Acid-base disordersmetabolic acidosis

Elena Levtchenko

October 22, 2013

Outline of the lecture

• Renal regulation of acid-base homeostasis

• Diagnostic approach in patients with acidosis

• Renal tubular acidosis (RTA)– Distal renal tubular acidosis (dRTA), type 1– Proximal renal tubular acidosis (pRTA), type 2– dRTA with hyperkalemia, type 4

• Diagnostic algorithm in patients with RTA

• Take home message

Maintanance of acid-base homeostasis

• Aim: maintain arterial pH 7.35-7.45

• Metabolism: production of acids (Manz et al. 2004)

• Systems involved in pH regulation:

– Extracellular and intracellular buffering

– Lung: excretion of CO2

– KidneyBidani et al. 2002

Renal regulation of acid-base homeostasis

• Bicarbonate reabsorption (~4000 mmol/1.73 m2/24 hrs)

• Acids and ammonium (NH4+)

excretion

Net acid excretion (NAE)

NAE = NH4+ + TA – HCO3

_

TA: titratable acid

L. Lee Hamm et al. 2008

Renal proximal tubule (PT)

• Reabsorption of ~ 80 % HCO3

_

• Different transport rate and mechanism in S1, S2 and S3 (highest in S1)

• NHE 8 on the apical membrane (Goyal et al. 2003, 2005)

NHE 3,

amiloride sensitive

H+-ATP-ase

NBC1

3 Na+ Citrate 2-

L. Lee Hamm et al. 2008

Renal ammonium generation and transport

NH4+ generation in PT cells

RhCG (apical)

RhBG (basolateral)

(Knepper 2008)

L. Lee Hamm et al. 2008

Role of Rhesus factor proteins in renal ammonium excretion and male fertility

Rh-factor family of proteins: homology to ammonia (NH3) -transport proteins in bacteria, fungi, plants, invertebrates

Non-erythroid members (RhCG and RhBG) are expressed in the kidney

Rhbg -/- mouse model: no acid-base abnormalities (Chambrey et al. 2005)

Rhbc -/- mouse model (Biver et

al. 2008) :- reduced body weight - decreased urinary ammonium excretion- reduced urine acidification

capacity after acid load - reduced male fertility due to

impaired ammonia secretion in epididymus

(Knepper 2008)

Regulation of PT acid-base transport

Acidosis: insertion of NHE3 and H+-ATP-ase function of NBC1 (alkalosis: opposite

effects)

secretion of endothelin – 1

secretion of cortisol

K+: increases HCO3

_ reabsorption

PTH: acute effect: decreases HCO3

_ via

cAMP PKA phosphorylation of NHE 3 inhibition

chronic acidosis: PTH net acid excretion

ATII: increases HCO3

_ reabsorption

L. Lee Hamm et al. 2008

Thick ascending loop of Henle (TAL)

• Reabsorption of ~ 20 % HCO3

_

• Acidosis: increases HCO3

_

reabsorption, alkalosis: no effect

• Loop diuretics: increases HCO3

_

reabsorption

L. Lee Hamm et al. 2008

Cortical collecting duct (CCD)

intercalated cells intercalated cells

L. Lee Hamm et al. 2008

Regulation of CCD acid-base transport

• Acute acidosis: H+ secretion, HCO3

_ reabsorption in type A IC

• Chronic acidosis: HCO3

_ secretion in type B IC (some type B cells

transform into type A cells), role of hensin (Schwartz et al. 2005)

• Na CL _ : AE1 in type A IC, HCO3

_ secretion in type B IC

• K+: K + / H+ ATPase (K + reabsorption, H+ excretion), increase H+ATPase insertion to the apical membrane

• Mineralocorticoids: rapid nongenomic stimulation of H+ATPase (independent of Na +) (toevoegen genomic effects)

• ET-1: in acidosis increase of ET-1 in renal interstitium, HCO3

_ secretion

and Na +/ H+ exchange

• PTH: stimulates distal nephron acidification

Diagnostic approach in patients with acidosis

• Step 1: obtain arterial (capillary) blood gas

analysis and plasma HCO3

_, Na +, K +, CL

_

• Step 2: distinguish simple from mixed type acid-base disorders

• Step 3: calculate blood Anion Gap (AG):– AG = (Na+ + K +) - (CL

_ + HCO3

_ )

– AG: unmeasured anions in plasma (albumin, and globulins):

• 1 g/dl albumin 2.5 - 4 meq/L AG

– Ca2+, Mg2+, Li+ (intoxication) AG– High IgG (cationic) AG

• Step 4: calculate urine Anion Gap (AG):– AG = (Na+ + K +) - CL

_

Emmet et al. 2002

Clinical causes of high and normal AG acidosis

High AG acidosis Normal AG acidosis

KetoacidosisGastrointestinal loss of HCO3

_

negative urine AG: U (Na+ + K +) < U Cl -

diarrhea

Diabetic (acetoacetate)

Alcoholic (-hydroxybutyrate)Starvation

Renal tubular acidosis hyperchloremic, positive urine AG :U (Na+ + K+) > Cl -

Proximal tubular acidosis (pRTA)

Lactic acid acidosis Distal tubular acidosis (dRTA) (low K +)

Toxins

Acetazolamide, topiramate (inhibitor of CA)

Generalized distal renal tubular defect (high K +)

Ethylene glycol, propylene glycol, methylalcohol, salicylate

MiscellaneousNH4+Cl ingestionSulfur ingestion

Distal renal tubular acidosis: type 1 dRTA

• Dysfunction of intercallated cells ( IC or type A IC): failure to produce acid urine

• Clinical diagnosis: pH urine > 5.5 when arterial pH < 7.34, normal AG, normal GFR

• NH4+Cl loading (100 mg/kg): failure to reduce urine pH < 5.3 during the following 6 hrs (Wrong and Davis 1959)

• Other features: hypokalemia, metabolic bone disease, nephrocalcinosis, nephrolithiasis

• In adults: mostly secondary, associated with autoimmune disease (Sjögren syndrome) (Wrong et al. 1993)

• Children: inherited forms

Inherited forms of type 1 dRTA

Autosomal dominant dRTA (Karet et al. 2009)

• Mutations in AE1 ( SLC4A1 gene) (most common mutation: R588 (arginin) in 6th transmembrane domain

• Dominant-negative mechanism: depending on mutation’s sort : mutated AE1 prevents expression of wild-type AE1 on basolateral membrane, ER retention (Quilty et al. 2002, Toye et al. 2002)

• Expression on the apical membrane (R901X, G609R) (Devonald et al. 2003).

• More severe disease in these individuals (Rungroj et al. 2004)

Autosomal recessive dRTA (Karet et al. 2009)

• Mutations in 3 genes:

SLC4A1 gene (other mutations than in AD dRTA); in some kindreds in combination with hemolytic anemia

Mutations in H+ ATPase subunits

AR dRTA with deafness: mutations in B1-subunit (ATP6V1B1 gene) mutations: mostly loss of function. In inner ear: expression in cochlea and

endolymphatic sac (high K+ 150 mM and pH 7.4 due to H+ ATPase)

AR dRTA with late onset hearing loss:

Mutations in a4-subunit ATP6V0A4 gene) (expression kidney, cochlea)

Other genes?

CO2 + H2O

H+ + HCO3 -

CAII

CAII deficiency (McMahon et al. 2001)

Combination dRTA and osteopetrosis

Proximal renal tubular acidosis: type 2 pRTA

• Defect in PT capacity to reabsorb HCO3_

(Rodriguez Soriano 1967, 2002)

• Normal distal capacity to acidify urine

(urine pH < 5.5 when plasma HCO3_ < 15

meq/L)

• Patients maintain normal acid-base balance with HCO3

_ supplements

• Hypokalemia not always present (reduced PT fluid reabsorption, hyperaldosteronism, increased fluid and alcali delivery to distal nephron; mostly absent in metabolic acidosis and aggravated by base suppletion)

• Hypercalciuria/nephrocalcinosis: absent or less severe (Lemann et al. 2000)

Rodriguez Soriano et al. 1972

Proximal renal tubular acidosis: type 2 pRTA

NHE 3,

amiloride sensitive

H+-ATP-ase

NBC1

3 Na+ Citrate 2-

• Most commonly: part of generalized proximal tubular dysfunction (renal Fanconi syndrome), combined with aminoaciduria, glucosuria, phosphaturia, LMW proteinuria

• Isolated pRTANBC1 mutations (SLC4A4 gene):

AR, severe metabolic acidosis (pH 7.1-7.2), bicarbonate +10 mEq/L (Igarashi et al. 2002)

In acidotic state: urinary pH < 5.5; short stature, ocular abnormalities (glaucoma, cataract) in all patients; basal ganglia calcifications; abnormal dentitionMost mutants are retained in ER

CAII: osteopetrosis (also distal acidification defect), defective bone resorption by osteoclasts

NHE3 mutations: not yet idenitfied in humans; NHE3 KO mice: mild metabolic acidosis(Schultheis et al. 1998)

Transient pRTA of infants (Rodriguez Soriano 1967),

growth retardation, good responce to alcali therapy

Hyperkalemic renal tubular acidosis: type 4 dRTA

• Aldosterone action: – Na + reabsorption lumen negative potential

required for K+ and H+ secretion – Direct activation of distal H+ ATPase (Winter et al.

2004)

True hypoaldosteronism: hyporeninemic hypoaldosteronism (diabetes, amiloidosis, TIN due to NSAID), adrenal dysfunction, ACE inhibition, ATII receptor antagonists, inhibition of aldosterone synthesis by heparin (Kutyrina et al. 1987)

Functional hypoaldosteronism: antagonists of MR (spironolactone), ENaC blockers (amiloride, triamterene, trimethoprim), cyclosporine therapy (interference with basolateral Na +/ K+ ATPase, NKCC2 and distal K+ channels (Karet 2009)

Karet 2009

• Pseudohypoaldosteronism type 1 (PHA 1)– Renal Na+ waisting, hyperkalemia, hyponatremia and metabolic acidosis– Elevated renin and aldosterone levels– Mineralocorticoid receptor (MR) mutations:

• AD, haploinsufficiency (mutant RNA degraded) (Geller et al. 2009)

– ENaC mutations • AR, loss of function (alpha, beta, gamma subunits), extremely rare (Geller 2009)

• Pseudohypoaldosteronism type 2 (PHA 2) (Gordon syndrome)– Hyperkalemic hypertension associated with (mild) acidosis– Impaired removal of distal NaCl cotransporter in DCT and increased

expression of ENaC and decreased expression of ROMK in CD– Mutations in WNK 1 and 4 (with no lysine [K] kinase), regulating NCC, ROMK,

ENaC (Kahle et al. 2009)

Mendelian forms of type 4 dRTA

Hyperchloremic normal AG metabolic acidosis

Mesure urine AG(Na+K)-CL

Positive (CL < Na+K)Negative (Cl> Na+K)

pH< 5.5Nl of laag K+

pH> 5.5Nl of laag K+

pH < 5.5 Hoog K+

pRTAIncreased FE Bicarb (10-

15%)

dRTACheck for renal

stones and nephrocalcinosi

s

Type 4 RTA

Fractional excretion of bicarbonate

Decreased (< 5%) = gastro-intestinaal losses of bicarbonate (urine pH <6.5)

Fractional excretion of bicarbonate (%) ={[HCO3]u / [HCO3]p} x {Pcr / Ucr} X 100

Diagnostic algorithm in patients with RTA

Treatment of RTA

• Correction of acidosis:– Na or K citrate or bicarbonate supplements

• pRTA 10-15 meq/kg/day;• dRTA 2-4 meq/kg/day in 4 doses)

– Further treatment depending on the cause

Take home message

• In patients with acidosis: – Anamnesis (diarrhea, medication use, intoxication, family history)– Clinical examination (growth parameters, blood pressure, exclude autoimmune

disease, bone disease)– Arterial (capillary) blood gas analysis simultaneously with blood and urine

electrolytes, renal function, bicarbonate, albumin prior to alkali supplements– Follow steps 1-4 determine sort of metabolic acidosis (high AG or normal AG,

renal or extrarenal)

• Renal RTA– primary or secondary (medications, autoimmune disorder, other renal disease)– distal or proximal; low/normal K+ or high K+

– MAKE DIAGNOSIS (DNA analysis, genetic counselling)

– FOLLOW PATIENT (acidosis might be transient!)

Fons Sapientiae by Jef Claerhout