[Pancreas transplantation: State of the art and future prospects]. / Transplantace pankreatu: soucasný stav a výhledy do budoucna.

During the past 30 years pancreas transplantation evolved into a routine procedure especially suitable for type 1 diabetic recipients undergoing simultaneously kidney transplantation significantly improving quality of life and life expectancy as compared with kidney only recipients. It provides insulin independence with near-normal glucose control without special dietary restriction, freedom from hypoglycemia and chance for halting or regression of microangiopathic diabetes complications. As a separate procedure, pancreas transplantation is carried out mainly in selected subjects suffering from severe hypoglycemic episodes and impaired hypoglycemia awareness or as a subsequent procedure in type 1 diabetic kidney recipients from both cadaveric or living donors. Five-year insulin independence rate following combined pancreas and kidney, pancreas only and pancreas after kidney procedures currently exceed 75, 50 and 62 %, respectively. Though the outcomes still continue to improve, the rate of pancreas transplants has reached a plateau in several European countries or even declines in the United States. Main reasons for that include fewer referrals from diabetes specialist, decreased donor quality, introduction of islet transplantation as a less invasive procedure but probably most of all probably insufficient information on the latest progress and trends achieved in this area. In the area of transplant therapy of diabetes Czech Republic traditionally ranks to the most active countries providing different transplant options according to individual clinical needs including islet transplantation.

Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The 'Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273). METHODS: In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier. RESULTS: We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found. CONCLUSION: We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY trial.

Prevalence and risk factors of polyomavirus BK replication in simultaneous pancreas/kidney transplant recipients from a single transplant center.

BACKGROUND: BK virus (BKV) replication is considered as a marker of risk for polyomavirus BK-associated nephropathy (PVAN). We evaluated the occurrence and risk factors for BKV DNA positivity following simultaneous pancreas/kidney transplantation (SPK). METHODS: Point prevalence of BK viruria and viremia was assessed in 183 SPK recipients. Real-time polymerase chain reaction was used with a detection threshold of 10(3) copies/mL. High-level BKV positivity was defined as viruria and/or viremia >10(7) and >10(4) copies/mL, respectively. BKV-positive patients were retested after 4-13 months and underwent an additional six-month clinical follow-up. RESULTS: Urine and serum BKV positivity was detected in 28 (17.3% of available samples) and 7 (3.8%) patients, with high-level viruria and viremia occurring in 6 (3.7%) and 3 (1.6%) patients, respectively. PVAN was biopsy-confirmed in 1 and suspected as a cause of progressive renal failure in another SPK recipient. Patients with single low-level viruria did not progress to high-level positivity or PVAN at follow-up. In multivariate analysis, pre-transplant diabetes duration and delayed graft function were independently associated with BKV positivity. CONCLUSIONS: Point prevalence of high-level BKV positivity and PVAN was low in SPK recipients from a single center. Diabetes duration and delayed graft function were independent risk factors for BKV replication.

Effect of acute hyperglycemia and/or hyperinsulinemia on polymorphonuclear functions in healthy subjects.

Abnormal immune functions of polymorphonuclear (PMN) cells occur in a variety of pathophysiological conditions. There exists a close link between glucose metabolism and PMN functions. The aim of this study was to assess the effect of short-term hyperglycemia and/or hyperinsulinemia on phagocytosis and respiratory burst of PMN cells in healthy subjects in vivo. The study was performed on 12 healthy subjects (mean age, 26.9+/-1.6 years; body mass index, 24.4+/-0.84 kg/m(2)). Acute hyperglycemia and/or hyperinsulinemia was induced by three 4-hour-long clamp studies-hyperglycemic hyperinsulinemic clamp (HHC), hyperinsulinemic euglycemic clamp (HEC), and isolated hyperglycemic clamp with insulin secretion blockade (HGC). Polymorphonuclear cell phagocytosis and PMN cell respiratory burst (mean percentage and mean fluorescent intensity of phagocyting/activated PMN cells, phagocytic, and respiratory burst indexes) were evaluated by flow cytometry under basal and stimulated conditions. Results detected during clamp studies were compared with those found during a control study with saline infusion. Significant reductions in the mean percentage of phagocyting cells measured under basal conditions after the HHC (6.7%+/-1.3% vs 12.1%+/-4.3%; P<.05) and HGC (4.5% +/-1.8% vs 9.9%+/-2.1%; P<.05) were found in comparison with the pre-clamp study period; however, these results did not differ significantly from those detected during the control clamp (CC) study. Significantly higher phagocytic (115.1+/-65 vs 35.8 +/-18.6; P<.05) and respiratory burst indexes (16.5+/-3 vs 10.1+/-1.4; P<.05) measured under basal conditions were found after HEC in comparison with the pre-clamp data. However, these data did not differ significantly from those found after the CC study. No significant differences in other parameters of detected PMN cell immune functions were found after HHC, HEC, and HGC. In conclusion, immune functions of PMN cells were not significantly influenced by short-lasting hyperglycemia and/or hyperinsulinemia induced in vivo by clamp techniques in healthy subjects compared to changes induced by the CC study. Further studies on the short-term effect of glucose metabolism on PMN functions in diabetic patients should be considered necessary.

Power spectral analysis of heart rate variability in patients with Charcot's neuroarthropathy.

Charcot's or neuropathic osteoarthropathy is one of the most debilitating orthopedic sequelae of diabetes mellitus. Distinguishing Charcot's neuroarthropathy from clinically similar conditions may be challenging. The neurovascular theory postulates that Charcot's neuroarthropathy may be secondary to sympathetic denervation of the lower-extremity vasculature. A convenient method for assessing autonomic neuropathy in patients with Charcot's neuroarthropathy is needed. Short-term power spectral analysis (PSA) of heart rate variability (HRV), a noninvasive and quantitative method for assessing autonomic neuropathy, may be advantageous compared with the traditionally used Ewing's cardiovascular reflex tests. However, there are limitations to the clinical use of PSA of HRV because of poor standardization. We standardized PSA of HRV and assessed autonomic neuropathy in 17 people with acute Charcot's neuroarthropathy using PSA of HRV versus Ewing's tests. More patients with Charcot's neuroarthropathy were diagnosed as having autonomic neuropathy with PSA of HRV than with Ewing's tests (94% versus 82%); however, no significant difference between the two methods was found. The results of this study suggest that PSA of HRV requires minimal patient collaboration and time expenditure compared with Ewing's tests and may be useful in detecting autonomic neuropathy in patients with Charcot's neuroarthropathy.

Comparison of microbial findings and resistance to antibiotics between transplant patients, patients on hemodialysis, and other patients with the diabetic foot.

UNLABELLED: Infectious complications of the diabetic foot may be influenced by impaired renal function and by immunosuppression therapy. AIMS: To assess differences in microbial findings and resistance to antibiotics between transplant recipients, hemodialysis patients, and other patients with the diabetic foot. METHODS: 207 patients treated in the foot clinic for diabetic ulcers from 12/1998 to 12/1999 were included into this retrospective study. Patients were divided into three groups (transplant, dialysis, and other patients). Occurrence of individual bacterial species and resistance to antibiotics was compared between study groups. RESULTS: Study groups did not differ significantly in ulcer grades defined by the Wagner classification or in the mean number of pathogens per patient. The prevalence of individual microorganisms did not differ between the study groups. However, the study groups differed significantly in the occurrence of microbial resistance to antibiotics. Transplant patients had more frequently Staphylococcus aureus resistant to oxacillin (P<.01), imipenem (P<.01), co-trimoxazole (P<.01), Enterococcus species resistant to ampicillin (P<.01), piperacillin (P<.01), and dialysis patients had more frequently Pseudomonas species resistant to piperacillin (P<.05) and cefpirom (P<.05) in comparison with the other two groups. CONCLUSIONS: Transplant patients had significantly more resistant microorganisms in comparison with dialysis and other patients with the diabetic foot. Empiric antibiotic selection based on general population data should be modified in transplant patients with diabetic foot according to actual susceptibility to antibacterial drugs.

Prevention of contrast-induced nephropathy in diabetic patients with impaired renal function: a randomized, double blind trial of sodium bicarbonate versus sodium chloride-based hydration.

AIMS: Diabetes mellitus and decreased renal function are important risk factors for contrast-induced nephropathy (CIN) in which oxidative stress damage may play a role. Alkalinization with sodium bicarbonate (NaHCO3) has been proposed as a means of reducing free-radical mediated renal injury; however, the effectiveness of NaHCO3 treatment to prevent CIN in high-risk patients remains uncertain. METHODS: We performed a prospective, randomized, double blind, sodium chloride (NaCl) hydration-controlled study of NaHCO3 in 120 diabetic patients with impaired renal function (serum creatinine ≥100 µmol/L) undergoing an elective procedure with use of low-osmolar contrast media. The primary endpoint was the incidence of CIN defined as creatinine increase of ≥25% and/or ≥44 µmol/L within 2 days after contrast. Secondary end-points were maximal changes in serum creatinine and estimated glomerular filtration rate. Urine F2-isoprostane levels were also assessed as measure of oxidative stress. RESULTS: There were no significant group differences in baseline characteristics except for the marginally lower age of the NaHCO3 treated patients (63 ± 11 vs. 67 ± 10 years; p=0.05). CIN occurred in 7 (11.5%) and 5 (8.5%) patients of the NaHCO3 and NaCl groups, respectively (p=0.76; incidence rate ratio 1.35; 95% CI 0.37-5.41). No significant differences were seen in secondary outcome measures and changes in the parameter of oxidative stress. CONCLUSIONS: In diabetic patients with renal function impairment sodium bicarbonate does not confer protection against contrast-induced nephropathy greater than sodium chloride-based hydration. Its specific role in mitigating oxidative stress damage in CIN is also not supported by our data.

Cured malakoplakia of the renal allograft followed by long-term good function: a case report.

BACKGROUND: Malakoplakia is an unusual chronic inflammatory disease with distinctive histopathological features rarely involving the parenchyma of a transplanted kidney, and to date less than ten cases have been reported. METHODS AND RESULTS: We present a case of malakoplakia of a kidney graft in a 31 year old woman after simultaneous kidney and pancreas transplantation, which was successfully treated with quinolones. After the treatment of malakoplakia, she was monitored regularly, and her renal and pancreas grafts functioned well for the following 9 years, which is 12 years post transplantation. Moreover, 1 year after treatment of malakoplakia she became pregnant and gave birth to a healthy child. CONCLUSION: Evaluation of a kidney biopsy sample represents the key to diagnosis of malakoplakia which is important for correct patient management. Treatment with antibiotics with intracellular penetration (quinolone type) may result in curing the disease. According to our knowledge, this is the first case of allograft renal malakoplakia after combined kidney and pancreas transplantation.

'Observing' diabetic neuropathy with corneal confocal microscopy: the effect of improvement of risk factors.

Evaluation of: Tavakoli M, Kallinikos P, Iqbal A et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet. Med. 28(10), 1261-1267 (2011). A recent observational study has evaluated whether a novel examination method, corneal confocal microscopy, can be used to detect changes in corneal nerve morphology following improvements of conventional risk factors in diabetic patients with mild-to-moderate neuropathy. At 2-year follow-up, improvement of glycemic control (HbA1c) correlated significantly with increases in corneal nerve fiber density. The results add new supportive evidence to data from previous studies of corneal confocal microscopy for its potential use as a convenient noninvasive technique in trials of therapeutic interventions for diabetic neuropathy. Since so far only intensive glycemic control has been proven as an effective measure, this could represent an important advance in the search for new treatment options for this major diabetic complication.

Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation.

OBJECTIVE: To assess the effect of normoglycemia following simultaneous pancreas/kidney transplantation (SPK) on neurological function and intraepidermal nerve fiber density (IENFD) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed vibration perception threshold (VPT) testing and autonomic function testing (AFT) and assessed IENFD in skin biopsies from the lower thigh and upper calf in 14 healthy control subjects and 18 patients with type 1 diabetes at the time of and at 21-40 (median 29) months post SPK. RESULTS: At baseline, significantly increased VPTs, pathological AFT results, and severe reduction in IENFD were present in SPK recipients. After SPK, an increase of IENFD in the thigh of more than one epidermal nerve fiber per millimeter was noted in three patients (median 4.1, range 1.9-10.2), but changes were not significant for the group as a whole. CONCLUSIONS: We conclude that either irreversible nerve damage might be present in some SPK recipients or that longer periods of normoglycemia might be needed to allow nerve regeneration.

Kidney retransplantation following graft loss to polyoma virus-associated nephropathy: an effective treatment option in simultaneous pancreas and kidney transplant recipients.

Polyomavirus-associated nephropathy (PVAN) has emerged as an important cause of graft loss following kidney transplantation. Experience with kidney retransplantation (reKT) in PVAN is very limited, especially in the setting of uninterrupted immunosuppression protecting the still functioning pancreatic graft after simultaneous pancreas/kidney transplantation (SPK). We present a review of five cases of reKT in four SPK recipients with Type 1 diabetes mellitus from a single centre (a second reKT was performed in one patient following first reKT failure due PVAN recurrence). Pre-emptive nephrectomy of the failed graft was performed in three of the cases and all kidney grafts for reKT were harvested from cadaveric donors. All patients are dialysis- and insulin-independent at 30 (9-55), median (range), months following last reKT with maintenance immunosuppression consisting of tacrolimus/sirolimus in three and cyclosporine A/mycophenolate mofetil in one patient. In conclusion, reKT represents an effective treatment option in SPK patients with kidney failure on account of PVAN. Use of interventions designed to reduce active viral replication, including pre-emptive nephrectomy of the failed graft, should be considered before reKT.

Advanced Diabetic Neuropathy: A Point of no Return?

Diabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel non-invasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

Efficacy and safety of tacrolimus compared with cyclosporin microemulsion in primary SPK transplantation: 3-year results of the Euro-SPK 001 trial.

BACKGROUND: Single-centre and retrospective studies suggest superiority of tacrolimus over cyclosporin as cornerstone immunosuppressive therapy for simultaneous pancreas-kidney (SPK) transplantation. This open-label, multicentre trial compared the efficacy and safety of tacrolimus with cyclosporin microemulsion (ME) in diabetic patients with end-stage renal disease undergoing their first cadaveric SPK transplantation. The 3-year results are reported. METHODS: Patients were recruited from 10 centres in Europe and one centre in Israel: 103 were randomized to receive tacrolimus (initial dose: 0.2 mg/kg/day p.o.) and 102 to cyclosporin-ME (7 mg/kg/day p.o.). All patients received concomitant rabbit anti-T-cell globulin induction, mycophenolate mofetil (MMF) and short-term corticosteroids. RESULTS: Fewer patients receiving tacrolimus (36.9%) than cyclosporin-ME (57.8%) were discontinued from treatment (P = 0.003). The initial episodes of biopsy-proven rejection were moderate or severe in just one out of 31 (3%) tacrolimus-treated patients compared with 11 out of 39 (28%) patients receiving cyclosporin-ME (P = 0.009). While 3-year patient and kidney survival rates were similar in the two treatment groups, pancreas survival was superior with tacrolimus (89.2 vs 72.4%; P = 0.002). Thrombosis resulted in pancreas graft loss in 10 patients receiving cyclosporin-ME and in only two treated with tacrolimus (P = 0.02). Overall adverse event frequency was similar in both groups, but MMF intolerance was more frequent with tacrolimus and hyperlipidaemia more frequent with cyclosporin-ME. CONCLUSIONS: In this 3-year study, tacrolimus was more effective than cyclosporin-ME in preventing moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreas survival and reduced the risk of pancreas graft thrombosis.

Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset.

The destruction of pancreatic beta-cells in type 1 diabetes mellitus is mediated by autoreactive T-lymphocyte clones. We initiated a prospective randomized controlled trial of polyclonal rabbit anti-T-cell globulin (ATG) in patients with type 1 diabetes within 4 weeks of diagnosis and with residual post-glucagon C-peptide levels still over 0.3 nmol/l. ATG was administered as an initial bolus of 9 mg/kg followed by 3 consecutive doses of 3 mg/kg. An interim analysis was performed to establish whether any significant changes in C-peptide production and insulin requirement had occurred that would justify the continuation of this pilot study. By May 2004, 11 subjects were assigned to treatment with ATG along with intensified insulin therapy and 6 to intensified insulin therapy with placebo, and were followed for a period of at least 6 months. During the first 12 months a significant difference in the insulin dose trends was found between the groups (p = 0.010) with a lower insulin dosage in the ATG group. There was also a difference in the glucagon stimulated C-peptide level trends of marginal significance (p = 0.068). Compared to values at screening, stimulated C-peptide levels significantly improved in the ATG group (p = 0.012) but not in the placebo group. Complete diabetes remission occurred in 2 patients in the ATG and in none of the placebo group. Glycosylated hemoglobin at 12 months tended to be lower in the ATG group (p = 0.088). Significant adverse effects of ATG treatment, mainly transient fever and moderate symptoms of serum sickness (7 and 6 subjects, respectively) were observed during the first month only. The interim analysis of this ongoing study suggests that short-term ATG therapy in type 1 diabetes of recent onset contributes to the preservation of residual C-peptide production and to lower insulin requirements in the first year following diagnosis.

Kidney transplantation in type 2 diabetic patients: a comparison with matched non-diabetic subjects.

BACKGROUND: Because they generally are older and frequently have co-morbidities, patients with type 2 diabetes mellitus and end-stage renal disease seldom are selected for renal transplantation. Thus, information on transplantation results from controlled studies in this high-risk category of patients is scarce. We have compared the results of kidney transplantations in type 2 diabetic patients with carefully matched non-diabetic subjects. METHODS: All first cadaveric renal transplants performed in type 2 diabetic patients from January 1, 1988 to December 31, 1998 in our centre were included. Non-diabetic controls were individually matched with diabetic patients with respect to year of transplantation, sex, age, selected immunological parameters, and graft cold ischaemia. RESULTS: We included 64 type 2 diabetic and 64 non-diabetic patients who were followed for a mean period of 37+/-27 and 41+/-31 months, respectively, after renal transplantation. Patient survival at 1 and 5 years post-transplant was 85 and 69 vs 84 and 74% (P=0.43, NS), while graft survival rates censored for patient death were 84 and 77 vs 82 and 77% for diabetic and non-diabetic subjects, respectively (P=0.52, NS). With graft survival results not censored for death with functioning graft, no significant change was seen (diabetic vs non-diabetic group: 77 and 54 vs 73 and 61%, P=0.19, NS). Age, but not the presence of diabetes, was the only factor significantly affecting patient survival when both patient groups were pooled. With regard to post-transplant complications requiring hospitalization, there was a significant difference only in the number of patients who had amputations (diabetic vs non-diabetic group: 8 vs 0, P=0.01). CONCLUSIONS: Patient and graft survival after kidney transplantation was similar in type 2 diabetic and matched non-diabetic subjects, with more amputations occurring in the diabetic group. Thus, at a single-centre level renal transplantation results almost equivalent to those in non-diabetic patients may be achieved in type 2 diabetes mellitus.