Lauri Kyllönen

Positron emission tomography in clinical islet transplantation.

The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants.

Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation

Delayed graft function (DGF), especially long-lasting DGF, complicates kidney transplant outcome. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute kidney injury marker; therefore, we tested whether urine NGAL could predict DGF, prolonged DGF (lasting over 14 days), or the quality of kidney function in transplant recipients without DGF (non-DGF). We collected urine samples from 176 recipients transplanted with deceased donor kidneys before and various days after transplantation. A total of 70 transplantations had DGF, of which 26 were prolonged. Patients who developed DGF had a significantly slower decrease in urinary NGAL compared with those without DGF, such that day 1 NGAL predicted DGF (area under the curve (AUC) 0.75) and predicted DGF in 15 of 112 cases with day 1 urine output over 1 l (AUC 0.70) and in 19 of 86 cases with a day 1 decrease in creatinine over 50 μmol/l (AUC 0.74). The urinary NGAL level on day 1 predicted prolonged DGF (AUC 0.75), which had significantly worse 1-year graft survival (73%), compared with shorter DGF (100%). In non-DGF, high day 3 NGAL (greater than the mean) was associated with significantly worse kidney function at 3 weeks compared with low NGAL, but not at 3 months and 1 year. NGAL did not correlate with long-term function in DGF. Hence, day 1 urinary NGAL predicted DGF even when it was not clinically expected early on, and importantly, it predicted prolonged DGF that led to worse graft survival.

Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival

The long‐term effects of cytomegalovirus (CMV) infections on kidney allografts are unknown. We examined the impact of persistent intragraft CMV infection on long‐term kidney allograft function and survival. CMV was diagnosed in 82/172 renal transplant recipients by antigenemia test and viral cultures. Biopsies from 48 of 82 patients taken after CMV infection and from 15 patients with no previous CMV infection detected were available for the immunohistochemical demonstration of CMV antigens and DNA hybridization in situ. Five‐year follow‐up data from these 63 patients were analysed. In 17 patients, CMV antigens and/or DNA persisted in the biopsy >2 months after the last positive finding in blood or urine. Patients with persistent intragraft CMV had reduced graft survival (P = 0.041) and Cox regression analysis showed persistent CMV as a risk factor for reduced graft survival (RR: 3.5). Recipients with persistent intragraft CMV had reduced creatinine clearance 1 and 2 years after transplantation (P = 0.007) and in multivariate logistic regression analyses including several potential pre‐ and posttransplant risk factors, persistent CMV was an independent risk factor for lower clearance at 1 and 2 years (OR: 4.4 and 4.9). Our novel findings show that persistent intragraft CMV infection was associated with reduced kidney allograft function and survival.

Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study.

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus‐MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC‐SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC‐SRL0.5 mg) and 327 patients 1 g MMF (TAC‐MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy‐proven acute rejection was lower in the TAC‐SRL2 mg group (15.7%) compared with the TAC‐SRL0.5 mg (25.2%, p = 0.003) and the TAC‐MMF groups (22.3%, p = 0.036). Six‐month graft survival was 91.0% (TAC‐SRL2 mg), 92.6% (TAC‐SRL0.5 mg) and 92.4% (TAC‐MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty‐four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC‐SRL2 mg, TAC‐SRL0.5 mg and TAC‐MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC‐SRL2 mg group (24.0%) compared with 19.4% (TAC‐SRL0.5 mg) and 11.0% (TAC‐MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.

Cytokine Gene Polymorphisms and Risks of Acute Rejection and Delayed Graft Function after Kidney Transplantation

Background. Pretransplantation identification of patients at an increased risk for adverse events would allow more individualized treatment strategies possibly improving long-term outcome. We studied cytokine gene polymorphisms of kidney allograft recipients and their donors to identify factors predisposing for acute rejection (AR) and delayed graft function (DGF). Methods. A total of 291 adult cadaver kidney recipients transplanted at a single transplantation centre between 1999 and 2002 were investigated. Recipients and donors were typed for TNF-&agr;(-308G/A), TGF-&bgr;1(codon 10T/C, codon 25C/G), IL-10(-1082G/A, -819C/T, -592C/A), IL-6(-174C/G), and IFN-&ggr;(+874T/A) polymorphisms using a SSP-PCR kit. An AR episode was defined based on clinical and histological findings (Banff criteria). Results. The incidence of AR was 17%. In univariate statistical analyses recipients with TNF-&agr; -308AA-genotype were found to be at a significantly increased risk for rejection (odds ratio [OR] 5.0, 95% CI 3.0–8.3, P=0.003). The association was independent from the patient-donor HLA-mismatch status. In addition, patients with IL-10 ACCACC, ATAATA, GCCATA (-1082A/G, -819C/T, -592C/A, respectively) haplotypes were predisposed to rejection (OR 1.9, 95% CI 1.1–3.1, P=0.016). Further, the combination of recipient TGF-&bgr;1 25GG-genotype and donor IL-10 -819T-allele was associated with rejection (OR 1.8, 95% CI 1.1–3.0, P=0.027). These variables remained significant risk factors also in a multivariate logistic regression analysis. The incidence of DGF was 22%. The risk was increased by a donor TNF-&agr; -308GA-genotype (OR 1.6, 95% CI 1.1–2.6, P=0.040). Conclusions. Our results confirm that cytokine gene polymorphisms influence the outcome of kidney transplantation. Our data especially identify the TNF-&agr; -308AA-genotype as a factor predisposing for AR episodes.

Incidence of Merkel cell carcinoma in renal transplant recipients

BACKGROUND The risk factors for Merkel cell carcinoma (MCC), a rare type of skin cancer, are poorly understood. Some evidence suggests that MCC is more common in individuals with abnormal immune function resulting from viral infection, autoimmune disease or organ trans- plantation. METHODS The national Renal Transplant Registry and the Finnish Cancer Registry data were searched for recipients of a renal transplant who were diagnosed with MCC. The MCC diagnoses were confirmed using immunohistochemistry. RESULTS Three cases of MCC were detected among 4200 individuals who underwent renal transplantation from 1967 to 2005 [expected number 0.05, standardized incidence ratio (SIR) 66, 95% CI 14-194, P <0.001]. The latency period between the transplant and detection of MCC ranged from 6 to 19 years. In all three cases, the cause of transplantation was an autoimmune disease. All three died from aggressive MCC with a survival time ranging from 0.5 to 2.1 years. CONCLUSIONS The results indicate that the risk of MCC is greatly increased among subjects who have undergone renal transplantation. The course of the disease appears aggressive in this patient population. The physicians who treat recipients of a kidney transplant should be aware of the substantially increased risk of MCC.

Impaired renal function after pregnancy in renal transplant recipients

Twenty-two renal transplant recipients had 29 post-transplant pregnancies and 39 male transplant recipients became fathers to 65 children between 1971 and 1991. Of the deliveries of the female patients, 62% took place between the third and sixth year after transplantation. Seven patients had 2 pregnancies. Mean follow-up time after the first posttransplant pregnancy was 7.5 years. The patients survived the pregnancy well, but the increase in serum creatinine concentration from the prepregnancy level, registered 3 months and 1 year after delivery, was higher than in matched control patients without pregnancy at corresponding times after transplantation (the increase in serum creatinine was 47.7 and 61.2 μmol/L in the pregnant patients versus −2.7 and 5.4 μmol/L in the control patients, P<0.0001 and P<0.02, respectively). All pregnant and control patients were alive at the end of follow-up, but the long-term graft survival of those with a pregnancy was significantly (P<0.005) worse than in the control patients. Ten-year graft survival was 69% in the pregnant versus 100% in the control patients. Although 80% of the neonates born to a mother with a transplanted kidney were below the mean for gestational age, the weight and length at birth were within normal limits and no severe intrauterine growth retardation was documented.

Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety.

Background. The aim of this prospective randomized study was to examine the effect of induction immunosuppression and low initial cyclosporine (CsA) on the onset of graft function and its long-term consequences. Methods. During 1999–2001, 155 patients were randomized to single 9 mg/kg dose antithymocyte globulin (ATG)-Fresenius (group A) or two 20-mg doses of basiliximab (group B) with reduced dose CsA or conventional CsA triple therapy without induction (group C). Results. Delayed function (DGF) was lower in group A than in groups B or C (5.7% vs. 24.1% and 15.9%, P<0.025) and need of dialysis was less in groups A and B compared to C (10.3 and 10.4 vs. 20.0 days, P<0.05). Acute rejections occurred in 11.3%, 12.1% and 20.5%, and the mean (median) time to rejection was 16 (13), 97 (46) and 101 (35) days in groups A, B, and C, respectively (P<0.005). One-and 5-year graft survivals (GS) were 98.1% and 90.6% (group A), 96.6% and 96.6% (group B), and 93.2% and 84.1% (group C). Five-year GS was significantly better in group B than in group C (P<0.05). The death censored 5-year GS in groups A, B, and C were 94.3%, 96.6%, and 90.0% (P=NS). Single high-dose ATG induction was associated with hemodynamic and pulmonary disturbances without, however, serious or long-term consequences. Conclusions. ATG induction significantly reduced DGF. Both induction regimens together with low initial CsA led to significantly less posttransplant dialysis and excellent survival. The high dose ATG was associated with significant hemodynamic and pulmonary side effects during drug infusion.

Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis.

Enterovirus 94 (EV‐94) is an enterovirus serotype described recently which, together with EV‐68 and EV‐70, forms human enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for enterovirus‐induced diseases. The cell types studied included human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV‐68 and EV‐94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV‐94 and EV‐68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T‐cell, or B‐cell characteristics. EV‐94 and EV‐70 were capable of infecting primary human umbilical vein endothelial cells, whereas EV‐68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV‐94 was able to damage pancreatic islet β‐cells, to infect, replicate, and cause necrosis in human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV‐D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV‐94 may be a potent pathogen and should be considered a potentially diabetogenic enterovirus type. J. Med. Virol. 82:1940–1949, 2010.

Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in renal transplant recipients.

Background. Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL). Methods. In this survey, 4,232 renal transplant recipients from Denmark, Finland, Norway, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms. Results. The prevalence of troublesome GI symptoms (GSRS>1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4–2.0) and constipation (OR: 1.3; 95% CI: 1.1–1.6), and sirolimus with indigestion (OR: 2.9; 95% CI: 1.0–8.1) and abdominal pain (OR: 2.2; 95% CI: 1.1–4.4). Conclusions. GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients.