untreated steady state 3 NHE‐3 H+ • Urine pH < 5.5; hypokalemia Na+ 3 NBCe1 + • Proximal tubule fails to reabsorb large + Na H COH ‐ATPase 1 2 3 + + ‐ 3HCO ‐ - - H H + HCO3 3 amounts of filtered HCO3 ; HCO3 spills into CA 2 urine increasingly with treatment; so that IV CA urine pH > 5.5 II u CO2 + H2O CO2 + H2O • Hypokalemia becomes worse with 2K+ bicarbonate therapy 3Na+ • Acquired forms often associated with Fanconi Syndrome Etiology of PRTA TREATMENT: PROXIMAL RTA Proximal RTA - Causes 1. Inherited – isolated pure bicarbonate wasting – Requires large amounts of alkali: mis-sense mutations in NBCe1/SLC4A4, several 10-20 mEq/Kg/day; typically increases urinary K loss examples associated with ocular abnormalities Requires large amounts of potassium 2. Inherited proximal-distal RTA (Type 3 RTA) with Potassium (K-Shohl’s: Polycitra®-LC: Citric osteopetrosis and ocular abnormalities, CA II acid 334 mg, sodium citrate 500 mg, and potassium citrate 550 mg per 5 mL (480 deficiency (Guibaud-Vainsel) mL) [alcohol free, sugar free]) 3. Acquired: Myeloma, ifosfamide, CA inhibitors, Thiazides may be helpful topiramate, heavy metals

1. Classical Distal RTA • Inherited o Autosomal Recessive Distal Renal Tubular o Autosomal Dominant • Acquired Acidosis • Features: 1. Classical Distal RTA – Type 1 o Complete or Incomplete 2. Generalized Distal RTA – Type 4 o The renal phenotype, in the complete form, consists of hyperchloremia, metabolic acidosis and impaired urinary acidification. Bone disease, nephrocalcinosis, and nephrolithiasis are common.

Cell Types ‐ Collecting Duct Lumen Interstitial space AE H+ + 1 Cl‐ ‐ ‐ HCO3 HCO3 NH + H+ H Type A 3 CA II H++‐ATPase Intercalated cell AE1 ‐ H+‐ATPase Cl Cl‐ 2 NH + CO2 + KCC4 H+ ‐ 4 H+ K+ 1 HCO3 H2O K+ H+,K+‐ATPase H+ + ‐ 4 HCO3 H+ H+ 3 CA II K+ CO2+ H2O + KCC4 ‐ H HCO3 Type B Cl‐ ‐ Cl‐ + Cl Intercalated cell K K+ Pendrin H+,K+‐ATPase H+

Type A Intercalated Cell: 4 Causes of dRTA Known Examples of Defects or Mutations Transport Abnormalities Causing Associated with Classical Distal RTA Metabolic Acidosis in “Distal” RTA 1. Deficiency or abnormality in H+-ATPase • Autosomal Recessive ATP6V1B1 Mutation with Deafness + • Autosomal Recessive ATP6V0A4 Mutation without 1. Defect in Net H deafness Secretion • Acquired Defect in H+-ATPase (Sjogrens) - - 2. Abnormality of the basolateral HCO3 /Cl 2. Decrease in NAE • Autosomal Dominant SLC4A1 Mutation 3. Apical backleak of H+ (gradient defect: amphotericin) because of decrease in 4. Carbonic Anhydrase II Deficiency – mixed PRTA-DRTA (Type 3 RTA) UAmV 5. Drug or toxin kidney injury: topiramate, ifosfamide

GLN cDRTA Disorders Associated With Acquired Classical Distal RTA + - K+ NH4 HCO3 • Autoimmune Disorders Na+ o Hyperglobulinemia- autoimmune diseases + Na • Sjogrens, thyroiditis, primary biliary cirrhosis H+ H+ Na+ H+ • Hypercalciuria and Nephrocalcinosis + H+ Na o Hypervitaminosis D, HPT, Graves’ disease 2CI- + • Drug or Toxin-induced Disease NH4 H+ MCT o Amphotericin B, ifosfamide, topiramate, lead, K+ lithium, tetracycline, toluene H O 2 NH3 {}+ • Tubulointerstitial Diseases H+ o MCD, classical analgesic nephropathy

Acquired tubule injury and cDRTA • Drug Toxicity o Increase in apical membrane permeability (gradient defect: amphotericin B) o Topiramate (CA inhibitor) Clinical Example o Ifosfamide (Prox and Distal Tubule cell injury) Case Presentation • Interstitial Disease o Nephrocalcinosis (Cause/Result) o Autoimmune –Sjogren’sSyndrome o Chronic Tubulointerstitial Disease Case 1 Question

• Na 140, K 2.5, Cl 125, HCO3 5 o AG 10 Which disease from list below is • BUN 28, Cr 1.7 most frequently associated with • ABG: pH 7.11, PaCO2 16, HCO3 5, PaO2 90 • Urine studies: dRTA? o pH 6.0, Cl 18, Na 35, K 40 a)Mixed connective disease o UAG = + 57

o UAm = 10 mEq/L b)Rheumatoid arthritis • Sicca complex: xerostomia, c) Lupus keratoconjunctivitis sicca, Schirmer’s positive d)Sjogren’s syndrome • SS-B positive, RF positive, SS-A negative

DuBose, TD; Am J Kidney Dis. 2009;54(5):965‐9

Kidney Biopsy: Sjogren’s Syndrome Diagnostic Features of Classical Distal RTA • Hypokalemia • Urine anion gap positive during acidosis + o Abnormally low NH4 excretion in face of acidosis • Urine pH > 5.5

• Modest bicarbonaturia, < 10% FEHCO3 > 5% • Absence of Fanconi syndrome • Abnormal calcium metabolism (hypercalciuria, nephrocalcinosis, nephrolithiasis, bone disease) o Low urine citrate • Hyperglobulinemia

Consequences of cDRTA Sources of Alkali for treatment of RTA • Shohl’s (Na+ citrate and citric acid) or • Bone Disease (Acidosis Hypercalciuria) Cytra 2 • Nephrocalcinosis o Sodium citrate 500 mg and citric acid 334 mg per 5 mL - + • Nephrolithiasis (480 mL). HCO3 equivalent 1 mEq/mL and Na 1 mEq/mL o Hypercalciuria and hypocitraturia • Acidosis leads to hypocitraturia • NaHCO3 Tablets • Progression of Renal Failure o 325 mg [3.8 mEq]; 650 mg [7.6 mEq] • Hypokalemia – may be severe at times • Baking soda (60 mEq/tsp.) • Pyelonephritis – difficult to irradicate • K-Lyte (25 or 50 mEq/tablet) • Polycitra (K+ Shohl’s), Urocit K, Oracit K, Cytra K • Stunted Growth (flavored) for stone formers • Granules, effervescent (Brioschi®) Distinguishing Features of Hyperkalemic Classification of dRTA (Generalized) DRTA –Type 4 RTA 1. Associated with Hypokalemia • Only variant associated with Classical Distal RTA (Type 1) hyperkalemia Defects of acid transporters in MCT • Collecting duct fails to excrete protons 2. Associated with Hyperkalemia and potassium o Situation arises when aldosterone is insufficient in quantity a. Mineralocorticoid Deficiency or activity b. Non-mineralocorticoid voltage o Or, intrinsic (genetic) or acquired molecular defect in transport of Na+, K+, and H+ defect (Defect of K secretion and H • Hyperkalemia contributes to acidosis + secretion in CCT and MCT) by blunting NH4 production and excretion

GLN Localization of Defect in Generalized DRTA Regulation of K+ Secretion by

+ + HCO ‐ K NH4 3 Principal Cell 1 CCT Lumen Interstitium Na+ Distal flow and Na+ Mineralocorticoid delivery of Na+ H+ H+ Na+ H+ MC receptor 3Na+ 3Na+ Na+ H+ Na+ Na+ 2CI‐ 2K+ 2K+ 2 + NH4 H+ K+ K+ K+ MCT H O 2 NH3 + {}H+ TTKG Low Urine 5.5 < pH > 5.5 + Principal Cell: CCT Urine NH4 Low

Transtubular Potassium Gradient Determinants of K+ Secretion (TTKG)

. Activity of parallel transporters and + + channels TTKG = [K ]urine ÷[K]plasma . Mineralocorticoid activity Uosm ÷Posm . Distal delivery of Na+ o Na+ and absorbable anions Non-renal etiology o Nonreabsorbable anions Hypokalemic patient: <3 . Tubular Flow Rate Hyperkalemic patient: >7 . Acid‐Base Status “Renal” hyperkalemia . Total Body K+ Homeostasis <7 in presence of hyperkalemia

Note: Unlike FE, the TTKG is not a % Drugs that Mimic or Clinical Features of Generalized Defect in Cause Type 4 RTA Distal Nephron Function •NSAIDs o Hyperkalemia o Urine pH < 5.5 or > 5.5 • ACE inhibitors, ARBs • Hyperkalemic DRTA urine pH > 5.5 • K-sparing diuretics: amiloride, • Typical SAD urine pH < 5.5 triamterene, spironolactone o Aldosterone deficiency or resistance o Low urinary ammonium excretion and •Heparin production • Cyclosporin A, tacrolimus (CNIs) o Tendency toward renal salt wasting in • TMP, pentamidine some o Volume expansion and hypertension

+ + Relationship Between K and NH4 in the Renal Tubule • Hyperkalemia decreases and Pathophysiological hypokalemia increases renal Classification of Clinical ammonium production + Syndromes of • NH4 Transport + + • K and NH4 compete for common site on Hyperkalemia and tALH Na‐2Cl‐K co‐transporter (lowers interstitial Am) Metabolic Acidosis + + • NH4 and K compete for K‐secretory site on basolateral membrane sodium pump

Pathophysiological Basis of Hyperkalemic Aldosterone Has Direct Na+- Acidosis and gDRTA (Type 4) Independent Affect on H+ • Abnormal CCD - MCD (intrinsic) Secretion in CCT and OMCD • Primary decrease in Aldosterone H+ mineralocorticoid (extrinsic) MC receptor • Voltage defect - compromises K+ H+ and K+ secretion – Abnormal ENaC - HCO3 – Chloride Shunt H+ Cl- c.a. II Cl-

Type A –Intercalated Cell Definition of Voltage Defect Renal Tubular Lumen Interstitial space Dysfunction • “Voltage defects” impairing ENaC 2K+ + + Na+ 3Na+ K and H secretion ‐ 0 +

Mineralocorticoid oInherited Receptor oAcquired K+ K+

Prototypical Voltage Defect: Principal Cell Autosomal Recessive Pseudohypoaldosteronism Type 1 Case 2 • A 38 year old woman presents with LUMEN BLOOD chronic weakness. FH is positive for HTN. Na+ PE is only remarkable for blood pressure of 148/100 K+ K+ • Lab: Na 141, K 6.0, Cl 109, HCO3 19, Mineralocorticoid creatinine 0.9, PRA and Aldosterone receptor both low, Urine: Na 75, K 41, Cl 50 • During follow up the following is noted: Na+ o HCTZ controls BP and improves hyperkalemia Epithelial sodium o Na restriction improves BP channel o K excretion in response to NaCl administration is subnormal but normal in response to NaHCO3

Pseudohypoaldosteronism-Type II Question (Familial Hyperkalemic Hypertension) • Phenotype: Adults with autosomal dominant What is the diagnosis? hypertension, volume expansion, low renin and aldosterone, mild hyperkalemic HCMA, normal a)PHA I GFR b)Hyporeninemic • Pathophysiology: Prototypical Voltage defect o Hyperkalemia (Responds to Na2SO4 i.v. = chloride shunt) hypoaldosteronism o Unresponsive to mineralocorticoid o Genetic Basis c)Hyperkalemic periodic • Inherited abnormalities of WNK 1 and WNK 4 Interacting paralysis Proteins o Affects NCCT expression at cell surface d)PHA II (Familial Hyperkalemic causing increase in NaCl absorption and Hypertension) decrease in K secretion. o Acidosis due to reduction in JH+ and UNH4+V • Treatment: thiazides and dietary salt restriction Drug Mechanisms of Type 4 Other Manifestations of RTA CNI Tubule Effects • Acquired Voltage defects impairing K+ and H+ secretion • CNI associated with Salt Sensitive oDrugs that interfere with Na+ channel: Hypertension, Hyperkalemia and Acidosis • Amiloride, triamterene, pentamidine, • Resembles phenotype of Familial trimethoprim Hyperkalemic Hypertension (PHA II) oDrugs that reduce Na,K‐ATPase and o Gain of function of NCC in DCT ROMK in CCD PC; and Increase NCC in • CNIs decrease WNK and SPAK expression, DCT: activating NCC in DCT • Calcineurin inhibitors: CsA, Tacrolimus

Voltage Defect Due to

Na+ Trimethoprim-Sulfamethoxazole 2K+ Cl‐ 3Na+ H+ Na+ • More prevalent with higher doses (>20mg/kg/d) • Hyperkalemia most frequent complication Cl‐ • Seen in children and older HIV-negative patients on “conventional” doses DCT • Reversible most often • Etiology of Metabolic Acidosis o Voltage Defect

o Hyperkalemia and decreased UAmV

Distal Convoluted Tubule: Site of CNI Activation of NCC

Pathophysiological Basis of Hyperkalemic Pathophysiological Basis of Hyperkalemic Acidosis Acidosis and gDRTA: Decrease in and gDRTA (Type 4) Aldosterone • Abnormal CCD - MCD (intrinsic) • Hyporeninemic • Primary decrease in hypoaldosteronism mineralocorticoid (extrinsic) • Inhibition of Aldosterone • Voltage defect – compromises H+ Synthase and K+ secretion o Unfractionated and LMW – Abnormal ENaC Heparin – Chloride Shunt • Addison’s disease Hyporeninemic Hypoaldosteronism Clinical Features Drugs and RAAS • Mean age, 65 years • Asymptomatic hyperkalemia (50-75%) • Impaired RAAS o Weakness-25% o Cyclo-oxygenase inhibitors • Cardiac Disorders o Renin inhibitors (aliskiren) Arrhythymia (25%), Hypertension and CHF o o Angiotensin converting enzyme • Hyperchloremic metabolic acidosis (>50%) inhibitors – ACE-Is • Renal insufficiency (70%) o AT1 receptor antagonists – ARBs • Diabetes mellitus (50%), Tubulointerstitial o Inhibitor of aldosterone synthesis: nephritis, or obstructive nephropathy are Heparin (un-fractionated and LMW) leading causes

Pathophysiology of Hyperkalemic Acidosis Treatment of Generalized Dysfunction and gDRTA: Intrinsic Kidney Tubule Impairment of the Nephron with Hyperkalemia • Tubulointerstitial abnormalities • Low potassium diet • Avoid drugs associated with hyperkalemia that affect collecting tubule o OTC NSAID’s cell function o Herbal Meds or High K foods: Chan su, Noni juice • Alkali therapy • Obstructive nephropathy • Loop Diuretic • Lupus nephritis • Thiazide for Familial Hyperkalemic • Sickle cell nephropathy Hypertension • Analgesic nephropathy • Sodium polysterene sulfonate (Kayexalate) • Fludrocortisone (0.1-0.3 mg/d) • Myeloma kidney o Avoid in hypertension, heart failure, edema o Combine with loop diuretic

Clinical Features of RTA

Stones/ Bone Disease Response Progression Nephrocalcinosis Causes cDRTA Yes, Yes, All manifesta- Familial; Not with Questions - Discussion tions respond to osteoma- Acquired Type 1 hypocitra- alkali alkali turia lacia, rickets gDRTA rare rare Alkali, low K Acquired Usual diet, loop DM, Type 4 diuretics, Obstruction, Kayexalate Drugs Thanks PRTA No, some KHCO3, Acquired or Not with hypercitra NaHCO3,thiazi inherited Type 2 des, U alkali -turia K increases with alkali Rx