Renal tubular acidosis (RTA) refers to a group of disorders characterized by defective renal acid-base regulation resulting in hyperchloremic metabolic acidosis despite normal or mildly reduced glomerular filtration rate. RTA is classified into three main forms: distal RTA associated with reduced urinary acid secretion, proximal RTA associated with impaired bicarbonate reabsorption, and hyperkalemic RTA associated with aldosterone deficiency or resistance. Diagnosis involves evaluating the serum anion gap, urine anion gap, urine pH, and response to acid loading tests or furosemide administration to distinguish between types and assess distal tubular acidification ability.
3. Abstract
• RTA can be a primary or secondary defect and res
ults either due to abnormality in bicarbonate ion ab
sorption or hydrogen ion secretion.
• Primary defects are common in children due to ge
ne mutation or idiopathic nature while secondary f
orms are more common in adults.
4. • Renal tubular acidosis (RTA) refers to a group of disorders char
acterized by defective renal acid-base regulation.
• The capacity for normal urinary acidification is impaired, resul
ting in net acid retention and hyper chloremic metabolic acidosis.
• Acid-base disequilibrium occurs despite a normal or only mildl
y reduced glomerular filtration rate(GFR).
• RTA is a poorly appreciated entity among physicians.
• A basic understanding of the mechanisms of disease is imp
ortant for management.
Introduction
5. • RTA is classified into 3 major forms: distal, proximal, and hype
rkalemic RTA.
• Distal RTA (type 1 RTA ) : is associated with reduced urinary acid secret
ion.
• Proximal RTA (Type 2 ) : is characterized by impaired bi
carbonate (HCO3) reabsorption.
• Hyperkalemic RTA (Type 4 RTA ) : is an acid-base disturbance gene
rated by aldosterone deficiency or resistance.
• Electrolyte and acid-base disturbances are key components of each di
sorder.
6. Common Causes of Distal (Type 1) Renal Tubular Acidosis
Primary lesions Sporadic gene mutations (idiopathic)
Hereditary mutations (SLC4A1,
ATP6V1B1, and many others)
Secondary processes Autoimmune
•Sjo¨ gren syndrome
•Systemic lupus erythematosus
•Rheumatoid arthritis
•Primary biliary cirrhosis
•Autoimmune hepatitis
Nephrotoxins
•Amphotericin B
•Lithium
•Trimethoprim
8. •Defects in one or more of following:
-H + ATPase
-HCO3/Cl anion exchanger
-H + K + ATPase
•Due to impaired H + excretion urine pH cannot be reduced to <5.5
•Inability to secrete H + distally is compensated by secreting K + lead
ing to Hypokalemia
Pathogenesis
9. •Lack of NaHCO3 distally, owing to lack H + to bind to tubular lumen, leads
to chloride absorbtion leading to hyperchloremia.
•Chronic metabolic acidosis: impairs citrate excretion leading hypo
citraturia
•Hypercalciuria:
-Increased calcium release from bone to buffer systemic acid
osis
-Acidosis induced downregulation of renal Calcium transport protei
n
-Increase distal sodium delivery
11. Miscellaneous
•Multiple myeloma
•Monoclonal gammopathy
•Light chain deposition disease
•Obstructive uropathy
•Nephrotic syndrome
•Medullary cystic kidney disease
Note: This list is not comprehensive and includes only the common and most clinically impo
rtant disease associations
16. Schematic model of HCO3 reabsorption in proximal convoluted tubule. The processes occurring are H secretion at the luminal m
embrane via a specific Na- H exchanger (NHE-3) and HCO3 transport at the basolateral membrane via a 1 Na-3 HCO3 cotransporter
(NBC-1). Cytoplasmic carbonic anhydrase II (CA II) and membrane-bound carbonic anhydrase IV (CA IV) are necessary to reabs
orb HCO3
17. Schematic model of H secretion in cortical collecting tubule.
The main pump for luminal H secretion in the type intercalated cell is a vacuolar HATPase. A H,K-ATPase is also involved in H secr
etion. Intracellularly formed HCO3 leaves the cell via Cl-HCO3 exchange, facilitated by an anion exchanger (AE1). Cytoplasmic carbo
nic anhydrase II (CA II) is necessary to secrete H.
20. Diagnostic Approach to a Patient Suspected to
Have RTA
• Appropriate attention to clinical and biochemical findings will lead in
most cases to the correct classification of the patient.
• Also, the judicious application of the different functional tests will allo
w to distinguish between the different pathogenic types of distal RTA.
• Rapid distinction between proximal and distal RTA can be quic
kly performed by the study of the urine anion or osmolal gaps.
• When a urine sample from a patient with hyperchloremic meta
bolic acidosis has a negative anion gap or an osmolal gap above 100
mmol/L, a gastrointestinal or renal loss of HCO3 or a previous intake of
an acid salt are the probable causes.
21. • Diagnosis of proximal RTA is established when the other disor
ders have been excluded.
• Surreptitious use of laxatives should be suspected in adults but is unu
sual in children.
• A low urinary Na content should indicate this possibility.
• Definitive diagnosis of proximal RTA is accomplished by the dem
onstration of a low urine pH at low plasma HCO3 concent
ration and by the presence of a normal urine PCO2 and a high urine H
CO3 excretion at normal plasma HCO3 concentration.
• This diagnosis warrants a complete study of other proximal tubul
ar functions.
• When a urine sample from a patient with hyperchloremic met
abolic acidosis has a positive anion gap or an osmolal gap below 10
0 mmol/L, a defect in distal urinary acidification should be suspected.
• The immediate step in the diagnostic work-up is to measure plasm
a K concentration.
22. • The GFR in isolated true RTA should be normal or only mildly red
uced.
• RTA is associated with abnormal potassium (K +) distribution in the ki
dney.
• K +derangement is also a frequent finding in RTA and can guide evalu
ation and treatment.
• Hypokalemia is characteristic of distal RTA and proximal RTA, while h
yperkalemia is indicative of hyperkalemic RTA.
• Some patients with proximal RTA may also have findings in
dicative of Fanconi syndrome.
• Nutritional deficiencies typical of Fanconi syndrome include hypop
hosphatemia, hyponatremia, and rarely, hypoglycemia or hypoproteine
mia.
24. Voltage-Dependent RTA
• A small number of patients with distal RTA express hyperkalemia rathe
r than hypokalemia.
• This variety of distal RTA is known as voltage-dependent RTA.
• Impaired acid secretion is a result of reduced distal tubular Na+ deliver
y or poor reabsorption, in contrast to the primary defect in H + transpo
rt observed in classic distal RTA.
• A favorable transepithelial voltage gradient cannot be main
tained, forcing retention of both K+ and H +.
25. Suggested algorithm for suspected renal tubular acidosis (RTA) in patients with non–a
nion gap metabolic acidosis and hyperkalemia.
26. • Anion Gap = Serum(Na+ + K+ )-(Cl- + HCO3
- )
• Purpose of using anion gap: metabolic acidosis resulting from bicar
bonate loss can be differentiated from accumulation of non volatile aci
ds
• Normal value : 14 – 18 mEq/L
• >20 is highly suggestive of presence of anion gap
• For every mEq of bicarb loss there is equal increase in serum chlori
de levels so anion gap remains within normal range
What is anion gap?
27. Urine Anion Gap
• Urine anion gap (UAG ) is an indirect measure of NH4
+ excretion, whic
h is not routinely determined in the clinical laboratory.
• However, it is measured by determining the urine concentrations of Na
+, K+ , and Cl - and is calculated as [Na + ] + [K + ] − [Cl - ].
• In general, NH4
+ is excreted with Cl - .
• A normal individual has a negative (from 0 to − 50) UAG (Cl
- > Na + + K + ), suggesting adequate excretion of NH4
+.
• On the other hand, a positive (from 0 to+ 50) UAG
(Na + + K + > Cl - ) indicates a defect in NH4
+ excretion.
• The UAG is used clinically to distinguish primarily
hyperchloremic metabolic acidosis due to distal renal tubular acidosi
s (RTA) and diarrhea.
28. Diagnostic approach to RTA
Step 1. Determine serum anion gap in metabolic acid
osis
Anion gap
The normal AG is usually 8 to 12 ± (4–6 mEq/L when accounts pot
assium)
AG= [Na + -(Cl - + HCO3
-)]
Total number of cations must be equal to anions to maintain this normal a
nion gap in renal tubular acidosis when bicarbonate decreases there is in
crease in chloride ion.
Albumin and phosphate are major unmeasured anions that cont
ribute to the AG. Phosphate concentration has less impact on the AG, bu
t for albumin decrease in 1 gm/dL results in a decrease in AG by 2.5–3.
The corrected AG thus can be calculated with albumin into account as giv
en below.
Corrected AG = Observed AG + 2.5 × (Routine Albumin – Measured
Albumin)
29. Step 2. Differentiate renal (RTA-low NH4 excretion) from extr
arenal causes (diarrhea-high NH4 excretion) of normal anion
gap acidosis
Urine anion gap (UAG)=Urine net charge
It is calculated by using the measured concentration of el
ectrolytes in the urine
UAG = (Na + K) – Cl (representing ammonia excretion)
Na + +k + + NH4
+ =CI - +80
NH4 =80- (Na + +K + +CI -)
So , UAG gives an approximate estimate of urinary NH + excretion :
NH4
+ =80 - UAG
30. • In healthy subjects consuming a Western diet, the urine anion gap i
s positive with a mean of 41 ± 9.
• In severe diarrhea with metabolic acidosis, urine ammonium ion will in
crease and be excreted with an anion (mostly chloride, although s
ulfates and phosphates may be present).
• The urine chloride concentration will increase and the am
monium excretion will be reflected by a less positive or ne
gative urine anion gap.
• The urine anion gap, however, will be positive in patients with som
e forms of RTA whereby renal ammoniagenesis is impaired.
• Impaired ammoniagenesis is the defect in type 4 RTA and is also seen
in distal (type 1) RTA
31. Urine osmolal gap In circumstances where urine anion gap is not reliab
le such as in presence of significant ketones ,bicarbonates or cations suc
h as lithium and high urine pH, the calculation of the urine osmolal ga
p may be useful.
The osmolal gap is determined as follows:
Urine osmolal gap = measured osmolality - calculated osmolality
The early morning urine osmolality is measured directly by an osm
ometer and calculated as given below:
Calculated urine osmolality = 2[Na+ + K+] + UUN/2.8 + Glucose/18
[Urinary levels of electrolytes are in mEq/L and urea as urinary urea
nitrogen (if urea then divides by 6) and glucose is in mg/dL].
Urinary NH4 excretion is considered appropriately high if the gap [10
0 mOsm/kg.
32. Step 3. To classify types of RTA
Urine pH
Low urinary sodium and urinary tract infection with urea-splitting organis
ms also can result in high urinary pH without any acidificati
on defect.
To rule out false positive high urinary pH, a modified acidification tes
t i.e., FF (Furosemide-fludrocortisone) test should be done.
Furosemide-fludrocortisone (FF) test is a practically feasible test for as
sessing the efficiency of urinary acidification mechanism.
Furosemide increases delivery of sodium ion in distal tubule and thus
enhances the urinary acidification mechanism.
Mineralocorticoids support furosemide in maintaining this gradient
This test also has an important role in diagnosing incomplete distal RTA.
33. Prerequisite and procedure for test:
Should be done with control run simultaneously, need overnight fasti
ng and normal s. potassium
First detect early morning urinary pH. If pH remained above 5.5 then
continue the test further.
• Give oral furosemide dose 1 mg/kg (max: 40 mg);
• Fludrocortisone -0.025 mg/kg (max: 0.1 mg) the night before the
test
• Measure urine pH hourly for next 4–6 h.
Urine pH below 5.5 any time during the test is an indication for norm
al distal acidification mechanism and rules out type I RTA
34. Defect Site of defect
Urine PH
( during
acidosis)
Urine PH
( after
furosemide )
K excretion
(baseline)
K excretion
(after
furosemide)
normal <5.5
Further
decrease
normal increased
H+ ATPase
Diffuse, cortical
CT.
˃5.5 ˃5.5 normal increased
H+ ATPase Medullary CT
alone.
˃5.5 <5.5 normal increased
Voltage defect Cortical CT
˃5.5 ˃5.5
decreased decreased
Furosemide test
35. • Definitive diagnosis of distal RTA is best reached with an NH4
+ load
ing test
• Administration of an acid load in the form of ammonium chloride (NH4
Cl -0.1 mg per kg ) should acidify urine (pH below 5.5 ) in a normally fu
nctioning kidney in an effort to buffer blood pH.
• In patients with distal RTA and impaired urinary H + and NH4
+ secr
etion, urinary pH will not decrease as expected.
36. Ammonium Loading Test
• Administer 100 mg/kg oral ammonium chloride (NH4Cl), ingested slowl
y with a meal.
• Urine pH and urine anion gap (UAG) should be measured at the begin
ning of the test and after 6 hours.
• Achieving a urinary pH <5.3 at 6 hours is indicative of a normal study
or the presence of proximal RTA.
• If urine pH remains >5.3, distal RTA is likely.
• At 6 hours following NH4Cl ingestion, normal patients or those with p
roximal RTA will develop a negative UAG.
• If the UAG remains positive at 6 hours, this result is diagnostic of distal
RTA.
37. Bicarbonate Loading Test
•Commence an intravenous infusion of sodium bicarbonate at 1 m
mol/kg/h. OR orally 2-4 mEq per kg per day for 2-3 days
•Serum bicarbonate (HCO3
- ), serum creatinine, urine pH, urine HCO
3
- , and urine creatinine levels should be measured at the begi
nning of the test, followed by hourly measurements until serum HCO3
- ap
proaches the normal range.
•The test is complete once serum HCO3
- is within or near normal li
mits (20 mEq per L) or when 3 urine samples show urine pH above 7.5
38. Ideally for measuring PCO2, urine collection should be under miner
al oil and, if measuring bicarbonate by blood gas machine, then calibr
ation accordingly should be done.
Urine pH , PCO2,and urine to blood PCO2
After bicarbonate load :
The urine-to-blood PCO2 gradient (U-B) should be greater than 20
mmHg in normal individuals ,urine PCO2 should exceed 70 mm
Hg ,and urine pH should be more than7.5
In classic type I RTA, with secretory defect, urine PCO2 is less than 50 m
mHg , (U-B) CO2 is less than 10 while in back leak (voltage ) defect of di
stal RTA, type II and IV RTA, it is greater than 20.
39. •Urinary bicarbonate can be accurately determined with the device for blo
od gas analysis and minimum sample required here is 0.3 mL
•A urine pH >7.5 or fractional excretion of HCO3
- >15% is di
agnostic of proximal RTA.
•Urine pH will be unchanged in normal patients or those with distal RTA.
•A fractional excretion of HCO3
- <5% excludes proximal RTA, and a valu
e of 5%-15% is indeterminate.
•The calculation of fractional HCO3
– excretion is as follows:
fractional excretion of HCO3
– (FE-HCO3 ) =
100 x(urine HCO3
– x plasma creatinine) /
(plasma HCO3
– x urine creatinine)
40. Causes of normal anion gap (hyperchloremic)
metabolic acidosis
GI Loss of HCO3
-
Diarrhoea, Ileostomy and Ureterosigmoidostomy
Renal Loss of HCO3
-
Proximal renal tubular acidosis Isolated channel defect, Fanconi syndrome, Famili
al, Cystinosis, Tyrosinemia, Multiple myeloma, Wilson disease, Ifosfamide, Osteopetrosi
s (type III), Carbonic anhydrase inhibitors, bladder obstruction
Reduced renal H+ secretion
Distal renal tubular acidosis (classic type I) Familial, Hypercalcemic/ hyper
calciuric states, Sjo¨gren syndrome, Autoimmune disease, Amphotericin, Renal transpl
ant
41. Type 4 renal tubular acidosis Hyporeninemic hypoaldosteronism, Tu
bulointerstitial disease
Defective mineralocorticoid synthesis/secretion, Addison disease, Acquired adren
al enzymatic defects (chronic heparin therapy), Congenital adrenal enzymatic d
efects
Inadequate renal response to mineralocorticoid, Sickle cell disease, Potassium- sparing
diuretic
Pseudohypoaldosteronism (type 1 and 2)
Early uremia,
Recovery from sustained hypocapnia
Treatment of diabetic ketoacidosis
Toluene inhalation with good renal function
HCl/HCl Precursor Ingestion/Infusion HCl, NH4Cl, Arginine Cl, Non-steroidal anti- inflam
matory drugs
42. Step IVa and IVb describe tests which are
exclusive for proximal and distal RTA respectively.
Step IVa.
In proximal channel defect following tests to be done further to differe
ntiate generalized form or isolated defect include TUBULAR REABSORP
TION OF PHOSPHATE (TRP).
It is measured on timed urine sample (6–24 h). More than 85 % of tubu
lar reabsorption of phosphate is normal.
Tubular re-absorption of phosphate depends on plasma phosphate and G
FR
Normal value is 2.8–4.4 mg/dL which will be low in Fanconi syn
drome.
43. The other quick method is to measure TmP/GFR :
TmP/GFR = Serum phosphate - (Urine phosphate x S.creatinine/
U. creatinine)
(b) Generalized aminoaciduria Proximal tubule absorbs 95–99 % of amin
o acids. When excretion of amino acids exceeds more than 5 % then t
ermed as generalized aminoaciduria and indicates Fanconi syn
drome.
(c) Glucosuria threshold of glucose absorption reduced in Fanconi syndro
me hence urinary sugar should be tested
(d) Tubular proteinuria (LMW proteinuria) urinary beta2-
microglobulin is excreted above upper limit of normal value in t
ubular defect.
44. Step IVb.
For distal RTA, tests below support the diagnosis further
a) Urinary calcium :24 h urinary calcium excretion of more than 4 mg/k
g/day or spot urine calcium/creatinine >0.2 indicate hyper
calciuria seen in type I RTA.
b) USG (KUB) :To look for medullary nephrocalcinosis in type I RTA
c) Urinary citrate :urinary citrate excretion is normal or high in pro
ximal RTA and hyperkalemic RTA, while reduced levels seen in distal
RTA, and in incomplete distal RTA.
Eyes/ear examination
should be done in both types of RTA as ear examination rules out deaf
ness associated with autosomal form of distal RTA and eye
examination when indicated in proximal RTA for example cystine cryst
als (slit lamp examination) in cystinosis (Fanconi syndrome).
47. types proximal Distal hyperkalemic Type IV
Plasma K N/low N/low High High
urine PH <5.5 >5.5 >5.5 <5.5
UAG positive Positive Positive Positive
Urine NH4 Low Low Low Low
FE HCO3 >10-15% <5% <5% 5-10%
U-B PCO2 >20 <20 </>20 >20
Other tubular
defects
Often
present
absent absent absent
Nephrocalcinosis absent present present absent
Poeme disease common
Often
present
uncommon absent
Urine Ca N increased High N/low
Investigations to differentiate types of RTA
48. Hyperchloremic (normal anion gap)metabolic acidosis
Urine anion gap
Negative
GIT loss
Acid intake
Positive
Suspect RTA
Urine PH,serum K, Na HCO3 loading test
Urine PH<5.5
Serum K low/N
U-B CO3>20 mmHg
FE HCO3>10-15%
Proximal RTA
Screen for other
tubular defects
Urine PH >5.5
Serum K LOW/N
U-B CO2<20mmHg
FE HCO3<5%
Classic type 1 RTA
(secretory defect)
Urine PH>5.5
Serum K high /N
U-B
CO2</>20
FEHCO3<5%
Hyperkalemic type1
RTA
(voltage defect)
Voltage defect and
secretory defect
Screen for
hypercalcemia and
nephrocalcinosis
Urine PH<5.5
Serum K high
U-B
CO2>20
FEHCO3 5-10%
Type 4 RTA
Screen for renal
parenchymal dis ,
plasma renin &
aldosteron
Decreased renal tubular reabsorption of HCO3- due to defective pump secretion or function ,or defect of CA-IV in the brush border membrane………BICARBONATURIA
Inability to secrete (NH4) in amounts adequate to keep pace with a normal rate of acid production :
-Secretory (rate) defect…….low rate of H+ secretion
-Gradient (permeability ) defect : defective function of H+ATPase, H+K+ATPase ,CL-HCO3-exchanger
Hyppokalemia is due to :
-Increased K+ loss in tubular lumen
-Increased urinary Na+ loss…….aldosterone stimulation…….increased tubular K+secretion, and decreased proximal tubular reabsorption
Metabolic acidosis with a normal anion gap =RTA OR Diarrhea
NB :
80 = the difference between unmeasured anions (sulphates-phosphates-organic acids ) , and cations (calcium –magnesium)
