Cystic fibrosis and the kidney

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Renal diseases in patients Renal diseases in patients with cystic fibrosiswith cystic fibrosis

F. CachatDepartment of PediatricsPediatric nephrology unit

Lausanne

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CF: possible renal manifestations

Birth

Hypo-electrolytemia

Pulmonaryinfections

Pulmonary transplantation

Kidney stonesNephrocalcinosis

Drugsnephrotoxicity

OtherGlomerulonephritis

DrugsNephrotoxicity

Cystic Fibrosis and the Kidney 3

CFTR expression in the kidney

CFTR expression, variable duringlife, predominantly in the proximaland distal tubules

CFTR function Cystic fibrosis

1) Inhibition of ENaC by CFTR activation2) Activation of luminal chloride conductance is a pre-

requisite for inhibition of ENaC3) This applies to the intestinal and airway epithelium where

CFTR is the dominating Cl- channel4) In the kidney, CFTR may function as a regulator of other

membrane conductances


CFTR expression in the kidney

• Expression of CFTR at every level of renal Expression of CFTR at every level of renal segmentssegments

• No renal dysfunction in patients with CF excretion of some drugs excretion of some drugs

(aminoglycosides) (aminoglycosides) (in exchange for chloride (in exchange for chloride reabsorbtion in the proximal segment ?)reabsorbtion in the proximal segment ?)

urinary concentration and dilution urinary concentration and dilution capacity of the kidneycapacity of the kidney


CFTR and polycystic kidney disease

• CFTR code for a chloride channel expressed at the apical level of the cell, regulated by cyclic AMP

• Fluid secretion (with chloride) is thought to be important in cyst formation and growth in patients with ADPKD

• Hypothesis: absence of CFTR should allow a decreased severity of ADPKD in patients or animal models with CF

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• No role (?) of CFTR in experimental experimental ADPKD mouse modelADPKD mouse model

• No protective effect of F508 mutation in a in a patient with ADPKDpatient 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)


Hypoelectrolytemia

• Recognized in about 5% of patients with CF

• includes: • HyponatremiaHyponatremia

• HypokalemiaHypokalemia

• Metabolic alkalosisMetabolic alkalosis

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Birth

Hypo-electrolytemia

Pulmonaryinfections



Drugsnephrotoxicity


Drugsnephrotoxicity


Hypoelectrolytemia

• 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)

• With hypokalemia secondary to K urinary and sweat losses, and metabolic alkalosis secondary to volume contraction and hyperaldosteronism

Hypoelectrolytemia

• Appears often in infant between 0 and 1 year of age

• Dramatic episodes with acute renal failure in case of heat stroke / dehydratation


Hypoelectrolytemia

• Risk factors• Age < 6 months• Breastfeeding• Late diagnosis• Heat stroke

• Prevention• Hydratation• Salt supplements• Medical follow up, iv rehydration if necessary


Hypoelectrolytemia

Important risk of sodium and water loss withconcomitant hypokalemia and metabolic alkalosis

secondary to CFTR mutation and worsened byparticular environmental conditions


Kidney stones

• Patients with CF are at an increased risk of :

• Nephrocalcinosis

• Kidney stones

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Birth

Hypo-electrolytemia

Pulmonaryinfections



Drugsnephrotoxicity


Drugsnephrotoxicity


Kidney stones

• Probably secondary to • DrugsDrugs (furosemide / prednisone) (hypercalcuria)

• Prolonged immobilizationProlonged immobilization (hypercalcemia and hypercalciuria)

• Secondary enteric hyperoxaluriaSecondary enteric hyperoxaluria (repeated antibiotic use with diminished oxalate metabolism in the gut and decreased available calcium secondary to exocrine pancreatic insufficiency)

Monohydrated calcium oxalate stones(whewellite)

Monohydrated calcium oxalate crystals(whewellite)


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


Kidney stones

• Urinary alterations found in patients with CF and kidney stones / nephrocalcinosis (and how to correct them)

• Diminished urinary volume ( diuresis)

• Hypocitraturia (potassium Haussman, potassium citrate)

• Hypercalciuria ( diuresis, hydrochlorothiazide)

• Hyperoxaluria ( diuresis, PO calcium intake)

Repeated antibiotics administration

Destruction of oxalobacter formigenes

enteric oxalate metabolism

free oxalate in the gut

Hyperoxaluria / nephrocalcinosisKidney stones

Pancreatic insufficiency

Decreased free calciumdecreased calcium / oxalate

complexion


Renal failure and CF

• Relatively rare event, before lung before lung transplantation, thanks to good therapeutic transplantation, thanks to good therapeutic drug monitoring (drug levels, drug drug monitoring (drug levels, drug interactions)interactions)

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Renal failure in patients with CF before lung transplantation

• Aminoglycosides

• NSAID

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Birth

Hypo-electrolytemia

Pulmonaryinfections



Drugsnephrotoxicity


Drugsnephrotoxicity


Aminoglycosides

• Patients with CF often need higher aminoglycosides dosage for correct therapeutic drug levels (increased tubular secretion)

• Nephrotoxicity linked to peak and through peak and through levels and duration of aminoglycoside levels and duration of aminoglycoside therapytherapy

• Acute tubular toxicity (2-microglobuline)• Chronic renal failure with repeated courses

of iv nephrotoxic antibiotics• Potentiation with colistin and/or NSAID

Al-Aloul M et al. Pediatr Pulmonol 2005;39:15-20

Transient Renal Failure Due to Simultaneous Ibuprofen and Transient Renal Failure Due to Simultaneous Ibuprofen and Aminoglycoside Therapy in Children with Cystic FibrosisAminoglycoside Therapy in Children with Cystic Fibrosis

Kovesi TA 1998;338:65-66Kovesi TA 1998;338:65-66

Combination of intravenous aminoglycoside and Ibuprofen can cause acute renal insufficiency

Ibuprofen and other NSAID interfere with the intrarenalproduction of PGE2 and prostacyclin, which cause renalvasodilation

If used, ibuprofen (or other NSAID) should be discontinued If used, ibuprofen (or other NSAID) should be discontinued during aminoglycosides therapyduring aminoglycosides therapy


Aminoglycosides

Proposed mechanisms of renaldamage: - Acute tubular necrosis- Renal vasoconstriction- Tubulo-interstitial nephritis


Tubulo-interstitial nephritis

• Allergic reactions to drugs (-lactams, NSAID) or infectious agents (streptococcus)

• Non-oliguric acute renal failure with hypokalemia and hypophosphatemia

• Dialysis steroids re severity of the disease

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. PaediatrResp Rev 2002;3:135-138

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Renal failure in patients with CF after lung transplantation

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Birth

Hypo-electrolytemia

Pulmonaryinfections



Drugsnephrotoxicity


Drugsnephrotoxicity

Important decrease of Important decrease of renal function in CFrenal function in CFpatients after lungpatients after lungtransplantationtransplantation

Numerous CF patientswith lung transplantwill need kidney replacement therapy/transplantation

Worse in CF patients Worse in CF patients than any other groupthan any other group

Later age at Tx / antibiotic use / infections / diabetes mellitus


Glomerulonephritis and CF

• IgA nephropathy in the most common chronic glomerulonephritis in patients with CF

• Link with high circulating plasma IgA levels ?

• Renal and systemic amyloidosis• Secondary to chronic infection

• Diabetic nephropathy• 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)


Urinary incontinence

• Stress incontinence secondary to pelvic floor instability and weakness, secondary to chronic cough

• Physiotherapy / lung transplantation


Summary

• 1) Patients with CF are at an increased risk of presenting both nephrocalcinosis and kidney stones (enteric hyperoxaluria)

• 2) Older CF patients can present proteinuria secondary to renal amyloidosis or diabetic nephropathy


Summary

• 3) Sodium deficit in children with CF increases the risk of aminoglycosides and NSAID nephrotoxicity

• 4) Aminoglycosides therapeutic drug level must be checked frequently

• 5) Non-oliguric acute renal failure is a typical presentation of aminoglycoside toxicity


Summary

• 6) In case of lung transplantation, careful follow up of renal function should be done

• 7) Newborns with CF can present during the neonatal period with generalized hypo-electrolytemia and metabolic alkalosis


Renal follow-up

• Plasma creatinin before every antibiotic course

• Renal ultrasonography q year• Urinary oxalate, calcium, creatinin and

urinary status q year• Inulin clearances q 3-4 years• Regular follow up of renal function in

patients with lung transplantation

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References: review

• Stephens SE, Rigden SPA. Cystic fibrosis and renal disease. Paediatric respiratory review 2002;3:135-138

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References: CF and normal renal function

• Wilson PD et al. Cystic fibrosis transmembrane conductance regulator in the kidney: clues to its role? Exp Nephrol 1999;7:284-289

• Morales MM et al. The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc 2000;72:1-10

• Kibble JD et al. Renal proximal tubule function is preserved in Cftr (tm2cam) deltaF508 cystic fibrosis mice. J Physiol 2001;532:449-457

• Todd-Turla KM et al. CFTR expression in cortical collecting duct cells. Am J Physiol 1996;270:F237-F244

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References: CF electrolytes / acid-base disorders

• Eigenmann P et al. Chronic metabolic alkalosis in an infant with cystic fibrosis. Eur J Pediatr 1991;150:669-670

• 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

• 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

• Beckerman RC et al. Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis. Pediatrics 1979;63:580-583

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References: CF and kidney stones

• Nathanson S et al. Lithiase urinaire et mucoviscidose. Arch Ped 2003;10:794-796

• Perez-Brayfield MR et al. Metabolic risk factors for stone formation in patients with cystic fibrosis. J Urol 2002;167:480-484

• Gibney EM et al. The association of nephrolithiasis with cystic fibrosis. Am J Kidney Dis 2003;42:1-11

• Von der Heiden R et al. Which factors account for renal stone formation in cystic fibrosis? Clin Nephrol 2003;59:160-163

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References: CF and drug side effects

• Drew J et al. Acute renal failure and cystic fibrosis. Arch Dis Child 2004;23:646

• Al-Aloul M et al. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005;39:15-20

• Bech B et al. Long-term outcome of lung transplantation for cystic fibrosis – Danish results. Eur J Cardio Thor Surg 2004;26:1180-1186

• Moffett BS et al. Ciprofloxacin-induced renal insufficiency in cystic fibrosis. J Cyst Fibrosis 2003;2:152-154

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References: CF and drug side effects

• Tan KHV et al. Aminoglycoside prescribing and surveillance in cystic fibrosis. Am J Respir Crit Care Med 2003;167:819-823

• Hoffmann IM et al. Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Pediatr Pulmonol 2002;34:375-377

• Hmiel SP et al. Progressive chronic kidney disease after pediatric lung transplantation. Am J Transplant 2005;5:1739-1747

• 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

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References: CF and chronic glomerulonephritis

• Westall GP et al. Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy. Nephron Clin Pract 2004;96:c70-c75

• Stirati G et al. IgA nephropathy in cystic fibrosis. J Nephrol 1999;12:30-31

• Waz WR et al. Clinical quiz. Renal amyloidosis. Pediatr Nephrol 1995;9:245-246

Cystic fibrosis and the kidney

Health & Medicine

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