Karlo Mihovilović

Fas receptor is required for estrogen deficiency-induced bone loss in mice

Bone mass is determined by bone cell differentiation, activity, and death, which mainly occur through apoptosis. Apoptosis can be triggered by death receptor Fas (CD95), expressed on osteoblasts and osteoclasts and may be regulated by estrogen. We have previously shown that signaling through Fas inhibits osteoblast differentiation. In this study we analyzed Fas as a possible mediator of bone loss induced by estrogen withdrawal. At 4 weeks after ovariectomy (OVX), Fas gene expression was greater in osteoblasts and lower in osteoclasts in ovariectomized C57BL/6J (wild type (wt)) mice compared with sham-operated animals. OVX was unable to induce bone loss in mice with a gene knockout for Fas (Fas –/– mice). The number of osteoclasts increased in wt mice after OVX, whereas it remained unchanged in Fas –/– mice. OVX induced greater stimulation of osteoblastogenesis in Fas –/– than in wt mice, with higher expression of osteoblast-specific genes. Direct effects on bone cell differentiation and apoptosis in vivo were confirmed in vitro, in which addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas-induced apoptosis in osteoclast lineage cells. In conclusion, the Fas receptor has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and inhibiting differentiation of osteoblast lineage cells. Modulation of Fas effects on bone cells may be used as a therapeutic target in the treatment of osteoresorptive disorders.

Safe Administration of Celecoxib to a Patient with Repeated Episodes of Nephrotic Syndrome Induced by NSAIDs

Nephrotic syndrome, with or without concomitant tubulointerstitial nephritis, is a rare renal adverse effect of NSAIDs. In the present report we describe a case of a 60-year-old Caucasian man who was admitted because of nephrotic syndrome following several days of use of meloxicam for hip osteoarthritis. Renal histopathology revealed minimal change disease, one of the commonest causes of nephrotic syndrome. The patient’s condition resolved rapidly upon discontinuation of meloxicam. Because he had already experienced two episodes of nephrotic syndrome after administration of diclofenac several years previously, it was concluded that the patient had renal hypersensitivity to both diclofenac and meloxicam. While waiting for the hip arthroplasty, he was prescribed celecoxib for pain control. After 1 month of regular celecoxib use the patient remained in remission with respect to nephrotic syndrome and had normal renal function. We conclude that challenge with a structurally distinct NSAID (such as celecoxib in this case) may be an option, under close surveillance, in a patient with a history of nephrotic syndrome associated with use of an NSAID when continued treatment with an NSAID is indicated.

Combined auxiliary split liver and kidney transplantation for type I primary hyperoxaluria and end-stage kidney disease.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease, caused by loss of function in liver-specific alanine-glyoxylate aminotransferase (AGT). Accumulation of oxalate in PH1 causes nephrocalcinosis and urolithiasis leading to end-stage kidney (ESKD) in 90% of patients. These patients are treated by combined liver and kidney transplantation (LKT). Liver transplantation (LT) in PH1 has traditionally been performed as an orthotopic whole LT. Combined auxiliary LKT may mitigate the risk of whole LT, because native liver is preserved. Between 2006 and 2012 three PH1 patients with ESKD caused by nephrolithiasis received combined LKT from deceased donor at our centre (Table 1). PH1 was confirmed by genetic testing for AGT mutation. The first two patients underwent combined whole LKT, while the third one received an auxiliary LKT. Immunosuppression was conventional (daclizumab, or basiliximab induction, maintenance with tacrolimus, or cyclosporin, together with mycophenolate mofetil and steroids). Delayed graft function occurred in one of the whole LKT patients and was treated by daily dialysis. The patient subject to auxiliary LKT underwent left hepatectomy, with orthotopic transplantation of the second and third donor liver segment and KT. Immediate function of both grafts was established. However, early post-transplant daily high-flux hemodialysis was performed to enhance oxalate removal. In all three patients, function of both grafts has remained stable throughout the entire post-transplant period (Fig. 1). All patients were advised to maintain high water intake and were treated with potassium citrate and a thiazide diuretic. In the patient with auxiliary LKT, protocol biopsy at one year post-transplant demonstrated no oxalate crystal deposition in the kidney graft. The present case of a combined auxiliary LKT is, to our knowledge, only the third published case. There was no PH1 recurrence in any of them (Elias et al., Onaca et al. and our case). As it is highly unlikely that a prospective trial comparing whole liver with auxiliary LT in PH1 patients will ever be performed, publication of each such case is important. Excellent results of auxiliary LKT (Elias et al., Onaca et al. and this report), may encourage auxiliary LT in PH1 patients, prior to development of significant kidney

Effect of mycophenolate mofetil on progression of interstitial fibrosis and tubular atrophy after kidney transplantation: a retrospective study

Objectives Chronic transplant dysfunction after kidney transplantation is a major reason of kidney graft loss and is caused by immunological and non-immunological factors. There is evidence that mycophenolate mofetil (MMF) may exert a positive effect on renal damage in addition to immunosuppression, by its direct antifibrotic properties. The aim of our study was to retrospectively investigate the role of MMF doses on progression of chronic allograft dysfunction and fibrosis and tubular atrophy (IF/TA). Setting Retrospective, cohort study. Participants Patients with kidney transplant in a tertiary care institution. This is a retrospective cohort study that included 79 patients with kidney and kidney–pancreas transplantation. Immunosuppression consisted of anti-interleukin 2 antibody induction, MMF, a calcineurin inhibitor±steroids. Primary outcome measures An association of average MMF doses over 1 year post-transplant with progression of interstitial fibrosis (Δci), tubular atrophy (Δct) and estimated-creatinine clearance (eCrcl) at 1 year post-transplant was evaluated using univariate and multivariate analyses. Results A higher average MMF dose was significantly independently associated with better eCrcl at 1 year post-transplant (b=0.21±0.1, p=0.04). In multiple regression analysis lower Δci (b=−0.2±0.09, p=0.05) and Δct (b=−0.29±0.1, p=0.02) were independently associated with a greater average MMF dose. There was no correlation between average MMF doses and incidence of acute rejection (p=0.68). Conclusions A higher average MMF dose over 1 year is associated with better renal function and slower progression of IF/TA, at least partly independent of its immunosuppressive effects.

Tacrolimus or Mycophenolate in Kidney Transplantation—Less, or More?

We have read with greatest interest a recently published paper in the American Journal of Transplantation by Bouamar et al (1). The authors reported a lack of association between the predose tacrolimus (Tac) concentration and subsequent acute rejection (AR) in kidney transplant recipients. Of note, in the Bouamar et al (1) paper, even Tac<5 ng/mL showed no associationwith an increased risk of AR, while in a multivariate analysis only the delayed graft function and induction therapy were associated with AR. While itmight be possible, as discussed by the authors, that even very low exposure to Tac may provide enough immunosuppression, there are several shortcomings of the Bouamar et al (1) paper, which make the interpretation of their results more difficult.

Tunnelled haemodialysis catheter and haemodialysis outcomes: a retrospective cohort study in Zagreb, Croatia

Objectives Studies have reported that the tunnelled dialysis catheter (TDC) is associated with inferior haemodialysis (HD) patient survival, in comparison with arteriovenous fistula (AVF). Since many cofactors may also affect survival of HD patients, it is unclear whether the greater risk for survival arises from TDC per se, or from associated conditions. Therefore, the aim of this study was to determine, in a multivariate analysis, the long-term outcome of HD patients, with respect to vascular access (VA). Design Retrospective cohort study. Participants This retrospective cohort study included all 156 patients with a TDC admitted at University Hospital Merkur, from 2010 to 2012. The control group consisted of 97 patients dialysed via AVF. The groups were matched according to dialysis unit and time of VA placement. The site of choice for the placement of the TDC was the right jugular vein. Kaplan-Meier analysis with log-rank test was used to assess patient survival. Multivariate Cox regression analysis was used to determine independent variables associated with patient survival. Primary outcome measures Patient survival with respect to VA. Results The cumulative 1-year survival of patients who were dialysed exclusively via TDC was 86.4% and of those who were dialysed exclusively via AVF, survival was 97.1% (p=0.002). In multivariate Cox regression analysis, male sex and older age were independently negatively associated with the survival of HD patients, while shorter HD vintage before the creation of the observed VA, hypertensive renal disease and glomerulonephritis were positively associated with survival. TDC was an independent risk factor for survival of HD patients (HR 23.0, 95% CI 6.2 to 85.3). Conclusion TDC may be an independent negative risk factor for HD patient survival.