The impact of APOL1, CAV1, and ABCB1 gene variants on outcomes in kidney transplantation: donor and recipient effects

Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long-term graft survival rates.     

Kidney Transplantation From Old Deceased Donors: Impact of Uric Acid Level—A Quarter-Century of Experience in One Transplant Center

Background

The long-term burden of higher donor age on graft function and survival after kidney transplantation remains uncertain. Because both recipient and donor characteristics have evolved and the general population age is on the increase, we looked at the causes of kidney graft outcome.

Renoprotective effect of pulsatile perfusion machine RM3: pathophysiological and kidney injury biomarker characterization in a preclinical model of autotransplanted pig

What's known on the subject? and What does the study add? Machine perfusion of kidney graft improves short term outcome. However, the technique still requires optimization, as the rate of delayed graft function remains high. Machine perfusion of kidney graft has significant benefits on chronic outcome in terms of interstitial fibrosis and kidney function. Improvement of the technique is possible using alternative perfusion fluids, such as fourth generation preservation solutions containing polyethylene glycol.

OBJECTIVES

• ? To assess the effect of machine perfusion (MP) on renal function recovery vs kidney preservation in static cold storage (CS), in a large animal preclinical model.
• ? To assess whether MP benefits are dependent on the preservation solution used.

METHODS

• ? Using an established autotransplantation pig kidney model associated with a contralateral nephrectomy we studied the impact of MP against the deleterious effects of warm ischaemia (WI; 60 min), then 22 h of cold ischaemia using MP or static CS, followed by autotransplantation.
• ? We used Berzer MP solution (MPS), recommended for MP, and Institut Georges Lopez preservation solution (IGL‐1), designed for CS.
• ? The pigs were divided into four study groups: MPS‐CS: static CS with MPS (n = 7); MPS‐MP: renal perfusion with MPS using the Waters Medical Systems (Rochester, MN, USA) RM3 pulsatile machine (n = 7); IGL‐CS: static CS with IGL‐1 solution (n = 7); IGL‐MP: renal perfusion with IGL‐1 solution (n = 7).
• ? The effect of ischaemia was determined using different variables: pig survival; plasma creatinine; proteinuria; oxidative stress; tubular sodium reabsorption rate; and tissue damage at 1 month.

RESULTS

• ? Pig survival was higher in MP and IGL groups compared to MPS‐CS.
• ? Plasma creatinine levels did not differ among the groups, but proteinuria assay showed significant benefits for the MP vs static CS groups.
• ? Histological evaluation of kidney grafts showed more injury in the CS groups than in the MP groups.
• ? Urinary measurement of tubular enzyme activity differed substantially among the groups, highlighting the benefits of MP in maintaining brush border integrity.

CONCLUSIONS

• ? In our model reproducing the conditions of deceased after cardiac arrest donors we show that MP decreases the risk of renal dysfunction and preserves kidney parenchyma.
• ? A non‐invasive urinary enzyme assay can provide valuable information on graft integrity.
• ? The preservation solution used is important as the wrong solution can decrease the benefits of MP.

     

Intraoperative diagnosis of rate-dependent bundle branch block

Rate-dependent left bundle branch block (LBBB) occasionally occurs during anaesthesia when the heart rate exceeds a critical value. While it is usually a benign disorder, it may mask the electrocardiographic manifestations of myocardial ischaemia and the ST-T wave pattern associated with LBBB may be mistaken for those of ischaemia, This case report presents two cases in which rate-dependent LBBB was clearly documented during the perioperative period. It demonstrates the use of pharmacologic agents (e.g., atropine and neostigmine) and physiologic manipulations (e.g., carotid sinus massage) to alter the heart rate and confirm the diagnosis of benign rate-dependent LBBB in the operating room. These interventions should be used with caution in patients who have hypertension, angina, cerebrovascular, or AV node disease or in the setting of myocardial ischaemia or severe bundle branch disease.     

The effect of two diphosphonates on the handling of calcium by rat kidney mitochondriain vitro

The effect of two diphosphonate compounds on calcium handling in rat kidney mitochondria has been studiedin vitro. Initial calcium uptake in the presence of an oxidisable substrate and ATP was not influenced by either diphosphonate tested. The release of accumulated calcium from the mitochondria was, however, delayed by these compounds and the effect was found to be dose dependent. Similarily, a second uptake of calcium, induced by re-addition of ATP following preliminary release, was also modified by diphosphonates, the mitochondrial suspensions incubated with diphosphonates accumulating more calcium than control suspensions. The effect of these compounds could not be detected on three mitochondrial ATPase systems. The results have been discussed in relation to knownin vivo effects of diphosphonates.     

Risk Factors of Hyperuricemia After Renal Transplantation and Its Long-term Effects on Graft Functions

Background

Hyperuricemia is a common complication in renal transplant recipients. Recent studies have suggested that hyperuricemia may contribute to the deterioration of graft function.

Early results of femoropopliteal bypass using a five millimeter «thin wall» polytetrafluoroethylene (Gore-Tex) prosthesis

We report the early results of a series of 86 femoropopliteal bypass operations in which a 5 mm diameter thin wall polytetrafluoroethylene (Gore-Tex) prosthesis was used. Sixty-five bypasses were implanted in men and 21 in women. Thirty bypasses were done in conjunction with an aortic bifurcation graft and 18 patients had a bilateral procedure. The indication for operation was severe claudication in 74 cases and critical ischaemia in 12 cases. The angiographic run-off was good (three patent vessels) in 22 limbs and poor (one or two patent vessels) in 64 limbs. The cumulative patency rate for the whole group was 62% after 18 months. Angiographic run-off and the indication for operation were both found to influence cumulative patency rate significantly (p=0.035 and p=0.055, respectively). We also compared the results obtained when run-off was poor with equivalent data from our own previously published series in which a standard 6 mm diameter Gore-Tex prosthesis was used. This shows a difference in patency rate, for example 57% against 37% after 18 months, in favour of the smaller bore thin wall graft.     

The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia

Background

Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated.

Methods

This was a 2 years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n?=?30), switched from allopurinol to febuxostat (switched group, n?=?25), or were newly prescribed febuxostat (febuxostat group, n?=?31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed.

Results

Serum uric acid in the switched and febuxostat groups was significantly reduced at 6 months (switched group; 8.49?±?1.32–7.19?±?1.14 mg/dL, p?<?0.0001, febuxostat group; 9.43?±?1.63–6.31?±?0.90 mg/dL, p?<?0.0001). In the allopurinol group, serum uric acid was increased (6.86?±?0.87–7.10?±?0.85 mg/dL, p?=?0.0213). eGFR was significantly increased (35.2?±?12.8–37.3?±?13.9 mL/min/1.73 m², p?=?0.0232), while mean arterial pressure (93.1?±?10.8–88.2?±?9.5 mmHg, p?=?0.0039) was significantly decreased at 6 months in the febuxostat group, resulting in the retention of eGFR for 2 years.

Conclusions

The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia.

     

Hyperuricemia after renal transplantation

Background

Hyperuricemia is a common complication after kidney transplantation, and may adversely affect graft survival.

Objective

To assess the prevalence of and predictors for development of hyperuricemia after renal transplantation.

Materials and Methods

Hyperuricemia was defined as a serum uric acid concentration of at least 7.0 mg/dL in men and 6.0 mg/dL in women. From March 2008 to May 2010, uric acid concentration was measured in 12,767 blood samples from 2961 adult renal transplant recipients (64% male and 36% female patients).

Results

Hyperuricemia was observed in 1553 patients (52.4%). The disorder frequently occurred in women (P = .003) and in patients with impaired renal graft function (P = .00). After adjustment for sex, serum creatinine concentration, diabetes mellitus, cyclosporine concentration, and dyslipidemia, only female sex (P = .03) and renal allograft dysfunction (P = .05) were associated with hyperuricemia after kidney transplantation.

Conclusion

Hyperuricemia is a common complication after kidney transplantation, and renal allograft insufficiency predisposes to higher uric acid concentration.     

Coffee consumption and urologic cancer risk: a meta-analysis of cohort studies

Objectives

Controversial results were reported among several epidemiologic studies on the relationship between coffee consumption and urologic cancer risk. We, therefore, conducted this meta-analysis to clarify these associations.

Methods

Electronic databases including Pubmed, Embase and Cochrane library were searched between January 1966 and August 2013 for eligible studies. Pooled relative risk (RR) and its 95 % confidence interval (CI) were calculated. All P values are two tailed.

Results

Thirteen cohorts were eligible for inclusion. As to prostate cancer (PCa), significant reverse association was found among highest versus none/lowest analysis with acceptable heterogeneity (RR 0.86, 95 % CI 0.79–0.95; I ² 25 %, P value for heterogeneity: 0.221). A pooled RR which assessed advanced PCa was 0.73 (with 95 % CI 0.50–1.07), and a slight stronger reverse association was found in fatal PCa. However, a slight insignificant reverse association, basing on 8 studies with 9 outcomes, was found in dose–response analysis (RR 0.98, 95 % CI 0.93–1.03). For kidney and bladder cancer, insignificant associations were found in both highest versus none/lowest analyses and dose–response analyses.

Conclusions

Our findings suggest that coffee consumption may reduce the risk of PCa. No associations were found with both bladder and kidney cancer. Further well-designed large-scaled cohort studies are warranted to provide more definitive conclusions.     

Myocardial ischaemic/ reperfusion injury in the anaesthetized rabbit: comparative effects of halothane and isoflurane

The effects of halothane and isoflurane anaesthesia on myocardial injury in rabbits subjected to coronary artery ligation and subsequent reperfusion were analyzed. Although halothane and isoflurane (at inspired concentrations of 1.0 and 1.5 per cent, respectively) exerted comparable effects on cardiovascular status during ischaemic and reperfusion phases, greater preservation of subcellular integrity (as assessed by mitochondrial and sarcoplasmic reticular ATPase activities and myocardial ionic alterations) and a lower incidence of ventricular fibrillation and severe hypotension occurred with halothane. Our results indicate that in studies of experimental myocardial ischaemia anaesthetics may, independently of cardiovascular actions, influence the nature and extent of resulting injury, possibly by virtue of their differing effects on subcellular membrane systems.     

Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy

Dyslipidemia is an independent risk factor for the development and progression of diabetic nephropathy (DN). In this review, we summarize mouse models with both diabetes and dyslipidemia, and their associated complications. We then discuss molecules potentially involved in deterioration of DN by dyslipidemia. We focus especially upon toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), since we have found that their mRNA levels are commonly increased in glomeruli of type 1 (streptozotocin [STZ]-induced) and type 2 (A-ZIP/F-1 lipoatrophic) diabetic mice. Gene expression of MRP8 and Tlr4 is further upregulated during worsening of STZ-induced DN by a high fat diet (HFD). Moreover, these HFD-induced changes are accompanied by enhanced gene expression of CCAAT element binding protein β and phosphorylation of c-Jun N-terminal kinase in the kidney, which have also been reported in pancreatic β cells under diabetic-hyperlipidemic conditions. Effects of a HFD upon DN are cancelled in Tlr4 knockout mice. Macrophages are the predominant source of MRP8 in glomeruli. In cultured macrophages, combinatorial treatment with high glucose and palmitate amplifies MRP8 expression in a Tlr4-dependent manner, and recombinant MRP8 protein markedly increases gene expression of the inflammatory cytokines interleukin-1β and tumor necrosis factor α. Here, we propose ‘macrophage-mediated glucolipotoxicity’ via activation of MRP8/TLR4 signaling as a novel mechanism of pathophysiology for DN.     

Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis

Purpose

Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients.

Methods

We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens.

Results

Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD ?9.94 μmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens.

Conclusions

Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events.     

Removal of the infrapatella fat pad during total knee arthroplasty: does it affect patient outcomes?

Purpose

The function of the infrapatella fat pad (IFP) is debated, but it is thought to have a biomechanical and biological role. Removal of the IFP during total knee arthroplasty (TKA) remains a matter of surgeon preference. This study sought to establish if removal of the IFP during TKA affected patient outcome.

Methods

Excision of the IFP (not removed, partially excised, or fully excised) and outcome data (Oxford knee Score (OKS) and EQ-5D) were recorded for 1,401 patients (1,417 TKA). There were no differences in the pre-operative scores between the groups.

Results

OKS and EQ-5D one-year postoperatively demonstrated significantly (p?ANOVA) improved total scores with preservation of the IFP. Patients with the IFP preserved had significantly better OKS associated with rising from a chair, pain, limping, giving way, and pain interfering with work.

Conclusions

This study suggests that preservation of the fat pad during TKA is associated with improved outcome. Surgeons routinely undertaking excision of the IFP should reflect whether this is clinically indicated and consider limiting IFP resection, if possible.     

Renal calcium, phosphorus, magnesium and uric acid handling: comparison between stage III chronic kidney disease patients and healthy oldest old

Introduction

It is known that chronic kidney disease (CKD) and senescence bring about a progressive reduction in glomerular filtration rate (GFR) and that in the former this is usually associated with an increase in the fractional excretion of calcium, phosphorus, magnesium, and uric acid. However, it has not yet been explained how these substances are excreted in the healthy oldest old. Thus, in the present study, we examined the renal handling of these substances in very aged people in comparison with CKD patients with similar GFR levels (stage III??CKD).

Materials and methods

Twenty volunteers were studied; 10 of them were healthy very old (VO) (??75?years old) individuals and 10 were stage III CKD patients. Exclusion criteria were as follows: presence of altered (abnormally high or low) plasma calcium, phosphorus, magnesium and uric acid, as well as previous diagnoses of diabetes mellitus and obstructive uropathy and use of drugs that could alter plasma levels of the studied substances. All volunteers were on a diet with the same content of these elements (3-day dietary register). We measured calcium, phosphorus, magnesium, uric acid, creatinine in serum plasma and morning urine, as well as serum parathyroid hormone level, in each volunteer. From these data, fractional excretion (FE) of these substances was obtained. A statistical analysis was carried out using the Wilcoxon test.

Results

Serum creatinine: 1.8?±?0.4?mg/dl (CKD) versus 0.8?±?0.2?mg/dl (VO), p?=?0.0002; serum calcium: 9.1?±?0.3?mg/dl (CKD) versus 8.7?±?0.4 (VO), p?=?0.022; serum magnesium: 2.3?±?0.2?mg/dl (CKD) versus 2.0?±?0.1 (VO), p?=?0.05; serum phosphorus: 3.9?±?0.5?mg/dl (CKD) versus 3.0?±?0.4?mg/dl (VO), p?=?0.002; serum uric acid: 6.6?±?1.5 (CKD) versus 5.2?±?1.4?mg/dl (VO), p?=?0.04; FE of calcium: 2.5?±?1?% (CKD) versus 0.8?±?0.3?% (VO), p?=?0.04; FE of magnesium: 7.2?±?4.1?% (CKD) versus 2.9?±?0.9?% (VO), p?=?0.02; FE of phosphorus: 25?±?9?% (CKD) versus 9.1?±?5.7(VO), p?=?0.001; FE of uric acid: 10?±?3?% (CKD) versus 8?±?5?% (VO), p?=?0.05.

Conclusion

Serum levels and FE of calcium, phosphorus, magnesium and uric acid were significantly higher in CKD patients compared to healthy very old people with similar GFR, except for serum magnesium and FE of uric acid, which were similar in both groups.     

Does the Hepatic Branch of Vagus Mediate the Secretion of Glucagon-Like Peptide-1 During the Roux-en-Y Gastric Bypass Surgery?

Objectives

The purpose of this study is to investigate the impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the level of fasting and postprandial serum glucagon-like peptide-1 (GLP-1) in type 2 diabetic mellitus rats.

Methods

Randomized block design, factorial experiment. Forty-five type 2 diabetic rats were divided into four groups: sham operation (S, n?=?10) and sham operation with the hepatic branch of the vagotomy (SV, n?=?11), Roux-en-Y gastric bypass (RYGB, n?=?12) and RYGB without preservation of the vagus (RYGBV, n?=?12). Levels of fasting and postprandial serum GLP-1 30 min after 50 % glucose solution (2 g/kg) by gavage were determined before surgery and postoperatively at 1, 4, and 8 weeks. Interactions between RYGB and the common hepatic branch were also assessed.

Results

Roux-en-Y gastric bypass surgery significantly increased the concentration of postprandial serum GLP-1 and maintained it at a higher level (P?GLP-1 at the initial stage (P?P?>?0.05). Both RYGB and vagotomy of the hepatic branch had no influence on fasting serum GLP-1 (P?>?0.05).

Conclusions

During RYGB surgery for the long-term treatment of T2DM, preservation of the hepatic branch of the vagus might have no impact on serum GLP-1 level.     

Clinical analysis of non-anastomotic aneurysms of implanted prosthetic grafts

Purpose

To investigate the features of non-anastomotic aneurysms (NAAs) of implanted prosthetic grafts through our case series and present a general review of NAAs.

Methods

We studied retrospectively, a series of NAAs of seven grafts in six patients treated between 2001 and 2010, and reviewed the data on NAAs reported between 1962 and 2009.

Results

The grafts in our series were implanted between 1986 and 2006. The primary surgical procedures were bypass between the axillary and femoral artery (n = 1), bypass between the subclavian artery and abdominal aorta (n = 1), bypass between the aorta and femoral artery (n = 1), bypass between the femoral and popliteal artery (n = 1), bypass between the femoral and femoral artery (n = 2), and bypass between the aorta and iliac artery (n = 1). The graft material was knitted Dacron in all cases and the implantation period ranged from 2.7 to 24 years (median 13.8 years). All NAAs originated from a hole in the graft. Reports of NAA have decreased dramatically, although according to the data, knitted Dacron accounted for 80 % of these implanted grafts.

Conclusions

Graft deterioration and the subsequent development of an NAA can occur even with the latest knitted Dacron grafts, even though the incidence is very low.     

Suspensory fixation versus novel transverse crosspin for femoral fixation in anterior cruciate ligament reconstruction

Background and aim

There is still no gold standard technique for graft fixation during anterior cruciate ligament reconstruction. We compared the functional outcomes of patients receiving either ToggleLoc with ZipLoop technology or Translig transverse crosspin device for femoral graft fixation.

Materials and methods

A total of 118 patients were randomly allocated into two groups to receive either Translig^® transverse crosspin (Translig group 1: n = 51, mean age 28.34 ± 7.83 years, age 18–40 years) or ToggleLoc with ZipLoop technology (ToggleLoc group: n = 67, mean age 26.85 ± 8.76, age 16-41 years) for femoral graft fixation. Early and 1-year assessment was made with Lysholm knee scale, International Knee Documentation Committee Scoring, Tegner Activity Level Scale, KT-1000 arthrometer and pivot shift test.

Results

Preoperative vs. postoperative functional parameters showed significant improvement in both groups. Two groups were similar in terms of Lysholm knee scale, IKDC and Tegner activity scores (p > 0.05). The KT-1000 arthrometer revealed slightly less anterior sliding in Translig group than that in ToggleLoc group (p > 0.05). ToggleLoc technique allowed a radiographically more horizontal placement of the graft than Translig technique.

Conclusion

Two distinct techniques used in this study are likely to be suitable for femoral graft fixation during anterior cruciate ligament reconstruction with the femoral tunnel being created via anteromedial approach.     

Uric acid-lowering and renoprotective effects of topiroxostat,a selective xanthine oxidoreductase inhibitor,in patients with diabetic nephropathy and hyperuricemia: a randomized,double-blind,placebo-controlled,parallel-group study (UPWARD study)

Background

Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study.

Methods

The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level.

Results

At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-to-creatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p?=?0.3206), but the changes in the estimated glomerular filtration rate (? 0.2 vs. ? 4.0 mL/min/1.73 m², p?=?0.0303) and the serum uric acid level (? 2.94 vs. ? 0.20 mg/dL, p?<?0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group.

Conclusion

These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients.