Calcineurin inhibitor-free immunosuppression in renal allograft recipients with thrombotic microangiopathy/hemolytic uremic syndrome.

Thrombotic microangiopathy (TMA) and hemolytic uremic syndrome (HUS) represent serious threats to kidney allograft recipients. During a 4-year period, among 850 kidney transplantations, seven recipients with primary HUS and seven recipients (eight transplants) with previous or de novo TMA/HUS were identified and given calcineurin inhibitor (CNI)-free immunosuppression by sirolimus (SRL), mycophenolate mofetil and steroids. Thirteen out of 15 transplantations were successful in the long term; resulting in a mean creatinine of 101 mumol/L (16.4 months follow-up). In patients maintained on CNI-free regimen, no TMA/HUS recurrences were observed. A high rate of acute rejections (53%) may indicate insufficient immunosuppressive power and/or a causative relationship between TMA/HUS and rejection. Wound-related complications were abundant (60%), and call for surgical/immunosuppressive countermeasures. Our experience supports the idea that CNI's are major offenders in TMA/HUS induction. Total CNI elimination seems essential, as the nephrotoxic combination CNI + SRL may promote TMA. Features of TMA/HUS should be carefully explored in recurrent 'high responders'.

Experience with cyclosporine in 1519 kidney transplantations from living donors in a national transplant programme, 1983-2002.

Following the introduction of cyclosporine as basic immunosuppression in our national transplant programme in 1983, the pool of grafts from living donors (LDs) was expanded 2 years later by also accepting LDs mismatched for 2 HLA haplotypes and living unrelated donors (LURDs), mostly spouses. A policy of approaching family members to promote donation was consistently pursued. During 1983 through 2002, nephrectomy was performed on 1519 LDs without mortality. From 1983 through 1988, our learning phase in managing cyclosporine-immunosuppression, 382 patients received first grafts from LDs. One-year graft survival (GS) rates were 94.4%, 90%, 89%, and 82% in 71 HLA identical, 260 haploidentical, 18 2-haplotypes disparate, and 33 LURD graft recipients, respectively. Corresponding half-lives were 15.8, 10.3, 11, and 9.1 years, respectively. Results improved in 1028 patients receiving first LD grafts from 1989 through 2002. Corresponding 1-year GS rates were 96.6% (n=117), 93.5% (n=650), 90.4% (n=73), and 88.8% (n=188), and half-lives were 30, 13.3, 13.5, and 12.3 years, respectively. Similar GS rates were observed in 109 recipients of repeat grafts from LDs. LDs contributed 44% and 21.6% of all first and repeat grafts transplanted, providing grafts to 11 patients (in 1983) increasing to 23 patients (in 2002) per million population per year (pmp/y). When added to grafts from cadaveric donors, 40 to 48 pmp/y were provided with a first or repeat graft since 1990, thus covering at least 65% of the national need for kidney transplantations.

Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial.

BACKGROUND: Statin therapy has been reported to reduce the acute rejection rate following renal transplantation in a pilot study. The present study is the first randomized, double-blind and adequately powered study to examine the effect of statins on acute rejection of renal allografts. METHODS: A total of 364 patients were randomly assigned to receive either fluvastatin 40 mg or placebo in combination with conventional cyclosporine-based immunosuppressive therapy. The primary end point was treated first acute rejection. Secondary end points included biopsy-proven rejection, histological severity of rejection, occurrence of steroid-resistant rejection, and serum creatinine at three months following transplantation. RESULTS: Fluvastatin was well tolerated; no patients developed myositis or rhabdomyolysis. There was no difference in the acute rejection rate [86 (47.3%) fluvastatin vs. 87 (47.8%) placebo] and no significant difference in the severity of rejection, steroid resistant rejection or mean serum creatinine at three months (160 micromol/L vs. 160 micromol/L). Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels increased following renal transplantation. With the exception of the increase in HDL-C, which was augmented, the increases in lipid parameters were significantly reduced by fluvastatin (total cholesterol +17.5% vs. 35.7%; LDL-C +6.3% vs. 46.7%; HDL-C +43.3% vs. 38.1%; triglyceride +52.2% vs 77.6%). CONCLUSIONS: Contrary to the reported effects of statins, fluvastatin had no effect on the incidence or severity of acute rejection following renal transplantation. There were no increases in adverse events. A significant and potentially beneficial alteration in the lipid profile was observed in the early post transplant period. We conclude that fluvastatin may be used safely to correct dyslipidemia in patients with end-stage renal failure through the peri-transplant period.

Intracerebral abscess caused by Nocardia otitidiscaviarum in a renal transplant patient--cured by evacuation plus antibiotic therapy.

We present a 50-year-old female who experienced generalized convulsion 3 months after a successful cadaveric renal transplantation. The first cerebral CT scan indicated cerebral frontal infarction. Repeat CT some days later revealed progressive lesions, and a highly malignant tumor or abscess was suspected. Antifungal and broad-spectrum antibacterial therapy was initiated. Cerebral MRI could not differentiate between these conditions, but a neutrophil granulocyte scan strongly suggested an infectious process. A stereotactic puncture of the frontal lobe was followed by temporary improvement. A severe progressive left-sided hemiparalysis gave indication for a craniotomy with evacuation of the abscess 9 days later. Culture of aspirated pus yielded growth of a gram-positive, rod-shaped bacterium, later identified as Nocardia otitidiscaviarum by sequencing the 16S rRNA. The patient was treated with meropenem plus rifampicin intravenously for 6 weeks followed by oral ciprofloxacin and rifampicin for 2 months. Due to pharmacokinetic interaction with rifampicin, the prednisolone dose was doubled, and the dose of tacrolimus had to be tripled for maintenance of adequate trough concentrations. Five months following cessation of antibiotic treatment, the patient has regained normal strength and function in her left-sided extremities and has a serum creatinine level of about 160 micromol/l (1.8 mg/dl).

[How to improve the rate of organ donation for transplantation?]. / Hvordan sikre best mulig tilgang på organer for transplantasjon?

Increasing shortage of organs for transplantation is a global phenomenon. In spite of a high kidney transplantation rate (45 per million population), the waiting list for kidney transplantation in Norway increased by 22% from 1996 to 1998. The waiting list for lung transplantation increased by 129% in the same period. The average annual number of cadaveric organ donors was 15.8 per million, with significant differences in donation rate between the health regions. Investigators have established the incidence of potential organ donors to be around 50 per million population per year. Failure to identify or support a potential donor and refusal of permission from relatives are important reasons why organ donation does not occur. We give a brief overview of programmes implemented in various European countries to increase organ donation. Improvement of donor hospitals organisation in order to support potential donor detection as well as training and motivation of hospital staff are considered important steps for increasing the organ donation rate.

[Pancreas transplantation--a review]. / Pancreastransplantasjon--en oversikt.

According to the International Pancreas Transplant Registry, more than 1,000 pancreas transplantations are now performed annually. When performed simultaneously with a kidney transplant, pancreas transplantation is a generally accepted treatment for type 1 diabetic patients with end stage renal disease, and the pancreas graft survival in this setting is equivalent to that of the kidney graft. The reported results of solitary pancreatic transplantation in non-uraemic diabetic patients have been less favourable due to a high rejection rate in combination with difficulties in rejection diagnosis and treatment. However, the introduction of new immunosuppressive drugs over the last few years has drastically improved the survival of solitary pancreatic grafts and allows for a rising enthusiasm. The majority of the 122 transplantations performed in Oslo so far were simultaneous kidney and pancreas transplantations. Duct occluded segmental grafts were used until 1988 when the pancreatico-duodenal technique with bladder drainage was introduced. In March 1998 we changed to enteric drainage of the exocrine pancreas due to a high percentage of lower urinary tract problems and bicarbonate loss associated with the bladder drainage technique. The positive impact of a functioning pancreas transplant on the recipient's quality of life is well recognised, whereas long-term beneficial effects on the secondary complications of diabetes are not well documented. A short overview of various aspects of pancreas transplantation is given, including experience with the 122 transplantations performed at the National Hospital, Oslo, Norway.

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.

Unrelated living donors in 141 kidney transplantations: a one-center study.

BACKGROUND: Kidney transplantation is the optimal treatment for the majority of patients with end-stage renal disease. However, the shortage of kidneys for transplantation is a global problem, and any attempt to improve the donor situation would be of benefit to the growing number of patients on transplant waiting lists. PATIENTS AND METHODS: Since 1984, we have transplanted 141 kidneys from genetically unrelated living donors. Donors were most often spouses and were accepted regardless of HLA match grade. Preemptive transplantation was performed in 39% of the patients. Standard triple-drug immunosuppression with prednisolone, cyclosporine, and azathioprine was used. The patients were followed from 6 months to 13 years. RESULTS: The incidence of acute rejection during the first 3 months after transplantation was higher in recipients of grafts from unrelated donors than in recipients of grafts from related living donors or cadaveric donors. However, unrelated living donor grafts survived significantly better than did cadaveric grafts (P < 0.02) and had a survival rate similar to that of living-related donor grafts mismatched for one or both HLA haplotypes. The perioperative complication rate for the donor was low. CONCLUSION: We consider unrelated living donors an excellent source for alleviating the shortage of donor kidneys.

Routine perioperative antibiotic prophylaxis in renal transplantation.

BACKGROUND: Perioperative antibiotic prophylaxis may prevent infection following renal transplantation but it also contributes to development of resistant microorganisms. With refined surgical techniques, improved graft preservation, and immunosuppressive monitoring during recent decades one can question the present use of perioperative antibiotic prophylaxis. We retrospectively evaluated the incidence of infection in our renal transplant centre where antibiotic prophylaxis is not routinely used in renal recipients. Concurrently we performed a survey of perioperative antibiotic use to establish the current world-wide practice. METHODS: Infection episodes were evaluated from records of 448 adult renal transplant recipients (January 1994 to August 1996) at our centre. A questionnaire was mailed to 103 centres addressing the number of kidney transplantations in 1995, donor source (living vs cadaveric) and details on use of perioperative antibiotic prophylaxis. RESULTS: Single-centre study. Renal transplantation was performed without antibiotic prophylaxis in 377 patients (84%). Thirteen patients (3.4%) had early postoperative infections, nine with urinary-tract infection tended to have urinary catheter for a longer period than those without infection (5.0 +/- 2.7 vs 3.4 +/- 1.4 days, P = 0.27) and cadaveric kidney recipients to have higher incidence of infections (4.5 vs 1.5% P = 0.14). All infection episodes were successfully treated. The infection incidence in 71 (16%) 'high-risk' patients selected for antibiotic treatment was 4.2%. World-wide survey. Data were obtained from 101 centres in five continents representing 10532 renal transplants. Ninety centres (89%) used perioperative antibiotic prophylaxis. CONCLUSION: The infection incidence in patients who did not receive perioperative antibiotic prophylaxis was the same as in a small group of selected patients who received prophylaxis. The incidence was lower than usually reported in the literature. In contrast perioperative antibiotic prophylaxis is given to all patients in almost 90% of transplant centres worldwide. A reduction of prophylactic antibiotic use is encouraged.

[Cadaver organ donation in Norway 1993-96]. / Organdonasjon fra avdøde givere i Norge 1993-96.

The annual number of cadaveric organ donors increased from 13.1 per million inhabitants in the period 1989-92 to 15.8 in the period 1993-96. Multiple organ harvesting was performed in 68% of the donors. There are significant differences in donation rate between health regions. An increase to 20 organ donors per year per million inhabitants is required to meet the anticipated need for organs. Strategies to increase organ donation are discussed.

Scandiatransplant: thirty years of cooperation in organ transplantation in the Nordic countries.

The Nordic organ exchange organization, Scandiatransplant was established in 1969. The organization, which covers a population of 23.9 million inhabitants, includes all 11 organ transplant centers in the 5 Nordic countries Denmark, Finland, Iceland, Norway and Sweden. The economy is solely based on transplant center fees. All Nordic patients waiting for an organ transplant are registered on one common waiting list. Rules for the exchange of organs are settled by unanimous decision, and the compliance to the rules is excellent. Kidney exchange is based on HLA matching, whereas the exchange of livers and hearts is based on clinical urgency. In 1997, 43% of the liver transplantations in Scandiatransplant were performed with an exchanged organ and the exchange rate for kidneys was 20%. Currently, the Scandiatransplant waiting list includes 1,538 patients waiting for a kidney transplant, 20 patients are waiting for a liver, 37 for a heart, and 156 patients are waiting for a lung transplant. The organ donation rate in Scandiatransplant has declined in recent years, from 16.0 per million population (PMP) in 1993 to a level of 13.5 PMP in 1997. The number of kidney transplants has varied between 800-900 per year during the past 10 years, corresponding to 33-38 transplants PMP. Approximately 30% of the renal transplants were performed with kidneys from living donors. The liver transplantation activity was approximately 7 PMP per year. Heart transplantation was performed at a rate of 4-5 PMP per year, and lung transplants at 4 PMP per year.

The national kidney transplant program in Norway still results in unchanged waiting lists.

1. Of 2,670 patients starting renal replacement therapy for end-stage renal disease in Norway from 1989-1997, 76% were candidates for transplantation. The annual need for transplantations increased from 47 to 64 grafts PMP as the number of elderly patients increased. The national waiting list has remained almost stable during the period from 1989-1997 at levels of 25-30 PMP, but the dialysis population has increased from 57-105 PMP. 2. A total of 1,681 transplants was performed at an annual rate varying between 38 and 46 grafts PMP. The grafts were procured from LDs in 41% and CDs in 59% of cases. Totally 69% of all patients in need were transplanted and 54% of all patients requiring replacement therapy for end-stage renal disease received a transplant. 3. Graft survival rates in recipients of first LD grafts (n = 641) were 91% and 77% at one and 5 years, respectively. One-year graft survival was 97% in HLA-identical grafts (n = 71), 92% in haploidentical grafts (n = 419), 88% in 2 haplotype-mismatched related grafts (n = 43), and 87% in spousal donor grafts (n = 108). 4. Graft survival rates in recipients of first CD grafts (n = 801) were 84% and 65% at one and 5 years, respectively. The rates were 86% and 74% in younger (n = 557) versus 78% and 46% in older (> 65 years) (n = 244) patients. Death with a functioning graft caused approximately 45% and 75% of all graft losses in younger and older patients, respectively. Cardiovascular disease was the major cause of death. 5. A significant beneficial effect of HLA-DR matching was observed in CD grafts performed after 1989, in particular in patients older than age 65.

Scandiatransplant: organ transplantation in the Nordic countries 1996.

The Nordic collaboration in organ transplantation was initiated nearly 30 years ago in the frame of Scandiatransplant. With a recent formalization of its structure, Scandiatransplant has become a modern organ exchange organization. The increasing activities of Scandiatransplant clearly reflect the continuously growing need for a close and firm Nordic collaboration in the transplantation field, for the benefit of the numerous patients waiting for an organ transplant.