Sławomir Zmonarski

The influence of non‐HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes

Non‐HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti‐angiotensin II type 1‐receptor‐activating antibodies (anti‐AT1R) have been mentioned to stimulate a severe vascular rejection, but the pretransplant screening has not been introduced yet. The aim of our study was to assess the incidence and importance of anti‐AT1R antibodies and their influence on renal transplant in the 1st year of observation. We prospectively evaluated the presence of anti‐AT1R antibodies in 117 consecutive renal transplant recipients in pre‐ and post‐transplant screening. Anti‐AT1R antibodies were observed in 27/117 (23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti‐AT1R(+) group. The patients with anti‐AT1R Abs >9 U/ml lost their graft more often. Biopsy‐proven AR was described in 4/27 (15%) pts in the anti‐AT1R(+) group and 13/90 (14.4%) in the anti‐AT1R(−) group, but more severe cases of Banff IIB or antibody‐mediated rejection (AMR) were more often observed in anti‐AT1R (+) 4/27 (15%) vs. 1/90 (1.1%) in anti‐AT1R(+) (P = 0.009). Patients with anti‐AT1R Abs level >9 U/ml run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti‐AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti‐AT1R‐positive ones lost the graft. Our study suggests monitoring of anti‐AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure, and graft loss.

Mycophenolate mofetil severely depresses antibody response to CMV infection in early posttransplant period

Estimation of anti-CMV-IgG and anti-CMV-IgM is considered a relatively inexpensive screening tool of CMV status. The aim of study was to estimate how the immunosuppressive protocol influence serum anti-CMV IgG and IgM concentration in renal graft recipients and to estimate the adequacy of anti-CMV-IgG concentration and anti-CMV-IgM index as screening parameters of active CMV disease in patients receiving different immunosuppression. The study group consisted of 33 patients with clinical signs of CMV disease who received one of three types of immunosuppression: (1) azathioprine (Aza) + cyclosporine (CyA) + prednisone (Pr), 20 patients; (2) mycophenolate mofetil (MMF) + CyA + Pr, eight patients; tacrolimus (Tac) + MMF, five patients. Patients were enrolled when the pp65-antigen (pp65) of PBL was positive within 1 to 5 months after transplant (75 patients tested). The IgM-i in the Aza + CyA + Pr group was higher than in MMF + CyA + Pr group (2.73 + 1.8 vs 1.08 +/- 1.07, P =.021). The IgM-i in the Aza + CyA + Pr group was higher than in Tac + MMF (2.73 +/- 1.8 vs 0.78 +/- 0.69; P =.014). There was no difference in IgM-i between MMF + CyA + Pr and Tac + MMF. There was no difference in relative increase of IgG-c among all groups but there was a difference in relative increase of IgM-i between Aza + CyA + Pr and MMF + CyA + Pr groups (6.7 +/- 9.4 vs 2.3 +/- 5.9; P =.007) and between Aza + CyA + Pr and MMF + Tac groups (6.7 +/- 9.4 vs 0.6 +/- 0.54; P =.003). Immunosuppressive protocols including MMF exert an inhibitory influence on B-cell response and synthesis of anti-CMV-IgM. It makes the anti-CMV-IgM index an inadequate rough screening diagnostic parameter of active CMV disease.

Non-HLA antibodies: angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) are associated with renal allograft injury and graft loss.

INTRODUCTION Non-HLA antibodies specific for angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) of vascular cells activate signaling pathways leading to cell proliferation and vascular injury. The aim of this study was to evaluate the impact of non-HLA antibodies on kidney allograft morphology and function in patients who underwent a kidney biopsy due to renal function impairment. PATIENTS AND METHODS The study included 65 consecutive renal transplant patients who were evaluated for the presence of non-HLA and anti-HLA antibodies at the time of transplant biopsy. Results of pre-transplant CDC cross-match were negative. A kidney allograft biopsy was performed between 6 days and 13 years (42 ± 49 months) after transplantation, and the diagnosis was made on the basis of the Banff criteria. The level >9 U/L of anti-AT1R and anti-ETAR antibodies was considered high. RESULTS A high level of non-HLA antibodies (anti-AT1R and/or anti-ETAR) was found in 7 (10.7%) of 65 patients at the time of biopsy. Graft loss in the non-HLA-positive patients was significantly higher (71% in non-HLA-positive cases after 7.8 ± 2.6 months vs 11% after 6 months in non-HLA-negative cases [P = .00099]). In these non-HLA-positive patients, the mean anti-AT1R level was 15.3 ± 9.4 U/L and the mean anti-ETAR level was 13.8 ± 8.6 U/L. In only 2 of these patients were anti-HLA antibodies additionally detected: anti-class I in 1 and anti-class II in both patients. The mean serum creatinine level was 2.34 ± 0.6 mg/dL at the time of biopsy. Results of an early biopsy revealed acute vascular rejection (Banff grade IIB). Chronic allograft injury was found (grading cg1-3, cv1-2, ci1-2, ct1-2) in the remaining 6 patients. C4d was present in 3 of 7 patients. CONCLUSIONS High levels of anti-AT1R and/or anti-ETAR antibodies were associated with morphological and functional allograft injury and graft loss in these study patients. Non-HLA antibodies can be helpful in assessing the risk of graft failure.

Evolution of Bone Disease at 2 Years After Transplantation: A Single-Center Study

Posttransplant bone disease is caused by renal osteodystrophy. We sought to examine bone mineral density (BMD) among 90 renal allograft recipients of mean age 42.7 +/- 11.4 years to identify factors preventing bone loss at 2 years posttransplant. Subjects treated with cyclosporine or tacrolimus plus azathioprine/MMF and prednisone underwent BMD estimates of the lumbar spine (LS) and of the proximal femur using dual energy x-ray absorptiometry (DEXA) at 3 months and every 6 months for 2 years. We assayed markers of bone remodeling: intact parathyroid hormone (iPTH), calcitriol, osteocalcin, and carboxyterminal telopeptide of type I collagen on day 3, as well as month 1 and every 6 months after transplantation. At the initial measurement, we observed osteopenia (OSP) among 35% in the LS and 52% in the femur: there was osteoporosis in 8.3%. The prevalence of OSP increased during the first year, thereafter decreasing to the initial value, but the rate of osteoporosis did not change significantly (8.3% vs 6.0%). BMD and Z-score decreased during the first and increased in the second year; 27% of patients regained initial values and 38% higher ones. BMD gains in the LS and femur were observed among subjects with higher calcitriol levels during the first 6 months (P < .01), higher osteocalcin (P < .05), higher estimated glomerular filtration rate during 1-24 months and in the tacrolimus group. Improvement of LS BMD occurred in younger patients (38 vs 46 years; P < .027); BMD gain in the femur correlated with higher levels of iPTH from 1-12 months (P < .01). The tacrolimus group showed higher Z-scores in the LS and femur at 24 months (P < .05). Two years after transplantation >60% of recipients showed stabilization or gain in bone mass. A sufficient calcitriol level in the early transplant period, an adequate iPTH, good renal function, and tacrolimus therapy prevented BMD disease progression.

Advanced age of renal transplant recipients correlates with increased plasma concentrations of interleukin-6, chemokine ligand 2 (CCL2), and matrix metalloproteinase 2, and urine concentrations of CCL2 and tissue inhibitor of metalloproteinase 1.

BACKGROUND Advanced age of renal transplant recipients (RTRs) has a negative impact on kidney allograft survival through impaired extracellular matrix degradation by the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system. Moreover, older RTRs are at risk of smoldering inflammation, known as inflammaging. AIM The aim of the study was to assess the impact of a RTRs age on plasma and urine concentrations of interleukin 6 (IL-6), chemokine ligand 2 (CCL2), and the MMPs/TIMPs system. MATERIAL AND METHODS One hundred fifty adult RTRs (8.7% ≥ 65 years) and 37 adult healthy volunteers (10.8% ≥ 65 years) were enrolled in the study. The studied factors (IL-6, CCL2, MMP-2, MMP-9, TIMP-1 and TIMP-2) were quantified in plasma and urine with enzyme-linked immunosorbent assay. The Mann-Whitney U test and Spearmans (rs) rank correlation were applied, and differences with a P < .05 were considered statistically significant. RESULTS There was a weak but significant positive correlation between increasing RTRs age and plasma IL-6 (rs = 0.18, P = .028), CCL2 (rs = 0.27, P = .001), and MMP-2 (rs = 0.20, P = .017), as well as urine CCL2 (rs = 0.16, P = 0.050) and TIMP-1 (rs = 0.20, P = .014) concentrations. CONCLUSIONS Advancing age of RTRs correlates with increasing plasma IL-6 and CCL2 concentrations, reflecting smoldering inflammation (known as inflammaging) and alterations in MMPs/TIMPs profiles, especially with increased plasma MMP-2 and urine TIMP-1 concentrations.

Urinary myeloid IgA Fc alpha receptor (CD89) and transglutaminase-2 as new biomarkers for active IgA nephropathy and henoch-Schönlein purpura nephritis

Background IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are glomerular diseases that share a common and central pathogenic mechanism. The formation of immune complexes containing IgA1, myeloid IgA Fc alpha receptor (FcαRI/CD89) and transglutaminase-2 (TG2) is observed in both conditions. Therefore, urinary CD89 and TG2 could be potential biomarkers to identify active IgAN/HSPN. Methods In this multicenter study, 160 patients with IgAN or HSPN were enrolled. Urinary concentrations of CD89 and TG2, as well as some other biochemical parameters, were measured. Results Urinary CD89 and TG2 were lower in patients with active IgAN/HSPN compared to IgAN/HSPN patients in complete remission (P < 0.001). The CD89xTG2 formula had a high ability to discriminate active from inactive IgAN/HSPN in both situations: CD89xTG2/proteinuria ratio (AUC: 0.84, P < 0.001, sensitivity: 76%, specificity: 74%) and CD89xTG2/urinary creatinine ratio (AUC: 0.82, P < 0.001, sensitivity: 75%, specificity: 74%). Significant correlations between urinary CD89 and TG2 (r = 0.711, P < 0.001), proteinuria and urinary CD89 (r = − 0.585, P < 0.001), and proteinuria and urinary TG2 (r = − 0.620, P < 0.001) were observed. Conclusions Determination of CD89 and TG2 in urine samples can be useful to identify patients with active IgAN/HSPN.

Balloon Dilatation for Removal of an Irretrievable Permanent Hemodialysis Catheter: The Safest Approach.

Long-term hemodialysis catheter dwell time in the central vein predisposes to fibrin sheath development, which subsequently causes catheter malfunction or occlusion. In very rare cases, the catheter can be overgrown with fibrin and rigidly connected with the vein or heart structures. This makes its removal almost impossible and dangerous because of the possibility of serious complications, namely vein and heart wall perforation, bleeding, or catheter abruption in deep tissues. We describe two cases in which standard retrieval of long-term catheters was not possible. Balloon dilatation of catheter lumens was successfully used to increase the catheter diameter with simultaneous tearing of the fibrin sheath surrounding it. This allowed the catheter to be set free safely. Based on this experience, we present recent literature and our point of view.

Different mortality predictor pattern in hemodialysis and peritoneal dialysis diabetic patients in 4-year prospective observation.

INTRODUCTION The aim was to identify factors carrying an ominous prognosis in a cohort of diabetic patients (pts) on a hemodialysis (HD) and peritoneal dialysis (PD) program. MATERIALS AND METHODS We analyzed survival rates of 61 diabetic dialysis pts (35 HD/26 PD). The participants were matched in baseline characteristics, standard indicators of dialysis care and laboratory parameters. The studied group was prospectively observed up to 4 years. RESULTS 21 pts (34.4%) survived the whole observation period. The annual mortality rate was 23.2%, with no difference between HD and PD. Irrespective of dialysis modality, the only factor associated with mortality in the Cox proportional hazard model was serum albumin lowering. Referring to dialysis modality, the HD survivors were characterized by lower IL-6 level, higher albumin concentration, and increased serum cholesterol values with higher cholesterol left in multivariate analysis; under PD therapy the only factor significantly associated with mortality was older age. In contrast to HD treatment, elevated cholesterol was a universal finding in PD patients, significantly above levels in HD, with a slight tendency to lower values in PD survivors. CONCLUSIONS 1. A difference in mortality predictor pattern appeared in diabetic patients treated by PD and HD. 2. In the PD group more advanced age had a decisive negative impact on survival whereas in the HD group the outlook was dependent on factors related to nutrition and inflammation. 3. Elevated cholesterol level was associated with survival benefit in HD patients, being a common abnormality in the PD group, without positive prognostic significance.

A rare variant route of the ulnar artery does not contraindicate the creation of a fistula in the wrist of a diabetic patient with end-stage renal disease.

A superficial variant route of the ulnar artery is a rare variation of the arterial system of the wrist. The route of the arteries in that region is extremely important for patients with end-stage renal disease due to the necessity to create an arteriovenous fistula for hemodialysis. It is thought that the vascular access is too often achieved by catheters or vascular prostheses because of that each possibility to create a fistula in the wrist region should be utilized. In our patient a rare variant route of the ulnar artery was observed in the wrist region. Instead of a deep route between the muscles the artery did not only run superficially, but, also untypically, first laterally and then medially. A variation of the ulnar arterys route may evoke a fear of hand ischemia after creation arteriovenous fistula for hemodialysis. The fear may be connected with blood supply throw the palmar arch which is created by radial and ulnar artery. This fear of the doctor may result in avoiding the attempt to create an arteriovenous fistula on the wrist. The authors demonstrate that the variant route of the ulnar artery is not a contraindication to the creation of a fistula on the wrist using the radial artery because of a fear of hand ischemia.

The sleeve method for creation of radiocephalic arteriovenous fistulas in patients with calcified vessels

Introduction Creation of an arteriovenous fistula (AVF) in patients with advanced atherosclerotic changes of the artery is often a challenge for the physician due to difficulties in suturing the vein to the side of the frangible artery. The sleeve technique relies on advancing the end of the artery into the lumen of the vein and protecting the anastomosis by adventitial sutures. Material and Methods The sleeve technique was performed in 23 patients with chronic kidney disease stage IV and V and included hemodialysis patients. Their mean age was 60.8 ± 14.8 years and hemodialysis treatment time 49.8 ± 40.2 months. The most frequent causes of chronic kidney disease are ischemic nephropathy (43%, n = 10) and type l diabetes (21%, n = 5). Only patients with extremely advanced atherosclerotic were recruited and analyzed. Results The primary patency rate was 67%, 59%, 44% and 28% at 6, 12, 24, and 36 months, respectively. The secondary patency rate was 67%, 61%, 50% and 37% at 6, 12, 24, and 36 months, respectively. In three patients the AVF failed directly after the operation. Delayed fistula failure occurred in seven patients. The overall success in the creation of a functioning fistula was achieved in 15 of the 23 patients (65%). No serious complications were observed. Conclusions In patients with calcified atherosclerotic plaques, which constitute a barrier or make it difficult to suture the vein to the side of the artery, the sleeve method may be considered as an alternative before abandoning the creation of a fistula on the forearm. The technique is much simpler than the standard end-to-side or side-to-side anastomosis.