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Nephrotoxicity

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Background

There are many nephrotoxic drugs used in Paediatric Oncology. Monitoring renal function in patients on treatment is essential for two main reasons:

  • To detect impaired renal glomerular function for chemotherapy dose modification. Drugs with renal clearance may need dose modification to avoid further toxicity to the kidney or other organs such as hearing with cisplatin and aminoglycosides.
  • To detect direct renal glomerular or tubular damage and associated complications such as tubular electrolyte loss.

Nephrotoxic drugs

Nephrotoxicity can be anticipated with several classes of drugs.

Cytotoxics

Cisplatin   Glomerular impairment - both acute and chronic decrease in GFR (dose related) 
proximal and distal tubular damage 
haemolytic uraemic syndrome (rarely) 
Carboplatin  is less nephrotoxic but renal damage has been reported (doses of 400mg/m2 are not associated with nephrotoxicity, but higher doses (800mg/m2) are 
Ifosfamide      proximal tubulopathy (Renal Fanconi syndrome)- this is more severe the younger the child 
distal renal tubular dysfunction (less common) 
glomerular impairment in association with tubulopathy 
haemorrhagic cystitis 
SIADH secretion 
Cyclophosphamide  Haemorrhagic cystitis and dilutional hyponatraemia 
Methotrexate      Precipitation in tubular and collecting ducts 
transient acute renal failure 
systemic complications increased in presence of impaired renal clearance 
increased nephrotoxicity when used in protocols with cisplatin 
Note: penicillins decrease MTX excretion 
BCNU/CCNU  Delayed progressive chronic nephropathy 
Melphalan  Can cause acute renal impairment 

Antibiotics

Aminoglycosides    renal glomerular dysfunction with decreased GFR 
renal tubular impairment and non oliguric azotaemia
Fanconi syndrome (rare) 
most side effects reverse with time 

Antifungals

Amphotericin B          soluble amphotericin B is very nephrotoxic but renal complications are uncommon with liposomal amphotericin 
80% of patients experience some nephrotoxicity 
impaired GFR common 
proximal and distal renal tubular damage with potassium, magnesium and protein loss 
renal tubular acidosis is early manifestation of tubular toxicity 
severity of toxicity decreases with hydration and sodium loading 
nephrotoxicity increased with prior renal impairment, hypovolaemia, acidosis, hyponatraemia, hypokalemia, hypomagnesemia, concomitant administration of other nephrotoxins 
all patients on amphotericin need very careful electrolyte monitoring 
essential to have adequate hydration, with potassium and magnesium supplementation 
side effects resolve with time 

Specific Nephrotoxic syndromes and symptoms

See also specific investigations for renal complications

Glomerular dysfunction

  • Increased Cr and Urea
  • Impaired GFR
  • Hypertension
  • Microscopic haematuria
  • proteinuria

Proximal tubular dysfunction

  • Decreased proximal reasborption of Na+, K+, Cl-, HCO3, PO4, Ca2+, Mg2+, glucose, uric acid
  • Loss of low molecular weight proteins (e.g. beta 2 microglobulin)

Distal tubular dysfunction

  • Decreased urine concentrating ability - diluted early morning urine
  • Maximum urine osmolality < 600 mosmol/kg

Renal tubular acidosis

  • Urine is alkaline pH > 5.5, elevated urine HCO3, systemic acidosis with HCO3 < 20 mmol/l
  • Hyperchloraemic metabolic acidosis may result from a proximal RTA or distal RTA

Hypocalcaemia

  • vomiting, irritability, tetany, seizures, prolonged QT interval, rickets long term
  • secondary to proximal tubulopathy

Hypokalaemia

  • CNS (fatigue, weakness, paraesthesia, cramps, rhabdomyolysis)
  • GI (constipation and ileus)
  • CVS (hypotension, arrhythmias, T wave flattening, prominent U waves, ST depression)
  • Renal (metabolic alkalosis, polyuria, polydipsia)

Hypomagnesaemia

  • Lethargy, confusion, tremor, fasciculations, nystagmus, tetany
  • Seizures
  • Prolonged PR and QT
  • Can cause associated hypokalaemia and hypocalcaemia

Hypophosphataemia

  • paresthesia, malaise, irritability, seizures, coma, paralysis
  • if prolonged, may cause osteomalacia, hypophosphataemic rickets

Metabolic acidosis

  • secondary to urinary bicarbonate loss (proximal RTA)
  • tachypnoea, abdominal pain, vomiting, fever, lethargy

Haemorrhagic cystitis

Drug induced haemorrhagic cystitis is caused by acrolein, a metabolic product of cyclophosphamide and ifosfamide

  • Bladder mucosal oedema, endothelial ulceration and telangiectasia
  • Detect by urine monitoring for microscopic or macroscopic haematuria
  • Prevent with hyperhydration and mesna uroprotection

Haemorrhagic cystitis can also occur in the post stem cell transplant setting. Here it is usually secondary to urinary infection with human polyoma virus (BK or JC viruses).

Treatment of haemorrhagic cystitis is supportive with bladder irrigation, platelet support +/- tranexamic acid. Surgical intervention may be required and is not always successful.

Renal Fanconi's Syndrome

  • May occur with Ifosfamide particularly > 54g/m2 cumulative dose
  • hypophosphataemia, hypokalaemia, glycosuria, proximal RTA, hypouricemia
  • decreased renal threshold for phosphate with decreased tubular reabsorbtion of PO4, increased fractional excretion of Na+, K+, Ca2+
  • increased urinary HCO3, amino acids
  • low molecular weight proteinuria (e.g. ß2 microglobulin)

Investigation of renal function

History and clinical examination
Review initial investigations
Review prior surgery, radiotherapy and chemotherapy
Check BP
Urinalysis - dipstix
Review all prescribed medications
Investigation of glomerular function
Serum creatinine and urea
51Cr or Tc99 EDTA GFR expressed as mls/min/1.73m2 (which is corrected for body surface area)
Blood and urine protein and albumin
Urine microscopy
Calculation of adult creatinine clearance (Cockroft and Gault)
Cr Cl = IBW x (140-age)/ 0.8(Crserum) (x .085 if female)
Where IBW = ideal body weight in kg
Serum Cr in mcmol/L 
Calculation of paediatric glomerular filtration rate calculation (Modified Schwarz estimate) 
GFR = (k x hgt) / (Crserum) x 88.4  
Where k = Premature infant 0.33
Infant <1yr 0.45
Child or adolescent girl .055
Adolescent boy 0.70 
Hgt = cm  
Serum Cr = mcmol/L 
GFR (1.73m2) = k x ht(cm)
                           --------------
                            Pcr(ųmol/L)  
k = 40 for all ages 
Limitations - formula is accurate in children with normal growth, normal nutritional state.
k value dependent on method of serum creatinine measurement  
Calculation of urinary fractional excretion
FE (a) = U(a) x PCr x 100%
                    ----------------
                    P(a) x UCr
P = plasma
U = urine
Cr = creatinine
(a) = Na+, K+, Mg2+ 
Proximal tubular function
Blood Na+, K+, Cl-, HCO3, Ur, Cr, Ca2+, glucose, Mg2+, PO4, urate
Urine Na+, K+, Cl-, HCO3, Ur, Cr, Ca2+, glucose, Mg2+, PO4, urate
Fractional excretion (FE) Na+, K+, Mg2+
Tubular reabsorbtion of PO4, max of PO4 Tmp/GFR 
Calculation of tubular maximum phosphate reasborption (TmP)
Tmp/GFR = Pp - (Up x PCr)
                      -----------------
                          Ucr 
P = plasma, U = urine Cr = creatinine   p = PO4
Distal tubular function
early morning urine, osmolality should be > 600 mosmol/kg
urine pH 
Renal acid base function
plasma and urine bicarbonate
plasma and urine pH
plasma bicarbonate < 20 mmol/l and presence of urine bicarbonate suggests proximal RTA
plasma bicarbonate < 20 mmol/l and absent urine bicarbonate (urine pH >5.5) suggests distal RTA or non renal cause 

Normal Renal Values

Child
7 days - 1 month  20 - 60 
1 month - 2 years  20 - 50 
2 - 4 years  20 - 60 
4 - 6 years  25 - 65 
6 - 10 years  25 - 70 
10 - 15 years  40 - 80 

From LabPlus

Renal threshold for phosphate:

  • 1.21-1.71 mmol/l 1-2yrs
  • 0.92-1.71 mmol/l 3-4 yrs
  • 1.0-1.72 mmol/l 5-8yrs
  • 1-1.66 mmol/l 9-12 yrs


GFR 87-174 ml/min/1.73 m2

Fractional excretion Na < 1%, K <20%, Mg <3%, PO4 <20%

Urine calcium excretion is assessed by urine calcium to creatinine ratio which is age dependent or 24hr urine calcium excretion (N<0.1mmol/kg/d)

Ratios 
<12 months <2
1 - 3 years  <1.5 
1 - 5 years  <1.1 
5 - 7 years  <0.8 
> 7 years  <0.6 

Urinary ß2 microglobulin <0.01 ug/mmol creatinine (diurnal variation max in morning)

Max Urine pH pH < 5.5 and Osmol >600 mosmol/kg

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  • Date last published: 01 January 2013
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network