Management of comorbidities in older patients with cystic fibrosis

Plant, Barry J.; Goss, Christopher H.; Plant, W.D.; Bell, Scott C.

doi:10.1016/s2213-2600(13)70025-0

Cited by 87 publications

(88 citation statements)

References 106 publications

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“…These exciting advances changed the clinical history of these patients and revealed novel disease-or therapy-related problems including renal dysfunction [30,31]. Muscular dystrophies are among the most common single gene disorders with DMD being the most frequent form affecting 1 of 3500 to 6000 newborn males.…”

Section: Discussionmentioning

confidence: 99%

Renal function in children and adolescents with Duchenne muscular dystrophy

Braat

Hoste

Waele

et al. 2015

Neuromuscular Disorders

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Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5-22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement ( 51 Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure >P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73 m 2 . Hyperfiltration (mGFR >150 mL/min/1.73 m 2 ) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R 2 = 0.45, p = 0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73 m 2 ). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass.

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Section: Discussionmentioning

confidence: 99%

Renal function in children and adolescents with Duchenne muscular dystrophy

Braat

Hoste

Waele

et al. 2015

Neuromuscular Disorders

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“…Of note, despite the abundant expression of CFTR in mammalian kidney which is localized at the apical surface of proximal tubules and distal tubules 28 , no overwhelming primary renal disease has been associated with CF. Nevertheless, as CF patients age and have an increased exposure to potentially nephrotoxic agents, such as antibiotics and high glucose, development of chronic renal disease has been commonly recognized 29, 30 . Given that CF-related nephropathies are frequently compounded by increasing age, pulmonary infection, malnutrition, liver dysfunction and insulin insufficiency 31 , chronic kidney damage has been considered as secondary manifestation due to the abnormalities in salt transport, infection, and development of cystic fibrosis related diabetes (CFRD) 29, 32 .…”

Section: Introductionmentioning

confidence: 99%

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis

Zhang

Wang

Chen

et al. 2017

Sci Rep

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Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl − channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in EpithelialMesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.Kidney fibrosis is a common histological manifestation of functional decline in most cases of end-stage kidney diseases. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation, leading to myofibroblast activation and an accumulation of extracellular matrix (ECM) [1][2][3] . While the cellular origin of myofibroblasts remains to be a subject of intensive debate, numerous animal and clinical studies have pointed to epithelial-to-mesenchymal-transition (EMT) from the tubular epithelial cells as one of the major contributors leading to the generation of myofibroblasts and overproduction of interstitial ECM 4-9 . A multitude of biochemical signaling pathways has been proposed to be associated with the development of kidney fibrosis [10][11][12] . While Wnt/β-catenin signaling is functionally important in normal kidney development 13, 14 , aberrant activation of Wnt/β-catenin signaling and subsequent downstream targets, such as matrix metalloproteinases (MMPs), fibronectin and snail, has been observed in the progression of tubulointerstitial kidney fibrosis in unilateral ureteral obstruction (UUO) model [15][16][17] and different types of kidney diseases [18][19][20][21] . Of interest, β-catenin is predominantly up-regulated in renal tubular epithelium of the fibrotic kidneys, suggesting that tubular cells are the major targets of canonical Wnt signaling. In addition, activation of β-catenin in tubular epithelial cells induces EMT, as well as the expression of several fibrosis-related genes in vitro [22][23][24] . These results suggest that activation of tubular β-catenin probably plays a critical role in the pathogenesis and progression of...

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“…CF-related diabetes, metabolic bone disease and multidrug-resistant pulmonary pathogens are some comorbidities in older CF patients (Plant et al, 2013). Although still uncommon, adult CF patients have a higher risk of gastrointestinal cancer compared to an age-matched non-CF population (Maisonneuve et al, 2013), which may be explained by the fact that CFTR is a tumor suppressor gene (Than et al, 2016).…”

Section: Life Expectancy In Cystic Fibrosismentioning

confidence: 99%

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

2016

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Cystic fibrosis (CF) is the most common life-threatening monogenic disease aﬄicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients.

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Management of comorbidities in older patients with cystic fibrosis

Cited by 87 publications

References 106 publications

Renal function in children and adolescents with Duchenne muscular dystrophy

Renal function in children and adolescents with Duchenne muscular dystrophy

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

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