RENAL TUBULAR ACIDOSIS

RENAL TUBULAR ACIDOSISDR MAHTABMBBS,DCH,DNB GMSH 16 CHD

DEFINITION RTA IS DISEASE STATE CHARECTERIZE BY NORMAL ANION GAP , METABOLIC ACIDOSIS IN SETTING OF NORMAL OR NEAR NORMAL GFR.

RENAL TUBULAR ACIDOSIS

First described clinically in 1935Confirmed as a renal tubular disorder in 1946Designated as RTA in 1951

1/28/20174Normal pH 7.35-7.45Narrow normal rangeCompatible with life 6.8 - 8.0 ___/______/___/______/___ 6.8 7.35 7.45 8.0AcidAlkaline

Basic terminology:CLINICAL TERMINOLOGYCRITERIANORMAL pH

Acidemia

Alkaemia

Normal PaCO2

Respiratory acidosis (failure)

Respiratory alkalosis(hyperventilation)

Normal HCO3

Metabolic acidosis

Metabolic alkalosis

7.4(7.35-7.45)

pH < 7.35

pH > 7.45

40(35-45mmHg)

PaCO2 >45mm Hg and low pH

PaCO2 20 is highly suggestive of presence of anion gapFor every mEq of bicarb loss there is equal increase in serum chloride levels so anion gap remains within normal rangeWhat is anion gap?

INCIDENCEPredominant age: All ages

Predominant sex: Male > Female (with regard to type II RTA )

TYPESDistal /classical type 1 RTAProximal / type 2 RTAHyperkalemic RTA / type 4 RTAType 3 ( combined proximal and distal RTA )

Type 1-Distal RTADistal RTA (dRTA) is the classical form of RTA. Inability of the distal tubule to acidify the urine. Due to impaired hydrogen ion secretion, increased backleak of secreted hydrogen ions, or impaired sodium reabsorption Urine pH >5.5.

PATHOPHYSIOLOGYIMPAIRED H+ EXCRETION AT DISTAL TUBULES.DAMAGED AND IMPAIRED FUNCTIONING OF ONE OR MORE TRANSPORTER OR PROTEIN Eg H+/ATPase, H+/K+ ATPase, hco3-/cl- anion exchanger Inability to secrete H+ is compensated by secretion of k+ so HYPOKALEMIA DEVELOP

HYPERCALCINURIA IS USUALLY PRESENT LEAD TO HYPERCALCINURIA LEDS TO NEPHROCALCINOSIS OR NEPHROLITHIASISCHRONIC METABOLIC ACIDOSIS IMPAIRE URINARY CITRATE EXCRETION LED TO HYPOCITRATURIA WHICH FURTHER INCREASE RISK OF CALCIUM DEPOSITION IN TUBULES.

excretedHCO3-

Distal RTA or RTA type 1Acidification defectH+

K+

Cl-

Secretory defects causing Distal RTA

Non secretory defects causing Distal RTAGradient defect: backleak of secreted H+ ions. Ex. Amphotericin BVoltage dependent defect: failure to generate and maintain an appropriate electrical gradient to favour h+ secretion ; hyperkalemic distal RTAimpaired distal sodium reabsorption ex. Obstructive uropathy, sickle cell disease, CAH, Lithium and amiloride etc.This form of distal RTA is associated with hyperkalemia (Hyperkalemic distal RTA)

RISK FACTORS and etiologyGeneticsAutosomal dominant or recessive. May occur in association with other genetic diseases (e.g., Ehlers-Danlos syndrome, hereditary elliptocytosis, or sickle cell nephropathy). The autosomal recessive form is associated with sensorineural deafness.

PRIMARY Sporadic or inherited (AR ,AD FORM ) AR A/W EARLY ONSENT OR AR A/W LATE ONSET SNDSYNDROME A/W TYPE 1 RTA MARFAN SYNDROMEWILSON DSEHLER DANLOS SYNDROME

SECONDARY CAUSE INTRINSIC RENAL DISEASE : INTERSTITIAL NEPHRITIS,PYELONEPHRITIS,TRANSPLANT REJECTION,SICKLE CELL NEPHROPATHY,LUPUS NEPHRITIS,NEPHROCALCINOSISUROLOGICAL : OBSTRUCTIVE UROPATHY,VUR,HEPATIC,CIRRHOSISTOXIN AND MEDICATION :AMPHOTERICIN B,LITHIUM,CISPLATIN,TOULENE

CLINICAL MANIFESTATIONSnon-anion gap metabolic acidosisgrowth failure ,ftt,polyuria,polydipsiaNephrocalcinosis,renal stonehypercalciuria hypokalemia - muscle weakness,neck flopiness,transient paralysisAR d RTA HAVE SENSIRINEURAL DEAFNESS, OVALOCYTOSIS,HEMOLYTIC ANEMIAAD d RTA PRESENT IS OLDER AGE OR DURIN ADULTHOOD WITH MILDER DISEASE

Type 2-Proximal RTADefect of the proximal tubule in bicarbonate (HCO3) reabsorption. Urine pH 15%)with administration of alkali for correction of acidosis

ETIOLOGY AND RISK FACTORMost cases occur as a part of Fanconis syndromeIsolated proximal RTA is rare. FANCONI SYNDROME IS CHARECTERISE BY GENERALISED PROXIMAL TUBULAR DYSFUNCTIONClinical manifestations -phosphaturia,glycosuria, aminoaciduria, uricosuria, and tubularproteinuria. The principal feature of Fanconi's syndrome is bone demineralization due to phosphate wasting.

RISK FACTORS

CAN BE INHERITED, PERSISTENT FROM BIRTH,AS COMPONENT OF FANCONI SYNDROMECAUSE OF P RTA IS MAY AR CONDITION LIKE CYSTINOSIS,LOWE DS,GALACTOSEMIA,WILSON DS, HEREDETARY FRUCTOSE INTOLERANCE ETC

Common Causes of TYPE II RTA

CLINICAL MANIFESTATIONSgrowth failure in the 1st year of lifepolyuriadehydrationanorexiavomitingconstipationhypotoniaPatients with primary Fanconi syndrome will have additional symptomsThose with systemic diseases will present with additional signs and symptoms specific to their underlying disease

CLINICAL FEATUREPatients with pRTA rarely develop nephrocalcinosis 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 D metabolism. In adults osteopenia is generally seen.

Mutation in CTNS gene(17p)--encodes novel protein:cystinosin(H+ driven cystine transporter)

Defect in metabolism of cystine

Accumulation of cystine crystals in major organsKidney, brain ,liver, eye,others

Cystinosis ( classic ex. Of Fanconi syndrome)

3 CLINICAL FORMInfantile /Nephropathic cystinosis-1st 2 years of life-severe tubular dysfuntion-if no t/t then ESRD till first decadeAdoloscents-mild-slower progression to ESRDBenign adult form with no kidney involvementForms

Diminished pigmentation: fair and blondFanconi syndrome: polyuria, polydipsiaGrowth failureRicketsFever: dehydration and decreased sweat productionOcular: photophobia, retinopathy, impaired visual acuityHepatosplenomegaly, delayed sexual maturation, hypothyroidismComplications: CNS abnormalities, muscle weakness, swallowing dysfunction, pancreatic insufficiency.Clinical Features of cystinosis

Diagnosis:1.Detection of cystine crystals in cornea2.Increased leukocyte cystine content3.Prenatal diag by CVS,amniocentesis

Diagnosis & Treatment

Early initiation of therapy is important.correcting the metabolic abnormalities associated with Fanconi syndrome or chronic renal failure. SPECEFIC THERAPY : cysteamine,which binds to cystine and converts it to cysteine: facilitates lysosomal transport and decreases tissue cystine.cysteamine eyedrops is requiredgrowth hormone for growth failureRENAL TRANSPLANTATION FOR RENAL FAILURE

Mutation in OCRL1 of X chromosome(XLR)

Encodes PIBPase in golgi network

Accumulation of PIBP(phosphatidylinisotol polyphosphate 5 phosphatase protein)

1.Changes in protein trafficking2.Defective actin cytosleleton polymerization3.Altered cell signalling for endocytosisLowe Syndrome (oculocerebral syndrome of lowe)

Clinical feature :progressive growth failure present in infancy, hypotonia, fanconi syndrome,significent proteinuria,blindness, renal insuffiiency often develop, charecteristic behavioural abnormalities (tantrum,stereotypic movement ,obsession etc

Clinical FeaturesHypotonia with hyporeflexiaSevere psychomotor retardartionBilateral cong CataractStrabismusInfantile onset GlaucomacheloidsFrontal bossingDeep set eyesChubby cheeksFair complexionRachitic rosaryFanconi syndrome

Diagnosis is clinical,molecular testing for OCLR gene is available.Prenatal Dx: slit lamp examination of mother(punctate white opacities)Treatment is symptomatic No specific therapy for renal ds and neurological deficit-cataract extraction-glaucoma control-physical and speech therapy-drugs to address behavioral problem.Diagnosis & Treatment

Type 3 RTA-Combined proximal and distal RTAExtremely rare autosomal recessive syndrome with features of both type I and type II (juvenile RTA).

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RTA IVRESULT FROM IMPAIRED ALDOSTERONISM PRODUCTION (HYPOALDOSTERONISM)OR ,IMPAIRED RENAL RESPONSIVINESS(PESUDO HYPOALDOSTERONISM)End organ target failure or low aldosterone:Loss of sodium hyponatremiaRetention potassium - hyperkalemiaAbsorption of chloride hyperchloremiaDecreased excretion of acids metabolic acidosisLoss of fluid - dehydration

Type IV RTA

ACUTECHRONICOBSTRUTIVE UROPATHYACUTE PYELONEPHRITISACUTE URINARY OBSTRUCTION

ALDOSTERONE UNRESPONSIVENESSACIDOSISHYPERKALEMIA

ETIOLOGYMedications: Nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, heparin/LMW heparin, calcineurin inhibitors (tacrolimus, cyclosporine) (1)Diabetic nephropathyObstructive nephropathyNephrosclerosis due to hypertensionTubulointerstitial nephropathiesPrimary adrenal insufficiencyPseudohypoaldosteronism(end-organ resistance to aldosterone)Sickle cell nephropathy

Clinical FeaturesGrowth failure(7.5 ,AND PLASMA HCO3- >22 TO 24 mEq/L

FRACTIONAL EXCRETION OF HCO3 AND URINE TO BLOOD CO2 GRADIENT ARE MEASURED.

DIAGNOSTIC APP TO RTA1. FIRST STEP CONFIRM PRESENCE OF NON ANIONIC GAP METABOLIC ACIDOSISIDENTIFY ELECTROLYTE ABN ,ASSESS RENAL FUNCTION,R/O OTHER CAUSE OF HCO3 LOSS EG DIARRHOEA (EXTREMELY COMMON) IN SUCH CASE DX SHOULD BE DELAYED FR FEW DAYSsERUM ELECTROLYTE,BUN ,CALCIUM,PHOSPHORUS,CREATININE,PH - VENOUS PUNCTURE IF AG IS PRESENT R/O LACTIC ACIDOSIS,IEM,TOXIN INGESTION

CONFIRM NON AG METABOLIC ACIDOSISURINARY PH 6 D RTAURINE ANION GAP POSITIVE GAP - DRTA NEGATIVE GAP - P RTAURINEANALYSIS OBTAINED TO DETERMINE PRESENCE OF GLYCOSURIA,PROTEINURIA,HEMATURIA, THESE SUGGEST MORE GLOBAL TUBULAR DAMAGE AND DYSFUNCTION RANDOM OR 24 HR URINE CALCIUM AND CREATININE MEASUREMENT WILL IDENTIFY HYPERCALCINEMIAUSG FOR STRUCTURAL ANOMALIES,OBSTRUCTIVE UROPATHY,NEPHROCALCINOSIS.

Approach to RTA

Ultrasound examination of a child with distal renal tubular acidosis demonstrating medullary nephrocalcinosis

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Radiology

TREATMENT MAINSTAY IS BICARBONATE REPLACEMENT ; P RTA 5- 20 eq /kg/24 hr D RTA 2-3 mEq/KG/24 hr Increased until bicarbonate level become normal ,alkali requirement decreases after age of 5 years but are required life long , correction of acidosis result in increase in the growth velocity.In form sod bicarbonate or sod citrate solution

D RTA 2-4meq /kg/24 hrFANCONI SYNDROME PHOSPHATE SUPPLIMENT D RTA - MONITOR FR HYPERCALCINURIA,IF SYMPTOMATIC HYPERCALCINURIA RECURRENT EPISODE OF HEMATURIA,NEPHROCALCINOSIS,NEPHROLITHIASIS REQUIRE THIAZIDE DIURETICS TO DECREASE CALCIUM EXCRETION

TYPE 4 RTA WITH CHRONIC HYPERKALEMIA REQUIRE SOD POTASSIUM EXCHANGE RESIN (KAYEXALATE)PROGNOSIS DEPEND UPON THE UNDERLUING CAUSE ISOLATED PROXIMAL RTA AND DISTAL RTAPT WITH SYSTEMIC ILLNESS AND FANCONI SYNDROME HAVING MORBIDITY Eg GROTH FAILURE,RICKETS,AND SIGN AND SYMP OF UNDERLYING DISEASE

Nelson Textbook of Pediatrics 20th editionPediatric Nephrology by RN Srivastava,A Bagga 6th editionReferences