Intraoperative Heparin Use during Upper Extremity Arteriovenous Access Creation Does Not Affect Outcomes.

BACKGROUND: There are conflicting data about the effect of heparin use on perioperative outcomes during upper extremity arteriovenous (AV) access creation. Our goal was to assess the effect of the use and degree of intraoperative heparin on perioperative outcomes after AV access creation. METHODS: All upper extremity AV access cases performed at a tertiary academic medical center between 2014 and 2017 were reviewed. Patient and procedural details including intraoperative heparin use and dosing as well as protamine use were analyzed. Full heparin dose was defined as 80-100 U/kg and partial heparin dose as less than 80 U/kg. Perioperative arterial thrombosis or distal embolism, hematoma, and early loss of primary patency within 30 days were evaluated. Multivariate analysis was performed to assess the effect of heparin use. RESULTS: There were 550 AV access cases identified: brachiocephalic (37.5%), brachiobasilic (29.3%), and radiocephalic fistulas (12.9%), and AV grafts (16.9%). Average patient age was 62.6 years and 58.9% were male. Full heparinization was used in 21.3%, partial heparinization in 58.7%, and no heparin was used in 20% of cases. Protamine was used in 94.9% of full heparin cases and 51.4% of partial heparin cases. No perioperative arterial thrombosis or distal embolism was observed. Perioperative wound hematoma rate was 3.4%, 3.1%, and 0.9% in full heparin, partial heparin, and no heparin cohorts, respectively (P = 0.42). Early loss of primary patency was 11.1%, 7.7%, and 6.4% for full heparin, partial heparin, and no heparin cases, respectively (P = 0.39). There were no differences in return to the operating room or perioperative survival. On multivariable analysis, full heparin use (odds ratio [OR] 3.82, 95% confidence interval [CI] 0.41-35.9, P = 0.24) and partial heparin (OR 4.03, 95% CI 0.5-32.6, P = 0.19) use were not significantly different from no heparin cases with respect to 30-day perioperative hematoma rate. Full heparin (OR 1.76, 95% CI 0.65-4.78, P = 0.26) and partial heparin (OR 1.13, 95% CI 0.46-2.75, P = 0.79) were not significantly different from no heparin cases with respect to early loss of primary patency. CONCLUSIONS: Intraoperative heparin use, at full or partial doses, did not affect perioperative outcomes after AV access creation. Overall complication event rate was low for all groups. AV access can be safely performed without intraoperative heparin use.

Monoclonal IgG4/2κ Deposition Following Eculizumab Therapy for Recurrent Atypical Hemolytic Uremic Syndrome in Kidney Transplantation.

Eculizumab is an emerging therapy for atypical hemolytic uremic syndrome (aHUS). Early identification and treatment of recurrent aHUS after kidney transplantation requires a high clinical suspicion but results in improved graft function and patient outcome. We present a patient who developed recurrent aHUS after kidney transplantation that responded to eculizumab therapy. A kidney biopsy was performed to confirm resolution of thrombotic microangiopathy 8 weeks after eculizumab treatment initiation and revealed no features of thrombotic microangiopathy. Instead, the biopsy revealed monoclonal immunoglobulin G (IgG)4/2κ deposition in the glomerular tufts, vasculature, and atrophic tubular basement membranes. IgG4/2κ deposits are a rare pathologic finding following eculizumab therapy, and the long-term effect of these deposits on kidney function remains unknown.

Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection
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Late occurrence of antibody-mediated rejection (AMR), defined as occurring 6 months after transplantation, is associated with poor renal allograft survival, compared to early acute AMR and acute cellular rejection. The proteasome inhibitor bortezomib has multiple immunomodulatory effects on plasma cells, the source of donor-specific HLA antibodies which mediate AMR. MATERIALS AND METHODS: Consecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375 mg/m2 on day 1, bortezomib 1.3 mg/m2 and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3 months of therapy, or documentation of opportunistic infection. RESULTS: Eleven patients were treated for late AMR (diagnosed at a median of 38 months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11 patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1 mg/dL (range 1.1 - 3.4 mg/dL), at a median follow-up of 50 months after AMR therapy (range 24 - 63 months). One patient was re-transplanted at 4 years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2 years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and class II DSA specificities; of these, 4 patients had negative class I DSA but persistent class II DSAs at 2 - 3 months post therapy. Only 1 patient who was positive for class II DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2 years' follow-up. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster. CONCLUSION: Renal allograft survival was 82% at 4 years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response.
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Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk.

Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

Outcomes of bisphosphonate therapy in kidney transplant recipients: a systematic review and meta-analysis.

Mineral and bone disorders that precede kidney transplantation are exacerbated in the post-transplant setting by tertiary hyperparathyroidism and immunosuppressive regimens. Bone mineral density (BMD) decreases following transplantation, leading to increased fracture risk. The effect of bisphosphonates on fracture is unknown. The aim of this study was to update estimates of change in BMD and fracture rates in bisphosphonate-treated kidney transplant recipients through meta-analysis. Studies comparing bisphosphonate therapy to standard of care were included if follow-up duration was more than 6 months. We performed random-effects meta-analysis to determine the effect of bisphosphonates on lumbar spine and femoral neck BMD and fracture rates. Bisphosphonates improved femoral neck and lumbar spine BMD compared with controls (0.055 g/cm(2) , 95% CI 0.012-0.099 and 0.053 g/cm(2) , 95% CI 0.032-0.074, respectively) without adversely affecting serum creatinine or calcium. This corresponded to an unweighted improvement in BMD of 6.0% and 7.4%, respectively. There was no difference in fracture incidence in the two groups. Bisphosphonate therapy in kidney transplant recipients is associated with a statistically significant improvement in BMD at the lumbar spine and femoral neck. There was no difference in fracture incidence. Bisphosphonates did not adversely affect allograft dysfunction or serum calcium levels.

Lower magnesium level associated with new-onset diabetes and pre-diabetes after kidney transplantation.

BACKGROUND: Hypomagnesemia is associated with increased peripheral insulin resistance in the general population. It is frequently seen after renal transplantation. We examined its role as a risk factor for new-onset diabetes after transplantation (NODAT) and new-onset pre-diabetes after transplantation (NOPDAT). METHODS: A retrospective analysis of 138 previously non-diabetic renal transplant recipients was conducted. Cox and logistic regression analyses were performed to examine the associations between 1-month post-transplant serum magnesium level and subsequent diagnoses of NODAT/NOPDAT. RESULTS: NODAT was diagnosed in 34 (24.6 %) and NOPDAT in 12 (8.7 %) patients. Median time to diagnosis of NODAT/NOPDAT was 20.4 months (interquartile range [IQR] 6.8-34.8). Median follow up for the entire group was 3.5 years (IQR 2.3-5.6). Mean magnesium level at 1 month after transplantation was significantly lower in patients subsequently diagnosed with NODAT/NOPDAT (1.60 ± 0.27 vs. 1.76 ± 0.29 mg/dl, p = 0.002). Cox regression analysis identified a trend towards developing NODAT/NOPDAT with lower baseline magnesium levels (hazard ratio 0.89 per 0.1 mg/dl increment in magnesium level, 95 % confidence interval [CI] = 0.78-1.01, p = 0.07); a stronger relationship between the two variables was seen at logistic regression analysis (odds ratio 0.81 per 0.1 mg/dl increment in serum magnesium (95 % CI 0.67-0.98, p = 0.03). CONCLUSIONS: A lower magnesium level at 1 month after transplantation may be predictive of a subsequent diagnosis of glucose intolerance or diabetes in renal transplant recipients. Whether replenishing magnesium stores can prevent development of these disorders requires further investigation.

Renal allograft failure predictors after PAK transplantation: results from the New England Collaborative Association of Pancreas Programs.

BACKGROUND: The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection. METHODS: Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure. RESULTS: Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year. CONCLUSIONS: In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.

Suppression of cell-mediated immunity by a donor-transmitted lymphocytic choriomeningitis virus in a kidney transplant recipient.

Infection with lymphocytic choriomeningitis virus (LCMV) in rodents, the primary host, is known to cause suppression of cell-mediated immunity. Serial determinations using a functional cell-mediated immune assay in a kidney transplant recipient with donor-transmitted LCMV also suggested profound suppression of cellular immunity. This suppression persisted in spite of reduction of immunosuppression. With the clearance of the virus there was reconstitution of the cellular immune response.

The changing survival scenario in gangrenous sigmoid volvulus: a four-decade study.

There is a suspicion that mortality in gangrenous sigmoid volvulus has considerably declined over the recent years. This study was aimed to assess if this is a genuine trend, applicable to the patients, of this study too, and to identify factors responsible for the change, if any. Seventy-eight patients operated for gangrenous sigmoid volvulus, in the last four decades of the just gone century, were analysed. Nine clinical parameters were studied to identify factors responsible for mortality and to see if there was a change in clinical presentation in the later decades. Mortality in the 4 studied decades varied between 15.4% and 65%. Differences were significant (p<0.05) only between the decades of the seventies and eighties and between bunched pre 1980 (48%) and post 1980 (20%) decades. A sea change in survival scene occurred at the end of the decade of the seventies. The change was not accompanied by a concomitant improvement in clinical presentation (p>0.05). Two facts which could explain improved survivals in the post. 1980 period were, the increased recognition of gangrene extending beyond the area of constriction and improved survival after primary anastomoses (p<0.05). These indicated a more accurate assessment of viability and the distance between the cut bowel ends, a stricter selection of cases for primary anastomosis and using Hartmann operation in doubtful situations. Mortality in gangrenous sigmoid volvulus, without knotting in the Indian population has genuinely declined from over 50% in an earlier time to 20% in the later 20 years of the last century, the watershed in the changed scenario being the year 1980.

Gastrointestinal complications following transplantation.

Gastrointestinal complications are common after kidney, liver, pancreas, heart, and lung transplantation. Complications can include gastrointestinal conditions preceding the transplantation, viral, fungal, and bacterial gastrointestinal infections, and gastrointestinal side effects of medications including immunosuppressive agents. Establishing the etiology of gastrointestinal complaints is often difficult because any one or a combination of these factors might be contributory in the same patient.

Use of an immune function assay to monitor immunosuppression for treatment of post-transplant lymphoproliferative disorder.

The first-line treatment for PTLD is reduction in immunosuppression, allowing partial reconstitution of cell-mediated immunity. However, there is a risk of inducing acute allograft rejection during clinical resolution of PTLD. A recently available assay, Immuknow, measures the cell-mediated immune response and could be used to monitor reduction of immunosuppression. We report a case of PTLD occurring in a pediatric kidney transplant recipient where the reduction in immunosuppression was serially followed using this assay and quantitative EBV-PCR. A rapid reduction to minimal immunosuppression was followed by resolution of PTLD. Later, when the cell-mediated immune response increased, with negative viral load, immunosuppression was gradually increased utilizing the assay to adjust dosing. Presently, there are no signs of PTLD and renal function remains normal.

Renal transplant survival from older donors: a single center experience.

HYPOTHESIS: Despite the observation that kidney transplantations from older donors have an increased risk of failure, the percentage of kidney donors 55 years and older has increased. We explored the risk of allograft failure in a single transplantation center with older (55-79 years) vs younger (18-54 years) donors. DESIGN: Retrospective cohort review with a mean follow-up of 32 months. SETTING: Academic transplant center. PATIENTS: Consecutive recipients (n = 324) of renal transplants from adult donors. INTERVENTIONS: Patients were divided into 4 groups based on donor status (living or deceased) and donor age (< or =54 or > or =55 years). MAIN OUTCOME MEASURES: Allograft survival and function, incidence of acute rejection. RESULTS: Recipients of older donor kidneys were significantly older (53.6 vs 43.6 years, P<.001). Seven allografts (12.7%) failed from 55 transplants from donors 55 years and older, compared with 41 allografts (15.2%) from 269 younger donors (P =.63). Renal function was superior following renal transplantation using younger donors (P =.004). However, renal function was acceptable in all groups, with a mean +/- SD serum creatinine level of 1.7 +/- 0.4 mg/dL (150 +/- 35 micro mol/L) among recipients of older donor kidneys. Allograft survival at 1, 2, and 3 years, censored for death with allograft function, did not differ when comparing older vs younger donors. CONCLUSIONS: Most patients receiving allografts from older donors do well. Older donor kidneys provide suitable renal function for many patients on dialysis awaiting transplantation.