1. Normal Anion Gap Acidoses Renal Tubular Acidosis
Jai Radhakrishnan, MD, MS, MRCP, FACC, FASN
Associate Professor of Clinical Medicine
Columbia University

2. Disclosures
None

3. Objective Physiology of renal acid handling
Diagnostic approach to Metabolic Acidosis with normal anion gap.
Case-based diagnostic workup of the RTA’s

4. Chemistry: 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

5.  [Na+] - ([Cl-] + [HCO3-])
Metabolic Acidosis: The “Anion Gap”
 [Na+] - ([Cl-] + [HCO3-])
~ mM/L
Na+
Cl-
HCO3-
Alb-
Na+
Cl-
HCO3-
Alb-
Nl Anion gap
M acidosis

6. Etiology of “normal anion gap” (A.K.A. “hyperchloremic”)
metabolic acidosis
1. GI bicarbonate loss (typically also with low K):
diarrhea
villous adenoma
pancreatic, biliary, small bowel fistulae
uretero-sigmoidostomy
obstructed uretero-ileostomy

7. GI Loss of HCO3-
Pancreas
Pancreas
HCO3-
Cl-
HCO3-
Cl-
Ileum
HCO3- K+
HCO3-
Ileum
Colon
Colon
Cl-
Normal
Diarrhea

8. Flooding the colon with HCO3- instead of Cl- drives K+ secretion
Na+ K+ K+
HCO3-
Cl-

9. Uretero-ileostomy Causes a Normal Anion Gap Acidosis
HCO3-
Cl-
Skin
ileal loop

10. Causes of a “normal anion gap” (A.K.A. “hyperchloremic”)
metabolic acidosis
2. Ingestions & infusions
ammonium chloride
hyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent) loss
proximal RTA
distal RTA
type IV RTA
early renal failure
acetazolamide
hydrated DKA

12. Proximal RTA (“Type II”)
HCO3-
(1) Na+
(3) HCO3- H+
CO2
H2O +
Na+
Defective
Na+ - dependent
resorption =
Fanconi’s
Syndrome
Na+
HCO3-
glucose
amino acids
urate
phosphate

13. Distal RTA
Na+ K+
Na+ K+
Aldosterone
Principal cell H+
ATP
ADP + Pi
HCO3-
Cl-
Cl-
a IC cell
HCO3-
Cl-
Cl- H+
ATP
ADP + Pi
b IC cell

14. H+ Net acid excretion = urinary NH4+ +
urinary “titratable acid” (H2PO4-) -
urinary HCO3-
NH4+
NH3 +
Not titratable;
need to measure
Titratable
acid H+
HPO4-- +
H2PO4-
HCO3- +
H2CO3
Present in
Prox RTA

15. Hyperkalemic distal RTA:
Na+ K+
Na+ K+
Aldosterone
Principal cell H+
ATP
ADP + Pi
HCO3-
Cl-
Cl-
a IC cell
HCO3-
Cl-
Cl- H+
ATP
ADP + Pi
b IC cell

16. ACIDOSIS IN HYPORENINEMIC HYPOALDOSTERONISM
5. Total Body K+ Excess Decreases Proximal Tubule
Acidification and Ammoniagenesis
via Intracellular Alkalosis K+
3. K+ entry
into proximal
tubule cells
Failed CCD
K+ secretion
HCO3-
(1) Na+
(3) HCO3- H+
CO2
H2O +
Na+
2. Total body
K+ excess H+
4. Alkalinization of
prox tubule cell
by K+/H+ exchange

17. DIAGNOSTIC APPROACH Minimum Urine pH Urinary Anion Gap
Plasma potassium 
Renal stones or Nephrocalcinosis
Prox. Tubular dysfunction
FEHCO3
Daily bicarbonate replacement needs

18. Urine pH vs. Plasma bicarbonate in RTA
Normal
Proximal
RTA
Urine pH
Distal RTA
Plasma [HCO3-] mM
(Oxford Textbook of Nephrology - Soriano et al, 1967)

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

20. A positive urine anion gap ~ no NH4+Cl excretion
(i.e. low renal tubule acidification)
Normal acidotic: closed circles
Diarrhea: closed triangles
Type 1 or IV RTA: open circles
Battle et al, NEJM 1988

21. Proximal RTA: Hypokalemia
Flooding the distal tubule with
HCO3- instead of Cl- in Proximal RTA drives K+ secretion
Na+ K+ K+
HCO3-
Cl-

22. Distal RTA: Hypokalemia
Na+ K+
Na+ K+
H + no
longer shunts
Na +
current so
K+ must
do so
Aldosterone
Principal cell H+
ATP
ADP + Pi
HCO3-
Cl-
Cl-
a IC cell
HCO3-
Cl-
Cl- H+
ATP
ADP + Pi
b IC cell

23. Hyperkalemic Distal RTA
Na+ K+
Na+ K+
Aldosterone
Principal cell
Low Aldosterone
Voltage defect H+
ATP
ADP + Pi
HCO3-
Cl-
Cl-
a IC cell
HCO3-
Cl-
Cl- H+
ATP
ADP + Pi
b IC cell

24. 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

25. FANCONI’S SYNDROME only in Proximal RTA
HCO3-
(1) Na+
(3) HCO3- H+
CO2
H2O +
Na+
Defective
Na+ - dependent
resorption =
Fanconi’s
Syndrome
Na+
HCO3-
glucose
amino acids
urate
phosphate

26. Fractional excretion of HCO3-

27. Fractional excretion of HCO3- Daily HCO3 Requirements Proximal Distal
>4 meq/kg
Distal
1-2 meq/kg
Hyperkalemic

28. J Am Soc Nephrol 13: , 2002

29. Positive Urinary anion gap
Urine pH
& plasma [K+]
Urine pH > 5.5
& low/nl[K+]
Distal RTA
(“Type I”):
secretory or
gradient defect
Urine pH < 5.5
& high[K+]
Hypo-
aldosteronism
RTA(type IV)

31. 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
Gynecol Obstet Invest 2007;63:39–44
ABG:
pH 7.25
pCO2 28 pO
total bicarbonate 15.1 mmol/l
base excess –13.7 mmol/l

32. Glycosuria, Phosphate, AA, Urate
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
Gynecol Obstet Invest 2007;63:39–44

33. 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%

34. 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: mEq/kg/d
Non-renal: rickets or osteomalacia

35. 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: , 2002

36. Case 2
Distal RTA
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:

37. Case 2: Distal RTA Minimum Urine pH Plasma potassium Renal stones/NC
 >5.5
Plasma potassium 
Low-normal
Renal stones/NC
YES
Prox. Tubular dysfunction No
FEHCO3
<3%
Daily bicarbonate replacement needs
<4 mmol/kg
Arch Intern Med. 2004;164:

38. Nephrocalcinosis/Recurrent Stones Consider Distal RTA

39. 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
Both sulfate and furosemide enhance H+ and K+ secretion in the cortical collecting tubule by increasing distal Na+ delivery and generating a high luminal electronegativity in the distal nephron thus permitting the simultaneous evaluation of distal H+ and K+ secretion capacities.
Kidney International (2007) 71, 1310–1316

40. Schirmer’s test positive
antibodies to the Ro/SSA and La/SSB +
Cryocrit +

41. Causes of distal RTA
J Am Soc Nephrol 13: , 2002

42. 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+ protein Urine Na130, K 15, Cl 120

43. Case 3 Hyper-kalemic Minimum Urine pH Plasma potassium Renal stones/NC
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
FEHCO3
<3%
Daily bicarbonate replacement needs
<4 mmol/kg

44. Type IV RTA: Etiology Aldosterone Voltage
Hyporenin/hypoaldo (CKD)
Addison
Congenital :enzymes
Voltage
PHA
Drugs: TMP, K-sparing, pentamidine
CNI (Na-K ATPas)
Multiple: Tubulointerstitial disease

45. Glycosuria, Phosphate, AA, Urate
RTA
Distal
Proximal UAG neg
Hyper-kalemic
Minimum Urine pH
 >5.5
+/- <5.5
<5.5
Plasma potassium 
Low-normal
High
Renal stones/NC
YES No
Prox. Tubular dysfunction
Glycosuria, Phosphate, AA, Urate
FEHCO3
<3%
15-20%
Daily bicarbonate replacement needs
<4 mmol/kg
>4 mmol/kg