Johann Morelle

CONCOMITANT USE OF SIMVASTATIN AND AMIODARONE RESULTING IN SEVERE RHABDOMYOLYSIS: A CASE REPORT AND REVIEW OF THE LITERATURE

Abstract Myopathy, including rhabdomyolysis, is a well-known, albeit rare complication of statin therapy. Predisposing factors include comorbidities and the concomitant use of cytochrome P-450 (CYP) 3A4 inhibitors. We report a case of severe simvastatin-induced rhabdomyolysis triggered by the addition of amiodarone to previously well-tolerated chronic statin therapy. Physicians should be aware of the risk of this potentially severe drug interaction. The dose of simvastatin should be reduced (to 20 mg daily) when concomitant treatment with amiodarone is required, or preference should be given to pravastatin, rosuvastatin or fluvastatin, which are not metabolised by the CYP 3A4.

Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis

Encapsulating peritoneal sclerosis (EPS) is a rare but severe complication of peritoneal dialysis (PD) characterized by extensive fibrosis of the peritoneum. Changes in peritoneal water transport may precede EPS, but the mechanisms and potential predictive value of that transport defect are unknown. Among 234 patients with ESRD who initiated PD at our institution over a 20-year period, 7 subsequently developed EPS. We evaluated changes in peritoneal transport over time on PD in these 7 patients and in 28 matched controls using 3.86% glucose peritoneal equilibration tests. Compared with long-term PD controls, patients with EPS showed early loss of ultrafiltration capacity and sodium sieving before the onset of overt EPS. Multivariate analysis revealed that loss of sodium sieving was the most powerful predictor of EPS. Compared with long-term PD control and uremic peritoneum, EPS peritoneum showed thicker submesothelial fibrosis, with increased collagen density and a greater amount of thick collagen fibers. Reduced osmotic conductance strongly correlated with the degree of peritoneal fibrosis, but not with vasculopathy. Peritoneal fibrosis was paralleled by an excessive upregulation of vascular endothelial growth factor and endothelial nitric oxide synthase, but the expression of endothelial aquaporin-1 water channels was unaltered. Our findings suggest that an early and disproportionate reduction in osmotic conductance during the course of PD is an independent predictor of EPS. This functional change is linked to specific alterations of the collagen matrix in the peritoneal membrane of patients with EPS, thereby validating the serial three-pore membrane/fiber matrix and distributed models of peritoneal transport.

AqF026 Is a Pharmacologic Agonist of the Water Channel Aquaporin-1

Aquaporin-1 (AQP1) facilitates the osmotic transport of water across the capillary endothelium, among other cell types, and thereby has a substantial role in ultrafiltration during peritoneal dialysis. At present, pharmacologic agents that enhance AQP1-mediated water transport, which would be expected to increase the efficiency of peritoneal dialysis, are not available. Here, we describe AqF026, an aquaporin agonist that is a chemical derivative of the arylsulfonamide compound furosemide. In the Xenopus laevis oocyte system, extracellular AqF026 potentiated the channel activity of human AQP1 by >20% but had no effect on channel activity of AQP4. We found that the intracellular binding site for AQP1 involves loop D, a region associated with channel gating. In a mouse model of peritoneal dialysis, AqF026 enhanced the osmotic transport of water across the peritoneal membrane but did not affect the osmotic gradient, the transport of small solutes, or the localization and expression of AQP1 on the plasma membrane. Furthermore, AqF026 did not potentiate water transport in Aqp1-null mice, suggesting that indirect mechanisms involving other channels or transporters were unlikely. Last, in a mouse gastric antrum preparation, AqF026 did not affect the Na-K-Cl cotransporter NKCC1. In summary, AqF026 directly and specifically potentiates AQP1-mediated water transport, suggesting that it deserves additional investigation for applications such as peritoneal dialysis or clinical situations associated with defective water handling.

Tenofovir-related acute kidney injury and proximal tubule dysfunction precipitated by diclofenac : a case of drug-drug interaction

We describe an HIV1-positive patient under long-term tenofovir treatment who developed a severe, biopsy-proven, acute tubular necrosis with proximal tubule (PT) dysfunction, precipitated by the very recent start of diclofenac, a nonsteroidal antiinflammatory drug (NSAID). Recent studies show that NSAIDs not only alter glomerular filtration but also multidrug resistance protein (MRP) 4-mediated PT secretion of several substrates. Since the patient tolerated tenofovir well for several years prior to diclofenac use, our observation suggests that diclofenac interfered with tenofovir clearance, thereby favoring its nephrotoxicity. NSAIDs should be avoided in patients under tenofovir.

Estimating GFR in the oldest old: does it matter what equation we use?

In coming decades, the Western world will face an epidemic of ageing. This forthcoming ‘grey epidemic’ will lead to an explosion of chronic diseases like chronic kidney disease (CKD). CKD is an important public health problem for several reasons. First, the prevalence of CKD is high [1], especially among patients aged 70 years and older [2]. Second, knowledge of the actual glomerular filtration rate (GFR) of a patient has important consequences in terms of medication, as the dosages of many drugs should be adapted according to renal function [3]. Finally, the cost and the burden of renal replacement therapy are high. Measurement of the GFR is the gold standard index of overall kidney function. Several equations derived from endogenous filtration markers were developed to estimate this GFR. However, the most accurate method for estimating GFR, especially in elderly patients, is topic of on-going debate [4]. A recent systematic review [5] showed that the modification of diet in renal disease (MDRD) equation [6] does not differ appreciably from the Cockcroft–Gault equation [7] in terms of the accuracy with which GFR is estimated and that there is limited but promising evidence concerning serum cystatin C level as a biomarker of kidney function in the oldest of the old [8, 9]. In the absence of well-validated equations, a variety of equations are currently used in research as well as in clinical practice to estimate GFR in the elderly. Therefore, this study was designed to determine differences in GFR estimated according to various equations in elderly patients and to investigate the clinical relevance of these differences at an individual patient level.

Periostin: a matricellular protein involved in peritoneal injury during peritoneal dialysis.

♦ Background: Periostin is a matricellular protein involved in tissue remodeling through the promotion of adhesion, cell survival, cellular dedifferentiation, and fibrogenesis. It can be induced by transforming growth factor beta and high glucose concentrations. We hypothesized that this protein might be expressed in the peritoneal cavity of patients on peritoneal dialysis (PD) and even more in patients with signs of encapsulating peritoneal sclerosis (EPS). ♦ Method: In this retrospective study, we included peritoneal biopsies from patients on PD with EPS (n = 7) and without signs of EPS (n = 10), and we compared them with biopsies taken during hernia repair from patients not on PD (n = 11) and during various procedures from uremic patients not on PD (n = 6). Periostin was localized by immunohistochemistry, scored semiquantitatively, and quantified by morphometry. Periostin protein concentrations were measured by ELISA in dialysates from 15 patients. Periostin messenger RNA was quantified in vitro in peritoneal fibroblasts. ♦ Results: In control biopsies, periostin was present in the walls of larger arteries and focally in extracellular matrix in the submesothelial zone. Patients on PD demonstrated interstitial periostin in variable amounts depending on the severity of submesothelial fibrosis. In EPS, periostin expression was very prominent in the sclerosis layer. The area of periostin was significantly larger in EPS biopsies than in control biopsies, and the percentage of periostin-positive area correlated with the thickness of the submesothelial fibrosis zone. Periostin concentrations in dialysate increased significantly with time on PD in patients without signs of EPS; in patients with EPS, periostin concentrations in dialysate were low and demonstrated the smallest increase with time. In vitro, periostin was found to be strongly expressed by peritoneal fibroblasts. ♦ Conclusion: Periostin is strongly expressed by fibroblasts and deposited in the peritoneal cavity of patients with EPS and with simple peritoneal fibrosis on PD. This protein might play a role in the progression of peritoneal injury, and low levels of periostin after prolonged time on PD might be a marker of EPS.

Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome

Background Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. Methods Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. Results HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. Conclusions We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.

Length of time on peritoneal dialysis and encapsulating peritoneal sclerosis : position paper for ISPD : 2017 update

Imperial College Renal and Transplant Centre,1 Hammersmith Hospital, London, UK; University Health Network and the University of Toronto,2 Toronto, ON, Canada; Renal Division,3 Ghent University Hospital, Ghent, Belgium; Kidney Research Center,4 Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Yale School of Medicine,5 New Haven, CT, USA; Central Manchester and Manchester Children’s NHS Foundation Trust,6 Manchester, UK; Department of Nephrology,7 University of Queensland at Princess Alexandra Hospital, Brisbane, Australia; Tsuchiya General Hospital,8 Faculty of Medicine, Hiroshima University, Japan; Institute for Applied Clinical Sciences,9 Keele University, Stoke-on-Trent, UK; Pontificia Universidade Catolica do Parana,10 Curitiba, Parana, Brazil; Division of Nephrology,11 Cliniques universitaires Saint-Luc, Brussels, Belgium, et Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; and St James’s University Hospital,12 Leeds, UK ISPD GUIDELINES/RECOMMENDATIONS

Complement activation and effect of eculizumab in scleroderma renal crisis.

Background:Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved. Methods:Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. Results:Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab.Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. Conclusion:SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors.

Water and solute transport across the peritoneal membrane

Purpose of reviewWe review the molecular mechanisms of peritoneal transport and discuss how a better understanding of these mechanisms is relevant for dialysis therapy. Recent findingsPeritoneal dialysis involves diffusion and osmosis through the highly vascularized peritoneal membrane. Computer simulations, expression studies and functional analyses in Aqp1 knockout mice demonstrated the critical role of the water channel aquaporin-1 (AQP1) in water removal during peritoneal dialysis. Pharmacologic regulation of AQP1, either through increased expression or gating, is associated with increased water transport in rodent models of peritoneal dialysis. Water transport is impaired during acute peritonitis, despite unchanged expression of AQP1, resulting from the increased microvascular area that dissipates the osmotic gradient across the membrane. In long-term peritoneal dialysis patients, the fibrotic interstitium also impairs water transport, resulting in ultrafiltration failure. Recent data suggest that stroke and drug intoxications might benefit from peritoneal dialysis and could represent novel applications of peritoneal transport in the future. SummaryA better understanding of the regulation of osmotic water transport across the peritoneum offers novel insights into the role of water channels in microvascular endothelia, the functional importance of structural changes in the peritoneal interstitium and the transport of water and solutes across biological membranes in general.