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IPNA-ESPN teaching course "Pediatric nephrology: Evidence-based statements and open questions", Moscow, Russia, October 22-24, 2013. Symposium 1: WATER & ELECTROLYTE DISTURBANCES IN CHILDREN WITH CKD
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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