Cystic fibrosis and the kidney


Published on

short review of potential renal involvment in children with CF form a clinical point of view

Published in: Health & Medicine
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Cystic fibrosis and the kidney

  1. 1. Renal diseases in patients with cystic fibrosis F. Cachat Department of Pediatrics Pediatric nephrology unit Lausanne
  2. 2. CF: possible renal manifestations Birth Hypo- electrolytemia Pulmonary infections Pulmonary transplantation Kidney stones Nephrocalcinosis Drugs nephrotoxicity Other Glomerulonephritis Drugs Nephrotoxicity
  3. 3. CFTR expression in the kidney Cystic Fibrosis and the Kidney CFTR expression, variable during life, predominantly in the proximal and distal tubules
  4. 4. CFTR function Cystic fibrosis <ul><li>Inhibition of ENaC by CFTR activation </li></ul><ul><li>Activation of luminal chloride conductance is a pre- </li></ul><ul><li>requisite for inhibition of ENaC </li></ul><ul><li>This applies to the intestinal and airway epithelium where </li></ul><ul><li>CFTR is the dominating Cl- channel </li></ul><ul><li>In the kidney, CFTR may function as a regulator of other </li></ul><ul><li>membrane conductances </li></ul>
  5. 5. CFTR expression in the kidney <ul><li>Expression of CFTR at every level of renal segments </li></ul><ul><li>No renal dysfunction in patients with CF </li></ul><ul><li> excretion of some drugs (aminoglycosides) (in exchange for chloride reabsorbtion in the proximal segment ?) </li></ul><ul><li> urinary concentration and dilution capacity of the kidney </li></ul>Cystic Fibrosis and the Kidney
  6. 6. CFTR and polycystic kidney disease <ul><li>CFTR code for a chloride channel expressed at the apical level of the cell, regulated by cyclic AMP </li></ul><ul><li>Fluid secretion (with chloride) is thought to be important in cyst formation and growth in patients with ADPKD </li></ul><ul><li>Hypothesis: absence of CFTR should allow a decreased severity of ADPKD in patients or animal models with CF </li></ul>Cystic Fibrosis and the Kidney
  7. 7. CFTR and polycystic kidney disease
  8. 8. CFTR and polycystic kidney disease <ul><li>No role (?) of CFTR in experimental ADPKD mouse model </li></ul><ul><li>No protective effect of  F508 mutation in a patient with ADPKD (relation to the nature of the mutation ?) (Persu A et al. CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2000;11:2285-2296) </li></ul>Cystic Fibrosis and the Kidney
  9. 9. Hypoelectrolytemia <ul><li>Recognized in about 5% of patients with CF </li></ul><ul><li>includes: </li></ul><ul><ul><ul><li>Hyponatremia </li></ul></ul></ul><ul><ul><ul><li>Hypokalemia </li></ul></ul></ul><ul><ul><ul><li>Metabolic alkalosis </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  10. 10. Hypoelectrolytemia <ul><li>Secondary to an increased loss of sodium and chloride through sweat (Na > 60 mmol/l and Cl > 90 mmol/l) (mutation being present in sweat glands) </li></ul><ul><li>With hypokalemia secondary to K urinary and sweat losses, and metabolic alkalosis secondary to volume contraction and hyperaldosteronism </li></ul>Cystic Fibrosis and the Kidney
  11. 11. Hypoelectrolytemia <ul><li>Appears often in infant between 0 and 1 year of age </li></ul><ul><li>Dramatic episodes with acute renal failure in case of heat stroke / dehydratation </li></ul>
  12. 12. Hypoelectrolytemia <ul><li>Risk factors </li></ul><ul><ul><ul><li>Age < 6 months </li></ul></ul></ul><ul><ul><ul><li>Breastfeeding </li></ul></ul></ul><ul><ul><ul><li>Late diagnosis </li></ul></ul></ul><ul><ul><ul><li>Heat stroke </li></ul></ul></ul><ul><li>Prevention </li></ul><ul><ul><ul><li>Hydratation </li></ul></ul></ul><ul><ul><ul><li>Salt supplements </li></ul></ul></ul><ul><ul><ul><li>Medical follow up, iv rehydration if necessary </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  13. 13. Hypoelectrolytemia Cystic Fibrosis and the Kidney Important risk of sodium and water loss with concomitant hypokalemia and metabolic alkalosis secondary to CFTR mutation and worsened by particular environmental conditions
  14. 14. Kidney stones <ul><li>Patients with CF are at an increased risk of : </li></ul><ul><ul><ul><li>Nephrocalcinosis </li></ul></ul></ul><ul><ul><ul><li>Kidney stones </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  15. 15. Kidney stones <ul><li>Probably secondary to </li></ul><ul><ul><ul><li>Drugs (furosemide / prednisone) (hypercalcuria) </li></ul></ul></ul><ul><ul><ul><li>Prolonged immobilization (hypercalcemia and hypercalciuria) </li></ul></ul></ul><ul><ul><ul><li>Secondary enteric hyperoxaluria (repeated antibiotic use with diminished oxalate metabolism in the gut and decreased available calcium secondary to exocrine pancreatic insufficiency) </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  16. 16. Monohydrated calcium oxalate stones (whewellite) Monohydrated calcium oxalate crystals (whewellite)
  17. 17. Cystic Fibrosis and the Kidney Renal ultrasound demonstrating medullary nephrocalcinosis in a child with cystic fibrosis. From: Stephens SE et al. Cystic fibrosis and renal disease. Paediatr Resp Rev 2002;3:135-138
  18. 18. Kidney stones <ul><li>Urinary alterations found in patients with CF and kidney stones / nephrocalcinosis (and how to correct them) </li></ul><ul><ul><ul><li>Diminished urinary volume (  diuresis) </li></ul></ul></ul><ul><ul><ul><li>Hypocitraturia (potassium Haussman, potassium citrate) </li></ul></ul></ul><ul><ul><ul><li>Hypercalciuria (  diuresis, hydrochlorothiazide) </li></ul></ul></ul><ul><ul><ul><li>Hyperoxaluria (  diuresis,  PO calcium intake) </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  19. 19. Repeated antibiotics administration Destruction of oxalobacter formigenes  enteric oxalate metabolism  free oxalate in the gut Hyperoxaluria / nephrocalcinosis Kidney stones Pancreatic insufficiency Decreased free calcium decreased calcium / oxalate complexion
  20. 20. Renal failure and CF <ul><li>Relatively rare event, before lung transplantation, thanks to good therapeutic drug monitoring (drug levels, drug interactions) </li></ul>Cystic Fibrosis and the Kidney
  21. 21. Renal failure in patients with CF before lung transplantation <ul><li>Aminoglycosides </li></ul><ul><li>NSAID </li></ul>
  22. 22. Aminoglycosides <ul><li>Patients with CF often need higher aminoglycosides dosage for correct therapeutic drug levels (increased tubular secretion) </li></ul><ul><li>Nephrotoxicity linked to peak and through levels and duration of aminoglycoside therapy </li></ul>Cystic Fibrosis and the Kidney
  23. 23. <ul><li>Acute tubular toxicity (  2-microglobuline) </li></ul><ul><li>Chronic renal failure with repeated courses of iv nephrotoxic antibiotics </li></ul><ul><li>Potentiation with colistin and/or NSAID </li></ul>Al-Aloul M et al. Pediatr Pulmonol 2005;39:15-20
  24. 24. Transient Renal Failure Due to Simultaneous Ibuprofen and Aminoglycoside Therapy in Children with Cystic Fibrosis Kovesi TA 1998;338:65-66 Combination of intravenous aminoglycoside and Ibuprofen can cause acute renal insufficiency Ibuprofen and other NSAID interfere with the intrarenal production of PGE2 and prostacyclin, which cause renal vasodilation If used, ibuprofen (or other NSAID) should be discontinued during aminoglycosides therapy
  25. 25. Aminoglycosides Cystic Fibrosis and the Kidney <ul><li>Proposed mechanisms of renal </li></ul><ul><li>damage: </li></ul><ul><li>Acute tubular necrosis </li></ul><ul><li>Renal vasoconstriction </li></ul><ul><li>Tubulo-interstitial nephritis </li></ul>
  26. 26. Tubulo-interstitial nephritis <ul><li>Allergic reactions to drugs (  -lactams, NSAID) or infectious agents (streptococcus) </li></ul><ul><li>Non-oliguric acute renal failure with hypokalemia and hypophosphatemia </li></ul><ul><li>Dialysis  steroids re severity of the disease </li></ul>Cystic Fibrosis and the Kidney
  27. 27. Tubulo-interstitial nephritis Renal histology showing the lymphocytic infiltration of tubulo-interstitial nephritis and acute tubular necrosis. Stain: period acid-Schiff From: Stephens SE et al. Cystic fibrosis and renal disease. Paediatr Resp Rev 2002;3:135-138
  28. 28. Renal failure in patients with CF after lung transplantation
  29. 29. Important decrease of renal function in CF patients after lung transplantation
  30. 30. Numerous CF patients with lung transplant will need kidney replacement therapy/ transplantation Worse in CF patients than any other group Later age at Tx / antibiotic use / infections / diabetes mellitus
  31. 31. Glomerulonephritis and CF <ul><li>IgA nephropathy in the most common chronic glomerulonephritis in patients with CF </li></ul><ul><ul><ul><li>Link with high circulating plasma IgA levels ? </li></ul></ul></ul><ul><li>Renal and systemic amyloidosis </li></ul><ul><ul><ul><li>Secondary to chronic infection </li></ul></ul></ul><ul><li>Diabetic nephropathy </li></ul><ul><ul><ul><li>30% of patients with CF present IDDM (and 30-50% of patients with IDDM will present diabetic nephropathy 5 to 10 years after initial diagnosis) </li></ul></ul></ul>Cystic Fibrosis and the Kidney
  32. 32. Urinary incontinence <ul><li>Stress incontinence secondary to pelvic floor instability and weakness, secondary to chronic cough </li></ul><ul><li>Physiotherapy / lung transplantation </li></ul>Cystic Fibrosis and the Kidney
  33. 33. Summary <ul><li>1) Patients with CF are at an increased risk of presenting both nephrocalcinosis and kidney stones (enteric hyperoxaluria) </li></ul><ul><li>2) Older CF patients can present proteinuria secondary to renal amyloidosis or diabetic nephropathy </li></ul>Cystic Fibrosis and the Kidney
  34. 34. Summary <ul><li>3) Sodium deficit in children with CF increases the risk of aminoglycosides and NSAID nephrotoxicity </li></ul><ul><li>4) Aminoglycosides therapeutic drug level must be checked frequently </li></ul><ul><li>5) Non-oliguric acute renal failure is a typical presentation of aminoglycoside toxicity </li></ul>Cystic Fibrosis and the Kidney
  35. 35. Summary <ul><li>6) In case of lung transplantation, careful follow up of renal function should be done </li></ul><ul><li>7) Newborns with CF can present during the neonatal period with generalized hypo-electrolytemia and metabolic alkalosis </li></ul>Cystic Fibrosis and the Kidney
  36. 36. Renal follow-up <ul><li>Plasma creatinin before every antibiotic course </li></ul><ul><li>Renal ultrasonography q year </li></ul><ul><li>Urinary oxalate, calcium, creatinin and urinary status q year </li></ul><ul><li>Inulin clearances q 3-4 years </li></ul><ul><li>Regular follow up of renal function in patients with lung transplantation </li></ul>Cystic Fibrosis and the Kidney
  37. 37. References: review <ul><li>Stephens SE, Rigden SPA. Cystic fibrosis and renal disease. Paediatric respiratory review 2002;3:135-138 </li></ul>
  38. 38. References: CF and normal renal function <ul><li>Wilson PD et al. Cystic fibrosis transmembrane conductance regulator in the kidney: clues to its role? Exp Nephrol 1999;7:284-289 </li></ul><ul><li>Morales MM et al. The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc 2000;72:1-10 </li></ul><ul><li>Kibble JD et al. Renal proximal tubule function is preserved in Cftr (tm2cam) deltaF508 cystic fibrosis mice. J Physiol 2001;532:449-457 </li></ul><ul><li>Todd-Turla KM et al. CFTR expression in cortical collecting duct cells. Am J Physiol 1996;270:F237-F244 </li></ul>
  39. 39. References: CF electrolytes / acid-base disorders <ul><li>Eigenmann P et al. Chronic metabolic alkalosis in an infant with cystic fibrosis. Eur J Pediatr 1991;150:669-670 </li></ul><ul><li>Desmazes-Dufeu N et al. Severe dehydration and August 2003 heat wave in a cohort of adults with cystic fibrosis. Presse Med 2005;34:647-648 </li></ul><ul><li>Bates CM et al. Cystic fibrosis presenting with hypokalemia and metabolic alkalosis in a previously healthy adolescent. J Am Soc Nephrol 1997;8:352-355 </li></ul><ul><li>Beckerman RC et al. Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis. Pediatrics 1979;63:580-583 </li></ul>
  40. 40. References: CF and kidney stones <ul><li>Nathanson S et al. Lithiase urinaire et mucoviscidose. Arch Ped 2003;10:794-796 </li></ul><ul><li>Perez-Brayfield MR et al. Metabolic risk factors for stone formation in patients with cystic fibrosis. J Urol 2002;167:480-484 </li></ul><ul><li>Gibney EM et al. The association of nephrolithiasis with cystic fibrosis. Am J Kidney Dis 2003;42:1-11 </li></ul><ul><li>Von der Heiden R et al. Which factors account for renal stone formation in cystic fibrosis? Clin Nephrol 2003;59:160-163 </li></ul>
  41. 41. References: CF and drug side effects <ul><li>Drew J et al. Acute renal failure and cystic fibrosis. Arch Dis Child 2004;23:646 </li></ul><ul><li>Al-Aloul M et al. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005;39:15-20 </li></ul><ul><li>Bech B et al. Long-term outcome of lung transplantation for cystic fibrosis – Danish results. Eur J Cardio Thor Surg 2004;26:1180-1186 </li></ul><ul><li>Moffett BS et al. Ciprofloxacin-induced renal insufficiency in cystic fibrosis. J Cyst Fibrosis 2003;2:152-154 </li></ul>
  42. 42. References: CF and drug side effects <ul><li>Tan KHV et al. Aminoglycoside prescribing and surveillance in cystic fibrosis. Am J Respir Crit Care Med 2003;167:819-823 </li></ul><ul><li>Hoffmann IM et al. Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Pediatr Pulmonol 2002;34:375-377 </li></ul><ul><li>Hmiel SP et al. Progressive chronic kidney disease after pediatric lung transplantation. Am J Transplant 2005;5:1739-1747 </li></ul><ul><li>Kovesi TA et al. Transient renal failure due to simultaneous ibuprofen and aminoglycoside therapy in children with cystic fibrosis. N Engl J Med 1998;338:65-66 </li></ul>
  43. 43. References: CF and chronic glomerulonephritis <ul><li>Westall GP et al. Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy. Nephron Clin Pract 2004;96:c70-c75 </li></ul><ul><li>Stirati G et al. IgA nephropathy in cystic fibrosis. J Nephrol 1999;12:30-31 </li></ul><ul><li>Waz WR et al. Clinical quiz. Renal amyloidosis. Pediatr Nephrol 1995;9:245-246 </li></ul>