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. [PubMed]).
1985 Castile R, Shwachman H, Travis W, Hadley CA, Warwick W, Missmahl HP. Amyloidosis as a complication of cystic fibrosis. Am J Dis Child 1985; 139:728-732. [PubMed]
Three patients with amyloidosis complicating CF are reported to add to the six patients previously recorded. The presenting problem was proteinuria in five patients, enlarged thyroid in three patients, and hepatosplenomegaly in one patient. The progression of proteinuria to nephrotic syndrome and oedema occurred in eight of the nine patients and indicated a very poor prognosis. The kidneys, adrenal glands, spleen, thyroid gland, liver, heart, and bowel were most frequently involved. Renal involvement was a frequent and devastating complication of amyloidosis in patients with cystic fibrosis.
Amyloidosis is a surprisingly rare complication of cystic fibrosis considering the severity and duration of pulmonary sepsis in most patients.Two cases had been reported by Ristow SC, et al, 1977; 131:886-888 [PubMed]) and others have been reported subsequently. Often renal or thyroid problems are associated.
1994 Sawyer S, Bowes G, Phelan PD. Vulvovaginal candidiasis in young women with cystic fibrosis. BMJ 1994; 308:1609. [PubMed]
Vulvovaginal candidiasis was more common in 55 women with CF than in controls (13 vs.4) and more difficult to treat. Many women with CF had recognized the association of the Candida infection with their use of antibiotics. The authors suggested women with CF should be given routine advice about the possibility of candidiasis.
This was an important paper as it is unlikely that women would be asked about such problems in a busy CF clinic for adults which are often “chest orientated” – yet adequate treatment of the candidiasis would significantly improve the patient’s quality of life. Somewhat analogous to this problem was the later recognition of the increased incidence of urinary incontinence in women with CF (see Cornacchia et al, 2001).
2001 Cornacchia M, Zenorini A, Perobelli S, Zanolla L, Mastella G, Braggion C. Prevalence of urinary incontinence in women with cystic fibrosis. BJU Internat 2001; 88: 44-48. [PubMed]
Of 176 women with CF, 41% were never incontinent, 35% were occasionally incontinent of urine but 24% of women were regularly incontinent. As urine loss is likely to be an under-reported problem, particularly in a CF clinic devoted to mainly chest problems, the authors suggest that women with CF should be asked directly about urinary incontinence as part of their routine follow-up. Pelvic floor muscle exercises were said to help. Also there was a similar report from Manchester Adult CF clinic (Orr A et al. BMJ 2001; 322:1521.[PubMed]).
These are really useful reports which would improve the recognition of a distressing and relatively common symptom in women with CF which may go unreported and cause considerable distress for many years.
2002 Hoffmann IM, Rubin BK, Iskandar SS, Schechter MS, Nagaraj SK, Bitzan MM. Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Pediatr Pulmonol 2002; 34:375-377. [PubMed]
A report of a 20-year-old patient with cystic fibrosis who developed acute nonoliguric renal failure associated with inhaled tobramycin. Clinical evaluation and renal biopsy findings were consistent with aminoglycoside-induced changes.
Renal failure due to inhaled aminoglycosides has not been previously reported. The incidence may rise, however, with the increased use of this treatment modality. Measurable tobramycin levels due to inhalational therapy with conventional dosing in the reported patient indicate that the drug can be systemically absorbed, and renal tubular toxicity may occur.
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] )
2000 Cornacchia M, Zenorini A, Perobelli S, Zanolla L, Mastella G, Braggion C. Prevalence of urinary incontinence in women with cystic fibrosis. BJU Internat 2001; 88: 44-48. [PubMed]
Of 176 women with CF, 41% were never incontinent, 35% were occasionally incontinent of urine but 24% of women were regularly incontinent.
As urine loss is likely to be an under-reported problem, particularly in a CF clinic devoted to mainly chest problems, the authors suggest that women with CF should be asked directly about urinary incontinence as part of their routine follow-up. Pelvic floor muscle exercises were said to help.
Also there was a similar report from Manchester Adult CF clinic (Orr A et al. BMJ 2001; 322:1521.[PubMed]).
These are really useful reports which would improve the recognition of a distressing and relatively common symptom in women with CF which may go unreported and cause considerable distress for many years.
2002 Heinzl B, Eber E, Oberwaldner B, Haas G, Zach MS. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2002; 33:32-37. [PubMed]
Inhaled antibiotics are an established treatment for chronic Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis (CF). However, inhaled antibiotics might also have prophylactic potential to delay acquisition of PA in early stages of the disease. From 1986-1989, all CF patients at this Austrian centre who experienced defined risk situations for acquisition of PA (28 patients) received inhaled gentamicin (80 mg BID for those < 12 months; 120 mg BID for those > 12 months) for a minimum of 3 years. Twelve patients had repeated risk situations and continued this prophylaxis without interruption during the entire study period (group 1). In the remaining 16 patients, inhaled antibiotics were discontinued at various times for a variety of reasons (group 2).
None of the patients in group 1, but 7 in group 2, became chronically infected with PA (P = 0.01). Lung function and chest X-ray scores were significantly worse in those 7 infected patients, when compared to the non infected ones in both groups. This suggests that long-term-prophylaxis with inhaled gentamicin can effectively delay acquisition of PA and decrease disease progression in children with CF.
This study from Austria appeared to start the year after the first report of eradication of early P. aeruginosa in 1985 (Littlewood JM et al. 1985. above). The treatment appeared to be very effective in avoiding chronic infection. However, a previous study of urinary NAG levels from the same group suggested some renal involvement so the gentamicin was stopped in some patients (Ring E, Eber E, Erwa W, Zach M. Urinary N-acetyl-beta-D-glucosaminidase activity in patients with cystic fibrosis on long term gentamicin inhalation. Arch Dis Child 1998; 78:540-543.[PubMed]).
2003 Drew J, Watson AR, Smyth A. Acute renal failure and cystic fibrosis. Archives of Disease in Childhood. 2003; 88:646. [PubMed] free PMC article
The authors, noticing the paucity of earlier reports of renal failure draw attention to a recent e-mail survey of members of the British Association for Paediatric Nephrology which revealed four cases of acute renal failure with combination antibiotic therapy in CF patients (three of four with ceftazidime and gentamicin). They suggest the increased incidence points to the need for increased vigilance when gentamicin and cephalosporin combinations are used to treat exacerbations, particularly if there is a potentially dehydrating state or pre-existing renal anomaly.
Further work was published confirming the occurence of renal failure in CF and the relationship to the use of intravenous gentamicin (Bertenshaw C et al. Thorax 2007; 62:541-545.[PubMed]; Smyth A et al. Thorax 2008; 63:532-535.[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.
The authors describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. They 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. The authors describe the first report of a lung transplant recipient who developed renal failure and vestibular injury after receiving inhaled tobramycin. They 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 intravenous gentamicin plus ceftazidime.
Neither IV nor inhaled gentamicin is now recommended in treating people with CF.
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 Prasad SA, Balfour-Lynn IM, Carr SB, Madge SL. A comparison of prevalence of urinary incontinence in girls with cystic fibrosis, asthma and healthy controls. Pediatr Pulmonol 2006; 41:1065-1068. [PubMed]
Another study on urinary incontinence – this time on younger patients. In recent years the physiotherapists have taken an increasing interest in bladder dysfunction in CF. Girls with CF aged 11 to 17 years were studied and urinary incontinence was reported by 17/51 (33%) girls, compared with only 4/25 (16%) of those with asthma and 2/27 (7%) healthy controls. The problem was associated with increasing severity of lung disease. (also described in adults with CF by Cornacchia et al, 2001 above[PubMed]; Orr A et al. BMJ 2001; 322:152.[PubMed]; and treatment discussed by McVean RJ et al. J Cyst Fibros 2003; 2:171-176.[PubMed])
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. Nephrol Dial Transpl 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.
The authors 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 previous 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).
2010 Andrieux A, Harambat J, Bui S, Nacka F, Iron A, Llanas B Fayon M. Renal impairment in children with cystic fibrosis. J Cyst Fibros 2010; 9:263-268. [PubMed]
A single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasis risk factors were assessed. The median calculated GFR (Schwartz) was 123, 161 and 155ml/min/1. 73m(2) in children aged 1, 6 and 15years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreatic insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively.
The authors concluded that renal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. A further study showing the potential for renal problems in children – presumably leading to the increasingly frequent renal problems reported in CF adults
2010 Guy EL, Bosomworth M, Denton M, Conway SP, Brownlee KG, Lee TW. Serum tobramycin levels following delivery of tobramycin (TOBI) via eFlow advanced nebuliser in children with cystic fibrosis. J Cyst Fibros 2010; 9:292-295. [PubMed]
Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow.Ten children (ages 2-16 years) receiving 300mg TOBI via eFlow for clinical reasons participated. Serum tobramycin levels were obtained 1hour post nebulisation. Nine children provided samples for urinary NAG, and 10 underwent audiology.Tobramycin levels were >1mg/L in 3 children (maximum 3. 8, 2 children aged 2 years). Urine NAG/creatinine levels were raised (>0. 94micromol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss.
The authors concluded that serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.
These results are worrying in view of the fact that the inhaled aminoglycosides are given for prolonged periods of time. Whether the “month on month off” regimen allows complete recovery of the renal tissue is unclear. Also it has been known for decades that the renal effects are to some extent cumulative. To this reviewer 300 mg bd of inhaled tobramycin has always seemed a very high dose when other studies have shown that 80 mg bd of tobramycin will prevent and eradicate early P. aeruginosa infection (Wiesemann HG et al. Pediatr Pulmonol 1998; 25:88-92. [PubMed]).
2013 Nazareth D. Walshaw M. A review of renal disease in cystic fibrosis. J Cyst Fibros 2013; 12:309-17. [PubMed]
Kidney disease is becoming increasingly common in CF. This review looks at the effect of CFTR on the kidney, the problems with measuring renal function effectively in CF, the causes and incidence of renal dysfunction, and its pathophysiology. Strategies to reduce aminoglycoside toxicity are discussed.
This is a fully referenced detailed review of an increasing problem in older people with CF.
2013 Anand A. Tullis E. Stephenson A. Nickel JC. Leveridge MJ. Pseudomonas aeruginosa bacteremia and prostatitis in a patient with cystic fibrosis. Canadian Urological Association Journal. 2013; 7:E1-3. [PubMed]
Patients with cystic fibrosis (CF) commonly suffer chronic respiratory infections, although systemic dissemination is relatively rare. Acute bacterial prostatitis presents dramatically and is believed to be mostly caused by local migration (with or without instrumentation) of the lower urinary tract and presents with a predictable microbial etiology. We report a case of a 26-year-old man presenting with acute Pseudomonas aeruginosa bacterial prostatitis due to hematogenous propagation from a chronic pulmonary infection.
2015 Wilcock MJ, Ruddick A, Gyi KM, Hodson ME. Renal diseases in adults with cystic fibrosis: a 40 year single centre experience. J Nephrol. 2015 Oct;28(5):585-91. doi: 10.1007/s40620-015-0179-z. Epub 2015 Feb 25 [PubMed]
In this study the authors report for the first time on the prevalence of all forms of renal disease in a cystic fibrosis population using a retrospective review of adult patients attending the Adult Cystic Fibrosis Department at the Royal Brompton Hospital.
The prevalence of all renal diseases in their population was 5.1%. The most commonly identified problem was renal stones. At 2.0% the prevalence of renal stones in adult patients with cystic fibrosis was comparable to the general population. A range of other renal diseases were identified, the next most common being drug-induced acute kidney injury.
2015 Reichman G, De Boe V, Braeckman J, Michielsen D. Urinary incontinence in patients with cystic fibrosis. Scand J Urol. 2015 Oct 19:1-4. [Epub ahead of print] [PubMed]
Questionnaires were used to determine the prevalence of incontinence in patients of the Cystic Fibrosis Clinic of the University Hospital in Brussels. Questionnaires were completed by 122 participants aged 6-59 years, showing an overall prevalence of 27% for urinary incontinence. Mainly adults reported urinary incontinence, with a prevalence of 11% in men and 68% in women aged 12 and above. The amount of urinary leakage was usually only a few drops and coughing mainly triggered it. Many of the participants had never mentioned this symptom to anyone.
– As in previous studies, the problem was particularly frequent in women with CF. It is relevant that a quarter of this study population refrained from coughing up phlegm and from physiotherapy. This may adversely affect their respiratory condition. So it is important to actively question and inform about this problem, to enable its detection and treatment.
Wilcock MJ, Ruddick A, Gyi KM, Hodson ME. Renal diseases in adults with cystic fibrosis: a 40 year single centre experience. J Nephrol. 2015 Oct;28(5):585-91. doi: 10.1007/s40620-015-0179-z. Epub 2015 Feb 25. 25712235 [PubMed]
The authors note there is a sizable literature describing renal disease in patients with cystic fibrosis. Previous studies have focused on single disease processes alone, most commonly renal stone disease or acute kidney injury. In this study we report for the first time on the prevalence of all forms of renal disease in a cystic fibrosis population.METHODS:
A retrospective review of adult patients with cystic fibrosis attending the Adult Cystic Fibrosis Department at the Royal Brompton Hospital was carried out by searching the department’s database to identify patients with renal problems and subsequently retrieving clinical information from medical notes.
The prevalence of all renal diseases in our population was 5.1 %. The most commonly identified problem was renal stones. At 2.0 % the prevalence of renal stones in adult patients with cystic fibrosis was comparable to the general population. A range of other renal diseases were identified, the next most common being drug-induced acute kidney injury.
The authors note a range of cystic fibrosis independent and attributable diseases has been identified but no cystic fibrosis specific disease. In contrast to other cystic fibrosis centres no increased prevalence of renal stones was found.
2015 Kellermann G, Anastasiadis AG, Dräger DL, Prall F, Hakenberg OW. Urinary Retention Due to Severe Pseudocystic Mucoid Degeneration of the Prostatic Matrix: A Rare Urologic Manifestation of Cystic Fibrosis. Urol Int. 2015 Feb 20. [Epub ahead of print] [PubMed]
Urologic manifestations of CF include infertility and azoospermia, nephrolithiasis, and stress urinary incontinence. In this report, the authors describe a 33-year-old male, who presented with recurrent urinary retention due to prostatic enlargement despite his young age. After transurethral resection, the voiding problems resolved. Histopathological examination revealed a severe pseudocystic mucoid degeneration of the prostatic matrix as a cause of his subvesical obstruction. Although these structural changes are most probably due to his underlying disease, detailed histologic features have not been described in the literature.
2017 Berg KH, Ryom L, Faurholt-Jepsen D, Pressler T, Katzenstein TL. Prevalence and characteristics of chronic kidney disease among Danish adults with cystic fibrosis. J Cyst Fibros. 2017 Nov 27. pii: S1569-1993(17)30958-X. doi: 10.1016/j.jcf.2017.11.001. [Epub ahead of print] [Pubmed]
With improved prognosis of CF, co-morbidities including chronic kidney disease (CKD) are becoming increasingly important. Identification of those at highest CKD risk is hence a priority. In this cross-sectional study, adults with CF attending the Copenhagen CF Centre at Rigshospitalet with ≥2 measurements of serum creatinine from 2013 to 2015 were included. Data was obtained from an electronic CF database, which contains anonymised clinical and laboratory data on all individuals attending the clinic. CKD was defined as a confirmed (≥3months apart) estimated glomerular filtration rate≤60mL/min/1.73m2.
Of 181 individuals, the CKD prevalence was 2.7% and increased to 11% after inclusion of lung transplanted patients. Individuals with CKD were generally older (median 39 (IQR, 36-45) vs. 31 (IQR, 24-39) years; p<0.001), diabetic (86% vs. 41%, p<0.001), with longer median duration of chronic pulmonary infection (28.3 (20.0-35.8) vs. 20.0 (9.9-34.7) years; p=0.008) and with longer intravenous aminoglycosides use (606 (IQR, 455-917) vs. 273 (IQR, 91-826) days, p=0.005).
– The chronic kidney disease prevalence is high and related to age, diabetes, chronic infection, transplantation and aminoglycosides use. The authors suggest their observations call for longitudinal studies investigating CKD predictors in adults with CF.
2017 Knauf F, Thomson RB, Heneghan JF, Jiang Z, Adebamiro A,Asplin JR, Egan ME, Alper SL, Aronson PS. Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion. J Am Soc Nephrol. 2017 Jan;28(1):242-249. doi: 10.1681/ASN.2016030279. Epub 2016 Jun 16. [Pubmed]
Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. The authors used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. In association with the profound defect in intestinal oxalate secretion, Cftr-/- mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice.
The authors concluded that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. They suggest future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
– The reported incidence of renal stones and nephrocalcinosis in CF is between 3% and 6% compared to 1% to 2% in age-matched controls.
2017 Stehling F, Büscher R, Grosse-Onnebrink J, Hoyer PF, Mellies U. Glomerular and Tubular Renal Function after Repeated Once-Daily Tobramycin Courses in Cystic Fibrosis Patients. Pulm Med. 2017;2017:2602653. doi: 10.1155/2017/2602653. Epub 2017 Jan 4. [PubMed] Free PMC Article
Introduction. Antibiotic treatment regimens against Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies. Methods. In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3 ± 10.1 (1-57)) in a once-daily dosing regimen and 10 who did not. Results. Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses. Conclusion. Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.
Dr Florian Stehling is from the University Children’s Hospital Essen, Germany
Santoro D, Postorino A, Lucanto C, Costa S, Cristadoro S, Pellegrino S, Conti G, Buemi M, Magazzù G, Bellinghieri G. Cystic Fibrosis: A Risk Condition for Renal Disease. Ren Nutr. J 2017 Nov;27(6):470-473. doi: 10.1053/j.jrn.2017.05.006. [PubMed]
Renal disease is reported as a relatively rare complication in adult patient with CF. The authors evaluated proteinuria and chronic renal failure (CRF) in a population of patients with CF. A retrospective study was carried out in a referral center for CF at University of Messina in Italy. They identified all patients with renal disease, characterized by proteinuria and/or CRF, during the period 2007 to 2012 and reviewed their medical records to assess influence on renal disease of genotype, number of pulmonary exacerbation, pancreatic insufficiency, pulmonary function, CF-related diabetes, and antibiotics courses. From a population of 77 adult patients with CF, they identified 9 patients with proteinuria (11.7%), and 11 patients (14.28%) with CRF. Mean age was 35.6 (+5.1 standard deviation) years, 55% were female and 33% had diabetes mellitus. Renal biopsy was performed in 3 patients because of nephrotic syndrome in 1 patient and proteinuria with renal failure in the other 2 patients. Renal amyloidosis was disclosed in 2, whereas IgA nephropathy in 1 patient. The ΔF508 mutation in homozygosis was present in 44% of patients with proteinuria (vs. 27% of our CF population, relative risk 2.07), whereas genotype ΔF508/N1303K in 22%. ΔF508 allele mutation was present in 77.7% of proteinuric patien
The authors concluded their study a higher prevalence of renal disease in patients with CF, than was previously described. The main reason may be related to increased life expectancy because of better management. Moreover, patients with ΔF508 homozygosis had higher risk of proteinuria.
Prof. Domenico Santoro is from the Department of Clinical and Experimental Medicne University Hospital AOU G, Messina, Italy
Nowakowski ACH. Cystic Fibrosis Kidney Disease: 10 Tips for Clinicians. Front Med (Lausanne). 2018 Aug 28;5:242. doi: 10.3389/fmed.2018.00242. eCollection 2018.[PubMed] Free PMC Article
Increased longevity in people with cystic fibrosis (CF) means that more people are surviving long enough to develop kidney complications. Nephrologists and their colleagues now face a steep learning curve as many of them encounter patients with CF related kidney disease (CFKD) for the first time. This article presents perspectives from a medical sociologist with CF on what renal health professionals should know about people with CFKD. It outlines challenges that people with CFKD as they age, framing these struggles as opportunities for clinicians to help these unique patients achieve and maintain their best possible quality of life.
Alexandra C H Nowakowski is a Medical sociologist and public health program evaluator living with cystic fibrosis. She studies the experience and management of chronic health conditions across the life course. Using mixed methods and diverse literatures, she explores how people age with and adjust to persistent health challenges. She focuses on social epidemiology, consequences of health, illness and identity, population health disparities, community based participatory research, and patient perspectives.
– The full article can be recommended.
Al-Aloul M, Nazareth D, Walshaw M. The renoprotective effect of concomitant fosfomycin in the treatment of pulmonary exacerbations in cystic fibrosis Clin Kidney J. 2019 Feb 7;12(5):652-658. doi: 10.1093/ckj/sfz005. eCollection 2019 Oct. [Pubmed] Free PMC Article
Fosfomycin, effective in Cystic Fibrosis (CF), competes with aminoglycosides at renal binding sites and may therefore afford a renoprotective effect when used in combination therapy. We explored this by using markers of acute renal tubular damage [N-acetyl-β-d-glucose-aminidase (NAG), alanine amino-peptidase (AAP) and β2-microglobulin]. Using a prospective randomized crossover trial design, at an acute pulmonary exacerbation, 18 adult CF patients received either 14 days of intravenous (IV) tobramycin or IV tobramycin and IV fosfomycin, both in combination with a second IV antibiotic (colomycin).
Urinary NAG (P = 0.003) and AAP (P = 0.03) following treatment with concomitant fosfomycin were lower than those after treatment with tobramycin and colomycin alone. Fosfomycin attenuated the total 24-h urinary protein leak (P = 0.0001). The 14-day improvements in all surrogate markers of exacerbation resolution (FEV1% predicted, FVC, white cell count and C-reactive protein) were similar for both treatment regimens.
The authors concluded the addition of fosfomycin reduces acute renal injury caused by IV aminoglycoside therapy in CF pulmonary exacerbations.
Dr M Al-Aloul is at Manchester University NHS Foundation Trust, Wythenshawe, UK, and the School of Biological Sciences, University of Manchester
Lai S, Mazzaferro S, Mitterhofer AP, Bonci E, Marotta PG. Pelligra F, Murciano M, Celani C, Troiani P, Cimino G, Palange P. Renal involvement and metabolic alterations in adults patients affected by cystic fibrosis. J Transl Med. 2019 Nov 25;17(1):388. doi: 10.1186/s12967-019-02139-4.[Pubmed] Free PMC Article
To evaluate the incidence, the manifestations of renal disease and the possible association with metabolic and endothelial dysfunction markers in the CF population. The authors performed a cross-sectional, observational study on 226 CF patients. Clinical and laboratory instrumental parameters (metabolic, inflammatory and endothelial dysfunction markers) were evaluated.They showed 65 patients with chronic kidney disease (CKD) and 158 patients with a reduced value of forced expiratory volume in 1 s (FEV1), of which 58 patients with a severe reduction of FEV1. Moreover 28 patients had undergone lung transplantation and them had a significant lower estimated Glomerular Filtration Rate (eGFR) with respect to the non-transplanted patients (p < 0.001). We reported also a significant association between lower eGFR value and serum triglycerides, total cholesterol and low-density lipoproteins (LDL) (p = 0.005, p < 0.001, p = 0.040; respectively), with a significant negative correlation between eGFR and serum triglycerides (r = - 0.28; p < 0.01). Moreover we found a significant association between lower eGFR value and serum uric acid (SUA) (p = 0.005), while we did not found an association with 25-hydroxy-vitamin-D value, serum glucose and hemoglobin A1c levels.
Their study showed a high prevalence of CKD in CF patients. Moreover they showed an increase of endothelial dysfunction and metabolic indexes in patients with reduced renal function, as SUA, serum triglycerides and LDL, suggesting the need for an early and complete screening of the main metabolic indexes to reduce cardiovascular risk and progression of renal damage, in particular in patients with lung transplant.
Dr Silvia Lai is at the Department of Translational and Precision Medicine, Nephrology and Dialysis Unit, “Sapienza” University of Rome,
Joseph Moryousef, Justin Kwong, Teruko Kishibe, Michael Ordon. Systematic Review of the Prevalence of Kidney Stones in Cystic Fibrosis. J Endourol 2021 Apr 28. doi: 10.1089/end.2021.0151. Online ahead of print.[Pubmed]
A study to investigate the prevalence of urolithiasis in cystic fibrosis (CF) and to summarize the available clinical features within this unique population. [for full details please see PubMed abstract)
The overall prevalence of stone formation in the CF population was 4.6% (137/2,982). The mean age of diagnosis was 25.1 ± 9.6 and ranged from 0.25 – 47. Ultrasound was the most common imaging modality for kidney stone diagnosis. There was no apparent sex difference, with a female to male ratio of 1:1. Surgical intervention was required in 37.8% (34/90) of cases. Stone recurrence was reported in 42.9% (33/77) of stone formers
Mr Joseph Moryousef of McGill University, Montreal, Quebec, Ca
Peder Berg, Majbritt Jeppesen, Jens Leipziger. Cystic fibrosis in the kidney: new lessons from impaired renal HCO3- excretion. Curr Opin Nephrol Hypertens 2021 Jul 1;30(4):437-443.doi: 10.1097/MNH.0000000000000725. [Pubmed]
Purpose of review: A key role of cystic fibrosis transmembrane conductance regulator (CFTR) in the kidney has recently been uncovered. This needs to be integrated into the understanding of the developed phenotypes in cystic fibrosis (CF) patients.
Recent findings: In the beta-intercalated cells of the collecting duct , CFTR functions in very similar terms as established in the exocrine pancreatic duct and both CFTR and SLC26A4 (pendrin) orchestrate regulated HCO3- secretion. Like in the pancreas, the hormone secretin is a key agonist to activate renal HCO3- secretion. In mice lacking CFTR or pendrin, acute and chronic base challenges trigger marked metabolic alkalosis because collecting duct base secretion is defective. Also in CF patients, the ability to acutely increase renal HCO3- excretion is markedly reduced.
Summary: The now much enlarged understanding of CFTR in the kidney may permit the measurement of challenged urine HCO3- excretion as a new biomarker for CF. We suggest a new explanation for the electrolyte disorder in CF termed Pseudo-Bartter Syndrome. The hallmark electrolyte disturbance features of this can be well explained by a reduced function of collecting duct Cl-/HCO3- exchange. Eventually, we suggest the diagnostic term distal renal tubular alkalosis to cover those disturbances that causes metabolic alkalosis by a reduced collecting duct base secretion.
Dr Peder Berg is in the Department of Biomedicine, Physiology, Health, Aarhus University, Aarhus, Denmark. For this work he was awarded the Gerd Döring award of the ECFS in 2021