Contraceptive Choices and Counseling in Norwegian Female Renal Transplant Recipients.

BACKGROUND: There are major gaps in the understanding of sexual and reproductive health in female renal transplant recipients. METHODS: In this Norwegian multicenter retrospective observational study, 118 female renal transplant recipients aged 22 to 49 years responded to a questionnaire on fertility, contraceptive use, and pregnancy. RESULTS: More than one-third (37%) of patients reported that they did not receive advice on contraceptive methods from health care personnel in the early post-transplant phase. These women used effective contraceptive methods less often. Nearly half of the patients (45%) reported that they had not received any advice on timing of conception after transplant. From 95 pregnancies after renal transplant, 52 (55%) resulted in live births. CONCLUSION: Counseling on contraceptive methods should be part of standard care in conjunction with transplantation. More than one-third of young female renal transplant recipients of reproductive age could not recall having received advice from health care personnel about contraceptive use, and nearly half of the patients did not receive preconceptional advice after transplant. Although the current study does not discriminate between lack of advice and recall bias, the findings signal the need for improved counseling on female sexual and reproductive health after renal transplant.

Scandiatransplant acceptable mismatch program (STAMP) a bridge to transplanting highly immunized patients.

BACKGROUND: Highly immunized patients are a challenge for organ transplantation programs. One way of increasing the likelihood of transplantation in this group of patients is to expand the possible donations by defining acceptable HLA mismatches. In the Scandiatransplant Acceptable Mismatch Program (STAMP), a de-centralized approach has been implemented in 2009. AIMS: The program has been improved during the years from utilizing HLA-A, -B, -DR matching only to include typing of all deceased donors for HLA-A, -B, -C, -DRB1 and -DQB1. The calculation of a transplantability score (TS) has been introduced in order to take both HLA and AB0 into consideration resulting in a more realistic picture of the transplantability chance. MATERIALS AND METHODS: Patients were selected for eligibility and results of immunisation status were prepared in each of the 9 tissue typing laboratories, while access to the program is finally governed by a common steering group of immunologists and clinicians. RESULTS: In the period from March 2009 until February 2015, 96 patients were transplanted within this program. The mean recipient age was 49 years and 57% were females, 30% of the patients were first transplants and of these 93% were females. The majority of the patients had 2-5 HLA-A, -B. -DR mismatches. The allograft survival at 60 months was 79.1%. Applying the TS to the cohort confirmed that patients with a low TS score had longer waiting times. CONCLUSION: The program has matured during the years and now proves to be a valid approach for transplanting highly immunized patients.

Obstetric and neonatal outcome of pregnancies fathered by males on immunosuppression after solid organ transplantation.

Immunosuppressive drugs may influence spermatogenesis, but little is known about outcome of pregnancies fathered by transplanted males. We estimated risk of adverse outcomes in pregnancies (with data after the first trimester) fathered by males that had undergone organ transplantation and were treated with immunosuppression. A population-based study, linking data from the Norwegian transplant registry and the Medical Birth Registry of Norway during 1967-2009 was designed. All Norwegian men undergoing solid organ transplantation were included. Odds ratios for major malformations, preeclampsia, preterm delivery (<37 weeks) and small-for-gestational-age were obtained using logistic regression. A total of 2463 transplanted males, fathering babies of 4614 deliveries before and 474 deliveries after transplantation were identified. The risk of preeclampsia was increased (AOR: 7.4, 95% CI: 1.1-51.4,) after transplantation compared to prior to transplantation. No increased risk was found for congenital malformations or other outcomes when compared with pregnancies before transplantation or with the general population (2 511 506 births). Our results indicate an increased risk of preeclampsia mediated through the transplanted and immunosuppressed father. Importantly, no increased risk was found for other adverse obstetric outcomes or malformations, which may reassure male transplant recipients planning to father children.

Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease.

AIMS/HYPOTHESIS: We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA). METHODS: Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n = 222) or, if available, a single live donor kidney (LDK; n = 171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n = 237). Survival was analysed by the Kaplan-Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics. RESULTS: Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean ± SD) after transplantation was 7.1 ± 5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p = 0.02) and DDK (p = 0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p < 0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988-1999). CONCLUSIONS/INTERPRETATION: Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.

A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation.

The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated.

Pregnancy and birth after kidney donation: the Norwegian experience.

Reports on pregnancies in kidney donors are scarce. The aim was to assess pregnancy outcomes for previous donors nationwide. The Medical Birth Registry of Norway holds records of births since 1967. Linkage with the Norwegian Renal Registry provided data on pregnancies of kidney donors 1967-2002. A random sample from the Medical Birth Registry was control group, as was pregnancies in kidney donors prior to donation. Differences between groups were assessed by two-sided Fisher's exact tests and with generalized linear mixed models (GLMM). We identified 326 donors with 726 pregnancies, 106 after donation. In unadjusted analysis (Fisher) no differences were observed in the occurrence of preeclampsia (p = 0.22). In the adjusted analysis (GLMM) it was more common in pregnancies after donation, 6/106 (5.7%), than in pregnancies before donation 16/620 (2.6%) (p = 0.026). The occurrence of stillbirths after donation was 3/106 (2.8%), before donation 7/620 (1.1%), in controls (1.1%) (p = 0.17). No differences were observed in the occurrence of adverse pregnancy outcome in kidney donors and in the general population in unadjusted analysis. Our finding of more frequent preeclampsia in pregnancies after kidney donation in the secondary analysis must be interpreted with caution, as the number of events was low.

Glomerular monocyte/macrophage influx correlates strongly with complement activation in 1-week protocol kidney allograft biopsies.

BACKGROUND: The specific role of monocytes/macrophages (MO) in kidney graft rejection is not yet fully elucidated. In a recent protocol biopsy study of living-donor recipients, we demonstrated massive capillary influx of MO, associated with severe complement activation and acute rejection (AR) 1 week after transplantation [Sund et al.]. To gain further insight into the possible relationship between MO and complement activation, we analyzed glomerular and interstitial MO in these biopsies. METHODS: Twenty-seven protocol biopsies were stained with antibodies to calprotectin (L1) and CD68 as markers for MO. Cells were counted as an average number per glomerulus and as an average number per defined visual field in the interstitium. Polymorphonuclear leukocytes (PMN) were counted in glomeruli and interstitium by light microscopy. Baseline specimens from 10 of the patients served as controls. The results were compared with data on deposition of complement from the foregoing study, and with histopathologic and clinical data on AR. RESULTS: Cases with diffuse C4d deposition in peritubular capillaries consistent with acute antibody-mediated rejection (AbAR) (n = 4) had significantly higher numbers of intraglomerular MO than the other protocol biopsies (L1: median 20.7 vs 3.6, p = 0.0002; CD68: median 10.1 vs. 2.0, p = 0.0008). With a cut-off of 10 L1-positive and 6 CD68-positive MO, the specificity for the diagnosis of AbAR was 96% and 91%, respectively. The number of interstitial MO was significantly higher in patients with AR than in those without, but in contrast to glomerular MO, interstitial MO could not discriminate between complement positive and negative AR. The number of glomerular and interstitial PMNs was significantly higher in the AbAR group than in the other protocol biopsies. CONCLUSIONS: The strong correlation between complement activation and early glomerular influx of MO in the kidney allograft suggests a causal relationship between these 2 events. At 1 week after transplantation, a number of 10 L1-positive and 6 CD68-positive MO per glomerulus indicates AbAR.

[Kidney transplantation in Norway--a historical perspective]. / Nyretransplantasjon i Noreg--eit historisk perspektiv.

Until the late 1950s, few treatment modalities for patients with chronic renal failure were available. The first successful renal transplantation was performed in Boston, USA in 1954 when a young man with renal failure received a kidney from his monozygotic twin brother. Tissue typing was not available, there were few options for immunosuppressive treatment, and dialysis could be offered for short-term treatment only. At the Surgical Department A of the National Hospital, Oslo, Norway, treatment of acute renal failure by hemodialysis was started in 1956 and the first renal transplantation in Scandinavia performed the same year. In 1963, the first renal transplantation at Ullevål Hospital, Oslo was performed, the first in Norway with a long-term function transplant. Since 1983, all renal transplantations in Norway have been performed at the National Hospital. In 1969, Scandiatransplant was established as an organisation for organ exchange between the Scandinavian countries, and a national program for renal transplantation in Norway was launched. The Norwegian renal transplant program is based on co-operation between regional and central hospitals and the transplant centre at the National Hospital. In recent years, the number of renal transplantations per year has been 180-200, i.e. 40-45 per million population. Approximately 40% of the transplanted kidneys come from living related or spouse donors. The results in terms of renal graft survival are good.

Living donor kidney transplants: a biopsy study 1 year after transplantation, compared with baseline changes and correlation to kidney function at 1 and 3 years.

INTRODUCTION: Chronic changes in biopsies from long-term stable kidney allografts have been reported to correlate with graft prognosis. Morphological changes in baseline ('zero-hour') biopsies have been described as well, but their importance for long-term prognosis have been less clear. The aim of the present study was to evaluate biopsy changes from baseline to 1 year after transplantation in patients receiving kidneys from living donors, and to assess the possible prognostic implications of these findings. METHODS: Light microscopical changes in 18 gauge full-core biopsies were scored semi-quantitatively in 33 patients 1 year after transplantation, and compared to baseline changes previously reported [1]. All cases were also examined with transmission electron microscopy. The semi-quantitative data from baseline and at 1 year were correlated with kidney function 1 and 3 years after transplantation. The reproducibility of baseline findings regarding arteriosclerosis and arteriolar hyalinosis was tested by comparison with biopsies 1 week after transplantation (n = 43). RESULTS: We found a significant increase in mesangial glomerular sclerosis (P<0.001), interstitial fibrosis/tubular atrophy (if/ta) (P = 0.002), and mononuclear cell interstitial infiltration (P = 0.003) after 1 year, compared to baseline changes. There was an increase of arteriosclerosis (P = 0.028) and arteriolar hyalinosis (P = 0.006) when compared to biopsies taken 1 week after transplantation, but not when compared to the 'zero-hour' findings. Electron microscopy revealed one case of recurrent immune-complex glomerulonephritis and another case of recurrent light chain deposition kidney disease. Comparing 1-week vascular findings with baseline gave a low level of reproducibility, probably due to sampling error. Baseline biopsy findings could not predict long-term kidney function. In the 1-year biopsy, if/ta was significantly correlated with serum creatinine (P = 0.007) and glomerular filtration rate (GFR) (P<0.001) at 1 year, with serum creatinine at 3 years (P = 0.011), and with the first-year cumulative dose of methylprednisolone (P = 0.004). Serum creatinine at 1 year, however, was found to be the most accurate predictor of 3-year kidney function (P<0.001). Donor age was correlated to kidney function at 3 years (P = 0.013) but not at 1 year after transplantation. CONCLUSION: Morphological changes in baseline biopsies of living donor kidneys tend to become more pronounced in well-functioning allografts during the first year after transplantation. In the 1 year biopsy, if/ta seems to be the most reliable variate for grading of chronic changes. However, 1-year serum creatinine predicted long-term kidney function more precisely than did the biopsy scores. Based on the results of the present study, a protocol 1-year biopsy does not seem warranted in the management of the graft recipient with a stable kidney function.

The role of HLA matching in renal transplantation: experience from one center.

The influence of serology-based HLA matching on the risk of acute rejection episodes and of graft loss was analyzed in a material of 678 living donor (LD) and 997 cadaveric donor (CD) renal transplantations performed in our center in the period 1989-97. In LD transplantation, recipients of HLA-identical sibling grafts had the lowest rejection risk and the best graft survival, with a half-life estimate of 30 years. One-HLA-haplotype mismatched grafts did better than two-haplotype mismatched related or unrelated donor grafts. Matching for HLA-DR significantly reduced the rejection risk of one-haplotype mismatched grafts. In CD first transplants, HLA-DR matched grafts had a lower incidence of rejection and better survival than HLA-DR mismatched grafts. Expected half-life for HLA-DR matched grafts was 12 years compared to less than 7 years for HLA-DR mismatched grafts. The effects of matching for HLA-A and -B did not reach statistical significance. In CD regrafts, a two-antigen mismatch for HLA-A or -DR led to a significantly poorer graft survival, but the panel-reactive antibody (PRA) status of the recipient was the most influential factor. In CD renal transplantation, we conclude that organ allocation based on matching for HLA-DR 1-14 is effective and not too difficult to obtain even in centers with a short patient waiting list.

A strong impact of matching for a limited number of HLA-DR antigens on graft survival and rejection episodes: a single-center study of first cadaveric kidneys to nonsensitized recipients.

BACKGROUND: A single-center study of 655 nonsensitized recipients of primary cadaveric kidney grafts is presented. RESULTS: Graft survival in serologically HLA-DR 1-10 antigen-matched grafts to nonsensitized recipients at 1 year was 90%, compared with 82% (P=0.004) and 73% (P=0.001) in one and two DR antigen-mismatched grafts. The corresponding figures at 5 years were 76%, 62%, and 56%, respectively. Matching for the DR antigens 11-14, or for some DR alleles only detectable by genomic typing, further improved graft survival, but the differences did not reach statistical significance. Matching also for the serologically defined HLA-A and -B antigens did not significantly further improve overall graft survival, but some effects for grafts surviving at least 1 year were observed. Among recipients of grafts mismatched for zero, one, or two HLA-DR antigens, acute rejection episodes were experienced in 48%, 64% (P<0.001), and 82% (P<0.001), respectively, within the first 3 months. HLA-A and -B mismatches showed no significant correlation to acute rejection episodes. CONCLUSION: Matching for the DR antigens 1-10 significantly secures and prolongs the survival of first cadaveric renal grafts. Our results also show that DR 1-10 antigen-matched combinations can often be obtained even in rather small recipient pools, when actively sought for.

Allospecific helper T-lymphocyte repertoire in monozygotic twins.

In the course of maturation in the thymus there is a selection of T lymphocytes based on the avidity between their T-cell receptors and HLA/peptide complexes expressed on stromal thymic cells. The repertoire of mature T lymphocytes is further modulated by encounters with foreign antigens. Thus, the antigen specific repertoire of the peripheral T-lymphocyte pool is determined by genetic and environmental factors. We recently reported that pairs of monozygotic twins often display significant differences in their allospecific cytotoxic T-cell repertoire, suggesting an important role of confrontation with foreign antigens on the CD8+ T-cell repertoire. We have now performed similar studies on the repertoire of allospecific CD4+ T lymphocytes. Using positively selected CD4+ T cells in limiting dilution analyses we compared the differences in the allospecific helper T-lymphocyte precursor frequencies (HTLpf) between pairs of genetically identical monozygotic twins and pairs of unrelated, HLA disparate individuals. We found that all monozygotic twin pairs and most unrelated pairs had similar HTLpf to the same stimulator, i.e. the 95% confidence intervals were overlapping. However, when studied in greater detail, the differences in HTLpf within monozygotic twin pairs were found to be significantly smaller than the differences within pairs of unrelated responders. Thus, we find evidence of an influence by environmental antigens also on the repertoire of allospecific CD4+ T cells, but polymorphic genetic factors seem to be more important here than for the repertoire of allospecific CD8+ T cells.

Morphological studies of baseline needle biopsies from living donor kidneys: light microscopic, immunohistochemical and ultrastructural findings.

Fifty-seven consecutive living donors (31 women and 26 men aged 20.7-72.3 years, mean 50.6 years) were subjected to needle biopsy during nephrectomy, immediately before removal of the kidney. By light microscopy, semiquantitative scoring (0-3) was performed for arteriosclerosis, arteriolar hyalinosis (hyalin arteriolosclerosis), glomerulosclerosis, interstitial mononuclear cell infiltration, and interstitial fibrosis/tubular atrophy. Whereas vascular changes were striking in many biopsies (arteriosclerosis grades 2-3: 28/54 cases, arteriolar hyalinosis grades 2-3: 15/55 cases), glomerular and tubulointerstitial changes were mostly low grade. The morphological changes tended to be more pronounced in middle-aged and older individuals, but, in particular, vascular changes were seen also in the younger age group. Immunofluorescence microscopy revealed glomerular granular staining for IgM in 52.7% of the cases, IgA in 9.1%), IgG in 1.8%, and C3 in 12.7%. The main ultrastructural finding was glomerulosclerosis; one case with diffuse glomerular IgA showed distinct dense deposits, and one case showed similar dense deposits without IgA deposition. Arteriolar wall deposition of C3 was found in 58.2% of the cases, and IgM in 10.9%. Especially C3 occurred both with arteriolar hyalinosis and in arterioles without light microscopic alterations. The observation of significant vascular changes in baseline biopsies is relevant especially in the differential diagnosis of chronic rejection and cyclosporine nephropathy. The immunohistochemical findings strongly indicate the occurrence of immunoglobulins and complement factor C3 in both glomeruli and arterioles without clinical or morphological signs of renal disease. The possible pathophysiological significance of such deposits remains, however, uncertain.

Monozygotic twins display differences in their allospecific cytotoxic T-cell repertoire.

The antigen-specific repertoire of peripheral blood T lymphocytes is generated by selection in the thymus followed by peripheral immunological events. While thymic selection is predominantly under genetic control, i.e. self-HLA molecules + self-peptides, confrontation with foreign antigens will lead to expansion of given T-cells, thus modifying the T-cell repertoire. To evaluate the relative importance of such modifying events the precursor frequencies (pf) of cytotoxic T lymphocytes (CTL) against given allogeneic HLA molecules were compared in six pairs of monozygotic twins. Using limiting dilution analyses, experiments with several different allogeneic stimulator/target cell donors were performed for each twin pair. In 12 out of 17 experiments, when the twins were tested against the same stimulator/ target cell donor, the CTL pf differed and the 95% confidence intervals were non-overlapping. This suggests that modifying effects by confrontation with foreign antigens play an important role in shaping the allospecific T-cell repertoire.

Analysis of alloreactive helper T lymphocyte precursor frequencies. Influence of interleukin-2 produced by the stimulating cells.

In the determination of alloreactive helper T lymphocyte precursor frequencies (HTLpf) by limiting dilution analysis (LDA), peripheral blood mononuclear cells (PBMC) are used as stimulating cells. Interleukin-2 (IL-2) production by stimulating T cells constitute a source of error in these assays. We found that 100-150 Gy of gamma irradiation was required to abrogate IL-2 production by stimulating PBMC. This dose of irradiation, however, greatly reduced their allostimulatory capability. Here we describe how non-irradiated PBMC, immunomagnetically depleted of T cells and thus of IL-2 producing cells, can be used as stimulators in assays to determine alloresponsive HTLpf.

Pretransplant plasma exchange or immunoadsorption facilitates renal transplantation in immunized patients.

Patients with preformed antibodies against HLA molecules accumulate on renal transplant waiting lists and have inferior graft survival compared with nonsensitized patients. One hundred patients were included in a program of pretransplant removal of antibodies by plasma exchange (n = 90) or immunoadsorption (n = 10) in addition to prednisolone and cyclophosphamide medication. After plasma exchange, the panel reactivity and the antibody titer were reduced in about half of the patients, and after immunoadsorption the panel reactivity fell in 6 of 10 patients. Of the 83 patients who received grafts, 17 received a graft from a living donor (LD) and 66 received a graft from a cadaver donor (CD). Patients with a positive crossmatch against their LD were included in the program and were thus grafted with a recent positive, current negative crossmatched organ. Fifteen CD graft recipients had a pretreatment positive crossmatch toward their donor. No episodes of hyperacute rejection were seen. One- and 4-year graft survival rates in LD transplants with a recent positive and current negative crossmatch were 77% and 64%, respectively. At 1 and 4 years, graft survival rates were 70% and 57% in pretreated first CD graft recipients (n = 27) and 61% and 47% in pretreated regrafted patients (n = 39), respectively. In this program, a high rate of transplantation among the sensitized patients was achieved. Graft survival was inferior to that seen in nonsensitized patients, but was comparable to graft survival in sensitized patients at other centers.