RENAL
1972 Oppenheimer
EH. Glomerular lesions in cystic fibrosis: possible relation to diabetes mellitus,
acquired cyanotic heart disease and cirrhosis of the liver. Hopkins Med J 1972;
131:351-366. [PubMed]
Glomerular changes were noted at autopsy in four of the five children with CF
who also had diabetes mellitus. Other factors were involved but “since
cyanotic heart disease, diabetes mellitus and biliary cirrhosis are important
complications of cystic fibrosis, it is apparent that greater numbers of cystic
fibrosis children with renal complications will be found and that with longer
survival renal insufficiency may become an important part of the cystic fibrosis
syndrome”.
A prophetic statement as indeed this proved to be the case and diabetes mellitus
proved a serious and increasing problem as survival increased. Also a variety
of nephrotoxic drugs such as aminoglycosides and colomycin were used repeatedly
over many years (Bertenshaw C. Watson AR. Lewis S. Smyth A. Survey of acute
renal failure in patients with cystic fibrosis in the UK. Thorax 2007; 62:541-545).
2000 Turner MA,
Goldwater D, David TJ. Oxalate and calcium excretion in cystic fibrosis. Arch
Dis Child 2000; 83:244-247. [PubMed]
A patient with CF had repeated calcium oxalate renal stones and prompted the
authors to investigate other children for risk factors for this recognised complication
of cystic fibrosis. They showed a positive correlation between oxalate excretion
and glycolate excretion in children with CF, 21 of 24 of whom had a calcium
excretion below the normal range. Hyperoxaluria may reflect the intestinal malabsorption
although correlation between excretion of oxalate and glycolate suggests that
certainly a portion of the excess oxalate is derived from metabolic processes.
The low urinary calcium observed here may protect children with CF from renal stones although these are a relatively common occurrence affecting up to 6.3% of patients (Gibney EM, Goldfarb DS. Am J Kid Dis 2003; 42:1-11. [PubMed] also Terribile M et al, 2006 below [PubMed] )
2003 Drew J. Watson AR. Smyth A. Acute renal failure and cystic fibrosis. Archives of Disease in Childhood. 88(7):646, 2003 Jul. [PubMed]
2004 Westall GP.
Binder J. Kotsimbos T. Topliss D. Thomson N. Dowling J. Wilson JW. Nodular glomerulosclerosis
in cystic fibrosis mimics diabetic nephropathy. Nephron 2004; 96:c70-75. [PubMed]
The
authors describe 3 adult CF patients, who on renal biopsy had histological evidence
of nodular glomerulosclerosis in the absence of abnormal glucose metabolism.
We speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis,
predisposes to the lesions described.
2005 Al-Aloul M.
Miller H. Stockton P. Ledson MJ. Walshaw MJ. Acute renal failure in CF patients
chronically infected by the Liverpool epidemic Pseudomonas aeruginosa strain
(LES). J Cyst Fibros 2005; 4:197-201.[PubMed]
Eight cases
of acute renal failure in adult CF patients, all occurring during the use of
intravenous aminoglycosides for the treatment of pulmonary exacerbations with
an epidemic multi-resistant Pseudomonas aeruginosa strain. Potential contributory
factors are discussed. These cases demonstrate another complication of infection
by epidemic Pseudomonas strains in CF, and confirm the need for effective segregation
policies to prevent this.
2005 Ahya VN. Doyle
AM. Mendez JD. Lipson DA. Christie JD. Blumberg EA. Pochettino A. Nelson L.
Bloom RD. Kotloff RM. Renal and vestibular toxicity due to inhaled tobramycin
in a lung transplant recipient. J Heart Lung Transplant 2005; 24:932-935. [PubMed]
The safety of inhaled tobramycin in transplant recipients,
however, has not been established. We describe the first report of a lung transplant
recipient who developed renal failure and vestibular injury after receiving
inhaled tobramycin. We review the literature regarding the safety of inhaled
tobramycin and discuss potential mechanisms that may promote systemic toxicity
in transplant recipients.
2005 Kennedy SE.
Henry RL. Rosenberg AR. Antibiotic-related renal failure and cystic fibrosis.
J Paediatr Child Health 2005; 41:382-383. [PubMed]
A case of unusually severe acute tubular necrosis occurring
in an adolescent with cystic fibrosis receiving i.v. gentamicin plus ceftazidime.
2005 Hoppe B. von
Unruh GE. Blank G. Rietschel E. Sidhu H. Laube N. Hesse A. Absorptive hyperoxaluria
leads to an increased risk for urolithiasis or nephrocalcinosis in cystic fibrosis.
Am J Kidney Dis 2005; 46:440-445. [PubMed]
Absorptive
hyperoxaluria and hypocitraturia are the main culprits for the increased incidence
of urolithiasis and nephrocalcinosis in patients with CF. The authors advocate
high fluid intake, low-oxalate/high-calcium diet, and alkali citrate medication,
if necessary. Additional studies are necessary to determine the influence of
Oxalobacter species or other oxalate-degrading bacteria on oxalate handling
in patients with CF.
2006 Terribile M,
Capuano M, Carnovale V, Ferra P, Petrarulo M, Marangella M. Factors increasing
the risk for stone formation in adult patients with cystic fibrosis. Nephrology
Dialysis Transplantation 2006; 21:1870-1875.[PubMed]
Detailed metabolic and ultrasound studies of 29 adult patients with
CF, 20 heterozygotes (CF-H) and 30 controls (C). 21% of those with CF and 15%
of CF-H had kidney stones. Those with CF had elevated uric acid but no other
differences compared with heterozygotes and controls. Lower urine volume and
acidic pH produced super saturation of CF urine with uric acid in contrast to
heterozygotes and controls. The authors considered high risk dietary advice
or medication aimed at reducing risk of stones.
In another series of people with CF 13% had history of renal stones, many were recurrent. People with CF in this present series had a high risk of nephrolithiasis, although we did not recognise this complication through the Eighties although this series was of adults. There have been sporadic reports since 1964 (Gebala A. Pol Med Sci Hist Bull 1964; 51:149-154. [PubMed]; Turner et al, 2000 above; Bertenshaw C et al, 2007 for acute renal failure below). Earlier Bohles & Michalk (Helv Paediatr Acta 1982; 37:267-272.[PubMed]) found patients with CF showed increased urinary concentrations of oxalate, phosphate, xanthine and uric acid, and decreased concentrations of magnesium and citrate, comparable to concentrations found in patients with calcium oxalate stones. However, compared to stone bearing controls their urine calcium concentration was markedly decreased. They suggested that hypocalciuria in CF seems to protect against nephrolithiasis despite the presence of lithogenic factors.
2007 Bertenshaw
C, Watson AR, Lewis S, Smyth A. A survey of acute renal failure in cystic fibrosis
patients in the United Kingdom. Thorax 2007; 62:541-545. [PubMed]
Between 1997 and 2004, 26 of the 55 identified cases consented to data extraction
and 24 had acute renal failure (ARF). In 21 cases (88%) an aminoglycoside, usually
gentamicin was prescribed at the onset of ARF or in the preceding week. This
study implicates intravenous aminoglycosides, particularly gentamicin, in the
aetiology of acute renal failure in cystic fibrosis.
This is an important study of one of the long term complications of life-long
therapy with potentially toxic drugs such as aminoglycosides with particular
emphasis on the use of gentamicin. The use of routine intravenous gentamicin
for people with CF represents suboptimal therapy as it is less effective against
Pseudomonas, more ototoxic and more nephrotoxic than tobramycin. Many of the
treatments, used repeatedly for many years, have renal side effects including
cyclosporine, the immunosuppressant used after lung transplantation.
2007 Etherington
C. Bosomworth M. Clifton I. Peckham DG. Conway SP. Measurement of urinary N-acetyl-b-D-glucosaminidase
in adult patients with cystic fibrosis: before, during and after treatment with
intravenous antibiotics. J Cyst Fibros 2007; 6:67-73. [PubMed].
Patients
with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous
antibiotics due to repeated and prolonged courses of therapy. Routine methods
of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG)
is a lysosomal enzyme present in the renal proximal tubular cells, with increased
excretion an indicator of renal tubular dysfunction. Urinary NAG, creatinine,
serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the
first out-patient visit following treatment with tobramycin or colistin. Urinary
NAG levels were corrected for urinary creatinine and expressed as a NAG ratio.
Patients who received>1 course of intravenous antibiotics during the study
period were included in a separate analysis of the cumulative effect of treatment.
RESULTS: 88 patients (44 female, 31 with CFRD) completed a single course of
intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The
median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN
were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed
between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up.
A highly significant difference in NAG excretion was observed on day 14 for
tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference
in NAG excretion was seen in patients with CFRD at all measured time points.
Patients with CFRD had a significantly worse clinical status and had received
more days of intravenous antibiotics over the previous 6 years. In 20 (80%)
of 25 patients who received>1 course of treatment during the study period,
baseline NAG levels were significantly higher in subsequent courses (p<0.001).
There was a significant correlation between previous exposure to colistin and
baseline NAG levels (r=0.389, p<0.001). CONCLUSIONS: Both tobramycin and
colistin cause acute renal tubular injury with a significant rise in urinary
NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular
damage. Cumulative damage is evident with repeated dosing. Previous exposure
to nephrotoxic antibiotics, especially colistin, is associated with elevated
baseline NAG levels. We recommend that colistin is reserved for patients with
resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin.
Serial longitudinal NAG measurements may be useful in patients with CF, especially
those with CFRD, to identify patients at risk of developing renal disease.
Measurement of urinary NAG in relation to aminoglycoside treatment has been periodically studied since our first European conference report in 1984 (Miller MG et al. Nephrotoxicity of aminoglycosides. In: Lawson D ed. Cystic fibrosis: horizons. John Wiley & Sons Chichester 1984; 271; also Glass S et al. J Cyst Fibros 2005; 4:221-225. [PubMed]; Ring E et al. Arch Dis Child 1998; 78:540-543. [PubMed]). All studies have shown transient rises of urinary NAG during aminoglycoside treatment indicating some tubular injury which recovers after the treatment; although in the Miller et al study the rise in NAG was increasingly greater with each additional course of aminoglycosides. With increasing longevity of people with CF the cumulative effect of these repeated minor renal injuries are likely to become more relevant as evidenced by the increasing problem of renal failure in people with CF (Smyth A et al. Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008; 63:532-535.). In some, the effect of repeated courses of intravenous aminoglycosides is worsened by the immunosuppressive drugs required after lung transplantation
Interestingly, urinary NAG levels were observed to rise after prolonged nebulised gentamicin used (successfully it must be added) to prevent Pseudomonas infection in children with CF and considered to present a risk of renal toxicity (Ring et al. Arch Dis Child 1998; 78:540-543. [PubMed]). However, subsequent publications on the long term use of nebulised gentamicin in non-CF bronchiectasis consider there to be negligible absorption and the treatment suitable for children ( Twiss TJ et al, 2005 [PubMed] and adults (Murray M P, et al, 2010.[PubMed]). In the UK it is advised that both nebulised and intravenous gentamicin are avoided in people with CF (Antibiotic Treatment for Cystic Fibrosis. CF Trust 3rd edition 2009).
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