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Home , Aminoaciduria, Anion gap, Bartter syndrome, Bicarbonate, Dehydration, Diabetes insipidus

Symposium on Pediatric

Approach to Renal Tubular Disorders

Arvind Bagga, Anurag Bajpai and Shina Menon

Department of , All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

Abstract. The renal tubule plays an important role in fluid and . Renal tubular disorders may affect multiple (e.g., ) or specific (e.g., nephrogenic insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders (focal segmental , , Lowe syndrome). Tubular dysfunction should be considered in all children with , , refractory , and metabolic . Careful clinical and laboratory evaluation is essential for appropriate diagnosis and specific management of these conditions. [Indian J Pediatr 2005; 72 (9) : 771-776] E-mail : [email protected]

Key words: ; Polyuria;

Renal tubules play an important role in fluid, electrolyte osmolality, and excretion of , , sugar and - homeostasis. Normal of and . These tests provide information on renal electrolytes, , calcium, , tubular handling of , , and and aminoacids and secretion of protons occur in various calcium, and ability to concentrate and acidify . specialized parts of the renal tubule. Renal tubular Depending on the clinical profile, abnormal screening disorders manifest with dysfunction that might be focal or tests are followed up with tests for specific tubular generalized. Important tubular functions and disorders functions and evaluation for a possible underlying associated with their dysfunction are shown in table 1. condition. The dysfunction may be secondary to a glomerular Tests for Urinary Acidification (e.g., focal segmental glomerulosclerosis) or be a primary defect in tubular function. Distinction between Renal tubular acidosis (RTA) and are important primary and secondary causes and precise causes of in children. These disorders characterization of the disorder is necessary for specific can be readily differentiated from most other causes of treatment. metabolic acidosis by estimation of the plasma . The following tests are useful in diagnosis and Features Suggesting Tubular Disorders characterization of RTA. Considering the spectrum of tubular functions, these Plasma anion gap: Anion gap represents the difference of disorders result in varied manifestations emphasizing the unmeasured anions and cations in the plasma, and is need for their consideration in many clinical conditions1 . measured as follows: Non-specific features mandate the need for high index of 2 + – – suspicion for these disorders . Tubular dysfunction Anion gap = Na – (Cl + HCO3 ) should be considered in all children with failure to thrive, The normal value of the plasma anion gap is 10-12 mEq/ polyuria, refractory rickets, hypokalemia and metabolic L. Accumulation of organic like lactate and acidosis (Table 2). acetoacetate, as in diabetic , and poisoning Assessment of Tubular Functions due to are characteristically associated with metabolic acidosis and an increased anion gap. Tubular function tests involve evaluation of functions of Normal anion gap in the presence of acidosis the (i.e., tubular handling of sodium, (hyperchloremic metabolic acidosis) suggests increased glucose, , calcium, bicarbonate and aminoacids) urinary (proximal RTA) or gastrointestinal loss (diarrhea) and distal tubule (urinary acidification and of bicarbonate or impaired excretion of H+ (distal concentration). The initial assessment of a child with RTA). suspected tubular disorder includes estimating levels of sodium, potassium, phosphate, pH and : Urine anion gap (net charge) (urine Na+ bicarbonate. Urine should be examined for pH and + K+ – Cl–) provides an estimate of urinary (NH +) excretion and is important in the evaluation of Correspondence and Reprint requests: Dr. Arvind Bagga, 4 Department of Pediatrics, All India Institute of Medical Sciences, hyperchloremic acidosis. Under normal circumstances, Ansari Nagar, New Delhi 110029, India. urine anion gap is positive due to the presence of

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TABLE 1. Common Disorders of Tubular Functions

Segment Function Disorder

Proximal tubule* Phosphate transport Hypophosphatemic rickets Glucose transport Renal glucosuria Aminoacid transport Isolated, generalized Bicarbonate transport Proximal RTA Ascending limb of Henle Sodium, potassium, transport Distal tubule Proton (H+) secretion Distal RTA Sodium, chloride transport Collecting duct Sodium, potassium transport Liddle syndrome transport Nephrogenic DI

*Generalized dysfunction of the proximal tubule (Fanconi syndrome) may be primary or secondary to various disorders (e.g., , Lowe syndrome) RTA renal tubular acidosis; DI

TABLE 2. Features Suggestive of Renal Tubular Disorders kg/day) (in order to achieve normal blood pH and bicarbonate, and urine pH > 7.4). Clinical • Growth retardation, failure to thrive Fractional excretion of bicarbonate: Fractional excretion • Polyuria, ; preference for savory of bicarbonate is a marker of proximal tubular handling of • Refractory rickets • Renal calculi, bicarbonate. The proximal tubule normally reabsorbs • Unexplained * almost all filtered bicarbonate (fractional excretion below 5%). A value greater than 15% indicates proximal RTA Laboratory • Hyperchloremic metabolic acidosis while levels are in the normal range in distal RTA. The • Metabolic with or without hypokalemia fractional excretion of bicarbonate should be calculated • with only after adequate alkalinization (see above). • Hypercalciuria with normal calcium urine bicarbonate × plasma Fractional excretion = × 100 * As in Liddle’s syndrome, syndrome of apparent mineralocorticoid of bicarbonate plasma bicarbonate × urine creatinine excess Tests for Phosphate Handling dissolved anions e.g., , phosphates. Metabolic + Phosphate homeostasis is chiefly regulated at the level of acidosis is associated with a compensatory rise in NH4 production, resulting in a negative urine anion gap. the proximal renal tubule. Plasma phosphate levels are + thus indicators of renal tubular handling. The fractional Patients with RTA typically show impaired renal NH4 excretion and a positive urine anion gap. excretion of phosphate determined on a timed (6-, 12- hr, 24-hr) urine specimen, is a widely used investigation Urine pH: Urine pH is an estimate of the number of free for phosphate handling. H+ ions in the urine which are secreted in response to metabolic acidosis. The presence of alkaline urine during urine phosphate x plasma creatinine Fractional excretion = × 100 metabolic acidosis suggests defective renal acidification, of phosphate (%) plasma phosphate × urine creatinine as in distal RTA.3 However, alkaline urine may also be found in patients with metabolic acidosis due to Tubular reabsorption of phosphate (%) = 100 - fractional excretion of extrarenal disorders, as in acute or chronic diarrhea. phosphate Occasionally, metabolic acidosis may need to be induced Tubular reabsorption of phosphate depends on plasma by oral administration of (0.1 g/kg) phosphate and glomerular rate and is not a before determining urine pH. This test is however satisfactory indicator of tubular phosphate handling. This cumbersome and not commonly used. has led to increasing use of ‘tubular maximum for phosphate corrected for GFR (TmP/GFR)’, a factor Urine to blood CO2 difference: Based on the observation that urinary CO excretion is an indicator of H+ secretion, independent of plasma phosphate and renal functions for 2 assessment of renal phosphate handling. TmP/GFR urine to blood CO2 difference is considered a satisfactory index of distal renal acidification. In the presence of (normal 2.8- 4.4 mg/dL) is an index of renal threshold for phosphate which can be determined by a nomogram4 (on normal blood bicarbonate, low urine to blood CO2 difference (< 10 mm Hg) suggests distal RTA; the levels timed urine samples) or directly as follows: are normal in proximal RTA (> 20 mm Hg). It is necessary urine phosphate × plasma that the difference be determined after adequate creatinine TmP/GFR (mg/dL) = Plasma phosphate — alkalinization with oral (2-4 mEq/ urine creatinine

772 Indian Journal of Pediatrics, Volume 72—September, 2005 Approach to Renal Tubular Disorders

Tests for Urinary Concentration of , with hyperkalemia attributed to an increased potassium load. Repeated early morning urine examination for osmolality or specific gravity should be performed in a child with TUBULAR SYNDROMES suspected urinary concentration defect. greater than 800 mOsm/kg (or specific gravity greater Tubular disorders can be classified into distinct than 1015) excludes a significant defect in urinary syndromes based on their presenting features. concentration. Individuals with low urine osmolality should undergo a water deprivation test after excluding Metabolic Acidosis and Hypokalemia RTA and chronic renal failure. The presence of low urine osmolality (< 300 mOsm/kg) in patients with elevated Hypokalemia is usually associated with metabolic (osmolality > 300 mOsm/kg, serum alkalosis. The occurrence of metabolic acidosis and sodium > 145 mEq/L) is diagnostic of diabetes insipidus. hypokalemia suggests RTA or gastrointestinal loss of Distinction between central (neurogenic) and nephrogenic bicarbonate (diarrhea, ureterosigmoidostomy). Distal diabetes insipidus is necessary, based on response to RTA is characterized by decreased proton excretion due administration of . Vasopressin can be to a proton pump defect or back diffusion of protons. The administered intranasally (10-20 µg) or subcutaneously (1- primary defect in proximal RTA is the reduced renal 3 µg) and the urine osmolality assessed at 1-2 hr. A rise in threshold for bicarbonate, resulting in bicarbonaturia. urine osmolality by more than 50% of baseline, one hour Proximal RTA may represent isolated or generalized after vasopressin administration, is diagnostic of central proximal tubular dysfunction; the latter (Fanconi diabetes insipidus; the increase of urine osmolality in syndrome) is characterized by bicarbonaturia, patients with nephrogenic diabetes insipidus is nil or phosphaturia, sodium and potassium wasting, glucosuria minimal. and aminoaciduria. Fanconi syndrome may be primary or frequently associated with inherited disorders like Wilson Water deprivation test: Patients with polyuria with no disease, galactosemia, cystinosis and Lowe syndrome. evidence of and normal serum sodium are kept off fluids for 6-8 hr, until exceeds 3% or Evaluation: The first step in the evaluation of a child with until 3 consecutive hourly urine osmolality values are hypokalemia and metabolic acidosis is to differentiate within 10% of each other. Urine osmolality more than 750 gastrointestinal bicarbonate loss from RTA. The presence mOsm/kg at the end of the evaluation is suggestive of of polyuria, preference for savory foods, failure to thrive . Osmolality less than 750 mOsm/kg and rickets, are suggestive of RTA. Gastrointestinal after water deprivation should be further evaluated after bicarbonate losses can be differentiated from RTA by administration of vasopressin. estimating the urine anion gap. Negative urine anion gap + indicates increased renal NH4 production (extrarenal Tests for Potassium Handling cause for metabolic acidosis), while positive gap suggests RTA. Once the diagnosis of RTA is established, it can be Renal tubular disorders may be associated with both categorized further (Fig. 1)5 . Children with proximal (type hypokalemia and hyperkalemia. Renal handling of 2) RTA should undergo evaluation for other proximal potassium depends on the total body content of the tubule functions (phosphate, electrolytes, glucose and , its daily intake, delivery of sodium and water to aminoacid excretion) and screening for an underlying the distal and the action of aldosterone. Random etiology (e.g., Wilson disease, cystinosis). Investigations in urine potassium exceeding 20 mEq/L in patients with children with distal (type 1) RTA include estimation of hypokalemia indicates renal potassium wasting. The urine calcium excretion, ultrasound for renal fractional excretion of potassium (FEK) may also be used and work-up for secondary causes (e.g., obstructive as an indicator of tubular function; FEK values exceeding uropathy, , chronic tubulointerstitial 40% (normal 10-20%) indicate tubular wasting. ). The action of aldosterone mediated sodium-potassium exchange in the distal renal tubule is evaluated by the Management: Management of RTA includes correction of transtubular gradient of potassium (TTKG), as given metabolic acidosis with bicarbonate supplements [sodium below: bicarbonate 7.5% (1 mEq/ml); Shohl (1 mEq/ml); urinary potassium × plasma Polycitra solution (2 mEq/ml)]. Bicarbonate requirement osmolality Transtubular gradient of potassium = is more in patients with proximal RTA (5-6 mEq/kg/day) plasma potassium × urinary osmolality compared to distal RTA (1-2 mEq/kg/day). Alkali therapy is usually combined with potassium replacement TTKG should be estimated when urinary osmolality to avoid severe hypokalemia. Potassium supplements in exceeds plasma osmolality; values below 5-7 in subjects patients with acidosis are usually administered as citrate with hyperkalemia imply impaired potassium secretion salts. Long-term potassium replacement is however not due to aldosterone deficiency or resistance. TTKG greater required in subjects with distal RTA. Patients with than 10 shall be found in patients with appropriate action proximal RTA often requires supplements of phosphate

Indian Journal of Pediatrics, Volume 72—September, 2005 773 Arvind Bagga et al

Hyperchloremic Metabolic Acidosis hypokalemic alkalosis. The presence of elevated suggests true (, glucocorticoid remediable aldosteronism, congenital adrenal hyperplasia) or apparent mineralocorticoid excess Urine net charge (Liddle syndrome, syndrome of apparent mineralocorticoid excess) (Fig. 2). These disorders can be classified further by determining blood levels of aldosterone and and assessing the response to Positive Negative treatment with and/or . Low RTA Diarrhea blood levels of aldosterone and lack of response to glucocorticoid and spironolactone is suggestive of Liddle syndrome. Bartter syndrome can be differentiated from Urine pH Gitelman syndrome by presence of hypercalciuria in the

FEbic former and hypomagnesemia in the latter. Urine - blood CO 2 , Hypokalemia

Urine chloride

Distal RTA Proximal RTA Urine pH > 5.5 Urine pH < 5.5 FE < 5% FE > 15% > 10 mEq/L bic bic < 10 mEq/L Urine-blood CO <10 mm Urine-blood CO >20 mm Renal loss 2 2 Extra-renal loss

Fig. 1. Approach to a patient with metabolic acidosis and hypokalemia. Urine net charge (urinary Na+ + K+ - Cl-) provides an estimate of renal ammonium production, differentiating between Nasogastric drainage renal and extrarenal causes of hyperchloremic acidosis. Record blood pressure Chronic use RTA renal tubular acidosis; FEbic Fractional excretion of bicarbonate

(Joulie solution, neutral phosphate solution) and small Normal doses of D. Specific therapy for an underlying High Bartter syndrome disorder (cysteamine for cystinosis, D-penicillamine for Hypomagnesemia Wilson disease and lactose free diet in galactosemia) is Gitelman syndrome possible in few patients. Follow-up includes regular assessment for growth and blood levels of electrolytes, Blood aldosterone pH and bicarbonate. Subjects with distal RTA are at risk for nephrocalcinosis, which should be screened for by ultrasound. Metabolic Alkalosis and Hypokalemia Normal Renal tubular causes of hypokalemia with alkalosis High Congenital adrenal hyperplasia* include a spectrum of conditions involving reduced Hyperaldosteronism Apparent mineralocorticoid excess electrolyte reabsorption (Bartter, Gitelman syndromes) or Liddle syndrome increased mineralocorticoid action (Liddle syndrome, Fig. 2. Approach to a patient with metabolic alkalosis and syndrome of apparent mineralocorticoid excess, hypokalemia. glucocorticoid remediable aldosteronism). These * Due to deficiency of the enzymes, 11β hydroxylase or 17α disorders should be differentiated from systemic causes hydroxylase including vomiting, hypomagnesemia, cystic fibrosis and diuretic use. Management : Treatment of Bartter syndrome consists of ensuring adequate hydration and potassium Evaluation: Initial evaluation should include history of supplementation (as chloride salts) along with upper gastrointestinal loss (vomiting and nasogastric indomethacin (2-4 mg/kg/day). Specific therapy with drainage), diuretic use and measurement of blood magnesium (50-100 mg/kg/day) in Gitelman syndrome pressure. Urine chloride helps in differentiating non-renal and in Liddle syndrome ameliorate biochemical (< 10 mEq/L)) from renal causes (> 20 mEq/L) of features of respective .

774 Indian Journal of Pediatrics, Volume 72—September, 2005 Approach to Renal Tubular Disorders

Hypercalciuria TABLE 3. Causes of Hypercalciuria

Patients with hypercalciuria may present with a variety of Secondary to Hypercalcemia features including renal stones and nephrocalcinosis, • , ‘frequency ’ syndrome, and abdominal • Inactivating mutations of the calcium sensing receptor pain. Hypercalciuria is defined as urinary calcium • excess • Granulomatous disorders - , excretion of more than 4 mg/kg/day. Calcium excretion may also be determined on spot urine samples; ratio of Without Hypercalcemia calcium to creatinine greater than 0.2 mg/mg beyond • Idiopathic hypercalciuria infancy is significant. Common causes of hypercalciuria • Distal RTA are shown in table 3.6 • Bartter syndrome • Therapy with loop , Evaluation: Initial evaluation of a patient with • Familial hypomagnesemia hypercalciuria includes estimation of blood levels of

Polyuria

Exclude RTA- pH, bicarbonate CRF- , creatinine Diabetes mellitus- Blood glucose, urine glucose

Urine osmolality Plasma osmolality

Plasma osmolality >300 mOsm/kg Plasma osmolality 290-300 mOsm/kg Urine osmolality < 300 mOsm/kg Urine osmolality < 750 mOsm/kg

Water deprivation

Urine osmolality

> 750 mOsm/kg < 750 mOsm/kg

Primary polydipsia Diabetes insipidus Vasopressin test

Rise in urine Rise in osmolality < 10% osmolality > 50% Nephrogenic DI Central DI Fig. 3. Approach to a patient with polyuria. DI diabetes insipidus

Indian Journal of Pediatrics, Volume 72—September, 2005 775 Arvind Bagga et al calcium, phosphate, creatinine, pH and bicarbonate. test should be done to distinguish between psychogenic Parathormone (PTH) and vitamin D (25-OH vitamin D) polydipsia and diabetes insipidus. levels should be estimated in patients with Management: Patients with nephrogenic DI benefit from hypercalcemia. treatment with indomethacin (2-3 mg/kg/day) and Management: The initial treatment for idiopathic diuretics. Solute restriction reduces renal solute hypercalciuria includes ensuring a high fluid intake and load and obligate water losses. Alkali replacement in restriction of dietary sodium and animal . patients with RTA and administration of indomethacin Administration of oral is beneficial in and potassium supplements in Bartter syndrome is reducing hypercalciuria and risk of formation of calculi. effective in reducing polyuria. Care must be taken to Dietary restriction of calcium intake is not only ineffective avoid dehydration; free access to fluids is necessary. but also harmful. A low calcium diet promotes oxalate reabsorption from the gut, resulting in its increased CONCLUSIONS urinary excretion (enteric ) and risk of forming calcium oxalate stones. Patients who do not should be aware of the protean clinical respond satisfactorily to the above treatment may benefit features of renal tubular disorders. Early recognition, from thiazide diuretics ( 1-2 mg/kg/ appropriate evaluation and specific management enable day). These cases should be monitored for relief of symptoms in many conditions. Patients need to dyselectrolytemia, and . All be followed up for prolonged periods for adequacy of patients should be regularly followed-up with estimation growth and renal functions. of urine calcium excretion and imaging for renal stones and calcification. REFERENCES Specific treatment for RTA and Bartter syndrome also 1. Rodriguez-Soriano J. Tubular disorders of electrolyte results in reduced excretion of urinary calcium. regulation. In Avner ED, Harmon WE, Niaudet P, eds. Polyuria Pediatric Nephrology. 5th edn. Baltimore; Lippincot Williams & Wilkins, 2004: 729-756. Polyuria (daily urine output > 2 L/m2) is a presenting 2. Van’t Hoff W. Renal tubular disorders. In Webb NJ, feature of a variety of tubular disorders including RTA, Postlethwaite RJ, eds. Clinical Pediatric Nephrology. 3rd edn. New York; Oxford Press, 2003: 103-112. resistance to the action of hormone (ADH) 3. Herrin TJ. Renal tubular acidosis. In Avner ED, Harmon WE, (nephrogenic diabetes insipidus) or aldosterone Niaudet P, eds. Pediatric Nephrology. 5th edn. Baltimore; (pseudohypoaldosteronism), and specific transport Lippincot Williams & Wilkins, 2004: 757-776. defects (Bartter and Gitelman syndromes).7 These 4. Walton RJ, Bijvoet OL. Nomogram for the derivation of renal disorders should be distinguished from other causes of tubular threshold concentration. Lancet 1975; 2: 309-310. 5. Postlethwaite RJ. The approach to a child with metabolic polyuria including diabetes mellitus, central diabetes acidosis or alkalosis. In Webb NJ, Postlethwaite RJ, eds. insipidus and . Clinical Pediatric Nephrology. 3rd edn. New York; Oxford Press, 2003: 61-72. Evaluation: The initial evaluation of patients with 6. Jones C, Mughal Z. Disorders of mineral and polyuria includes estimation of blood levels of glucose, nephrocalcinosis. In Webb NJA, Postlethwaite RJ, eds. Clinical electrolytes, pH, bicarbonate, calcium, creatinine and Pediatric Nephrology. 3rd edn. New York; Oxford Press, 2003: osmolality. Urine osmolality should be examined on an 73-102. early morning specimen. Patients with high plasma 7. Muglia LJ. Majzoub JA. Disorders of the . In osmolality (> 300 mOsm/kg) and low urine osmolality (< Sperling MA, eds. Pediatric Endocrinology. 2nd edn. Philadelphia; WB Saunders, 2000; 289-322. 300 mOsm/kg) have deficiency or resistance to the action 8. Diabetes insipidus. In Bajpai A, Sharma J, Menon PSN, eds. of ADH, which should be clarified further based on Practical Pediatric . 1st edn. New Delhi; Jaypee response to the hormone (Fig. 3).8 The water deprivation 2003: 17-23.

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