Normal Anion Gap Acidoses
Renal Tubular Acidosis
Jai 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-])
~ 10-12 mM/L
Alb-
AlbHCO3-
HCO3Na+
Na+
Cl-
Cl-
Nl Anion gap
M acidosis
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
GI Loss of HCO3-
Pancreas
Pancreas
HCO3-
Ileum
HCO3-
HCO3-
Ileum
Cl-
Cl-
Cl-
Normal
Colon
K+
HCO3-
Diarrhea
Colon
HCO3-
Flooding the colon with
instead of Cl- drives K+ secretion
Na+
K+
HCO3-
Cl-
K+
Na+
K+
Uretero-ileostomy Causes a Normal Anion Gap
Acidosis
HCO3-
Skin
Cl-
ileal loop
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
Proximal RTA (“Type II”)
HCO3
Na+
-
H+
H+
(1) Na+
(3) HCO3-
CO2 + H2O
Na+
HCO3glucose
amino acids
urate
phosphate
Defective
Na+ - dependent
resorption =
Fanconi’s
Syndrome
Distal RTA
Na+
Na+
K+
K+
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
ClCl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
Net acid excretion =
urinary NH4+
+
urinary “titratable acid” (H2PO4-)
urinary HCO3NH4+
NH3
+
H2PO4-
HPO4--
+
H+ +
Not titratable;
need to measure
HCO3-
Titratable
acid
Present in
Prox RTA
H2CO3
Hyperkalemic distal
RTA:
Na+
Na+
K+
K+
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
ClCl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
ACIDOSIS IN HYPORENINEMIC HYPOALDOSTERONISM
5. Total Body K+ Excess Decreases
Proximal Tubule
Acidification and Ammoniagenesis
via Intracellular Alkalosis
HCO3
Na+
-
H+
H+
(1) Na+
(3) HCO3-
CO2 + H2O
1. Failed CCD
K+ secretion
2. Total body
K+ excess
3. K+ entry
into proximal
tubule cells
K+
H+
4. Alkalinization of
prox tubule cell
by K+/H+ exchange
DIAGNOSTIC APPROACH
Minimum Urine pH
Urinary Anion Gap
Plasma potassium
Renal stones or
Nephrocalcinosis
Prox. Tubular
dysfunction
FEHCO3
Daily bicarbonate
replacement needs
Urine pH vs. Plasma bicarbonate in RTA
Urine pH
Normal
Proximal
RTA
Distal RTA
Plasma [HCO3-] mM
(Oxford Textbook of Nephrology - Soriano et al, 1967)
Urinary Anion Gap
• Urine (Na+K) – Cl
Unmeasured anions-unmeasured cations
• 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.
19
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
Proximal RTA: Hypokalemia
Flooding the
distal tubule
with
HCO3- instead
of Cl- in
Proximal RTA
drives K+
secretion
Na+
K+
HCO3-
Cl-
K+
Na+
K+
Distal RTA:
Hypokalemia
H + no
longer shunts
Na +
current so
K+ must
do so
Na+
Na+
K+
K+
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
ClCl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
Hyperkalemic
Distal RTA
Na+
Na+
K+
K+
Principal cell
Low
Aldosterone
Voltage defect
Aldosterone
ATP
H+
HCO3-
ADP + Pi
ClCl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
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
Na+
-
H+
H+
(1) Na+
(3) HCO3-
CO2 + H2O
Na+
HCO3glucose
amino acids
urate
phosphate
Defective
Na+ - dependent
resorption =
Fanconi’s
Syndrome
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+]
Urine pH > 5.5
& low/nl[K+]
Hypoaldosteronism
RTA(type IV)
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.
Proximal RTA
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
ABG:
pH 7.25
pCO2 28
pO 2 100
total bicarbonate 15.1 mmol/l
base excess –13.7 mmol/l
Case 1: Proximal RTA
Minimum Urine pH
<5.5
Plasma potassium
Low-normal
Renal stones/NC
Prox. Tubular
dysfunction
FEHCO3
Daily bicarbonate
replacement needs
No
Glycosuria,
Phosphate, AA,
Urate
15-20%
>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
———————————
PHCO3 x UCr
• Proximal RTA: FE HCO3>15-20%
FEHCO3
=
x
100
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
Distal RTA
–
–
–
–
–
–
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
Case 2: Distal RTA
Minimum Urine pH
>5.5
Plasma potassium
Lownormal
Renal stones/NC
Prox. Tubular
dysfunction
FEHCO3
Daily bicarbonate
replacement needs
YES
No
<3%
<4
mmol/kg
Arch Intern Med. 2004;164:905-909
Nephrocalcinosis/Recurrent Stones
Consider 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+ protein
Urine 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
Hyperkalemic
Minimum Urine pH
<5.5
Plasma potassium
High
Renal stones/NC
No
Prox. Tubular
dysfunction
No
FEHCO3
Daily bicarbonate
replacement needs
<3%
<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
Proximal
UAG neg
Hyperkalemic
Minimum Urine pH
>5.5
+/- <5.5
<5.5
Plasma potassium
Lownormal
Low-normal
High
YES
No
No
No
Glycosuria,
Phosphate, AA,
Urate
No
<3%
15-20%
<3%
<4
mmol/kg
>4 mmol/kg
<4 mmol/kg
Renal stones/NC
Prox. Tubular
dysfunction
FEHCO3
Daily bicarbonate
replacement needs