Factores de riesgo individuales

Cystinosis Dent disease Mitochondriopathies Fanconi-Bickel glycogenosis Tyrosinemia

Wilson disease Lowe syndrome Galactosemia

Hereditary fructose intolerance Idiopathic Fanconi syndrome

Therapeutic strategies 4

Fluids, NaCl, KCl, NaHCO3, PO4, calcitrol, carnitine, specific therapy, organic solute replacement unnecessary

Broad proximal tubular dysfunction 0

Phosphaturia (TRP <85% with low serum PO4) PRTA (bicarbonate therapy >3 mEq/kg/day) Aminoaciduria (quantitative urine amino acids) Tubular proteinuria (B2-microglobulinuria) Glucosuria

Potassium wasting (TTKG >12)

Salt wasting (FENa >1% with elevated renin)

Tubular disease

P. Goodyer · I. Eisenstein · I. Zelikovic

Proximal tubulopathy (Fanconi syndrome)

63

Tubular disease

P. Goodyer · I. Eisenstein · I. Zelikovic

Proximal tubulopathy (Fanconi syndrome)

1 – Fanconi syndrome should always be distin-guished from diseases associated with an isolated defect in renal proximal tubular transport. In cystinuria, amino acid wasting is restricted to cystine, ornithine, lysine and artinine. In hereditary hypophosphatemia, proximal tubular reabsorption of phosphate is de-pressed but aminoaciduria is absent. For details, see algorithms on Rickets and Hypophosphatemia. ISHG, a relatively benign condition, is caused by a genetic defect in the Na⁺-glucose cotransporter, SGLT2.

2 – In the early 1930s, Fanconi (Switzerland), DeToni (Italy) and Debre (France) described a renal tubular syndrome in children characterized by massive urinary wasting of electrolytes, glucosuria and pro-teinuria, causing acidosis, rickets and severe failure to thrive. In retrospect, it is evident that these patients had cystinosis (see below) and exhibited broad dys-function of the proximal tubule. The defect in phos-phate reabsorption may be assessed by calculating the tubular reabsorption of phosphate: 1 – (urine PO4/ serum PO₄) × (serum creatinine/urine creatinine); val-ues of less than 0.85, in the face of hypophosphatemia, demonstrate the defect. proximal tubular losses of bicarbonate may be massive with acidosis requiring replacement of 10–20 mEq/kg/day; losses of this mag-nitude in the face of a nonanion gap acidosis indicate proximal RTA. Aminoaciduria may be quantifi ed on an automated analyzer and normalized for urine creati-nine; all amino acid transport systems are affected.

LMW proteins are normally fi ltered through the glom-erulus and reabsorbed (>95%) by endocytosis; in Fan-coni syndrome there may be several grams of LMW protein excreted per day; this is best proven by mea-suring the 24-hour excretion of ␤2-microglobulin or retinol binding protein. Glucosuria may be detected by standard dipsticks or by direct quantifi cation. There is no simple test for salt wasting which distinguishes a proximal tubular defect from dysfunction at more distal sites, but Fanconi syndrome is associated with NaCl losses of >1% of the fi ltered load in the face of volume contraction: fractional excretion of sodium = (urine Na/serum Na) × (serum creatinine/urine creati-nine) × 100%. Potassium wasting is identifi ed by cal-culating the trans-tubular potassium gradient (TTKG)

>12. TTKG = (urine K) × 300/urine osmolarity); normal range = 4–6. Some of the patients with Fanconi syn-drome also have hypercalciuria.

3 – In adults, the most common cause of Fanconi syndrome is drug toxicity and this should also be con-sidered in children; it may be noted following

chemo-therapy with ifosfamide or cisplatin. Heavy metal poisoning, glue sniffi ng, and other drugs have also been reported to cause proximal tubular dysfunction.

4 – Most pediatric referrals for Fanconi syn-drome involve a hereditary disease; proximal tubular dysfunction may involve all transport mechanisms or may affect only a few (‘partial Fanconi syndrome’).

Cystinosis nearly always causes a complete Fanconi syndrome and the diagnosis is confi rmed by measure-ment of leukocyte cystine on an automated amino acid analyzer or by slip lamp identifi cation of corneal crys-tals. Cystinosis is due to mutations of the cystinosin gene on chromosome 17p13, encoding a lysosomal membrane protein which selectively permits cystine to exit from the lysosome into the cytoplasm. Mechan-ical disruption of lysosomes or interference with the endocytotic membrane recycling pathway causes a broad, severe disturbance of proximal tubule transport functions. Dent disease is X-linked and caused by mu-tations of a chloride channel gene (CLCN5) which dis-rupts normal endocyctotic mechanisms; most patients with Dent disease are characterized by hypercalciuria, massive LMW proteinuria and chronic renal failure.

Proximal tubule dysfunction is quite variable depend-ing on the mutation. Mitochondriopathies are occa-sionally associated with lactic acidosis and may be maternally inherited (mitochondrial genes) or due to autosomal-recessive (nuclear genes) defects in the electron transport chain. The mitochondriopathies often have neuromuscular manifestations, may have episodes of rapid deterioration during intercurrent ill-ness and usually require tissue diagnosis. In Fanconi-Bickel syndrome, children present with hepatomegaly due to glycogenosis of the liver and kidneys; The syn-drome is caused by mutations in the facilitated GLUT2.

Massive glucosuria is a prominent feature in addition to other proximal tubule dysfunctions. Proximal tubule dysfunction is often incomplete in Wilson disease and tyrosinemia where it can fl uctuate with metabolic cri-sis. In glactosemia, hereditary fructose intolerance and Lowe syndrome there are usually characteristic extrarenal features which bring the patient to medical attention.

5 – Aminoaciduria and phosphaturia may be seen in hyperparathyroidism states, but this is uncom-mon in children.

6 – In general, the strategy for supportive thera-py of Fanconi syndrome is to replace fl uid and the inorganic solutes lost in the urine. Amino acids, LMW

proteins and glucose do not usually deplete metabolic pools as long as adequate nutrition is maintained. On the other hand, NaCl supplementation (2–8 mEq/kg/

day) to avoid chronic volume contraction often im-proves growth failure. Dose may be titrated to plasma renin if there is no growth improvement. The bicar-bonate requirement may vary from 2 to 20 mEq/kg/day depending on the severity of tubular dysfunction; this may also be conveniently supplied as Na/K citrate (ci-trate consumes H⁺ when metabolized in the Krebs cy-cle). Oral phosphate supplements (25–100 mg elemen-tal phosphate/kg divided in 3–4 doses/day) are adjust-ed to assure that serum phosphate comes into the nor-mal range 45–60 min after each dose. The aim is to provide adequate serum phosphate for bone mineral-ization and linear growth. However, phosphate serves as an oral calcium binder, stimulating PTH release.

Since proximal tubular synthesis of 1,25(OH)₂ vitamin D may also be affected, oral calcitriol 10–40 ng/kg/day in 2 divided doses is usually needed to avoid hyper-parathyroidism, under close monitoring of urine cal-cium levels, and periodic renal sonogram to prevent hypercalciuria and nephrolithiasis. Depending on the underlying disease, specifi c therapy (such as cysta-mine in cystinosis) is indicated.

Selected reading

Fanconi G: Die nicht diabetischen Glykosurien und Hyperglykämien des älteren Kindes. Jahrb Kinder-heilk 1931;133:257–300.

Forman JW: Cystinosis and Fanconi syndrome;

in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 789–806.

Gahl WA, Theoene JG, Schneider J: Cystinosis.

N Engl J Med 2002;347:111–121.

Hsu SY, Tsai IJ, Tsau YK: Comparison of growth in primary Fanconi syndrome and proximal renal tubular acidosis. Pediatr Nephrol 2005;20:460–464.

Kuwertz-Broking E, Koch HG, Marquardt T, Rossi R, Helmchen U, Muller-Hocker J, Harms E, Bulla M:

Renal Fanconi syndrome: fi rst sign of partial respiratory chain complex IV defi ciency. Pediatr Nephrol 2000;14:495–498.

Santer R, Steinmann B, Schaub J: Fanconi-Bickel syndrome: a congenital defect of facilitative glucose transport. Curr Mol Med 2002;2:213–227.

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64

Polyuria

^/

Renal salt wasting

FENa⁺ >1%

Urine osm = 200–400 mosm/l

Fanconi syndrome 0 Primary

salt-losing states 1

Salt and water replacement 2

Urinary tract obstruction Nephronophthisis Bartter syndrome Gitelman syndrome Pseudohypoaldosteronism Adrenogenital syndrome

NDI Central DI

X-linked

Autosomal recessive Drug-induced Hypercalcemia Hypokalemia

Water replacement 4 DDAVP

Congenital Acquired Renal free water loss 3

FENa⁺ <1%

Urine osm <200 mosm/l

Tubular disease

P. Goodyer · I. Eisenstein · I. Zelikovic

Polyuria

65

Tubular disease

P. Goodyer · I. Eisenstein · I. Zelikovic

Polyuria

1 – Polyuria is divided into conditions where high urine volume refl ects renal tubular salt wasting and those in which there is primary free water loss. To make this distinction, the patient must be in a state of relative volume contraction (may be confi rmed by el-evated plasma renin; avoid assessment during rapid intravenous fl uid infusions). Under these conditions, a fractional excretion of sodium (FENa⁺) >1% indicates a salt-losing state. FENa⁺ = [Urine sodium/serum sodium] × [serum creatinine/urine creatinine] × 100%.

If FENa⁺ is <1% under these conditions, the next goal is to determine whether polyuria is due to an osmotic solute such as glucose or mannitol; urine osmolarity less than 150 mosm/l suggests dysfunction of the col-lecting duct and free water loss.

2 – Children with polyuria due to the renal Fan-coni syndrome are readily identifi ed by tests of proxi-mal tubular dysfunction (tubular reabsorption of phos-phate, proximal RTA, aminoaciduria, LMW proteinuria, etc.). For details, see algorithm on Faconi syndrome.

3 – Obstructive uropathy damages the distal nephron causing polyuria from defective reabsorption of both salt and water in collecting duct. Polyuria is also characteristic of several inherited salt-losing con-ditions (exposure to diuretic drugs should be excluded by history). Nephronophthisis (medullary cystic ease complex) is a group of autosomal-recessive dis-eases caused by mutations in several genes. In over 90% of the cases of juvenile nephronophthisis (NPHS1) polyuria is noted in childhood well before progressive renal insuffi ciency becomes evident between 10 and 20 years. In Europe, NPH1 accounts for 10–15% of chil-dren with ESRD. While FENa⁺ may refl ect salt-wasting, urine is usually dilute, implying that polyuria may also refl ect free water losses from collecting duct dysfunc-tion associated with characteristic medullary cysts and interstitial disease. Bartter syndrome is caused by mutations in various genes involved in salt reabsorp-tion by the thick ascending limb of the loop of Henle;

the syndrome is mimicked by furosemide and associ-ated with striking hypercalciuria. In Gitelman syn-drome, the gene for sodium/chloride reabsorption in the distal convoluted is mutated, but salt losses are modest and often only mild polyuria exists; hypocalci-uria is a characteristic fi nding. Pseudohypoaldosteron-ism and adrenogenital syndrome are easily distin-guished by the presence of acidosis and/or hyperkale-mia.

4 – In many of the conditions associated with salt wasting, the principal of therapy is replacement of fl uids and electrolyte losses in the urine.

5 – Children who present with polyuria due to renal free water losses, must fi rst be distinguished from those with psychogenic polydipsia. Since any form of chronic polyuria washes out the renal medul-lary concentrating gradient, the initial response to water deprivation or vasopressin may be blunted;

most fl uid restriction ± daily intranasal or subcutane-ous DDAVP (0.5–2 µg) for 2–3 days may sometimes be needed to demonstrate a completely normal renal response. Classical NDI is an X-linked disease (females are asymptomatic or mildly affected) caused by inacti-vating mutations of the vasopressin receptor in the renal collecting duct. A rare autosomal-recessive form of NDI is due to mutations of the aquaporin II gene, preventing water fl ux through the collecting tubule.

Important conditions leading to secondary NDI include hypercalcemia, hypokalemia, sickle cell disease, chronic renal failure and drugs (lithium, demeclocy-cline). In infant males, polyuria and urine osmolarity of 50–100 mosm/l are evident in the fi rst days of life, but water loss increases rapidly in the postnatal period and should be diagnosed as quickly as possible to avoid brain injury from dehydration. Whenever pos-sible, urgent molecular diagnosis is advisable. A short water deprivation test is also diagnostic, but great care must be taken to avoid excessive dehydration; body weights are taken every 30 min. Water is withheld until urine osmolarity reaches a plateau as indicated by an hourly increase of <30 mosm/l for 3 successive hours or until body weight drops by 3%. DDAVP (0.5–2 µg) is then administered subcutaneously and urine osmolar-ity is measured 60 minutes afterward. In children with CDI, urine osmolarity is low (<200 mosm/l) but rises by

>50% following DDAVP. CDI may be congenital or secondary to pituitary ablation by trauma or tumors.

In children with inherited NDI, urine osmolarity is also low (50–150 mosm/l) and there is no signifi cant increase (<20%) after DDAVP. Intermediate results may refl ect partial CDI or mild NDI mutations.

6 – The distinction between salt-wasting states and diabetes insipidus is crucial since the approaches to therapy are quite different. In NDI, the strategy is to create mild volume contraction with hydrochlorothia-zide (1–2 mg/kg/day) and restricted renal solute load;

naprosyn (5–10 mg/kg/day in divided doses) may then be used to blunt the compensatory production of renal prostaglandin. The combination of these effects enhances proximal tubular fl uid reabsorption. Con-versely, the use of a diuretic in Bartter syndrome may be life-threatening, since marked volume contraction already exists. The strategy here is to introduce naprosyn plus oral salt supplements (4–8 mEq/kg/day);

naprosyn again blunts prostaglandin production, re-ducing intraglomerular pressure and, thus, the fi ltered load of salt. Doses are adjusted to bring plasma renin to 2–3 times normal. Therapy of other conditions in this algorithm involves additional considerations, but replacement of salt or free water is important in each one.

Selected reading

Bichet DG, Fijiwara TM: Nephrogenic diabetes insipidus; in Sciver C, Beaudet A, Sly W, Valle D (eds): The Metabolic and Molecular Bases of Inher-ited Disease. New York, McGraw-Hill, 2001, vol III, pp 4909–4932.

Pinelli JM, Symington AJ, Cunningham KA, Paes BA:

Case report and review of the prenatal implications of maternal lithium use. Am J Obstet Gynecol 2002;

187:245–249.

Robben JH, Knoers NV, Deen PM: Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 2006;291:

F257–F270.

Saunier S, Salomon R, Antignac C: Nephronoph-thisis. Curr Opin Genet Dev 2005;15:324–331.

Saxena A, Hanukogulu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A: Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes. J Clin Endocrinol Metab 2002;87:3344–3350.

Zelikovic I: Hypokalaemic salt-losing tubulopathies:

an evolving story. Nephrol Dial Transplant 2003;

18:1696–1700.

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66

Hypouricemia

Normal or decreased uric acid excretion (urinary uric acid <0.34 mg/dl GFR*)

* Mean uric acid excretion for children older than 2 years

Serum uric acid <2 mg/dl

Determine urinary uric acid excretion /

Increased uric acid excretion (urinary uric acid >0.57 mg/dl GFR**)

** Mean +2 SD for children older than 2 years

Medications 0 Ex. allopurinol Metabolic disorders 1 Xanthinuria 2

Medications 3

Idiopathic renal hypouricemia 4 Generalized proximal tubular defect 5 SIADH, extracellular volume expansion 6 Diabetes mellitus 7

Tubular disease

J. Smith · F.B. Stapleton

Hypouricemia

67

Tubular disease

J. Smith · F.B. Stapleton

Hypouricemia

1 – Urinary uric acid concentration is determined by glomerular fi ltration of uric acid as well as by a complex array of reabsorption and secretion process-es of this substance in the renal tubule. Uric acid excretion (in a urine sample) is expressed as uric acid (Ua) excretion per deciliter of GFR which is calculated according to the formula (UUa × SCr/UCr), where Cr is creatinine and U and S are concentrations in mg/dl in urine and serum, respectively.

2 – The table lists some of the medications that are associated with hypouricemia. Allopurinol, a com-petitive inhibitor of the enzyme xanthine oxidase, is the most commonly implicated medication which leads to hypouricemia by decreased uric acid produc-tion.

3 – Persistent hypouricemia has been associated with defi ciencies of enzymes such as nucleoside phos-phorylase and PP-ribose-P-synthetase.

4 – Xanthinuria is an autosomal-recessive dis-order caused by a defi ciency of the enzyme xanthine dehydrogenase (and, in some cases, also aldehyde oxidase) and characterized by xanthine urolithiasis, myopathy, and polyarthritis.

5 – Hypouricemia and uric acid stones may develop due to administration of drugs that inhibit tubular reabsorption or increase tubular secretion of uric acid (table).

6 – Idiopathic renal hypouricemia is an inherited disorder caused by a defect in the proximal tubular urate/anion exchanger URAT1 which leads to renal urate wasting. The disease is characterized by exer-cise-induced acute renal failure and nephrolithiasis.

7 – Generalized defects in proximal tubular func-tion may lead to renal urate wasting. Examples include idiopathic Fanconi syndrome, cystinosis, Wilson dis-ease and galactosemia. Hodgkin disdis-ease and paren-teral alimentation are also associated with uricosuria and hypouricemia.

8 – In SIADH, antidiuresis results in expansion of the extracellular fl uid compartment, which then leads to increased urinary excretion of uric acid.

9 – The development of hyperglycemia, glucos-uria and osmotic diuresis is associated with decreased urate reabsorption in the proximal tubule.

Selected reading

Baldree LA, Stapleton FB: Uric acid metabolism in children. Pediatr Clin N Am 1990;37:391–418.

Cameron JS, Moro F, Simmonds HA: Gout, uric acid and purine metabolism in paediatric nephrology.

Pediatr Nephrol 1993;7:105–118.

Hediger MA, Johnson RJ, Miyazaki H, Endou H:

Molecular physiology of urate transport. Physiology 2005;20:125–133.

Icihida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T: Clinical and molecular analysis of patients with renal hypouricemia in Japan: infl uence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004;15:164–173.

Stapleton FB, Linshaw MA, Hassansein K: Uric acid excretion in normal children. J Pediatr 1978;92:911.

Table. Selected medications associated with hypouricemia

Decreased uric acid production Allopurinol

Azouridine Orotic acid Oxypurinol

Increased uric acid secretion Ascorbic acid (high dose) Citrate

Dicumarol

Most diuretics (acutely, before extracellular volume contraction) Estrogens

Glycerol guaiacholate Glycine

Halofenate

Outdated tetracyclines (Fanconi syndrome) Iopanoic acid (radiocontrast agent) Meglumine iodipamide Phenylbutazone Phenol sulfophthalein p-Nitrophenylbutazone Probenecid Salicylates (high dose)

Sodium diatrizoate (radiocontrast agent)

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68

Hyperuricemia

^/

Positive medication history / (e.g. diuretics)

Negative family history

Examine extracellular fluid volume status

Normal ECF volume Increased ECF volume Decreased ECF volume

Cell lysis Hemolysis Polycythemia Leukemia/lymphoma Tumor lysis syndrome Exercise, acidosis/alkalosis 0 Hypertension 1

Hereditary/metabolic conditions 23 Miscellaneous conditions

Hypothyroidism Hypoparathyroidism Psoriasis

Sarcoidosis Obesity Starvation Down syndrome

Acute renal failure 4 Congestive heart failure

Diarrhea 5

Nephrogenic diabetes insipidus

Elevated serum uric acid level (table 1)

Complete medical and family history

Positive family history

Increased uric acid excretion*

* see ‘Hypouricemia’, for values of urinary acid excretion Genetic diseases 2

HGPRT deficiency (Lesch-Nyhan syndrome) PRPS overactivity G6P deficiency

(glycogen storage disease type 1)

Decreased uric acid excretion*

Uromodulim disorders 3 FJHN

MCKD2

In document ESTUDIO DE LA CONDUCTA ANTISOCIAL Y/O DELICTIVA EN UNA MUESTRA COLOMBIANA DE ADOLESCENTES DE (página 83-89)