Renal Tubular Disorders Management demystified

Dr. Atul Deokar M.D Pediatrics

Introduction


Glomerulus produces an enormous volume of ultrafiltrate daily Tubules modify the UF by selective reabsorption and secretion of various solutes to maintain body homeostasis

Classification of renal tubular disorders Primary or Secondary

PRIMARY INHERITED OR SPORADIC  CYSTIC DISEASES PCKD (AR or AD), cortical cysts, nephronophthisis, medullary sponge kidney  DYSPLASTIC DISEASES Renal aplasia, dysplasia, MCDK (uni or bilateral)  HEREDITARY DISEASES WITH TUBULAR TRANSPORT DEFECTS Hartnup disease, Fanconi syn, Lowes syn, Cystinosis, Wilsons dis, Galactosemia, RTA (many types), Vit D resistant rickets, Nephrogenic Diabetes Insipidus

Classification Primary Inherited



HEREDITARY DISEASES WITH INTRARENAL DEPOSITION OF METABOLITES Fabrys disease, Hurler syndrome HEREDITARY DISEASES WITH LITHIASIS Hyperoxaluria, Xanthinuria, L- glyceris aciduria, Lesch- Nyhan syn, Cystinuria, Glycinuria MISCELLANEOUS Sickle cell anemia, Bartters syndrome, Total and partial lipodystrophy
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Classification - Secondary
 

  

PYELONEPHRITIS TUBULO - INTERSTITIAL DISEASES Infections, Drugs, NSAIDs, antibiotics, Radiation OBSTRUCTIVE UROPATHY HEAVY METAL P Lead, Mercury, Cadmium ELECTROLYTE DISTURBANCE Hypokalemia, Hypercalcemia ENDOCRINE Glucocorticoid deficiency, Aldosterone deficiency or excess, ADH deficiency or excess
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Case 1
  

2yr 2 month old female child 2nd deg consanguinity Chief complaints - loose motions since 5 days - generalized weakness since 2 days for which she was hospitalized elsewhere for a day - h/o polyuria / nocturia

Case 1 Physical signs

  

 

8kg, Ht- 77cm, both below 3rd percentile Pallor, normothermic, no dehydration E/o rickets open AF, dental caries, rachitic rosary, widened wrists, double malleoli On enquiry, delayed eruption of teeth Cardiovascular and central nervous system examination not contributory

Case 1 - Investigations
Hb 8.0 g%, TC- 8200 BUN 7mg%, S. creatinine 0.5mg%, S. Na 132mEq/L, K 2.7mEq/L, Cl 107mEq/L Blood gas pH 7.295, pCO2 23.9, HCO3 12.7 Simultaneous urine pH 7.5 S. Ca 8.6mg%, P 3.5mg%, ALP 411 U X ray of left wrist frank rickets with cupping USG KUB increased parenchymal echogenicity of both kidneys
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US image shows early calcification lining the medullary pyramids

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Case 1 - Investigations
Urine spot calcium/ creatinine ratio 1.5 Urine glucose absent UAA normal Serum vitamin D levels normal

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Introduction to Renal Tubular Acidosis



RTA is a clinical syndrome in which either an inherited or acquired renal tubular defect leads to failure to maintain a normal plasma bicarbonate conc in the presence of a normal rate of acid production from diet and metabolism Clinically, it is characterized by a normal anion gap (AG), hyperchloremic metabolic acidosis (MA), bicarbonaturia, reduced urinary excretion of titrable acid and ammonia and an elevated urinary pH.
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Types of Renal tubular acidosis (RTA)



Type 1 RTA Distal RTA defect in hydrogen ion secretion by the distal tubule Type 2 RTA Proximal RTA defect in bicarbonate reabsorption by the proximal tubule Type 4 RTA Hyperkalemic RTA impaired distal nephron secretion of both H+ and K+ ions
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Distal RTA
Distal renal tubular acidosis (dRTA) was recognized as a distinct entity by Albright et al[1] in 1946. The clinical syndrome described consisted of hypokalemia, hyperchloremic metabolic acidosis, inability to lower urine pH below 5.5, nephrocalcinosis, and nephrolithiasis. Additional features included osteomalacia or rickets.
[1] Albright F, Burnett CH, Parson W: Osteomalacia and late rickets. the various etiologies .for each etiological subgroup, and the relationship between osteomalacia and Milkman's syndrome. Medicine 1946; 25:399-479

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PATHOPHYSIOLOGY
DEFECT IN H+ SECRETION CHRONIC MA DECREASED REABSORPTION OF NA+, K+ LEACHING OF BONE CAUSING OSTEOPENIA AND HYPERCALCIURIA SOLUTE DIURESIS NEPHROCALCINOSIS NEPHROLITHIASIS

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CLINICAL FEATURES


In infancyFailure to thrive, poor weight gain.  Recurrent vomiting.



May have episodes of life threatening metabolic acidosis precipitated by minor infections. In childhood- delayed physical milestones, short stature, rickets and bony deformities. Polyuria and polydipsia are constant features. Older children- myalgia, fatigue and muscle weakness.
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Clinical approach to classification of renal tubular acidosis (RTA) in patients with normal or low plasma potassium

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Classic dRTA- Treatment

Long-term treatment of classic dRTA requires  Alkali administration equivalent to the sum of endogenous acid production and amount of accompanying bicarbonate wastage. In general, total replacement therapy needed is 1 to 2 mEq/kg daily.  Greater amounts are required in children 8 to 10 mEq/kg 1. the need for base deposition in growing bone 2. bicarbonate wastage in children > in adults.  Maintenance of alkali therapy for an indefinite period is necessary.
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Classic dRTA- Treatment



In children, alkali therapy will allow normal growth and amelioration of hypokalemia, proximal myopathy, polyuria, and listlessness. Na citrate (Shohls solution) or Na bicarbonate is administered orally K supplementation may be necessary in few patients at 2 to 4 mEq/kg/day. This can also be given as modified Shohls solution containing Na and K citrate to treat both acidosis and hypokalemia
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Classic dRTA treatment & monitoring



Vitamin D should not be administered initially as it may precipitate nephrocalcinosis. When rickets persists despite sustained correction of acidosis, Vitamin D may be given Monitoring - Periodic blood gas estimation to maintain serum HCO3 between 22 24 mEq/L - height monitoring - Urinary calcium excretion - Serum Ca, P, Alk phos and Xrays for bone healing - Annual USG for nephrocalcinosis
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Medullary nephrocalcinosis minimally dense

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Medullary nephrocalcinosis - completely dense filling the medullary pyramids

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Type 1 Distal RTA Primary defect DCT & Collecting Tubule Age of onset Infancy and early childhood Defect in acid secretion AR, AD

Type 2 Proximal RTA PCT Premature babies (Immature kidneys) Defect in bicarbonate reabsorption AR

Pathogenic mechanism Inheritance CF polyuria, recurrent vomiting in both

FTT, impaired Growth retardation, feat growth and rickets of inher dis - cystinosis, galactosemia, GSD type1 Fanconi syndrome 29

Type 1 Distal RTA Type 2 Proximal RTA Serum HCO3Features c MA  Min UpH  Urine excrn K+ Ca++  U anion gap %FEHCO310 15mEq/L > 5.5 Increased Increased Positive < 3 5% Usually 15 20mEq/L < 5.5 N/Increased Normal Negative > 10 15% -/+ 5 10 Cysteamine in cystinosis Diet in galactosemia 30

Nephrocalcinosis ++ Oral bicarbonate to correct S pH (mEq/kg/day) 1 3 adult 4 15 child

Tests to differentiate dRTA and pRTA



Acid loading test - Oral administration of 0.1 g/kg NH4Cl. Record blood gas and urine pH before & hourly after the dose for 4 hours - Can produce severe acidosis Bicarbonate titration - Record urine pH & serum HCO3 during bicarbonate infusion - Requires strict adherence to protocol, cumbersome Oral bicarbonate or citrate - Gradually increase dose till s HCO3 reaches 22mEq/L - Larger doses (>5 mEq/kg/day) required in proximal RTA

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Hyperkalemic RTA (type 4)



These are disorders with defect in both H+ ion and K+ ion secretion in the cortical part of collecting tubule (CCT) caused by aldosterone deficiency or resistance Infants with type 4 hyperkalemic RTA present with
Severe failure to thrive Vomiting and dehydration due to salt wasting. S/S of the primary disease ambiguous genitalia and hyperpigmentation in CAH.

Older children may be asymptomatic.

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Type 4 RTA - INVESTIGATIONS & TREATMENT



Inv - Hyperchloremic metabolic acidosis with normal anion gap, Serum K+ - increased, Urine Ph < 5.5 in severe acidosis. Normal BUN and S Creatinine. USG abdomen for renal size and anomalies. Renin and aldosterone levels, other hormone assays17 OH Progesterone. Treatment - K+ restriction to control hyperkalemia. - Furosemide to increase K+ excretion. - Alkali therapy to correct metabolic acidosis. - Mineralocorticoid supplementation.
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Case 2


8 month old boy with chief complaints of failure to thrive, recurrent episodes of vomiting and polyuria. Hospitalised twice before for dehydration On examination, Child weighed 5.5 kg for a birth weight of 3 kg. He was normotensive, had no evidence of rickets, and systemic examination was normal.
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Case 2
Investigations revealed Hb -12.1g%, BUN - 8mg%, S. creatinine - 0.4 mg%, S. Na -131mEq/l, K -2.5mEq/l, Cl -90mEq/l, Blood gas pH - 7.52, HCO3 - 30mEq/l. Urinary chlorides 35mEq/l Blood levels of aldosterone are markedly increased.

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Bartters syndrome


These are a group of rare renal tubular disorders characterized by

Hypokalemia  Metabolic alkalosis  Severe hyperreninemia  Secondary hyperaldosteroism  Hyperplasia of the JGA  Increased urinary excretion of prostaglandins.  Normal blood pressure

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The three types of disorders encountered are1. Classical Bartters syndrome 2. Neonatal Bartters syndrome 3. Gitelmans syndrome.

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NaCl enters cell from lumen via an Na-2Cl-K cotransporter Na exits via Na,K-ATPase system

K is recycled into lumen via K channel to permit contus functioning of NKCC2 Cl leaves cell via Cl channel or in cotransport with K
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NaCl enters via NaCl cotransporter Na leaves by Na,K-ATPase system

Cl leaves by Cl channel at the basolateral membrane or K-Cl cotransporter at lumen

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CLINICAL FEATURES
 

History of maternal polyhydramnios and prematue delivery. Stormy neonatal course due to severe electrolyte and water disturbance including hypercalciuria During first 2 yrs of life      

Polyuria, Polydipsia Vomiting Salt craving Tendency to dehydration Failure to thrive Growth retardation , if early therapy not initiated.
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CLINICAL FEATURES ( Ctd.)



Late childhoodFatigue  Muscle weakness  Cramps  Recurrent episodes of carpopedal spasm



Most have a distinctive appearance



Thin, with small muscles, triangular face, prominent forehead, large eyes and drooping mouth.

 

ALWAYS NORMOTENSIVE. Often diagnosis suspected in an asymptomatic child with hypokalemia found in routine investigation.

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LABORATORY INVESTIGATIONS
   

Outstanding finding is HYPOKALEMIA (K between 1.5 and 2.5 mEq/L) Hypochloremia and metabolic alkalosis. Hypercalcemia and hypophosphatemia Increased fractional excretion of Na, K, Cl.
Urinary chloride is greater than 10 mEq/L .  Urinary K+ is more than 10 mEq/L despite hypokalemia.  Urin. Ca is more than 4 mg/kg/day in neonatal variant.


Blood levels of renin and aldosterone are markedly high.

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Genetics
Inherited disorder Type of Gene inheritance localization AR 15q15-21 Gene product

Neonatal Bartters type 1 Neonatal Bartters type 2 Classic Bartters type 3 Gitelmans syndrome

NKCC2

AR

11q24

ROMK

AR

1p36

ClC-Kb

AR

16q13

NCCT
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TREATMENT
 

Potassium supplementation in the form of KCl (1 to 3 mEq/kg/day or more) Use of prostaglandin synthetase inhibitors :
Indomethacin (2 to 5 mg/kg/day ) Ibuprofen (30mg/kg/day) Ketoprofen (20mg/kg/day)

Indomethacin is most freq used and well tolerated. S/E - nausea, vomiting, abdominal pain, peptic ulcer, renal dysfn Maintenance of indomethacin therapy essential during surgical procedures.
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Summary


Variety of renal tubular disorders, few of them with single gene defects Apart from growth retardation & rickets, symptoms include frequent GI symptoms, anemia and proximal muscle weakness Finding of a normal BUN/ S. creatinine does not exclude a serious renal disorder

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Summary


Screening tests should include blood gases, serum electrolytes, s. calcium, phosphorus, alkaline phosphatase, urine specific gravity or osmolality, 24 hour urine volume and USG KUB Specialized tests may be needed after review by a pediatric nephrologist to arrive at the precise diagnosis and institute specific management

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THANK YOU
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