Long-term cardiovascular outcomes in type 1 diabetic patients after simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation.

AIMS/HYPOTHESIS: Mortality due to cardiovascular disease (CVD), particularly coronary artery disease (CAD), is high in type 1 diabetic patients with end-stage renal disease (ESRD). We aimed to determine whether normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, could improve long-term outcomes compared with living donor kidney-alone (LDK) transplantation. METHODS: We studied 486 type 1 diabetic patients with ESRD who underwent a first SPK (n = 256) or LDK (n = 230) transplant between 1983 and 2012 and were followed to the end of 2014. Data were retrieved from the Norwegian Renal Registry and hospital records. Kaplan-Meier plots and multivariate Cox regression, with correction for recipient, donor and transplant factors, were used to examine potential associations between transplant type and all-cause and CVD- and CAD-related mortality. RESULTS: Median follow-up time was 7.9 years (interquartile range 4.3, 12.9). The adjusted HR for CVD-related deaths in SPK recipients compared with LDK recipients was 0.63 (95% CI 0.40, 0.99; p = 0.047), while the HRs for all-cause and CAD-related mortality were 0.81 (95% CI 0.57, 1.16; p = 0.25) and 0.63 (95% CI 0.36, 1.12; p = 0.12), respectively. Compared with the LDK group, SPK recipients were younger and received grafts from younger donors. Cardiovascular mortality was higher in patients transplanted between 1983 and 1999 compared with those who received their grafts in subsequent years. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and ESRD, SPK transplantation was associated with reduced long-term cardiovascular mortality compared with LDK transplantation.

One-year protocol biopsies from ABO-incompatible renal allografts compared with a matched cohort of ABO-compatible allografts.

INTRODUCTION: Early acute antibody-mediated rejection (ABMR) occurs more frequently in ABO-incompatible (ABOi) than in ABO-compatible (ABOc) kidney transplantation. This could lead to increased inflammation/scarring in the ABOi grafts. Protocol biopsy data in ABOi kidney recipients are scarce. METHODS: A single-center retrospective matched cohort study was conducted. Eighty adult living donor (LD) renal transplant recipients without HLA donor-specific antibodies (DSA) transplanted between 2009 and 2012 were included; 20 ABOi and 60 ABOc controls matched for donor age and transplantation year. Protocol biopsies at one yr were scored according to the Banff classification. Three sums of scores were constructed: tubulointerstitial inflammation (t + i = 0 vs. >0), microvascular inflammation (g + ptc = 0 vs. >0), scarring/hyalinosis (ci + ct + cv + ah ≤ 1 vs. >1. Scores and presence of subclinical rejection (SCR) at one yr were compared. RESULTS: Protocol biopsy findings at one yr in the ABOi vs. ABOc matched control group were not statistically different: (t + i) > 0, 30% vs. 20%; (g + ptc) > 0, 5% vs. 8%; (ci + ct + cv + ah) > 1, 85% vs. 60%, respectively. No transplant glomerulopathy occurred. SCR rate at one yr was 30% vs. 18%, subclinical ABMR 5% vs. 7% (all with de novo HLA DSA). CONCLUSION: One-year protocol biopsies of ABOi and ABOc LD recipients do not differ in chronic changes, inflammation, or SCRs.

In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone.

AIMS/HYPOTHESIS: In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone. METHODS: Estimated GFR (eGFR) was calculated in SPK (n = 25) and LDK (n = 17) recipients in a stable phase 3 months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy). RESULTS: SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1 years. Mean HbA1c levels during follow-up were 5.5 ± 0.4% (37 ± 5 mmol/mol) and 8.3 ± 1.5% (68 ± 16 mmol/mol) in the SPK and LDK group, respectively (p < 0.001). Compared with SPK recipients, LDK recipients had wider GBM (369 ± 109 nm vs 281 ± 57 nm; p = 0.008) and increased mesangial volume fraction (median 0.23 [range 0.13-0.59] vs 0.16 [0.10-0.41]; p = 0.007) at follow-up. Absolute eGFR change from baseline was -11 ± 21 and -23 ± 15 ml min(-1) 1.73 m(-2) (p = 0.060), whereas eGFR slope was -1.1 (95% CI -1.7, -0.5) and -2.6 (95% CI -3.1, -2.1) ml min(-1) 1.73 m(-2) per year in the SPK and LDK group, respectively (p = 0.001). CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone.

Long-term risks for kidney donors.

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Laparoscopic repair of incisional hernia in solid organ-transplanted patients: the method of choice?

Due to immunosuppressive (IS) therapy, incisional hernias are overrepresented in the organ-transplanted (Tx) population with larger defects, a high rate of recurrence, and a tendency toward more seromas and infectious problems. Thirty-one Tx/IS patients with a control group of 70 non-IS patients with incisional hernia (6/7 recurrences) were included in a prospective interventional study. Both cohorts were treated with laparoscopic ventral hernia repair (LVHR). Follow-up time and rate was 37 months and 95%. One hundred LVHR's were completed as there was one conversion in the Tx/IS group. No late infections or mesh removals occurred. Recurrence rates were 9.7% vs. 4.2% (P = 0.37) and the overall complication rates were 19% vs. 27% (P = 0.80). The Tx/IS group had a higher mesh-protrusion rate (29% vs. 13%, P = 0.09), but also larger hernias. Polycystic kidney disease was overrepresented in the Tx cohort (44% of kidney-Tx). Incisional hernias in Tx/IS patients may be treated by LVHR with the same low complication rate and recurrence rate as non-IS patients. By LVHR, the highly problematic seroma/infection problems encountered in Tx/IS patients treated by conventional open technique seem almost eliminated. The minimally invasive procedure seems particularly rational in the Tx/Is population and should be the method of choice. (ClinicalTrials.gov number: NCT00455299, date: 5 May 2006).

The effect of an educational intervention for renal recipients: a randomized controlled trial.

AIM: The purpose of this randomized controlled trial was to test the efficacy of an educational intervention on renal recipient's knowledge, compliance, self-efficacy, and quality of life. METHODS: In total, 159 renal recipients were randomized to the intervention (N = 77) or control group (N = 82). A total of 139 participants reached second measure point (7-8 wk post-Tx), and 120 participants reached third measure point (six months post-Tx). The intervention consisted of five tailored one-to-one sessions. Primary outcome was measured by a knowledge questionnaire. Secondary outcomes were measured by "The General- Self-efficacy Scale," SF-12 and by number of patient observations (Compliance). RESULTS: Significantly higher levels of knowledge were found in the experimental group compared with the control group at both measure points (p = 0.002 and p = 0.004). Compliance was significantly higher in the experimental group at second measure point (p = 0.000). At third measure point, the experimental group reported significantly better scores on self-efficacy (p = 0.036) and mental score of quality of life (p = 0.001). CONCLUSIONS: This structured, tailored educational intervention, applied in a 7-8 wk post-transplant period, increased renal recipients' levels of knowledge on both short and long terms. Furthermore, the intervention was beneficial for patients' compliance, self-efficacy, and mental quality of life.

Renal recipients' educational experiences in the early post-operative phase--a qualitative study.

Renal recipients need to acquire significant amount of knowledge for their life post-transplantation. More knowledge on kidney recipients' experiences after transplantation with regard to the patient education provided is needed. Sixteen renal recipients were interviewed 4-6 weeks post-transplantation about content and methods in the patient education programme. Data were analysed in the hermeneutic tradition. The patients experienced barriers towards learning in the early post-operative phase. Kidney transplantation was expressed as a 'turning point in life', causing learning difficulties because of both physical and mental stress. Survival knowledge was the label for topics concerning medication and rejection as they were experienced as essential for life. Situational knowledge, that is, knowledge related to recipients' individual life situations, requires further details in the main topics provided. The difference between knowing and practising what was taught was experienced as troublesome. The recipients expressed that a supportive learning atmosphere characterized by patience, respect, continuity and active participation was essential. This study revealed new knowledge about renal recipients' need for individual application of the educational content, as well as cognitive difficulties, and other factors impacting on learning in the early post-operative phase. The patients' perspective is an important and useful aid in creating effective interventions in this field.

Patients' level of knowledge measured five days after kidney transplantation.

BACKGROUND: Kidney recipients' knowledge is important in terms of coping with short-term problems posed by transplantation and the long-term outcome. Little attention has been given to the development of instruments for measuring patient's knowledge in this field. AIM: The purpose of this study was to describe the development of a knowledge questionnaire for kidney recipients and to explore possible factors related to the knowledge level. METHODS: The sample consisted of 159 kidney recipients at a Norwegian transplant center, answering the questionnaire five d post-transplantation. RESULTS: The questionnaire was generated on the basis of literature review and clinical experience - and was pilot tested. Mean score of the questionnaire was 11, of 19 obtainable points. Longer duration of kidney disease was significantly correlated with an increased knowledge level, whereas the longer the time on dialysis prior to transplantation and post-operative complications were found to have significantly negative impact on total knowledge score. CONCLUSIONS: The positive impact of disease duration may suggest that insight gained over time makes patients better prepared for the transplantation itself and for life post-transplant. However, the negative impact of dialysis duration could be attributed to impaired cognitive function imposed by chronic dialysis treatment. Further research is needed regarding the questionnaire's responsiveness to educational interventions.

Age, gender, and body mass index are associated with renal function after kidney donation.

Renal function is thoroughly evaluated before live kidney donation. However, some donors experience impaired recovery of renal function after donation. Our aim was to assess estimated glomerular filtration rate (eGFR) and mean relative (%) increase in creatinine one yr after donor nephrectomy. The study was based on retrospective data from kidney donors during the period 1997-2009. Pre-operative and one-yr follow-up data were available for 721 of 1067 donors. Mean relative increase in creatinine and eGFR were stratified by gender, body mass index (BMI), and age at donation. At one yr post-donation, overweight (BMI > 5 kg/m(2) ) women 50 yr or older experienced the lowest eGFR of 49.6 ± 8.8 mL/min/1.73 m(2) . Men younger than 50 yr with normal weight (BMI < 25 kg/m(2) ) had the highest eGFR of 66.6 ± 10.4 mL/min/1.73 m(2) . Overweight men 50 yr or older had the highest relative increase in creatinine of 49.4% compared to pre-donation. Men under 50 yr with normal weight had the smallest increase in creatinine of 35.2%. In multivariate analysis, older age (p < 0.001), male gender (p < 0.001), and overweight (p = 0.01) were associated with relative increase in creatinine after donation. Potential donors should be offered counseling regarding overweight, as this is a modifiable risk factor.

One- and five-year follow-ups on blood pressure and renal function in kidney donors.

It is considered safe to donate a kidney if internationally accepted medical criteria are fulfilled. However, some donors have encountered hypertension, proteinuria and impaired renal function after donation. The study was based on retrospective data on 908 donors, donating in the period 1997-2007. Preoperative and follow-up data were collected from patient files and the Norwegian Living Donor Registry. Follow-up data were available for 665 donors at 1 year after donation, and 256 donors at 5 years after donation. We calculated the estimated glomerular filtration rate (eGFR) using the four variable Modification of Diet in Renal Disease equation. At 1 and 5 years after donation, the prevalence of hypertension was 11.7% and 27.1% respectively compared to 2.6% before donation. Proteinuria was present in 3.3% and 1.6% at 1 and 5 years. Mean eGFR was 56.1 ± 10.8 ml/min/1.73 m² at 1 year and 61.0 ± 11.8 ml/min/1.73 m² at 5 years. Mean blood pressure was 122.5 ± 10.6/76.2 ± 7.5 mmHg at donation (n = 908), 124.3 ± 14.2/77.9 ± 8.2 mmHg at 1-year (n = 649) and 127.2 ± 15.4/78.8 ± 8.3 mmHg at 5-year follow-ups (n = 247). We found no evidence of further decline in renal function beyond the initial decrement following nephrectomy.

CD4+ T cells persist for years in the human small intestine and display a TH1 cytokine profile.

Studies in mice and humans have shown that CD8+ T cell immunosurveillance in non-lymphoid tissues is dominated by resident populations. Whether CD4+ T cells use the same strategies to survey peripheral tissues is less clear. Here, examining the turnover of CD4+ T cells in transplanted duodenum in humans, we demonstrate that the majority of CD4+ T cells were still donor-derived one year after transplantation. In contrast to memory CD4+ T cells in peripheral blood, intestinal CD4+ TRM cells expressed CD69 and CD161, but only a minor fraction expressed CD103. Functionally, intestinal CD4+ TRM cells were very potent cytokine producers; the vast majority being polyfunctional TH1 cells, whereas a minor fraction produced IL-17. Interestingly, a fraction of intestinal CD4+ T cells produced granzyme-B and perforin after activation. Together, we show that the intestinal CD4+ T-cell compartment is dominated by resident populations that survive for more than 1 year. This finding is of high relevance for the development of oral vaccines and therapies for diseases in the gut.

Minimally invasive renal auto-transplantation: the first report.

BACKGROUND: Regarding transplant surgery, the minimally invasive revolution was started in 1995 by laparoscopic living donor nephrectomy (L-LDN). In 2006, we made the first report on a minimally invasive technique for kidney transplantation; restricted to a 7-9 cm transverse incision targeted on the anastomotic area of the iliac vessels, and with the meticulously prepared kidney placed in a fitting, retroperitoneal pouch lateral to the skin incision. MATERIALS AND METHODS: By combining "hand-assisted laparoscopic nephrectomy" and "minimally invasive kidney transplantation" - using the same incision (7-8 cm) for hand-assistance, kidney harvesting, and transplantation - we have during 2009 conducted "minimally invasive renal auto-transplantation" in two patients. RESULTS: In both cases, the postoperative course was uneventful. When examined 3 mo postoperatively, both auto-transplants were shown to have excellent function by renal scintigraphy. CONCLUSIONS: Renal auto-transplantation, a traditionally major surgical procedure, can be made minimally invasive by a similar incision as that used for L-LDN. Taking into regard the highly traumatic conventional incisions, we expect the generally proven minimally invasive benefits to be considerable.

Minimally invasive living donor nephrectomy - introduction of hand-assistance.

Conventional open living donor nephrectomy (LDN) technique is perceived as a barrier for expanding living donor programmes. Thus, minimal invasive surgery techniques have been advocated to overcome this hurdle. The aim of this study was to evaluate our experience on minimally invasive LDN. During the last decade we have gradually expanded the use of minimally invasive LDN with various techniques; strictly laparoscopic versus hand-assisted, and laparoscopic versus retroperitoneoscopic. This study is based on 305 consecutive minimally invasive LDN's, from 1998 to 2009. By multiple regression analysis, minimally invasive hand-assisted technique was shown to be associated with a significantly lower risk of major complications and intraoperative incidents, as well as reduced warm ischemia and operative time. In our opinion, the introduction of hand-assisted technique is probably the most significant single factor for improved results, although accumulated experience and developments in equipment will contribute. Our experience indicates that learning curves are facilitated by the use of hand-assisted technique. Improvements in surgical outcomes following donor nephrectomy may enhance living donor programmes.

Chronic allograft nephropathy--a clinical syndrome: early detection and the potential role of proliferation signal inhibitors.

Chronic allograft nephropathy (CAN) leads to the majority of late graft loss following renal transplantation. Detection of CAN is often too late to permit early intervention and successful management. Most current strategies for managing CAN rely on minimizing or eliminating calcineurin inhibitors (CNIs) once CAN has become established. The proliferation signal inhibitors everolimus and sirolimus have potent immunosuppressive and antiproliferative actions, with the potential to alter the natural history of CAN by reducing CNI exposure whilst avoiding acute rejection. Whilst data will be forthcoming from a number of clinical trials investigating this potential, we discuss early detection of CAN and the rationale for a role for this class of agent.

Resident memory CD8 T cells persist for years in human small intestine.

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for >1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

Transcriptional and functional profiling defines human small intestinal macrophage subsets.

Macrophages (Mfs) are instrumental in maintaining immune homeostasis in the intestine, yet studies on the origin and heterogeneity of human intestinal Mfs are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMos), were largely replaced within 3 wk, whereas two subsets with features of mature Mfs, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptional analysis showed that all Mf subsets were markedly distinct from PBMos and dendritic cells. Compared with PBMos, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMos.

Quality of life after randomization to laparoscopic versus open living donor nephrectomy: long-term follow-up.

BACKGROUND: The aim of this randomized study was to compare patient-reported outcome after laparoscopic versus open donor nephrectomy during 1 year follow-up. The evidence base has so far not allowed for a decision as to which method is superior as seen from a long-term quality of life-perspective. METHODS: The donors were randomized to laparoscopic (n=63) or open (n=59) nephrectomy, with follow-up at 1, 6, and 12 months. Primary outcomes were health status (SF-36) and overall quality of life (QOLS-N). Secondary outcomes were donor perception of the surgical scar, the donation's impact on personal finances, and whether the donor would make the same decision to donate again. RESULTS: There was a significant difference in favor of laparoscopic surgery regarding the SF-36 subscale bodily pain at 1 month postoperatively (P<0.05). Analysis based on intention to treat revealed no long-term differences between groups in SF-36 scores. When subtracting the reoperated/converted donors of the laparoscopic group, significant differences in favor of laparoscopy were revealed in the subscales bodily pain at 6 months (P<0.05) and social functioning at 12 months (P<0.05). No significant differences were found in QOLS-N scores between groups. CONCLUSIONS: Laparoscopic donor nephrectomy is an attractive alternative to open donor nephrectomy because of less postoperative pain. However, long-term comparison only revealed significant differences in favor of laparoscopy when adjusting for reoperations/conversions. Both groups reached baseline scores in most SF-36 subscales at 12 months and this may explain why possible minor benefits are hard to prove.

Cardiac Assessment of Patients With Type 1 Diabetes Median 10 Years After Successful Simultaneous Pancreas and Kidney Transplantation Compared With Living Donor Kidney Transplantation.

BACKGROUND: In recipients with type 1 diabetes, we aimed to determine whether long-term normoglycemia achieved by successful simultaneous pancreas and kidney (SPK) transplantation could beneficially affect progression of coronary artery disease (CAD) when compared with transplantation of a kidney-alone from a living donor (LDK). METHODS: In 42 kidney transplant recipients with functioning grafts who had received either SPK (n = 25) or LDK (n = 17), we studied angiographic progression of CAD between baseline (pretransplant) and follow-up at 7 years or older. In addition, computed tomography scans for measures of coronary artery calcification and echocardiographic assessment of left ventricular systolic function were addressed at follow-up. RESULTS: During a median follow-up time of 10.1 years (interquartile range [IQR], 9.1-11.5) progression of CAD occurred at similar rates (10 of 21 cases in the SPK and 5 of 14 cases in the LDK group; P = 0.49). Median coronary artery calcification scores were high in both groups (1767 [IQR, 321-4035] for SPK and 1045 [IQR, 807-2643] for LDK patients; P = 0.59). Left ventricular systolic function did not differ between the 2 groups. The SPK and LDK recipients were similar in age (41.2 ± 6.9 years vs 40.5 ± 10.3 years; P = 0.80) and diabetes duration at engraftment but with significant different mean HbA1c levels of 5.5 ± 0.4% for SPK and 8.3 ± 1.5% for LDK patients (P < 0.001) during follow-up. CONCLUSIONS: In patients with both type 1 diabetes and end-stage renal disease, SPK recipients had similar progression of CAD long-term compared with LDK recipients. Calcification of coronary arteries is a prominent feature in both groups long-term posttransplant.

Antibody-secreting plasma cells persist for decades in human intestine.

Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19+ PC subset was dynamically exchanged, whereas of two CD19- PC subsets, CD45+ PCs exhibited little and CD45- PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45- PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19- PC subsets support selection and maintenance of protective PCs for life in human intestine.