Presentor- Dr. Bikramjit Singh JafraModerator- Dr. V.R. Anand

Co-Moderator- Dr. Ankit Mangla

ENUMERATE RENAL TUBULAR FUNCTIONS,TESTS TO EVALUATE TUBULAR DISORDERS & MGT OF A CHILD WITH RTA

RENAL TUBULAR FUNCTIONS

RENAL TUBULAR FUNCTIONSWater and electrolytes are freely filtered at

glomerulusThe electrolyte content of ultrafiltrate “At the beginning of the PCT = that of plasma”Tubular reabsorption vs tubular secretion

determine the final water content and electrolyte composition of urine

Movement of solute in nephronBulk movement in proximal portionsFine adjustments in distal portions

RENAL TUBULAR FUNCTIONS cont…Responsible for the reabsorption of more than 99% of the

water and sodium in the ultrafiltrate.65% of sodium and water is reabsorbed by the proximal tubule25% by thick ascending limb of Loop of Henle5% by distal convoluted tubule2-3% by the cortical collecting tubule

Regulate acid-base balanceMineral homeostasisExcretion of organic acids and drugsHas specialized transporters and channels located in the

Tubular cell membranesApical memb.Basolateral side (interstitial side)

NORMAL GLOMERULUS

Kidneys contribute to acid–base balance byReabsorption of filtered HCO3 Excretion of H+

Because loss of filtered HCO3 − is equivalent to addition of H+ to the body, all filtered bicarbonate should be absorbed before dietary H+ can be excreted.

Reabs. of filtered bicarbonate 85% in PCT15% in the distal segments (thick ascending

limb and outer medullary collecting tubule)

NORMAL URINARY ACIDIFICATION

The renal acid-base homeostasis may be broadly divided into two processes:

1. Reabsorption of filtered HCO3In the proximal convoluted tubule

2. Excretion of fixed acids Through the titration of urinary buffers and the

excretion of ammonium, which takes place primarily in the distal nephron

Physiology Of Renal Acidification

H+ from water is secreted by the Na+-H+ exchanger on the luminal membrane

H+ combines with filtered HCO3- resulting in the formation of H2CO3, which splits into H2O and CO2 in the presence of carbonic anhydrase IV

CO2 diffuses freely back into the cell, combines with OH− (from H2O) to form HCO3− in the presence of carbonic anhydrase II, and returns to the systemic circulation via a Na+-HCO3− cotransporter situated at the basolateral membrane of the cell

In the collecting tubule, H+ is secreted into lumen by H+ATPase

HCO3− is returned to the systemic circulation by the HCO3–-Cl− exchanger located on the basolateral membrane

The H+ secreted proximally and distally in excess of the filtered HCO3− is excreted in the urine either as titratable acid or as NH4+

RENAL TUBULAR ACIDOSIS

Comprises a gp of tubular transport defects charac. by inability to appropriately acidify the urine with resultant met. ac.

Normal anion gap (hyperchloremic) metabolic acidosis in the setting of normal or near-normal glomerular filtration rate

In contrast, the term “UREMIC ACIDOSIS” is applied to patients with low GFR in whom metabolic acidosis is accompanied by normo- or hypochloremia and an increased plasma anion gap

DEFINITION OF RTA

Type 1 (Distal)Type 2 (Proximal) isolatedMultiple/Global tubular dysfunction (Fanconi

syn.)Type 3 (Combined)Type 4 (Hyperkalemic)

TYPES OF RTA

Prox tubule defectType 2= Bicarbonate reabs defectLoss in urine of

NaKHCO3ClUric acidPO4 (Rickets)

B’cause distal acidification mech is intact, so H+ is sec in urine

pH of urine <5.5 (acidic)

RTA TYPE II

CAUSES OF PROXIMAL RTA(type2)Primary Sporadic Inherited

Inherited renal disease (idiopathic Fanconi)

Sporadic (mc), AD,AR X-linked (Dent disease)

Inherited syndromes Cystinosis Tyrosinemia type 1 Galactosemia Oculocerebral dystrophy

(Lowe syndrome) Wilson disease

Hereditary fructose intolerance

Secondary Intrinsic renal disease

Autoimmune diseases (Sjögren syndrome)

Hypokalemic nephropathy Renal transplant rejection

Hematologic disease (Myeloma) Drugs

Gentamicin Cisplatin Ifosfamide Sodium valproate

Heavy metals Lead Cadmium Mercury

Organic compounds (Toluene) Nutritional (Kwashiorkor) Hormonal (Primary

hyperparathyroidism)

Charac. by global dysfunc. of prox. tub.GlycosuriaPhosphaturiaGen. aminoaciduria

In addition impaired abs. ofWaterHCO3-NaKOrganic acids

Plasma conc of Glucose & aa are within N range, but those of PO4- are low

Cystinosis & use of Ifosamide are common causes among children

Fanconi's syndrome:

Extremely rare, ARFeatures of both type I and type II (juvenile RTA)Term Type 3 RTA was abandoned as the charac of

prox RTA were transient & acidosis was primarily d/t distal acidification defect

d/t Inherited carbonic anhydrase II deficiency (k/a Guibaud-Vainsel syn.)

CFOsteopetrosisRenal tubular acidosisCerebral calcificationMental retardation

Combined proximal and distal RTA(type3)

Distal tub defectType 1= Acid excretion defectB’cause distal tubule defective, so H+ not sec in lumenpH of urine >5.5Kidney sec K+ in place of H+ l/t hypokalemiaAs no H+ in lumen to bind to HCO3, so NaHCO3 is lost

in urineAs HCO3 lost, so kidney reabs. Cl- l/t hyperchloremiaHypercalciuria l/t stoneHypocitraturiaBone buffer (CaCO3) starts to combat chronic acidosis

l/t bone disease

RTA TYPE I

CAUSES OF DISTAL RTA(type1)Primary Sporadic Inherited

Inherited renal diseases AD/AR AR with early-onset

hearing loss AR with later-onset hearing

loss Inherited syndromes

associated with type I renal tubular acidosis

Marfan syndrome Wilson syndrome Ehlers-Danlos syndrome

Familial hypercalciuria

Secondary Intrinsic renal

Interstitial nephritis Pyelonephritis Transplant rejection Sickle cell nephropathy Lupus nephritis Nephrocalcinosis Medullary sponge kidney

Urologic Obstructive uropathy Vesicoureteral reflux Cirrhosis

Toxins or medications Amphotericin B Lithium Toluene Cisplatin

RTA + HyperK + Ability to appropriately acidify urineDefect

Impaired aldosterone poductionUnresponsiveness to aldosterone

AldosteroneStimulates H+ ATPaseStmulates K+ sec. in exchange for Na reabs by CD

EffectsNa lost in urineH2O lost in urineK+ not sec. (Hyperkalemia)H+ not sec. (Acidosis)

RTA TYPE IV

CAUSES OF TYPE IV RTAPrimary Sporadic Genetic

Hypoaldosteronism

Addison disease Congenital adrenal

hyperplasia Pseudohypoaldost

eronism (type I or II)

Secondary Urologic

Obstructive uropathy Intrinsic renal

Pyelonephritis Interstitial nephritis

Systemic Diabetes mellitus Sickle cell nephropathy

Drugs Trimethoprim/sulfamethoxazole Angiotensin-converting enzyme

inhibitors Cyclosporine Prolonged heparinization

Addison disease

APPROACH

Pointers towards renal tubulopathyFailure to thriveDelayed physical milestones and weaknessPolyuriaPolydypsiaResistant rickets (RTA type 2)Unexplained hypertensionConstipationCraving for salt & savory foods

When to suspect renal tubular disorders?

Historym/c complain:“my child is not growing”Other specific complaints include:

Polyuria Polydipsia Constipation Episodic weakness Gross hematuria and recurrent UTI’s Seizures and recurrent fevers

Antenatal and birth history Polyhydroaminos Premature delivery

Family history Similar complaints in siblings, renal stones and hearing impairment

H/O & EXM.

Physical examination:General appearance

“dehydrated” or malnourishedWeight and height percentiles (often below 5th percentile)Blood pressure

Low/normal- exception hypertension (monogenic) such as Liddle’s syndrome will have hypertension (Stage II)

RicketsP/A

Renal /abdominal massAmbiguous genitalia/ hyperpigmentationGeneralized hypotonia

H/O & EXM. Cont…

1st step= Complete urine exm.Specific gravity

Most children with salt wasting tubulopathy have sp.gr. of <1010 (dilute urine, corresponding to urine osm. of <300 mOsm/kg)

Children who can conc. their urine have sp. gr. of >1020 (Renal tubulopathy can be ruled out)

Urine pH <5.5 = distal tub. acidification mech. is intact

Proteinuria Even 1+ pr. in a dilute urine is significant

Glycosuria In abscense of Hypergycemia indicates Fanconi syn

Microscopy RBCs & Ca oxalate (as in hypercalciuria)

INVESTIGATIONS

Confirm the presence of a normal anion gap metabolic acidosis

Identify electrolyte abnormalitiesAssess renal functionR/o other causes of bicarbonate loss such as diarrheaBlood anion gap [Na+] − [Cl− + HCO3−]<12 = Absence of an anion gap>20 =Presence of an anion gapIf such an anion gap is found, then R/O other diagnoses

Lactic acidosis IEMToxins

APPROACH cont…

Urinary anion gap (uAGAP) (U Na+ + U K+) - U Cl-Normal uAGAP is 0 +/- 5 mΣq/L and reflects the urinary

concentration of ammoniumIn distal acidification defect of dRTA, urinary ammonium

excretion is decreased and hence, the uAGAP will be positive

In contrast, a negative uAGAP indicates presence of ammonium and an intact distal acidification mechanism as seen with diarrhea (urinary chloride excretion is higher than the sum of sodium and potassium since the increased urinary ammonium in urine has to bind with negatively charged chloride ions to be excreted)

Spot urine for calcium and creatinine ratioAssist in evaluation of hypercalciuria in

dRTASome forms of Bartter’s syndromeDent’s disease

Normal ratio is age dependant< 0.8 in infants below 6 months<0.5 in 6 months – 18 months< 0.20 in >18 months age

Abdominal ultrasonography:NephrocalcinosisHydronephrosisHydroureterPost void residual urine

S. magnesium concentrationS. PTH assay (for Rickets)Urinary acidification tests

TREATMENT

The mainstay of therapy in all forms of RTA is bicarbonate replacement

Patients with pRTAOften require large quantities of bicarbonate,

up to 20 mEq/kg/24 hr, in the form of sodium bicarbonate or sodium citrate solution

Patients with Fanconi syndromeUsually require phosphate supplementation

MGT OF A CHILD WITH RTA

Patients with dRTABase requirement is generally in the range of 2-4

mEq/kg/24 hr, although patients’ requirements varyShould be monitored for the development of

hypercalciuriaPt with symptomatic hypercalciuria (recurrent episodes of

gross hematuria), nephrocalcinosis, or nephrolithiasis can require thiazide diuretics to decrease urine calcium excretion

Patients with type IV RTARequire chronic treatment for hyperkalemia with sodium

potassium exchange resin (Kayexalate)

MGT OF A CHILD WITH RTA cont…

Depends on associated diseaseGood with therapyPatients with treated isolated proximal or

distal RTA generally demonstrate improvement in growth, provided serum bicarbonate levels can be maintained in the normal range.

Patients with systemic illness and Fanconi syndrome can have ongoing morbidity

PROGNOSIS

Nephrocalcinosis, nephrolithiasis (type I)Hypercalciuria (type I)Hypokalemia (type I, type II if given

bicarbonate)Hyperkalemia (type IV, some causes of type I)Osteomalacia (type II due to phosphate

wasting)

COMPLICATIONS

REVISION

Children with RT disorders present with polyuria, polydipsia, delayed physical milestones and inadequate growth

Detailed h/o along with appropriate investigations can often lead to a specific diagnosis

Majority of children can be treated with simple medications

Early diagnosis (preferably before 2 years age) can minimize the morbidity and improve growth of these children

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