Renal Tubular Acidosis_SUNIL

8/3/2019 Renal Tubular Acidosis_SUNIL

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RENAL TUBULAR

ACIDOSIS

-S.SUNIL KUMAR

INTERNEE



CASE

A 35 year old woman, a nursing homeassistant, presents with chronic acidosis that is

difficult to manage. Lab evaluation showed Na

143, K 2.8 Cl 118, HCO3 15 BUN 18, Cr 0.7.

ABG reveals ph 7.38 Pco2 31, Pao2 100. U/A

results were normal with urine ph of 5.0. Urine

Na was 40 K 5 and Urine Cl 150.



Which disorder best characterizes this pts

syndrome?

A. Diuretic abuse

B. Laxative abuse

C. Distal renal tubular acidosis

D. Proximal renal tubular acidosis

E. Type 4 renal tubular acidosis



OUTLINE

Renal tubular acidosis (RTA) is applied to a

group of transport defects in the reabsorption

of bicarbonate (HCO3-), the excretion of hydrogen ion (H+), or both.

The RTA syndromes are characterized by a

relatively normal GFR and a metabolic

acidosis accompanied by hyperchloremia and a

normal plasma anion gap.



OBJECTIVES

Physiology of Renal acidification.

Types of RTA and characteristics

Lab diagnosis of RTA Approach to a patient with RTA

Treatment



Physiology of Renal Acidification

Kidneys excrete 50-100 meq/day of non carbonicacid generated daily.

This is achieved by H+ secretion at different levels inthe nephron.

The daily acid load cannot be excreted as free H+ions.

Secreted H+ ions are excreted by binding to either buffers, such as HPO42- and creatinine, or to NH3 to

form NH4+. The extracellular pH is the primary physiologic

regulator of net acid excretion.



Renal acid-base homeostasis may be

broadly divided into 2 processes:

1. Proximal tubular absorption of HCO3-

(Proximal acidification)

2. Distal Urinary acidification.

Reabsorption of remaining HCO3- that

escapes proximally.

Excretion of fixed acids through buffering &Ammonia recycling and excretion of NH4

+.



Proximal tubule physiology

Proximal tubule contributes to renalacidification by H+ secretion into the tubular lumen through NHE3 transporter and by

HCO3- reabsorption. Approx. 85% of filtered HCO3

- is absorbed bythe proximal tubule.

The remaining 15 % of the filtered HCO3- isreabsorbed in the thick ascending limb and inthe outer medullary collecting tubule.



Proximal tubule physiology

Multiple factors are of primary importance in

normal bicarbonate reabsorption

The sodium-hydrogen exchanger in theluminal membrane(NHE3).

The Na-K-ATPase pump

The enzyme carbonic anhydrase II & IV

The electrogenic sodium-bicarbonate

cotransporter(NBC-1).



.



Ammonia recycling

Ammonium synthesis and excretion is one of

the most important ways kidneys eliminate

nonvolatile acids.

Ammonium is produced via catabolism of

glutamine in the proximal tubule cells.

Luminal NH4+ is partially reabsorbed in the

thick ascending limb and the NH3 then

recycled within the renal medulla



Ammonia Recycling



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+.



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).



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 cells make up the remainder.



Alpha-Intercalated Cells are thought to be the

main cells involved with H+ secretion in the

CT.

This is accomplished by an apically placed H+-

K +-ATPase and H+-ATPase with a basolateral

Cl-/HCO3- exchanger and the usual basolateral

Na+ - K + ATPase.





Beta-Intercalated Cells in contrast to the above

have a luminal Cl-/HCO3- exchanger and a

basolateral H+-ATPase.

They play a role in bicarbonate secretion into

the lumen that is later reabsorbed by the CA

IV rich luminal membrane of medullary

collecting duct.



CCT H+ secretion is individually coupled to Na+ transport. Active Na+ reabsorptiongenerates a negative lumen potential favoring

secretion of H+ and K + ions.

In contrast theMCT secretes H+ ionsindependently of Na+.

M edullary portion of the Collecting duct isthe most important site of urinaryacidification



Principal cells



Aldosterone and Renal acidification

Favors H+ and K+ secretion through enhancedsodium transport.

Recruits more amiloride sensitive sodiumchannels in the luminal membrane of thecollecting tubule.

Enhances H+-ATPase activity in cortical and

medullary collecting tubules. Aldosterone also has an effect on NH4+

excretion by increasing NH3 synthesis



Summary

H+ secretion, bicarbonate reabsorption and NH4+ production occur at the proximal tubule. Luminal CAIV is present in the luminal membrane at this site and

inM

CT. NH4+reabsorption occurs at TAL of loop of Henle

and helps in ammonia recycling that facilitates NH4+excretion atMCT.

H+ secretion occurs in the CCT either dependent or independent of Na availability and in the MCT as anindependent process..



OBJECTIVES

Physiology of Renal Acidification.



Treatment



TYPES OF RTA

Proximal RTA (type 2)

Isolated bicarbonate defect

Fanconi syndromeDistal RTA (type 1)

Classic type

Hyperkalemic distal RTA

Hyperkalemic RTA (Type 4)



PROXIMAL RTA

Proximal RTA (pRTA) is a disorder leading to

HCMA secondary to impaired proximal

reabsorption of filtered bicarbonate.

Since the proximal tubule is responsible for the

reabsorption of 85-90% of filtered HCO3- a

defect at this site leads to delivery of large

amounts of bicarbonate to the distal tubule.



This leads to bicarbonaturia, kaliuresis and

sodium losses.

Thus patients will generally present withhypokalemia and a HCMA.



.



CAUSES

Primary - Familial or spor adicDysproteinemic states - Multiple myeloma (pRTA and dRTA), amyloidosis

(pRTA and dRTA), light chain disease, cr yoglobulinemia, and monoclonal

gammopathy

CA-related conditions - Osteopetrosis (anhydr ase II deficiency),

acetazolamide, and mafenide

Drug or toxic nephropathy - Lead, cadmium, mer cur y, str eptozotocin,

outdated tetr acycline, and if osfamide (pRTA and dRTA)

Hereditary disorders - Cystinosis, galactosemia, Wilson disease, her editar y

f r uctose intoler ance, glycogen stor age disease type I, tyrosinemia, and Lowe

syndrome

Interstitial renal conditions - Sjögr en syndrome, medullar y cystic disease

(pRTA and dRTA), Balkan nephropathy, and r enal tr ansplant r ejection (pRTA

and dRTA)

Miscellaneous - Paroxysmal noctur nal hemoglobinur ia, malignancy, nephrotic

syndrome, and chronic r enal vein thrombosis



Isolated defects in PCT function are rarely

found.Most patients with a pRTA will have

multiple defects in PCT function with

subsequent Fanconi Syndrome.

The most common causes of Fanconi

syndrome in adults are multiple myeloma and

use of acetazolamide.

In children, cystinosis is the most common.



pRTA is a self limiting disorder and fall of serum HCO3_ below 12 meq/l is unusual, asthe distal acidification mechanisms are intact..

Urine ph become remains acidic(<5.5) mostly but becomes alkaline when bicarbonate lossesare corrected.

FEHCO3 increases(>15%)with administration

of alkali for correction of acidosis



Cause of hyokalemia in Type 2 RTA

Metabolic acidosis in and of itself decreases pRT Na+ reabsorption leading to increaseddistal tubule delivery of Na+ which promotes

K + secretion. The pRTA defect almost inevitably leads to

salt wasting, volume depletion and secondaryhyperaldosteronism.

The rate of kaliuresis is proportional to distal bicarbonate delivery. Because of this alkalitherapy tends to exaggerate the hypokalemia.



P atients with pRTA rarely develop

nehrosclerosis or nephrolithiasis. This is

thought to be secondary to high citrate

excretion.

In children, the hypocalcemia as well as the

HCMA will lead to growth retardation, rickets,

osteomalacia and an abnormal vitamin Dmetabolism. In adults osteopenia is generally

seen.



DISTAL RTA

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 acidemia. The serum HCO3- levels

are very low <12 meq/l. I t 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.



A summar y of the causes of dRTA (type I) is as f ollows: Primary ±

Idiopathic, isolated, and spor adic

Tubulointerstitial conditions ±

Renal tr ansplantation, chronic pyelonephr itis, obstr uctive uropathy, and

leprosy

Genetic ±

Familial, Mar fan syndrome, Wilson disease, Ehlers-Danlos syndrome,

medullar y cystic disease (dRTA and pRTA), and osteopetrosis

Conditions associated with nephrocalcinosis ±

Hyperoxalur ia, pr imar y hyper calciur ia, hyper thyroidism, pr imar y

hyperpar athyroidism, vitamin D intoxication, milk-alkali syndrome, and medullar y sponge kidney



Autoimmune disorders ±

Chronic active hepatitis, pr imar y biliar y cirr hosis,

Sjögr en syndrome (dRTA and pRTA), systemic lupuser ythematosus, autoimmune thyroiditis, pulmonar y

fibrosis, and vasculitis

Drugs and toxicity ±

Amphoter icin B, analgesics, lithium, toluene, if osfamide (dRTA and pRTA)

Hypergammaglobulinemic states ±

Myeloma (both dRTA and pRTA), amyloidosis (dRTA

and pRTA), and cr yoglobulinemia Miscellaneous - Hepatic cirr hosis and acquir ed

immunodeficiency syndrome (AIDS) (possibly)



The most common causes in adults are

autoimmune disorders, such as Sjögren's

syndrome, and other conditions associated

with chronic hyperglobulinemia.

In children, type 1 RTA is most often a

primary, hereditary condition.



Secretory defects causing Distal RTA



Non secretory defects causing Distal RTA

Gradient defect: backleak of secretd H+

ions. Ex. Amphotericin B

Voltage dependent defect: impaired distalsodium transport ex. Obstructive uropathy,

sickle cell disease, CAH, Lithium and

amiloride etc.

This form of distal RTA is associated with

hyperkalemia(Hyperkalemic distal RTA)



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 distalhydrogen ion secretion.

Serum potassium is reduced in 50% of

patients. This is thought to be from increasedkaliuresis to offset decreased H+ and H-K-ATPase activity.



Type 4 RTA (Hyperkalemic RTA)

This disorder is characterized by modestHCMA with normal AG and association withhyperkalemia.

This condition occurs primarily due todecreased urinary ammonium excretion.

Hypoaldosteronism is considered to be the

most common etiology. Other causes include NSAIDS, ACE inhibitors, adrenalinsufficiency etc.



Mechanism of action





In contrast to hyperakalemic distal RTA, the

ability to lower urine ph in response to

systemic acidosis is maintained.

Nephrocalcinosis is absent in this disorder.



OBJECTIVES

Physiology of Renal Acidification.



Treatment



Lab 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 HCO3- losses and

who is not taking acetazolamide or ingesting

exogenous acid.



Functional evaluation of proximal

bicarbonate absorption

Fractional excretion of bicarbonate

Urine ph monitoring during IV administration

of sodium bicarbonate. FEHCO3 is increased in proximal RTA >15%

and is low in other forms of RTA.



Functional Evaluation of Distal Urinary

Acidification and Potassium Secretion

Urine ph

Urine anion gap

Urine osmolal gap Urine Pco2

TTKG

Urinary citrate



Urine ph

In humans, the minimum urine pH that can beachieved 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 toassess the distal acidification processadequately .

Urine sodium should be known and urine

should not be infected.



Urine Anion Gap

Urine AG = Urine (Na + K - Cl).

The urine AG has a negative value in most

patients with a 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.



Ther e ar e, however, two settings in which

the ur ine AG cannot be used.

When the patient is volume depleted with a ur ine sodium concentr ation below 25

meq/L.

When ther e is incr eased excr etion of

unmeasur ed anions



Urine osmolal gap

When the urine AG is positive and it is unclear

whether increased excretion of unmeasured

anions is responsible, the urine ammonium

concentration can be estimated from

calculation of the urine osmolal gap.

UOG=Uosm - 2 x ([Na + K]) + [urea

nitrogen]/2.8 + [glucose]/18.

UOG of >100 represents intact NH4 secretion.





TTKG

TTKG is a concentr ation gr adient between the tubular fluid at the end of the cor tical collecting tubule and the plasma.

TTKG = [Ur ine K ÷ (Ur ine osmolality /

Plasma osmolality)] ÷ Plasma K. Nor mal value is 8 and above.

Value <7 in a hyper kalemic patient indicateshypoaldosteronism.

This f or mula is r elatively accur ate as long as the ur ine osmolality exceeds that of the plasma ur ine sodium concentr ation is above 25 meq/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 andUTI.



OBJECTIVES




Treatment







OBJECTIVES




Treatment



Treatment

Proximal RTA

A mixture of Na+ and K+ salts, preferably

citrate, is preferable.

10 to 15 meq of alkali/kg may be required per

day to stay ahead of urinary losses.

Thiazide diuretic may be beneficial if large

doses of alkali are ineffective or not well

tolerated.



Distal RTA

Bicarbonate wasting is negligible in adults who can

generally be treated with 1 to 2 meq/kg of sodium

citrate (Bicitra) or bicarbonate.

Potassium citrate, alone or with sodium citrate(Polycitra), is indicated for persistent hypokalemia or

for calcium stone disease.

For patients with hyperkalemic distal RTA, high-

sodium, low-potassium diet plus a thiazide or loop

diuretic if necessary.



Hyperkalemic RTA

Treatment and prognosis depends on theunderlying cause.

Potassium-retaining drugs should always bewithdrawn..

Fludrocortisone therapy may also be useful inhyporeninemic hypoaldosteronism, preferablyin combination with a loop diuretic such asfurosemide to reduce the risk of extracellular fluid volume expansion.

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Renal Tubular Acidosis_SUNIL

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