The gold standard of thyroid nodule examination? Prospective validation of the ACR TI-RADS in a secondary referral center.

The aim of this prospective study was the validation of the risk stratification of thyroid nodules using ultrasonography with the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and partly in comparison to American Thyroid Association (ATA) guidelines in a secondary referral center. Fine needle aspiration biopsy (FNA) (n=605) and histological examinations (n=63) were the reference standards for the statistical analysis. ACR TI-RADS cut-off value: TR4 with sensitivity 85.7 %, specificity 54.1 %, PPV 58.5 %, accuracy 67.7 % (AUC 0.738; p<0.001). ATA cut-off value: "high suspicion" with sensitivity 80 %, specificity 83.3 %, PPV 80 %, accuracy 81.8 % (AUC 0.800; p=0.0025). 18.4 % nodules (3 malignant) could not be assigned to a proper ATA US pattern group (p<0.0001). Both ACR TI-RADS and ATA have allowed fair selection of nodules requiring FNA with superiority of ACR TI-RADS according to classification of all thyroid nodules to the proper group. According to ACR TI-RADS almost one third of the patients were incorrectly classified with 17.9 % missed thyroid carcinomas, exclusively micropapillary carcinomas, even though, the amount of FNA would be reduced to 48 %.

Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Severe Epidermal Nerve Fiber Loss in Diabetic Neuropathy Is Not Reversed by Long-Term Normoglycemia After Simultaneous Pancreas and Kidney Transplantation.

Whether nerve fiber loss, a prominent feature of advanced diabetic neuropathy, can be reversed by reestablishment of normal glucose control remains questionable. We present 8-year follow-up data on epidermal nerve fiber (ENF) density and neurological function in patients with type 1 diabetes after simultaneous pancreas and kidney transplantation (SPK) with long-term normoglycemia. Distal thigh skin biopsies with ENF counts, vibration perception thresholds (VPTs), autonomic function testing (AFT) and electrophysiological examinations were performed at time of SPK and 2.5 and 8 years after SPK in 12 patients with type 1 diabetes. In comparison to controls, baseline ENF density, VPT and AFT results of patients indicated severe neuropathy. At follow-up, all SPK recipients were insulin independent with excellent glycemic control and kidney graft function; however, the severe ENF depletion present at baseline had not improved, with total ENF absence in 11 patients at 8-year follow-up. Similarly, no amelioration occurred in the VPT and AFT results. Numerical improvement was seen in some electrophysiological parameters; however, statistical significance was achieved only in median motor nerve conduction velocity. ENF loss and functional deficits in advanced diabetic peripheral neuropathy are rarely reversible, even by long-term normoglycemia, which underscores the importance of neuropathy prevention by early optimal glycemic control.

Portal versus systemic venous drainage of the pancreatic graft: the effect on glucose metabolism in pancreas and kidney transplant recipients.

Two different methods of graft venous drainage are used in pancreas transplantation: portal (PVD) and systemic (SVD). PVD is considered to be more physiologic due to its similarity to venous outflow of the native pancreas. The aim of our study was to compare glucose metabolism in Type 1 diabetic recipients of kidney and pancreatic grafts with PVD versus SVD by intravenous glucose tolerance test (IVGTT). We examined 28 insulin-independent patients after simultaneous pancreas and kidney transplantation: 14 recipients with PVD of the pancreatic graft and 14 with SVD after a mean post-transplant period of 1 year. All recipients had stable good function of the kidney graft. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA1c), and standard IVGTT with coefficient of glucose assimilation (KG) calculation were assessed. Insulin sensitivity and production were evaluated using the homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR], homeostasis model assessment of B-cell function [HOMA-B]). Total C-peptide and insulin secretions were calculated as areas under the curves (AUCs) from the serum levels during the IVGTT. PVD and SVD groups did not differ in age, body mass index (BMI) and duration of post-transplantation period (P ≥ .05). We did not find any significant difference in fasting glycemia, HbA1c, KG, HOMA-IR, parameters of C-peptide level, fasting insulin level, and response during IVGTT. HOMA-B and AUC of insulin level were higher in the SVD group (45.1 ± 35.1 versus 19.8 ± 15.5, P =.03 and 1075 ± 612 versus 1799 ± 954 mIU/L/60 minutes, P < .03, respectively). In the PVD group, 1 patient had an abnormal response to the glucose stimulus, 8 patients had an impaired glucose tolerance, and 5 patients had a normal glucose tolerance. In the SVD group, an abnormal response was present in none, impaired glucose tolerance in 4, and normal glucose tolerance in 10 recipients. Athough this was not a prospectively randomized trial, we conclude that the change of surgical technique from SVD to PVD did not lead to any substantial change in terms of glucose tolerance.

Effect of tacrolimus versus cyclosporine on glucose metabolism of pancreas and kidney recipients in the late (> 8 years) posttransplant period.

Diabetogenic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare the glucose metabolism in type 1 diabetic kidney and pancreas recipients on tacrolimus (Tacro) versus cyclosporine-based (Cyclo) immunosuppression in the late posttransplant period. We examined 26 insulin-independent patients with stabile good renal function. They were at least 7 years after simultaneous pancreas and kidney transplantation and with unchanged immunosuppressive therapy for at least 6 years. The mean follow-up in Tacro (n = 13) and Cyclo (n = 13) groups were 9.7 ± 1.9 and 10.9 ± 1.3 years, respectively (P = .08). Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA(1c)), a standard intravenous glucose tolerance test (IVGTT) with coefficient of glucose assimilation (K(G)) calculation and trough Tacro/Cyclo levels were assessed. Insulin sensitivity and insulin secretion were evaluated using the homeostasis model assessment (HOMA-IR, HOMA-B). Total C-peptide and insulin secretions were calculated as areas under the curves (AUC) from the serum levels during the IVGTT. Tacro and Cyclo groups did not differ in age and body mass index. We did not find any significant difference in any examined parameters of glucose metabolism (fasting glycemia, insulin and C-peptide levels, HbA(1c,) IVGTT with K(G), HOMA-IR, HOMA-B, AUC of C-peptide and AUC of insulin; P > .05). Two patients in the Tacro group and none in the Cyclo group had K(G) <0.8%/min. Seven recipients in the Tacro group and eight in the Cyclo group had the normal glucose tolerance with K(G) ≥ 1.2%/min. Trough Tacro or Cyclo levels did not correlate with any of examined parameters. The use of different types of calcineurin inhibitors in type 1 diabetic pancreas and kidney recipients had no effect on glucose metabolism in the late posttransplant period.

Similar early complication rate in simultaneous pancreas and kidney recipients on tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus immunosuppressive regimens.

INTRODUCTION: We compared the incidence of severe complications among 123 consecutive simultaneous pancreas and kidney (SPK) recipients randomized for treatment either with tacrolimus plus mycophenolate mofetil (MMF) or tacrolimus plus sirolimus during their initial postoperative hospital stay. METHODS: Patients with type 1 diabetes mellitus (T1DM) and renal failure with no age limit who underwent SPK were randomly assigned to tacrolimus/sirolimus or tacrolimus/MMF immunosuppressive protocols. We analyzed the rate of adverse events that led to death, graft loss, operative revision, or prolonged hospital stay. RESULTS: From 2002 to 2009, 62 recipients were included in the MMF and 61 in the Rapamycin (Rapa) groups. More than 2/3 of recipients suffered from at least 1 complication: 74% MMF and 77 % Rapa group (P > .05). No patient died in the MMF and 3 in the Rapa group (P = .11). Pancreas graftectomy was performed in 13% of the MMF group and in 5% of the Rapa group (P = .20). Ten of 62 recipients in the MMF and 13/61 in the Rapa group required operative treatment of wound infections (P = .49). There were no differences in the rates of gastrointestinal bleeding (11% and 8%), kidney lymphocele (6% and 5%), ileus (1.6% both), pancreatic leak (1.6% both), or ureteral leak (0 and 3%) between the groups. CONCLUSION: We did not observe a difference in the rate of severe postoperative complications between groups. With the use of extraperitoneal placement of the pancreatic graft, fluid collections and wound infections remain the most frequent albeit curable postoperative complications.

Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond.

The Immunosuppression in Pancreas Transplantation was historically based on the fact that the pancreas is an extremely immunogenic organ. Quadruple drug therapy with polyclonal or monoclonal antibodies induction was the mainstay therapy since the introduction of Cyclosporine A. In the modern era of Immunosuppression, Mycophenolate Mofetil replaced Azathioprine while Tacrolimus-another potent calcineurin inhibitor-had-and still has-a difficult challenge to replaced Cyclosporine A, due to its potential diabetogenic effect. Thanks to the first two EuroSPK studies which prospectively tried to answer several questions in that field. But, the future challenge will be in understanding the impact of innate immunity and ischemic reperfusion injuries on the long-term graft function. Hopefully, new drugs will be available and tested to block unspecific deleterious reactions to attenuate the proinflammatory response. It will be the aim of the third Euro SPK Study.

Metabolic effect of sirolimus versus mycophenolate mofetil on pancreatic graft function in the early posttransplant period.

Metabolic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare effects of tacrolimus-based immunosuppression in conjunction with sirolimus (RAPA) versus mycophenolate mofetil (MMF) on glucose metabolism in type 1 diabetic recipients following a simultaneous pancreas and kidney transplantation (SPK). We examined 30 insulin-independent patients after SPK with venous systemic drainage of the pancreatic graft. All recipients had good kidney graft function. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA(lc)), standard intravenous glucose tolerance test (IVGTT), and trough RAPA levels were assessed in pancreas recipients before elective steroid withdrawal. Insulin sensitivity was evaluated using the homeostasis model assessment (HOMA-IR). The groups did not differ in age, BMI, posttransplant period, steroid daily dose, HbA(lc), and fasting glycemia. We did not find any significant difference in the IVGTT response. Area under the curve of insulin levels during IVGTT and HOMA-IR were significantly lower in the RAPA group. Trough levels of RAPA had no significant impact on any of the examined parameters. Glucose tolerance measured with the use of IVGTT was similar in patients treated with RAPA and MMF. However, recipients on sirolimus treatment had significantly lower insulinemia during the test and consequently more favorable indices of insulin action as assessed by HOMA-IR.

Severe depletion of intraepidermal nerve fibers in skin biopsies of pancreas transplant recipients.

BACKGROUND: The minimally invasive method of skin biopsy with intraepidermal nerve fiber (IENF) counts may be used to analyze nerve regeneration in pancreas transplant (PTx) recipients. We assessed IENF counts as a database for long-term follow-up of diabetic neuropathy. METHODS: Skin biopsies were performed using a 3-mm punch from lower thigh and upper calf areas of 16 (13 pancreas/kidney, 3 pancreas alone) PTx patients (mean +/- SD: age, 45+/-8 years; type 1 diabetes duration, 27 +/- 8 years) at 1 month posttransplant. Ten healthy gender- and age-matched controls (C) were also examined. After fixation and freezing, 40-microm sections were stained using rabbit polyclonal antibody to the panaxonal marker PGP 9.5 followed by mouse antirabbit IgG antibody conjugated with rhodamine. Samples were imaged with a digital camera, mounted on a microscope, and equipped for fluorescence. The average number of IENF per millimeter length of epidermis was derived. Clinical neuropathy was assessed by foot vibration perception thresholds (VPT) with a biothesiometer (normal values < mean + 2 SD of C). RESULTS: Significantly lower IENF densities were found in skin biopsies from PTx (PTx vs C: thigh, 0.74 +/- 0.88 vs 9.74 +/- 2.41 IENF/mm; calf, 0.34 +/- 0.91 vs 7.66 +/- 3.16 IENF/mm; P < .001). IENF were totally absent from the thigh and calf samples of 7 and 12 PTxs, respectively. Clinical neuropathy (VPT > 21 V) was present in all but one PTx. CONCLUSIONS: Severe intraepidermal nerve fiber depletion is present in the lower limb area of pancreas transplant recipients with neuropathy. Long-term follow-up would probably be necessary to assess the possibility of posttransplant nerve fiber regeneration.

A prospective comparison of bladder versus enteric drainage in vascularized pancreas transplantation.

In previous years, the number of pancreas transplants has increased significantly. Debate continues over the optimum technique for exocrine drainage. Enteric drainage (ED) has recently been increasingly popular owing to the long-term complications of bladder drainage (BD). We prospectively evaluated 40 consecutive pancreas transplant recipients undergoing either bladder (n = 20) or enteric (n = 20) drainage. After simultaneous kidney-pancreas transplantation 1-year patient, kidney, and pancreas graft survival rates were 95%, 95%, 85% for the BD group, and 90%, 85%, 85%, for the ED group. Surgical complications were not significantly different between the two groups. The incidence of acute rejection, major infections and cytomegalovirus disease were also similar. The length of the initial hospital stay was likewise comparable. However, the BD group was characterized by a slight increase in the number of urologic complications, metabolic acidosis, and dehydration. Our results suggest excellent patient and graft survival irrespective of the drainage technique.

A prospective comparison of bladder versus enteric drainage in vascularized pancreas transplantation.

Although the number of pancreas transplants has increased significantly in previous years, debate continues concerning the optimum technique for exocrine pancreas drainage. Enteric drainage (ED) has recently been increasingly popular due to the long-term complications with bladder drainage (BD). We prospectively assigned 40 consecutive pancreas transplant recipients to either bladder (n = 20) or enteric (n = 20) drainage. Patient, kidney, and pancreas graft survival rates at 1 year after simultaneous kidney-pancreas transplantation were 95%, 95%, 85%, for BD group and 90%, 85%, 85% for ED group, respectively. Surgical complications were not significantly different between the two groups. The incidence of acute rejection, major infections, and CMV disease were similar between groups. The length of the initial hospital stay was likewise comparable. However, the BD group showed a slight increase in the number of urologic complications, metabolic acidosis, and dehydration. Based on the results of our study, patient and graft survivals were excellent irrespective of technique.

[Recurrent polyomavirus infections in kidney transplants (BK virus nephropathy)]. / Opakovaná polyomavirová infekce transplantované ledviny (BK virus nefropatie).

BK-virus nephropathy was recently recognised as a new complication that affects renal allografts and causes dysfunction. We report a case of a recipient of simultaneous kidney-pancreas allografts. Fourteen months after the transplant, the renal allograft became dysfunctional with elevation of serum creatinine level. The diagnosis of BK-virus nephropathy was established by needle renal biopsy with immunohistochemical detection of human polyoma virus. Immunosuppressive therapy was reduced but progressive dysfunction developed and the patient had to undergo a renal retransplantation 11 months after the diagnosis of the infection. Due to repeated renal dysfunction, needle biopsy was performed, and the diagnosis of repeated BK-virus nephropathy was established six months after the retransplantation. The pancreas allograft has functioned well for the entire period.

Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation.

Only marginally improved results have been observed in standard autonomic function tests (AFT) in follow-up studies after simultaneous pancreas and kidney transplantation (SPK). We therefore used power spectral analysis (PSA) of heart rate variability (HRV) to assess the effect of SPK on autonomic neuropathy in patients with type I diabetes mellitus (DM I). We evaluated 82 patients with DM I who were insulin and dialysis free following SPK. Both pre- and posttransplant (at [mean +/- SD], 25 +/- 15 months post-SPK) examinations were performed in 29 patients. Posttransplant evolution was examined in another 60 patients with two serial examinations at 20 +/- 20 and 43 +/- 27 months after SPK. Comparisons included 32 age-matched healthy controls and 13 patients with kidney transplant alone (KTA) matched for age and duration of DM I at a comparable time point posttransplant. Short-term time (modified Ewing battery) and frequency domain (PSA of HRV: LF-low, HF-high frequency, and TP-total spectral power) analysis was performed with a telemetric, on-line, computer-aided system. Significantly worse results in all standard AFT and PSA indexes were obtained for SPK patients compared with controls at all time points. No significant improvement was seen in SPK patients in the posttransplant period and no differences were found compared with KTA patients. Thus the results of a power spectral analysis of HRV failed to show improvement following SPK. This examination adds little positive information to that obtained from standard autonomic function tests.