Normal Anion Gap AcidosesRenal Tubular AcidosisJai Radhakrishnan, MD, MS, MRCP, FACC, FASN

Associate Professor of Clinical Medicine

Columbia University

Disclosures

• None

Objective

• Physiology of renal acid handling

• Diagnostic approach to Metabolic Acidosis with normal anion gap.

• Case-based diagnostic workup of the RTA’s

Chemistry: Carbonic Acid

• Carbonic Acid.– [ H+ ] x [ HCO3

- ] = k1 x H2CO3 = k2 x [ CO2 ] x [ H2O ]

• Simplified – H2CO3 is not of clinical interest

– [H2O] is constant in-vivo

– PCO2 is more familiar than [CO2]:

• [ H+ ] x [ HCO3- ] = k x PCO2

• [ Modified Henderson Equation. ]• Hasselbalch Modification

4

Metabolic Acidosis: The “Anion Gap”

Na+

Cl-

HCO3-

Alb-

[Na+] - ([Cl-] + [HCO3-])

Na+

Cl-

HCO3-

Alb-

Nl Anion gapM acidosis

~ 10-12 mM/L

1. GI bicarbonate loss (typically also with low K):diarrheavillous adenomapancreatic, biliary, small bowel fistulaeuretero-sigmoidostomyobstructed uretero-ileostomy

Etiology of “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Pancreas

Ileum

Colon

Pancreas

Ileum

Colon

GI Loss of HCO3-

HCO3-

HCO3-

Cl-

HCO3-

Cl-

K+ HCO3-

Normal Diarrhea

Cl-

Flooding the colon with HCO3

- instead of Cl- drives K+ secretion

Na+Na+

K+K+

Cl-

HCO3-

K+

Uretero-ileostomy Causes a Normal Anion Gap Acidosis

ileal loop

HCO3-

Skin

Cl-

2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)

3. Renal bicarbonate (or equivalent) loss• proximal RTA• distal RTA• type IV RTA

early renal failureacetazolamidehydrated DKA

Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)

metabolic acidosis

Proximal RTA (“Type II”)

HCO3- (1) Na+

(3) HCO3-

H+

CO2 H2O+

H+

Na+

Na+

HCO3-

glucoseamino acidsuratephosphate

DefectiveNa+ - dependentresorption =Fanconi’sSyndrome

Distal RTA

Na+

K+

Na+

K+

Principal cell

IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+

ATP

ADP + Pi

H+

ATP

ADP + Pi

Cl-

Aldosterone

Net acid excretion =urinary NH4

+

+urinary “titratable acid” (H2PO4

-)-

urinary HCO3-

H+

NH4+

NH3

+

HCO3-

+

H2CO3

HPO4-- +H2PO4

-

Not titratable;need to measure

Present inProx RTA

Titratableacid

Hyperkalemic distal RTA:

Na+

K+

Na+

K+

Principal cell

IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+

ATP

ADP + Pi

H+

ATP

ADP + Pi

Cl-

Aldosterone

ACIDOSIS IN HYPORENINEMIC HYPOALDOSTERONISM

2. Total body K+ excess

K+

3. K+ entryinto proximal tubule cells

HCO3- (1) Na+

(3) HCO3-

H+

CO2 H2O+

H+

Na+

H+

4. Alkalinization of prox tubule cellby K+/H+ exchange

1. Failed CCD K+ secretion

5. Total Body K+ Excess Decreases Proximal Tubule Acidification and Ammoniagenesisvia Intracellular Alkalosis

DIAGNOSTIC APPROACHMinimum Urine pH

Urinary Anion Gap

Plasma potassium 

Renal stones or Nephrocalcinosis

Prox. Tubular dysfunction

FEHCO3

Daily bicarbonate replacement needs

Uri

ne p

H

Plasma [HCO3-] mM

Normal

ProximalRTA

Distal RTA

(Oxford Textbook of Nephrology - Soriano et al, 1967)

Urine pH Urine pH vs.vs. Plasma bicarbonate in Plasma bicarbonate in RTARTA

19

Urinary Anion Gap

• Urine (Na+K) – Cl

• Proton is partially excreted as NH4

(unmeasured cation)• The gap is usually Zero or Negative• In dRTA the anion gap will remain

zero or positive• In other acidoses, the gap will

become more negative.

Unmeasured anions-unmeasured cations

A positive urine anion gap ~ no NH4+Cl excretion

(i.e. low renal tubule acidification)

Normal acidotic: closed circlesDiarrhea: closed triangles

Type 1 or IV RTA: open circles

Battle et al, NEJM 1988

Flooding the distal tubule with HCO3

- instead of Cl- in Proximal RTA drives K+ secretion

Na+Na+

K+K+

Cl-

HCO3-

K+

Proximal RTA: Hypokalemia

H + nolonger shuntsNa +

current soK+ mustdo so

Na+

K+

Na+

K+

Principal cell

IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+

ATP

ADP + Pi

H+

ATP

ADP + Pi

Cl-

Aldosterone

Distal RTA: Hypokalemia

HyperkalemicDistal RTA

Na+

K+

Na+

K+

Principal cell

IC cell

IC cell

HCO3-

Cl-

HCO3-

Cl-

Cl-

H+

ATP

ADP + Pi

H+

ATP

ADP + Pi

Cl-

AldosteroneLow Aldosterone

Voltage defect

Nephrocalcinosis/Kidney Stones

• Distal RTA (High Incidence)– Alkaline urine: Calcium

phosphate precipitation– Acidosis: Increased citrate

reabsorption by proximal nephron

• Proximal RTA (Not Seen):– Urine pH not high– Citrate not absorbed

FANCONI’S SYNDROME only in Proximal RTA

HCO3- (1) Na+

(3) HCO3-

H+

CO2 H2O+

H+

Na+

Na+

HCO3-

glucoseamino acidsuratephosphate

DefectiveNa+ - dependentresorption =Fanconi’sSyndrome

Fractional excretion of HCO3-

Fractional excretion of HCO3-

Daily HCO3 Requirements

• Proximal– >4 meq/kg

• Distal– 1-2 meq/kg

• Hyperkalemic– 1-2 meq/kg

J Am Soc Nephrol 13:2160-2170, 2002

Positive Urinary anion gap

Urine pH& plasma [K+]

Urine pH < 5.5 & high[K+]

Hypo-aldosteronismRTA(type IV)

Urine pH > 5.5 & low/nl[K+]

Distal RTA(“Type I”):secretory or

gradient defect

Case 1• A 55-year-old woman presents with complaints of lethargy, thirst, muscle

weakness and generalized body pains. Previous ED visits with hypokalemia.

• Her serum potassium level was 2.6 mmol/l.• Other Electrolytes:

– sodium 138 mmol/l – chloride 116 mmol/l– HCO3 17 mmol/l– BUN/Creatinine normal – Glucose 75mg/dL

• Urine analysis: pH 5.4, 2+ glucose• Urine anion gap: -20

Proximal RTA

ABG: pH 7.25 pCO2 28pO 2 100total bicarbonate 15.1 mmol/lbase excess –13.7 mmol/l

Case 1: Proximal RTA

Minimum Urine pH <5.5

Plasma potassium  Low-normal

Renal stones/NC No

Prox. Tubular dysfunction

Glycosuria, Phosphate, AA,

Urate

FEHCO3 15-20%

Daily bicarbonate replacement needs

>4 mmol/kg

FEHCO3

• Intravenous infusion of sodium bicarbonate at a rate of 0.5 to 1.0 meq/kg per hour

•                      UHCO3   x   PCr

 FEHCO3    =    ———————————    x    100                              PHCO3   x   UCr

• Proximal RTA: FE HCO3>15-20%

Clinical Features of Proximal RTA

• Urine pH depends on plasma [HCO3-]• Fractional HCO3- excretion high (15-20%) at nl plasma

[HCO3-]• Plasma [K+] reduced, worsens with HCO3- therapy• Dose of daily HCO3- required: 10-15 mEq/kg/d• Non-renal: rickets or osteomalacia

Causes of Proximal RTA• Primary isolated proximal RTA

– hereditary (persistent)      • a. autosomal dominant      • b. autosomal recessive associated with mental retardation and ocular

abnormalities    – Sporadic (transient in infancy)

• Secondary proximal RTA   – in the context of Fanconi syndrome (cystinosis, galactosemia, fructose

intolerance, tyrosinemia, Wilson disease, Lowe syndrome, metachromatic leukodystrophy, multiple myeloma, light chain disease)     

– drugs and toxins (acetazolamide, outdated tetracycline, aminoglycoside antibiotics, valproate, 6-mercaptopurine, streptozotocin, iphosphamide, lead, cadmium, mercury)     

– other clinical entities (vitamin D deficiency, hyperparathyroidism, chronic hypocapnia, Leigh syndrome, cyanotic congenital heart disease, medullary cystic disease, Alport syndrome, corticoresistant nephrotic syndrome, renal transplantation, amyloidosis, recurrent nephrolithiasis)

J Am Soc Nephrol 13:2160-2170, 2002

Case 2

• A 38-year-old woman was admitted with severe weakness (3rd episode)

• PMH: artificial tears for dry eyes

• Laboratory– Urine pH 7.1– sodium 141 mEq/L– potassium 3.0 mEq/L– carbon dioxide 14 mEq/L– chloride 114 mEq/L– S creatinine 0.8 mg/dL (70.7

µmol/L)– Albumin 4.3– Urinary anion gap +4

Arch Intern Med. 2004;164:905-909

Distal RTA

Case 2: Distal RTA

Arch Intern Med. 2004;164:905-909

Minimum Urine pH  >5.5

Plasma potassium  Low-normal

Renal stones/NC YES

Prox. Tubular dysfunction

No

FEHCO3 <3%

Daily bicarbonate replacement needs

<4 mmol/kg

Nephrocalcinosis/Recurrent StonesConsider Distal RTA

Furosemide/Fludrocortisone Test

• Baseline urine sample

• Oral administration of furosemide (40 mg) and fludrocortisone (1 mg).

• Fluid intake ad libitum.

• Urine q1h x 6 h after the baseline sample.

• Failed to acidify their urine to pH<5.3

Kidney International (2007) 71, 1310–1316

• Schirmer’s test positive

• antibodies to the Ro/SSA and La/SSB +

• Cryocrit +

Causes of distal RTA

J Am Soc Nephrol 13:2160-2170, 2002

Case 3

50 year old male with NIDDMhas been prescribed a low Na diet for HTN. He presents to the ER with marked weakness.

Labs: 130|98|18 280

8.0 |20|1.3

Urine pH 5.0, 1+ proteinUrine Na130, K 15, Cl 120

Case 3

50 year old male with NIDDMhas been prescribed a low Na diet for HTN. He presents to the ER with marked weakness.

Labs: 130|98|50 280

8.0 |20|1.3

Urine pH 5.0, 1+ protein

Hyper-kalemic

Minimum Urine pH <5.5

Plasma potassium  High

Renal stones/NC No

Prox. Tubular dysfunction

No

FEHCO3 <3%

Daily bicarbonate replacement needs

<4 mmol/kg

Type IV RTA: Etiology

• Aldosterone – Hyporenin/hypoaldo (CKD)– Addison– Congenital :enzymes

• Voltage– PHA– Drugs: TMP, K-sparing, pentamidine

CNI (Na-K ATPas)

• Multiple: Tubulointerstitial disease

RTA

Distal ProximalUAG neg

Hyper-kalemic

Minimum Urine pH  >5.5 +/- <5.5 <5.5

Plasma potassium  Low-normal

Low-normal High

Renal stones/NC YES No No

Prox. Tubular dysfunction

No Glycosuria, Phosphate, AA,

Urate

No

FEHCO3 <3% 15-20% <3%

Daily bicarbonate replacement needs

<4 mmol/kg

>4 mmol/kg <4 mmol/kg