West Visayas State University – College of Medicine – Batch 2020

Block XIX
Module 4 Acute Renal Tubular Acidosis
Lecture 4
03/ 21/ 19
Dr. Agnes Villaflor

TOPIC OUTLINE ANION GAP

I. Normal Renal Function • The anion gap is the difference in the measured
II. Features of Renal Tubular Acidosis cations and anions in serum, plasma, or urine
III. Physiology of Renal Acidification
IV. Renal Tubular Acidosis: Definition
• Represents anions other than bicarbonate and chloride
V. Types of RTA and characteristics required to balance sodium’s positive charge
VI. Laboratory diagnosis of RTA • Normal Anion Gap = 12 ± 2 mEq/L
VII. Approach in a patient with RTA • Increase when:
VIII. Treatment
IX. Take Home Points • Plasma concentration of K+, Ca2+, Mg2+ is decreased
Review Questions • Concentration of anions or charge in plasma increased
References • Organic anions e.g. lactate, and foreign anions e.g.
Appendices
ethylene glycol accumulates in the blood
• Ketoacidosis, lactic acidosis
LECTURER BOOK REFERENCE OLD TRANS
• Decreases when:
• Cations are increased or when plasma albumin is
decreased
I. NORMAL RENAL FUNCTION
• Conditions associated with metabolic acidosis (see
PROXIMAL TUBULE
appendices)
• Reabsorption:
HCO3- (90%) – carbonic anhydrase III. PHYSIOLOGY OF RENAL ACIDIFICATION
Carbonic anhydrase inhibitors block reabsorption of • Kidneys excrete 50-100 mEq/day of non-carbonic acid
HCO3- and is therefore useful in alkalinizing urine generated daily
Calcium • This is achieved by H+ secretion at different levels in
Glucose the nephron
Amino acids • The daily acid load cannot be excreted as free H + ions
NaCl, water • Secreted H+ ions are excreted by binding to either
buffers, such as HPO42- and creatinine, or to NH to
DISTAL TUBULE form NH4+
• Na+ reabsorbed • The extracellular pH is the primary physiologic
• H+ (NH4+ or phosphate salts) excreted regulator of net acid excretion (pH is the primary drive
• Molar competition between H+ and K+ to excrete H+)
• Aldosterone If acidemia, urine should also be acidic, if alkalemia,
urine should also be basic
II. OUTLINE In renal tubular acidosis, there is acidemia but
• Renal tubular acidosis (RTA) is applied to a group of difficulty in acidification of urine
transport defects in the reabsorption of bicarbonate • Renal acid-base homeostasis may be broadly divided
(HCO3-), the excretion of hydrogen ion (H+), or both. into 2 processes:
Difficulty in acidification of urine Proximal tubular absorption of HCO3-
• The RTA syndromes are characterized by a relatively ─ Proximal Acidification
normal GFR and a metabolic acidosis accompanied by Distal Urinary Acidification
hyperchloremia and a normal plasma anion gap. ─ Distal tubule reabsorption of remaining HCO3-
• Features of Renal Tubular Acidosis that escapes proximally
Metabolic acidosis ─ Excretion of fixed acids through buffering and
Normal anion gap ammonia recycling and excretion of NH4
Hyperchloremia Mostly proximal acidification
Hypokalemia – paresis/paralysis and acidotic For every one HCO3- absorbed, one H+ secreted
breathing (if musculoskeletal in origin, it usually
involves proximal muscles) A. PROXIMAL TUBULE PHYSIOLOGY
• Proximal tubule contributes to renal acidification by H +
METABOLIC ACIDOSIS secretion into the tubular lumen through NHE3
• High Anion Gap MA transporter and by HCO3 reabsorption
• Normal Anion Gap MA

CCetC Group No. 2 1 of 10

MD 3 Alviar, Aportadera, Araneta
• Approximately 85% of filtered HCO3 is absorbed by the
proximal tubule
• The remaining 15% of the filtered HCO3 is reabsorbed
in the thick ascending limb and in the outer medullary
collecting tubule
• Multiple factors are of primary importance in normal
bicarbonate reabsorption: REMEMBER!
The sodium-hydrogen exchanger in the luminal
membrane (NHE3) – sodium hydrogen counter
transporter in the lumen
The Na-K-ATPase pump (basolateral membrane) –
active transporter extruding Na+, making the
charge in the proximal tubule negative, attracting
more Na+ and driving H+ secretion
Enzyme carbonic anhydrase II (inside the cell) and
IV (in the lumen)
Electrogenic NA-HCO3 cotransporter (NBC-1)
Figure 2. Diagram of Ammonia Recycling. Source: Doc’s slides

C. DISTAL URINARY ACIDIFICATION

• The thick ascending limb of Henle’s loop reabsorbs
about 15% of the filtered HCO3 load by a mechanism
similar to that present in the proximal tubule, i.e.
through Na+-H+ apical exchange (NHE3)

D. H+ SECRETION
• The collecting tubule (CT) is the major site of H+
secretion and is made up of the medullary collecting
duct (MCT) and the cortical collecting duct (CCT)
• Alpha and beta-intercalated cells make up 40% of
the lining while Principal cells and collecting tubule
Figure 1. Important factors in bicarbonate reabsorptions. Source: Doc’s
slides cells make up the remainder
• Alpha-intercalated cells are thought to be the main
B. AMMONIA RECYCLING cells involved with H+ secretion in the CT
• Ammonium synthesis and excretion is one of the most • This is accomplished by an apically placed H+-K+
important ways kidneys eliminate nonvolatile acids ATPase and H+-ATPase with a basolateral Na+-K+
• Ammonium is produced via catabolism of Glutamine in ATPase
the proximal tubule cells
• Luminal NH4 is partially reabsorbed in the thick
ascending limb and the NH3 then recycled within the
renal medulla
• Ammonia passively diffuses in and out of the cell, it has
no transporter
• It concentrates in the lumen up to the medullary duct
and then goes out in the interstitium and is being
recycled within the loop of Henle
• It is trapped to form the ammonia, joins with hydrogen
and is secreted as acid
• The medullary interstitial NH3 reaches high
concentrations that allow NH3 to diffuse into the tubular
lumen in the medullary collecting tubule, where it is
trapped as NH4+ by secreted H+. Figure 3. Important factors in H+ secretion. Source: Doc’s slides

• Beta-intercalated cells in contrast to the above have a

luminal Cl-/HCO3- exchanger and a basolateral H+-
ATPase

CCetC
Block XIX: Acute Renal Tubular Acidosis 2 of 10
MD 3
• They play a role in bicarbonate secretion into the lumen
that is later reabsorbed by the carbonic anhydrase
(CA) IV rich luminal membrane of medullary collecting
duct
• CCT H+ secretion is individually coupled to Na+
transport. Active Na+ reabsorption generates a
negative lumen potential favoring secretion of H + and
K+ ions
• In contrast the MCT secretes H+ ions independently of
Na+
• Medullary portion of the collecting duct is the most
important site of urinary acidification
E. ALDOSTERONE AND RENAL ACIDIFICATION
• Favors H+ and K+ secretion through enhanced sodium
transport
• Recruits more Amiloride-sensitive sodium channels in
the luminal membrane of the collecting tubule
• Enhances H+-ATPase activity in cortical and medullary
collecting tubules
• Aldosterone also has an effect on NH4+ excretion by
increasing NH3 synthesis
Spironolactone, a K-sparing diuretic, antagonizes
aldosterone, net effect will be acidosis while
increasing K+ conc., a characteristic of type 4 RTA
F. SUMMARY OF RENAL PHYSIOLOGY
• H+ secretion, bicarbonate reabsorption and NH4+
production occur at the proximal tubule. Luminal
Carbonic anhydrase (CA) IV is present in the luminal
membrane at this site and in MCT
• NH4+ reabsorption occurs at TAL (thick ascending limb)
of loop of Henle and helps in ammonia recycling that
facilitates NH4+ excretion at MCT (medullary Collecting
duct)
• H+ secretion occurs in the CCT (cortical collecting duct)
either dependent or independent of Na availability and
in the MCT as an independent process
V. TYPES OF RENAL TUBULAR ACIDOSIS
PROXIMAL RTA (TYPE 2)
• Isolated bicarbonate defect
• Fanconi Syndrome
Most often due to generalized proximal tubular
dysfunction, manifested by:
Glycosuria
Generalized aminoaciduria
Phosphaturia
DISTAL RTA (TYPE 1)
• Classic Type
Include hypokalemia, non-AG metabolic acidosis, low
urninary NH4+ secretion (positive UAG, low urine
NH4+), and inappropriately high urine pH (>5.5)
Most patients have hypocitraturia and hypercalciuria
= nephrolithiasis, nephrocalcinosis, and bone disease
are common
HYPERKALEMIC RTA (TYPE 4)
Hyperkalemia is disproportionate to the reduction in
GFR because of coexisting dysfunction of potassium
and acid secretion.
Urinary ammonium excretion is invariably depressed,
and renal function may be compromised (example
due to diabetic nephropathy, obstructive uropathy, or
chronic tubulointerstitial disease)

IV. RENAL TUBULAR ACIDOSIS

A defect in acidification Figure 4. Location of RTA. Source: Doc’s slides
In a state of acidosis; the urine is not acidic due to
sequestration
Metabolic acidosis and hypokalemia increase renal
synthesis and excretion NH4+ = increased urine pH
(>6)
Metabolic acidosis due to gastrointestinal losses (i.e.
diarrhea) with a high urine pH can be differentiated
from RTA through the measurement of urinary NH4+
secretion; LOW excretion in RTA as compared to
HIGH excretion in diarrhea
INCREASED urine ammonium levels = extrarenal
cause
DECREASED urine ammonium level = renal cause of
acidosis
Figure 5. Summary of Types of RTA. Source: ADEOS

CCetC
Block XIX: Acute Renal Tubular Acidosis 3 of 10
MD 3
A. PROXIMAL RENAL TUBULAR ACIDOSIS: TYPE 2
• Proximal RTA (pRTA) is a disorder leading to
hyperchloremic metabolic acidosis (HCMA) secondary
to impaired proximal reabsorption of filtered
bicarbonate
• Since the proximal tubule is responsible for the
reabsorption of 85-90% of filtered bicarbonate, a defect
at this site leads to delivery of large amounts of
bicarbonate to the distal tubule
• This leads to bicarbonaturia, kaliuresis, potassium in
the urine, and sodium losses.
• Generally present with hypokalemia and HCMA
Figure 6. Defects associated with Proximal RTA. Source: Doc’s slides
• Isolated defects in PCT function are rarely found. Most
patients with pRTA will have multiple defects in PCT
function with subsequent Fanconi Syndrome
• The most common causes of Fanconi syndrome in
adults are (1) multiple myeloma (plasma cell dyscracia)
and (2) use of acetazolamide
• In children, cystinosis is the most common
• At times, pRTA is a self-limiting disorder and fall of
serum HCO3- below 12 mEq/L is unusual
• Urine pH remains acidic (<5.5) mostly due to the
acidification at the distal tubule but becomes alkaline
when bicarbonate losses are corrected
• FEHCO3 increases (>15%) with administration of alkali
or bicarbonate for correction of acidosis
FEHCO3 = fractional excretion of HCO3, one of the
procedures that will identify a proximal from a distal
RTA
(supplementary notes)
Due to generalized proximal tubular dysfunction
characterized as:
Glycosuria generalized aminoaciduria, and
phosphaturia (Fanconi syndrome)
Low plasma [HCO3-] because HCO3- is not
reabsorbed normally in the proximal tubule
Urine pH is acidic (pH <5.5)
Therapy with NaHCO3 will enhance renal
potassium wasting and hypokalemia
CCetC
Block XIX: Acute Renal Tubular Acidosis
MD 3
Proximal RTA (Type 2) is caused by an impairment
of HCO3 - reabsorption in the proximal tubules
Often secondary to various autoimmune, drug
induced, infiltrative, or other tubulopathies or results
from tubular injury from inherited diseases (Wilson’s
disease, cystinosis, tyrosinemia, galactosemia,
hereditary fructose intolerance, glycogen storage
disease type 1, and Lowe’s syndrome) in which
endogenous metabolites accumulates
Most cases occur in the context of Fanconi’s
syndrome wherein the proximal tubule functions are
deranged
Isolated proximal RTA is rare. Thus other features of
Fanconi syndrome are:
Hyperphosphaturia
Hyperuricosuria
Hypercalciuria
Nonselective aminoaciduria
Glycosuria
In addition to hyperchloremic acidosis, rickets and
osteomalacaia are the predominant effects of
Fanconi’s syndrome
Rare form of infantile primary proximal renal tubular
acidosis (pRTA) with isolated proximal tubular
bicarbonate wasting is due to homozygous mutation
of the proximal tubule basolateral sodium-
bicarbonate co transporter (NBCI)
This co transporter is important as it is the main
mechanism by which bicarbonate moves from the
proximal tubule cell back into the blood
Normal renal tubular function: 80% of bicarbonate is
reabsorbed in the proximal tubule and 5 % is excreted
In proximal RTA, only 60% of bicarbonate is
reabsorbed and 25% is excreted; it is accompanied
by loss of potassium
(end of supplementary notes)
CAUSES OF PROXIMAL (TYPE 2) RTA
• Primary
Idiopathic, sporadic
Familial: cystinosis, tyrisonemia, hereditary
fructose intolerance, galactosemia, glycogen
storage disease (type 1), Wilson’s diseases,
Lowe’s Syndrome
• Fanconi Syndrome
Generalized proximal tubule dysfunction
Proximal loss of phosphate, uric acid, glucose,
amino acids
• Acquired
Multiple myeloma
Carbonic anhydrase inhibitors (azetazolamide) –
given in patients with glaucoma; so exercise
caution especially if with concomitant chronic
kidney disease
Other drugs: amphotericin B, 6-mercaptopurine
4 of 10
 Heavy metal poisoning (Lead, Copper, mercury,
Calcium)
Amyloidosis
Disorders of protein, carbohydrates, amino acid
metabolism
Hypophosphatemia, hypouricosuria, renal
glycosuria with normal serum glucose
CAUSES OF HYPOKALEMIA IN TYPE 2 RTA
• Metabolic acidosis in and of itself decreases pRT Na +
reabsorption leading to increased distal tubule delivery
of Na+ which promotes K+ secretion
• The pRTA defect almost inevitably leads to salt
wasting, volume depletion and secondary
hyperaldosteronism
• The rate of kaliuresis is proportional to distal
bicarbonate delivery. Because of this, alkali therapy
tends to exaggerate hypokalemia
• Patients with pRTA rarely develop nephrosclerosis or
nephrolithiasis. This is thought to be secondary to high
citrate excretion. (citrate is a crystal inhibitor)
• In children, the hypocalcemia as well as the HCMA will
lead to growth retardation, rickets, osteomalacia and
an abnormal vitamin D metabolism. In adults,
osteopenia is generally seen
SUMMARY OF PROXIMAL RTA
• Massive loss of bicarbonate d/t reabsorption defect –
metabolic acidosis
• HCO3- wasting, Net H+ excess
• Absorption of chloride – hyperchloremia
• Loss of potassium – hypokalemia (low to normal)
• Kidneys try to compensate for the acidosis – urine ph
low < 5.5 (although high initially)
B. DISTAL RENAL TUBULAR ACIDOSIS: TYPE 1
• Distal RTA (dRTA) is a disorder leading to HCMA
secondary to impaired distal H+ secretion
• It is characterized by inability to lower urine pH
maximally (<5.5) under the stimulus of systemic
academia. Serum HCO3- very low <12 meq/L
• It is often associated with hypercalciuria, hypocitraturia,
nephrocalcinosis, and osteomalacia
• The term incomplete distal RTA has been proposed to
describe patients with nephrolithiasis but without
metabolic acidosis
Hypocitraturia is the usual underlying cause
• It’s not the level of Ca+ in the serum but the level of
Ca+ in the urine that predisposes stone formation
• The most common cause in adults are autoimmune
disorders, such as Sjogren syndrome, and other
conditions assoc. with chronic hyperglobulinemia
• In children, type 1 RTA is most often a primary,
hereditary condition
CCetC
Block XIX: Acute Renal Tubular Acidosis
MD 3
Figure 7. Defects associated with Distal RTA. Source: Doc’s slides
(supplementary notes)
Decreased excretion of titratable acids = acidification
defect
Impairment of distal acidification
Inability to lower urine pH maximally below 6.0 under
acid load in the presence of systemic metabolic
acidosis or after acid loading as a result of impaired
hydrogen ion secretion or bicarbonate reabsorption
in the distal nephron
Pathomechanism is inability to secrete H+
adequately (secretory defect or classic distal RTA)
Mutations affecting subunits of the H+-ATPase
proton pump on the luminal surface impair hydrogen
ion secretion and account for most forms of the
autosomal recessive dRTA and are often associated
with early onset sensorineural hearing loss
Autosomal dominant dRTA results from mutation
involving the chloride – bicarbonate exchanger on
the basolateral membrane
Marble brain disease – syndrome of osteoporosis,
short stature, and mental retardation is due to
mutations in carbonic anhydrase II
Urinary potassium wasting, and defective urinary
concentration are characteristic of dRTA.
Calcium is released from the bone to buffer the
effects of acid and results in hypercalciuria
Enhanced proximal citrate absorption accounts for
the hypocitraturia
Hypercalciuria and hypocitrauria predisposes to
nephrocalcinosis and formation of calcium
phosphate stones.
Other features distal RTA include hypokalemia,
hypocitraturia, hypercalciuria, nephrocalcinosis, and
nephrolithiasis
Inability to secrete hydrogen ion through
transporters
Defect of H+ secretion in the distal tubule,
potassium is also lost
(end of supplementary notes)
5 of 10
• A high urinary pH (5.5) is found in the majority of
patients with a secretory dRTA
• Excretion of ammonium is low as a result of less NH4+
trapping. This leads to a positive urine anion gap
• Urine PCO2 does not increase normally after a
bicarbonate load reflecting decreased distal hydrogen
ion secretion
• Serum potassium is reduced in 50% of patients. This is
thought to be from increased kaliuresis to offset
decreased H+ and H-K-ATPase activity

NONSECRETORY DEFECTS CAUSING DISTAL RTA

• Gradient defect (hypoK): back leak of secreted H+ ions;
ex. amphotericin B
• Voltage-dependent defect (hyperK): impaired distal
sodium transport. Ex. Obstructive uropathy, sickle cell Figure 8. Typical KUB X-ray with Distal RTA. Source: Doc’s slides
Nephrocalcinosis: calcium deposits in renal
disease, CAH, lithium and amiloride, etc. This form of
parenchyma
distal RTA is associated with hyperkalemia
(hyperkalemic distal RTA)
C. HYPERKALEMIC RTA: TYPE 4
• This disorder is characterized by modest HCMA with
CAUSES OF DISTAL (TYPE 1) RTA
normal AG (anion gap) and association with
• Primary
hyperkalemia
Idiopathic, sporadic
• This condition occurs primarily due to decreased
Familial – autosomal dominant, autosomal
urinary ammonium excretion
recessive
• Hypoaldosteronism is considered to be the most
• Secondary
common etiology. Other causes include NSAIDs, ACE
Autoimmune (SLE, Sjogren’s, RA)
inhibitors, adrenal insufficiency, diabetics, etc.
Hereditary hypercalciuria, hyperparathyroidism,
• The ability to lower urine pH in response to systemic
Vitamin D intoxication, hypergammaglobulinemia
acidosis is maintained
Drugs (ampothericin-B, ifosfamide, lithium)
• Absent nephrocalcinosis - the only distal RTA without
Chronic hepatitis
nephrocalcinosis
Obstructive uropathy
• In contrast to voltage hyperkalemic distal RTA, the
Sickle cell anemia
ability to lower urine pH in response to systemic
Renal transplantation
acidosis is preserved.
SUMMARY OF DISTAL RTA
• First described, classical form
• Distal defect leads to decreased H+ secretion
• H+ builds up in blood (acidotic)
• K+ secreted instead of H+ (hypokalemia)
• Urine pH >5.5
• Hypercalciuria, hypercitraturia
• Renal stones

Figure 9. Defects associated with Hyperkalemic RTA. Source: Doc’s

slides

CCetC
Block XIX: Acute Renal Tubular Acidosis 6 of 10
MD 3
(supplementary notes)
RTA TYPE IV
Hypoaldosteronism or deficiency of aldosterone
In generalized distal nephron dysfunction (type 4
RTA), hyperkalemia is disproportionate to the
reduction in GFR because of coexisting
dysfunction of potassium and acid secretion.
Urinary ammonium excretion is invariably
depressed, and renal function may be
compromised, for example, due to diabetic
nephropathy, obstructive uropathy, or chronic
tubulointerstitial disease
End organ target failure or low aldosterone:
─ Loss of sodium – hyponatremia
─ Retention or decreased excretion of potassium
– hyperkalemia
Absorption of chloride – hyperchloremia
Decreased excretion of acids – metabolic acidosis
(end of supplementary notes)
CAUSES OF HYPERKALEMIC (TYPE 4) RTA
• Acquired causes
• Decreased renin
Diabetic nephropathy
NSAIDS
Interstitial nephritis
• Normal renin, decreased aldosterone
ACEIs, ARBs
Heparin
Primary adrenal response
• Decreased response to aldosterone
Medications: K+ sparing diuretics (spinorolactone
– blocks the transport system), TMP-SMX,
pentamidine, tacrolimus
Tubulointerstitial diseases: sickle cell, SLE,
amyloid, diabetes
SUMMARY OF HYPERKALEMIC RTA
• Aldosterone deficiency or distal tubule resistance to
aldosterone
• Impaired function of NA+/K+/H+ (cation) exchange
mechanism
• Decreased H+ and K+ secretion leading to plasma
buildup of H+ and K+ (hyperkalemia)
• Urine pH <5.5
D. TYPE 3 RTA
• Very rare
• Used to designate mixed RTA and proximal RTA of
uncertain etiology
• Now describes genetic defect in Type 2 carbonic
anhydrase (CA2), found in both proximal, distal
tubular cells and bone
CCetC
Block XIX: Acute Renal Tubular Acidosis
MD 3
VI. LABORATORY DIAGNOSIS OF RTA
• RTA should be suspected when metabolic acidosis is
accompanied by hyperchloremia and a normal plasma
anion gap (Na+ - [Cl- + HCO3-] = 8 to 16 mmol/L) in a
patient without evidence of gastrointestinal bicarbonate
losses and who is not taking acetazolamide or
ingesting exogenous acid.
• In a patient with metabolic acidosis, request Na +, K+,
Cl- and an ABG
A. FUNCTIONAL EVALUATION OF PROXIMAL
BICARBONATE ABSORPTION
• Fractional excretion of bicarbonate:
Urine pH monitoring during IV administration of
sodium bicarbonate
FEHCO3 (Fractional Excretion of Bicarbonate) is
increased in proximal RTA >15% and is low in
other forms of RTA
Because when you give bicarbonate in a setting of
low systemic bicarbonate, the normal proximal
tubule should reabsorb it but a defective proximal
tubule will Increase secretion of administered
bicarbonate
B. FUNCTIONAL EVALUATION OF DISTAL
URINARY ACIDIFICATION AND POTASSIUM
SECRETION
• Urine pH
• Urine anion gap
• Urine osmolal gap
• Urine pCO2
• TTKG (transtubular potassium gradient)
• Urinary citrate
URINE PH
• In humans, the minimum urine pH that can be achieved
is 4.5 to 5.0
• Ideally, urine pH should be measured in a fresh
morning urine sample
• A low urine pH does not ensure normal distal
acidification and vice versa
• The urine pH must always be evaluated in conjunction
with the urinary NH4+ content to assess the distal
acidification process adequately
• Urine sodium should be known and urine should not be
infected
URINE ANION GAP (UAG)
• UAG = Urine (Na + K - Cl).
• Urine AG has a negative value in most patients with
normal AG metabolic acidosis
• Patients with renal failure, type 1 (distal) renal tubular
acidosis (RTA) or hypoaldosteronism (type 4 RTA) are
unable to excrete ammonium normally. As a result, the
urine AG will have a positive value
7 of 10
• When testing the anion gap make sure that the patient
has normal creatinine or kidney function, otherwise, the
defect in HCO3 absorption may be due to decreased
GFR
• There are however two settings in which the urine AG
cannot be used:
When he patient is volume depleted with a urine
sodium concentration below 25 meq/L
When there is increased excretion of unmeasured
anions

URINE OSMOLAL GAP

• When the urine AG is positive and it’s unclear whether
increased excretion of unmeasured anions is
responsible, the urine ammonium concentration can be Figure 10. Summary of Urinary Evaluation of RTA. Source: Doc’s
estimated from calculation of the urine osmolal gap slides

• UOG = Uosm – 2x [ (Na + K)] + [urea nitrogen]/2.8 +

VII. APPROACH
[glucose]/18
• In this patient we want to differentiate whether its
• UOG of >100 represents intact NH4 secretion
proximal or distal, so we give an acid load
• If considering proximal, we load NaHCO3 and test the
URINE PCO2
FEHCO3 and the urine and blood HCO3 level
• Measure of distal acid secretion
• If distal, we load ammonium chloride and get the
• In pRTA, unabsorbed HCO3 reacts with secreted H+
osmolal gap to approximate ammonia secretion
ions to form H2CO3 that dissociates slowly to form CO2
in MCT
• Urine-to-blood pCO2 is <20 in pRTA
• Urine-to-blood pCO2 is >20 in distal RTA reflecting
impaired ammonium secretion

TRANSTUBULAR POTASSIUM GRADIENT (TTKG)

• Transtubular K+ concentration gradient
• Important when trying to evaluate the role of
aldosterone
• TTKG is a concentration gradient between the tubular
fluid at the end of the cortical collecting tubule and the
plasma

• Normal value is 8 and above

• Value <7 in a hyperkalemic patient indicates
hypoaldosteronism and possibly type 4 RTA
• This formula is relatively accurate as long as the urine
osmolality exceeds that of the plasma
• urine sodium concentration is above 25meq/L

URINE CITRATE
• The proximal tubule reabsorbs most (70-90%) of the
filtered citrate
• Acid-base status plays the most significant role in
citrate excretion
• Alkalosis enhances citrate excretion, while acidosis
decreases it
• Citrate excretion is impaired by acidosis, hypokalemia,
high animal protein diet and UTI Figure 11. Diagnostic work-up for RTA. Source: Doc’s slides

CCetC
Block XIX: Acute Renal Tubular Acidosis 8 of 10
MD 3
 VIII. TREATMENT c. Corticosteroid therapy is useful in hyperkalemic
A. PROXIMAL RTA TREATMENT RTA, preferably with a loop diuretic
• A mixture of Na+ and K+ salts, preferably citrate. d. A high-potassium diet is indicated for patients
• 10 – 15 meq of alkali/kg may be required per day to suffering from distal RTA
stay ahead of urinary losses 3. A patient presents with the following findings:
• Thiazide diuretic may be beneficial if large doses of positive UAG, > 5.5. Urine pH, low K+ levels, and
alkali are ineffective or not well tolerated low Urine NH4.What is your impression?
• Vitamin D a. Proximal RTA
b. Hyperkalemic RTA
B. DISTAL RTA TREATMENT c. Distal RTA
• Bicarbonate wasting is negligible in adults who can
d. Type 4 RTA
generally be treated with 1 to 2 meq/kg of sodium 4. The following are causes of hyperkalemic RTA
citrate (Bicitra) or bicarbonate EXCEPT:
• Potassium citrate, alone or with sodium citrate
a. NSAIDs use
(Polycitra), is indicated for persistent hypokalemia or
b. SLE
for calcium stone disease (affects three mechanisms:
c. Diabetes insipidus
hypokalemia, acidosis and stone formation)
d. Sickle cell disease
• For patients with hyperkalemic distal RTA, high- 5. TRUE OR FALSE: Bicarbonate therapy is the
sodium, low-potassium diet plus a thiazide or loop mainstay of treatment.
diuretic if necessary
Answers: CCCCT
C. HYPERKALEMIC RTA TREATMENT
• Treatment and prognosis depend on the underlying REFERENCES
cause • ADEOS notes
• Potassium-retaining drugs should always be withdrawn • Dr. Agnes Villaflor’s lecture
• Fludrocortisone therapy may also be useful in
hyporeninemic hypoaldosteronism, preferably in
combination with a loop diuretic such as furosemide to
reduce the risk of extracellular fluid volume expansion
• Dietary restriction of sodium

IX. TAKE HOME POINTS: DISTINGUISHING RTA

TYPES
• Type 1: renal stones, hypercalciuria, high urine pH
despite metabolic acidosis
• Type 2: think acetazolamide and bicarbonate wasting;
Fanconi’s syndrome
• Type 4: aldosterone deficiency and hyperkalemia
• Mainstay of treatment of RTA: BICARBONATE
THERAPY

REVIEW QUESTIONS
1. Metabolic acidosis with increased anion gap can
be due to increased acid production, due to the
following conditions EXCEPT:
a. Ethanol intoxication
b. Starvation or fasting
c. Acute kidney failure
d. Increased acetoacetic acid production
2. Which of the following statements is correct
regarding RTA treatment?
a. Potassium citrate is indicated for persistent
hyperkalemia in distal RTA
b. Vitamin C is used as a supplement in treating
proximal RTA

CCetC
Block XIX: Acute Renal Tubular Acidosis 9 of 10
MD 3
 West Visayas State University – College of Medicine – Batch 2020
Block XIX
Module 4 Acute Renal Tubular Acidosis
Lecture 4
03/ 21/ 19
Dr. Agnes Villaflor

APPENDICES

Table 1. Conditions associated with metabolic acidosis

Metabolic Acidosis with Normal Anion Gap
Causes Conditions
Diarrhea, fistula or drainage,
GIT loss of bicarbonate surgery for NEC, ileal loop conduit,
use of anion exchange resins
Renal loss of bicarbonate Renal tubular acidosis
Addition of HCl, NH4HCl, arginine,
lysine
Other causes
Hyperalimentation
Dilutional acidosis
Metabolic Acidosis with Increased Anion Gap
Causes
Increased acid production
Increased lactic acid
Organic acidosis
Increased sulfuric acid
Decreased acid excretion
Conditions
Increased beta-hydroxybutyric acid
and acetoacetic acid production
Starvation or fasting
Ethanol intoxication
Tissue hypoxia, muscular
exercise, ethanol ingestion,
Systemic diseases e.g. leukemia,
DM, cirrhosis, inborn errors of
metabolism
Methanol, ethylene glycol,
paraldehyde, salicylate, NSAIDs
Methionine administration
Acute kidney failure
Chronic kidney disease

Table 2. Summary of Findings for RTA Types

Primary defect Serum K+ Urine pH Causes
- autoimmune (SLE, Sjogren’s)
>5.5
- hypercalciuria
Type 1 (distal) H+ secretion ↓ low to normal *note: renal
- drugs (ampothericin-B, ifosfamide, lithium)
stones
- hypergamma-globulinemia
- multiple myeloma
- acetazolamide
Type 2 <5.5 though high - heavy metal poisoning (lead, copper, mercury)
HCO3 ↓ low to normal
(proximal) initially - amyloidosis
- disorders of protein, carbohydrate, amino acid
metabolism
- aldosterone deficiency
- diabetic nephropathy
aldosterone
Type 4 - spinorolactone
deficient, cation high <5.5
(hyperkalemic) - interstitial nephritis
exchange ↓
- obstructive uropathy
- renal transplant

Table 3. Summary of Additional Findings in RTA

Feature Type 1 Type 2 Type 4
Nephrolithiasis present absent absent
Nephrocalcinosis present absent absent
Osteomalacia present present absent
Growth failure +++ ++ +++
Hypokalemic muscle weakness ++ + -
Alkali therapy low dose (2-4meq/ kg) high dose (2-14meq/ kg) low dose (2-3meq/ kg)
Response to therapy good fair fair
Plasma HCO3 variable, maybe <10 meq/L 14-18 meq/L 15-29 meq/L
Plasma Cl- increased increased increased
Plasma K+ mildly to severely decreased mildly decreased mildly to severely
decreased
Plasma anion gap normal normal normal
GFR normal or slightly decreased normal or slightly decreased normal to moderately
decreased
FEHCO3 <5% >15% <5%
Urine pH during acidosis >6.0 ≤5.5 ≤5.5

CCetC Group No. 2 10 of 10

MD 3 Alviar, Aportadera, Araneta