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An Unusual Cause of Renal Failure

An Unusual Cause of Renal Failure. Dr Claire Hathorn SpR , RHSC Edinburgh 11 th May 2010. Presentation. 11 month old boy Vomiting for 1 week Diarrhoea for 2 days Oliguria for 1 day PMH: nil of note FH: Half-brother died at 15/12 of Gaucher’s disease. Initial Management.

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An Unusual Cause of Renal Failure

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  1. An Unusual Cause of Renal Failure Dr Claire Hathorn SpR, RHSC Edinburgh 11th May 2010

  2. Presentation • 11 month old boy • Vomiting for 1 week • Diarrhoea for 2 days • Oliguria for 1 day • PMH: nil of note • FH: Half-brother died at 15/12 of Gaucher’s disease

  3. Initial Management • Treated as viral gastroenteritis • Difficult IV access • Naso-gastric fluids • No clinical improvement • Phlebotomy undertaken

  4. Diagnosis • ACUTE RENAL FAILURE • Urea 25 • Creatinine 559 • Potassium 7.7 • pH 7.38 • Hypertension 120/70

  5. Management • Salbutamol nebulisers • Sodium Bicarbonate • Insulin / Dextrose • Calcium Resonium • Amlodipine • HDU

  6. Further Investigation & Management • Renal Ultrasound • Bilateral calculi causing obstruction • Bilateral percutaneous nephrostomy insertion • PICU post-procedure

  7. Renal Ultrasound: 02.11.09

  8. Renal Ultrasound: 02.11.09

  9. KUB 06.11.09

  10. Progress • Renal function normalised within 24 hours • Hypertension persisted • Urinary cystine 431 umol/mmol (4-24) ornithine 16 (<13) lysine 95 (10-79) arginine 29 (<11) • Diagnosis: CYSTINURIA

  11. Medical Management • Potassium citrate • Low salt diet • High fluid intake 2.5 litres/m2/day • Urine sample from mother

  12. Further Procedures • Lithotripsy • Percutaneous nephrolithotomy • Ureteric stent insertion

  13. Post-operative course • Complications: • Urinary Tract Infections • Urinoma • Norovirus gastroenteritis • Adenovirus LRTI • IV & Naso-gastric fluids • Parenteral nutrition

  14. Subsequent Investigations • Close outpatient follow-up • Normal renal function • Urinary cystine levels: several above 1250 umol/l solubility threshold • Urine pH: 7.5 – 8

  15. Ongoing Management • Potassium citrate • Trimethoprim • Amlodipine • Atenolol • Fluid intake: Aim 1200ml/day

  16. Discussion

  17. Cystinuria • History • Epidemiology & Genetics • Pathophysiology • Classification • Clinical features • Investigation • Management

  18. History • 1810 Wollaston: ‘cystic oxide’ urinary calculi • 1833 Berzelius named ‘Cystine’ • 1908 Cystinuria = inborn error of metabolism • 1955 Autosomal recessive inheritance • 1961 Reduced intestinal absorption of cystine • 1963 Penicillamine first used • 1993 Gene identified on chromosome 2 • 1997 Gene identified on chromosome 19

  19. Cystinuria • Autosomal recessive aminoaciduria • 6-8% of all stones in children • Difficult management • Risk of progressive renal impairment

  20. Epidemiology & Genetics • 1 in 1000 to 1 in 17000 (Europe & USA) • Mutations of 2 genes identified • SLC3A1 & SLC7A9 • Chromosomes 2 & 19 • Knoll et al. Cystinuria in childhood & adolescence: recommendations for diagnosis, treatment & follow-up. Pediatric Nephrology. 2005;20:19-24

  21. Pathophysiology • Defective amino acid transporter in proximal tubule • Impaired transport of cystine, ornithine, lysine & arginine • Poor solubility at physiological pH – precipitation & recurrent calculus formation • Impaired intestinal absorption of cystine

  22. Classification Knoll et al. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment and follow-up. Pediatric Nephrology. 2005;20:19-24

  23. Frequency of urinary cystine concn in healthy subjects, heterozygotes & homozygotes for cystinuria (log) Knoll et al. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment and follow-up. Pediatric Nephrology. 2005;20:19-24

  24. Clinical Features • 1st stone may form at any age • > 80% under 20 years • Phenotype more severe in males • 60% recurrent calculi • Some infants exhibit a severe form initially with partial resolution at 2 - 4 years • Renal impairment due to recurrent obstruction & infection

  25. Diagnosis • Consider in all stone-formers, particularly young children • Early diagnosis & treatment is essential to reduce stone formation and preserve renal function • ? Antenatal diagnosis

  26. Investigation • USS • Light microscopy of urine sediment • Urine Amino acids • 24 hr collection • Spot urine • Stone analysis • Cystine > 100 umol/mmol is diagnostic • 150 - homozygous

  27. Typical hexagonal cystine crystal in urine Goldfarb D. Cystinuria. Encyclopedia of Life Sciences.

  28. Management • Aims: • reduce urinary cystine concentration • remove stones • Urine dilution • Urine alkalinisation • Reduction of cystine concentration

  29. Diet • Low methionine • Reduce protein-rich food: limited in children • Adults < 0.8 grams/day • Low salt

  30. Fluids • High fluid intake: day & night • 1.5-2 litres/m2/day Cochat et al. Nephrolithiasis related to inborn errors of metabolism. Pediatric Nephrology. 2010;25:415-424 • 3 litres/day Knoll et al. Cystinuria in childhood & adolescence: recommendations for diagnosis, treatment & follow-up. Ped Neph. 2005;20:19-24 • ? Need for gastrostomy

  31. Urine Alkalinisation • Aim for pH 7.5 - 8 • Potassium citrate • Sodium bicarbonate • Acetazolamide Tiselius HG. New horizons in the management of patients with cystinuria. Current Opinion in Urology. 2010;20:169-173 Sterret et al. Acetazolamide is an effective adjunct for urinary alkalinisation in patients with uric acid and cystine stone frmation recalcitrant to potassium citrate. Urology. 2008:72;278-281

  32. Curve of increasing cystine solubility with increasing urinary pH

  33. Chelating Agents • If urine dilution & alkalinisation is insufficient to control stone formation • Cleave disulphide bond in cystine cysteine • Captopril • Tiopronin (alpha-mercaptopropionylglycine) • D-penicillamine

  34. Captopril • Positive effect on cystine stone formation Cohen et al. Clinical effect of Captopril on the formation & growth of cystine calculi. J Urol. 1995;154:164-6 Perazella et al. Successful treatment of cystinuria with Captopril. Am J Kidney Dis. 1993;21:504-7 • Not confirmed by other studies Chow et al. Medical treatment of cystinuria: results of contemporary clinical practice. J Urol. 1996;156:1576-8 • In difficult cases with high cystine excretion, combination therapy with MPG may be justified Tiselius et al. Guidelines on urolithiasis. Eur Urology. 2001;40:362

  35. Tiopronin (α-MPG) • Favoured due to milder side-effects • Rash, arthralgia, proteinuria, nephritic syndrome • Efficacy dependant on pH • Dose 300-1200mg, titrated according to cystine level

  36. 31 patients treated with Tiopronin Follow-up: median 8.8 years (0.4-12) Daily dose 0.5-3g (median 1.5g) Aim urine cystine concn <1200 umol/l 60% reduction in stone formn (p<0.001) 72% reduction in active stone removal (p<0.05) Side-effects not mentioned Lindell et al. Urol Res. 1995;23(2):111-117 Clinical course and cystine stone formation during tiopronin treatment

  37. Penicillamine • Effective • Little info re safety & efficacy in children • Use limited by toxicity • 85% in a Japanese series (n=15) Asanuma et al. Clinical study on cystinuria in children – stone management & prevention of calculi recurrence. Nippon Hinyokika. 1998;89:758 • 25% in a UK study Stephens AD. Cystinuria & its treatment:25 years experience at St Bartholomew’s Hospital. J Inherited Metabolic Disease. 1989;12:197

  38. Penicillamine: Recent American Experience • Retrospective study over 18 years • Children’s Hospital, Philadelphia • 11 children, 7 male • Mean age 7.4 yrs(1.2-12.5) • Gradual initiation to target dose over 4-6 wks • Aim: 20mg/kg/day • Cystine levels monitored DeBerardinis et al. Penicillamine therapy in pediatric cystinuria: experience from a cohort of American children. J Urology. 2008;180(6):2620

  39. Penicillamine: Study Results • 6 pts: 20 mg/kg/day, 5 pts: up to 40 mg/kg/day • 2 significant toxicities over 1203 patient months • Generalised aminoaciduria • Elastosis perforans serpiginosa rash • Minor SE eg arthralgia – use not limited • 6 pts had stone recurrences, all during periods of poor compliance • No pt complying with Rx had stones

  40. Penicillamine: Study Conclusions • Penicillamine can be considered a first line Rx • Low incidence of side effects with gradual initiation of treatment • Implications for other diseases eg Wilson’s DeBerardinis et al. Penicillamine therapy in pediatric cystinuria: experience from a cohort of American children. J Urology. 2008;180(6):2620

  41. Urological Interventions • Shock wave lithotripsy • Ureteroscopy • Percutaneous nephrolithotomy • Open surgery

  42. Principles of Management • Aggressive medical therapy • Gentle stone-removing surgery • High life-long compliance required • Careful follow-up • Specialist clinics

  43. Future • Treatment principles unchanged for a long time • Low research activity • New techniques in molecular biology may be helpful

  44. Patient • 6 urological procedures in 6 months since diagnosis • Fluid intake generally inadequate • Persistently raised urinary cystine levels • ? Need for gastrostomy • ? Need for chelating agent

  45. Any Questions?

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