Yassine Bouatou

Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity

BackgroundVoriconazole is metabolized by cytochrome P450 (CYP) 2C19 and CYP 3A4. Drug-drug interactions and genetic polymorphisms modulate their activities.Case presentationA 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range.ConclusionThe integration of drug-drug interactions and pharmacogenetics data is crucial to interpret drug concentrations correctly, thus preventing suboptimal exposure to voriconazole.

Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction

Objectives A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure–a measure of diastolic LV dysfunction–increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the distribution of active and inactive MGP in human myocardium. Methods We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss. Results Among Flemish and Swiss, E/e’ (6.78 vs. 6.73) and dp-ucMGP (3.94 μg/L vs. 4.20 μg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e’ increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P≤0.026); the odds ratios for having E/e’ ≥ 8.5 were 1.99, 3.29 and 2.36, respectively (P≤0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P≤0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 μm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field). Conclusions Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure.

Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR.

Atypical Hemolytic Uremic Syndrome Recurrence after Renal Transplantation: C3-Glomerulonephritis as an Initial Presentation

Abstract Risk for atypical hemolytic uremic syndrome (aHUS) recurrence after renal transplantation is low with an isolated membrane cofactor protein mutation (MCP). We report the case of a 32-year-old woman with a MCP who underwent kidney transplantation with a good evolution at 12 months. At 15 and 35 months, 2 episodes of thrombotic microangiopathy (TMA), after a miscarriage and a preeclampsia, were misinterpreted as triggered by tacrolimus. After each episode however serum creatinine returned to baseline. Five years after transplantation, she had a self-limited rhinosinusitis followed 3 weeks later by an oliguric renal failure. Her complement profile was normal. Graft biopsy showed C3 glomerulonephritis with no “humps” on electron microscopy. No significant renal function improvement followed methylprednisolone pulsing. A second biopsy showed severe acute TMA lesions with C3 glomerular deposits. Despite weekly eculizumab for 1 month, dialysis was resumed. A new workup identified the “at-risk” complement factor H haplotype. Thus, aHUS recurrence should be ruled out in aHUS patients considered at low recurrence risk when a TMA is found in graft biopsy. Prompt eculizumab therapy should be considered to avoid graft loss as aHUS recurrence can first present as a C3 glomerulonephritis.

ABO incompatible kidney transplantation from an anti-hepatitis C virus antibody-positive RNA-negative donor into an anti-hepatitis C virus antibody-negative recipient.

Dear Sirs, At the time of severe shortage of deceased donors, continuous efforts are needed to avoid discarding potential living donors. Anti-hepatitis C virus (HCV)-positive donors are not considered suitable candidates for living kidney donation [1]. However, little is known regarding outcomes of such a procedure. Watanabe et al.[2] reported successful living kidney transplantation from an anti-HCV antibodypositive-HCV RNA-negative donor into an anti-HCV antibody-negative recipient. Donor and recipient were one HLA identical haplotype, ABO identical and immunosuppression was low. At 24 months post-transplant, the recipient was free of liver disease with negative HCV RNA. Increased mortality risk has only been studied among recipients of anti-HCV antibody-positive kidneys retrieved from deceased donors [3]. A 66-year-old male, blood type O, had been on dialysis since 2007 for cholesterol emboli nephropathy. Evaluation of his 62-year-old wife, blood type A, showed positive antiHCV antibodies in serum (cutoff index 4.7 > 1.0; enzyme immunoassay), HCV RNA detection by RT-PCR inferior to 15 UI/ml (undetectable defined as < 15 UI/ml), normal serum liver enzymes, and Fibroscan. A multidisciplinary round was agreed on the transplantation, and informed consent was obtained from both the donor and the recipient. Immunosuppression consisted of 375 mg/m rituximab 4 weeks before the transplantation, tacrolimus, mycophenolate mofetil and prednisolone starting 1 week preoperatively, and basiliximab induction. As anti-A antibodies were below 1:8, specific immunoadsorption was not required. The transplantation was successful with a serum creatinine level of 86 lmol/L at discharge. At follow-up, Norovirus enteritis was diagnosed at day 21 and asymptomatic cytomegalovirus reactivation at day 30. One year post-transplant, the recipient’s liver function tests remained normal, anti-HCV antibodies were negative, and HCV RNA was undetectable. A liver biopsy was not deemed indicated. Protocol kidney biopsies performed at 3 and 12 months showed no rejection. To our knowledge, we report the first ABO incompatible kidney transplantation from an anti-HCV antibodypositive-HCV RNA-negative donor into an anti-HCV antibody-negative recipient. Even with high immunosuppression level, our recipient was free of liver disease and HCV acute infection at one year follow-up. Presence of serum HCV RNA seems to better predict the risk of HCV transmission by kidney transplantation [4]. It was however not used in initial studies evaluating the risk associated with using HCV-positive kidneys in organ transplantation [3]. Potential donors who had HCV exposure without HCV infection might not transmit the virus. We advocate the fact that anti-HCV antibody-positiveRNA-negative people, whether spontaneously or after antiviral therapy, deserve consideration for living kidney donation. Outcomes of patients receiving HCV-positive kidneys versus patients remaining on the transplant waiting list should be studied, with comprehensive analyses of competing risks [1].

Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis

Background Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients’ access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. Methods and findings To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55–3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05–6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. Conclusions In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. Trial registration National Clinical Trial protocol ID: NCT03438058.

A population-based approach to assess the heritability and distribution of renal handling of electrolytes

The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population.

Carbimazole-induced, ANCA-associated, crescentic glomerulonephritis: case report and literature review.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is a rare complication of antithyroid drug use that was first described with propylthiouracil. We describe an ANCA-associated rapidly progressive glomerulonephritis in a patient treated with carbimazole during 6 months for Graves disease that resulted in end-stage renal disease. A 66-year-old man treated with carbimazole for Graves disease was admitted for macroscopic hematuria and edema of the lower extremities. Laboratory work-up showed elevated serum creatinine (435 μmol/L), mixed hematuria, nephrotic range proteinuria, and a low positive c-ANCA titer with proteinase-3 specificity. Renal biopsy showed necrotizing, crescentic, pauci-immune glomerulonephritis. Carbimazole was discontinued and hemodialysis was initiated as well as high-dose glucocorticoids and pulses of intravenous cyclophosphamide. Despite immunosuppressive treatment, the patient remained dialysis-dependent at 6 months after diagnosis. Graves disease remained in remission after carbimazole withdrawal. ANCA-associated vasculitis manifesting as glomerulonephritis is a potential adverse effect of all antithyroid drugs. Although prognosis is usually good, end-stage renal disease may ensue in rare cases. Physicians should have a high index of suspicion in patients receiving antithyroid drugs who present with symptoms or signs suggestive of progressive renal disease.

Aryl hydrocarbon receptor expression by macrophages and lymphocytes within infiltrates in BK polyomavirus associated nephropathy

BACKGROUND BK virus nephropathy (BKPyVN) is a major complication after renal transplantation. Little is known about the intra renal immune response during BKPyVN. The role of macrophages remains elusive. The activation of aryl hydrocarbon receptor (AHR) - a transcription factor involved in drug metabolism - plays a key role in inflammation and viral tolerance through modulation of macrophages polarization. Since AHR has not been studied in kidney transplantation, our aim was to compare the AHR expression within renal grafts in BKPyVN with T-cell mediated rejection (TCMR) as a control. METHODS We evaluated AHR expression in kidney grafts from BKPyVN (n=8) with TCMR as control (n=6) among cases with available frozen material for AHR gene intragraft transcription measurement and stainings for AHR, CD68 and CD45. RESULTS AHR transcription was higher in BKPyVN grafts versus TCMR (p=0.03). While CD68+ or CD45+ cell expression did not differ within infiltrates (median score=3 in both groups; p=1.0 and 0.69, respectively), a higher proportion of nuclear AHR expression was found in BKPyVN for CD68+ and CD45+ cells when compared with TCMR (score median 2 vs 0; p=0.007 and 1 vs 0; p=0.013, respectively). CONCLUSIONS We describe for the first time a higher expression of AHR in inflammatory cell infiltrates from BKPyVN versus TCMR renal biopsies. Further studies are required to explore AHR as a potential target in the modulation of inflammatory response in BKPyVN with known modulating ligands.

Lipodystrophy Increases the Risk of CKD Development in HIV-Positive Patients in Switzerland: The LIPOKID Study

Introduction Antiretroviral therapy has improved the life expectancy of patients living with HIV. However, lipodystrophy syndrome (LD) remains prevalent, affecting mostly patients treated with first-generation antiretroviral drugs. This syndrome is characterized by changes in body fat distribution with or without associated metabolic changes. Here, we studied whether clinically evaluated LD is independently associated with chronic kidney disease (CKD) development (sustained estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2) in HIV-positive patients. Methods We conducted a prospective cohort study (the LIPOKID Study) among all the patients from the Swiss HIV Cohort Study (SHCS) with an eGFR >60 ml/min per 1.73 m2 upon their entry into the cohort with more than 3 months of follow-up from January 2002 to August 2016. Cox regression models were used to estimate the association between LD and CKD development. Results Among the 5384 patients included, 1341 (24.9%) developed LD during the follow-up. The mean follow-up time was 72.3 months (SD ±48.4). In total, 252 patients (4.7%) reached the primary endpoint after a median time of 51.3 months (±SD 39.9 months) from inclusion. A diagnosis of LD significantly increased the risk of an eGFR on univariate analysis (hazard ratio [HR] = 2.72; 95% confidence interval [95% CI] = 2.07−3.58; P < 0.001) and remained significantly higher after adjustment for known HIV and non-HIV risk factors for CKD (HR = 2.37; 95% CI = 1.67−3.36; P < 0.001). The effect of LD on CKD was not mediated through the use of nephrotoxic antiretroviral drugs. Conclusion Lipodystrophy syndrome is independently associated with CKD after adjustment for previously reported risk factors.