[Show abstract][Hide abstract] ABSTRACT: Background
Neutrophil gelatinase-associated lipocalin (NGAL) is a marker for acute kidney injury. We studied whether serum NGAL predicts delayed graft function (DGF) and recovery of kidney function after transplantation.
Serum NGAL was analyzed using commercial ELISA and point-of-care (POC) (Triage®, Biosite) methods. Serum samples were collected from 176 consecutive, deceased-donor kidney recipients just before transplant surgery and on day 1 and 14 after transplantation. The first 132 samples were analyzed with both methods and the remaining samples with the POC method.
The correlation between the ELISA and POC methods was 0.89, p < 0.0001 and hence the POC method was used for the remaining analyses. DGF was seen in 66/176 patients. Day 1 sNGAL was significantly higher in DGF (588 ng/ml, SD 189.6) compared to early graft function (355 ng/ml, SD 166.2, p < 0.0001) and this difference persisted on day 14. Day 1 sNGAL predicted DGF with an area under the curve (AUC) of 0.853 (CI 0.792-0.914, p < 0.0001). At the optimal cutoff level of 423 ng/ml the sensitivity was 87% and the specificity 77%. In a multivariate analysis, day 1 sNGAL emerged as an independent predictor of DGF. The sNGAL also predicted DGF lasting longer than 14 days with an AUC of 0.825 (CI 0.751-0.899, p < 0.0001). At the optimal cutoff level of 486 ng/ml, the sensitivity was 80% and specificity 75%.
Serum NGAL predicts clinically significant DGF and is useful in the care of kidney transplant recipients.
[Show abstract][Hide abstract] ABSTRACT: IntroductionThe clinical course of cytomegalovirus (CMV) infections in the current era is poorly described. We characterized the symptoms and outcome of all CMV infections in a large cohort of kidney transplant recipients. Among 1129 kidney transplant recipients transplanted between 2004 and 2011 in Charité Universitätsmedizin Berlin and Helsinki University Hospital, 297 patients with CMV infection were characterized.ResultsCMV disease occurred in 217/1129 patients (19.2%), and CMV infection in 297/1129 (26.3%). Gastrointestinal symptoms were recorded in 58% and fever in 47% patients with primary CMV disease, compared to 46% and 27% patients with symptomatic CMV reactivation, whereas leukopenia or thrombocytopenia were seen in only 17–28% patients, and malaise in 9–10%. Tissue-invasive CMV gastroenteritis was confirmed in 11% and CMV pneumonia in only 1% of patients with CMV disease. Only 1 patient died because of CMV infection (mortality 0.3%). Virus-related factors or the use of secondary prophylaxis did not predict the risk of recurrence, which occurred in 33% patients.Conclusion
In conclusion, CMV disease remains a common problem after kidney transplantation. Gastrointestinal symptoms were common, especially in patients with primary CMV infection, whereas bone marrow suppression, hepatopathy, or malaise were seen less frequently.
[Show abstract][Hide abstract] ABSTRACT: Although longer pretransplant dialysis has been associated with poor kidney transplant outcome, no data about this association exist from the current era or from Europe. We studied the association of pretransplant dialysis duration on outcomes after kidney transplantation across two different time periods.
All recipients of first kidney transplantation between 1990 and 2010 in Finland were included (N=3,105) in this observational follow-up study of an inception cohort. The association of the duration of pretransplant dialysis with patient and graft survival after transplantation was analyzed with multivariable Cox regression and competing risk analyses. The association of pretransplant dialysis duration with the risk of specific causes of death (cardiovascular, infectious, or other) was analyzed using competing risk analysis.
Longer duration of pretransplant dialysis was an independent risk factor for patient death after transplantation (risk ratio [RR] 1.14 per 1-year increase) in the whole study population, but not for graft loss. Risk of death was increased in patients with greater than 12 months of pretransplant dialysis. After further adjustment in patients transplanted in 2000 to 2010, longer duration of dialysis remained an independent risk factor (RR 1.23 per 1-year increase). Longer duration of dialysis was an independent predictor of death resulting from cardiovascular diseases (RR 1.14 per 1-year increase), but not for other causes.
The risk of death associated with longer duration of dialysis has not decreased over time, but remains an independent predictor of patient death after kidney transplantation because of increased risk of death resulting from cardiovascular diseases.
[Show abstract][Hide abstract] ABSTRACT: The annual number of kidney transplantations in Finland is 150 to 200. Successful kidney transplantation improves the patient's quality of life and prognosis and is cost-effective as compared with dialytic therapy. Only a few per cent of transplantations are made from a living donor. Waiting times for kidney transplantations have become longer in the last few years. Whereas attempts should be made to better identify potential brain-dead organ donors in order to increase kidney transplantations, transplantations from living donors could also reduce the disproportion between the availability and the need of organs.
[Show abstract][Hide abstract] ABSTRACT: Studies on dialysis modality and survival have shown conflicting results, mostly due to insufficient and varying control of confounding factors. Using comprehensive data on a well-defined patient cohort, we therefore investigated the association of dialysis modality with survival on chronic renal replacement therapy (RRT) and whether this association varies between subgroups of patients.
Survival analyses included all adult patients entering chronic RRT in Finland between 2000 and 2009 and used information obtained from the Finnish Registry for Kidney Diseases and the Finnish Kidney Transplant Registry. In our primary intention-to-treat (ITT) analysis, we calculated relative risk of death according to dialysis modality on Day 91 from RRT start, comparing peritoneal dialysis (PD) to haemodialysis (HD). Relative risks were adjusted for putative confounders. Interactions between treatment groups and other variables were estimated.
Of the total 4463 patients, 42% died during the 10 years of follow-up. Median survival time was 5.2 years. In unadjusted ITT analysis, relative risk of death of PD patients was 0.65 (95% CI 0.58-0.73, P < 0.001) compared with HD patients. With adjustment for 26 variables, the corresponding relative risk of death was 1.07 (95% CI 0.94-1.22, P = 0.33). When censoring at time of kidney transplantation, the result was similar with a relative risk of death of 1.09 (95% CI 0.95-1.25, P = 0.24) on PD compared with HD.
PD is associated with several factors generally related to good prognosis. After comprehensive adjustment for putative confounding factors with the ITT analysis approach, we found no significant difference in survival between PD and HD patients.
[Show abstract][Hide abstract] ABSTRACT: The incidence and clinical course of polyomavirus-associated nephropathy (PyVAN) in our well-HLA-matched kidney transplant population mainly on low-dose cyclosporine-based triple-drug immunosuppression has not been described in detail. We aimed to characterize our patients with PyVAN and BK virus (BKV) viremia.
Among 166 kidney transplantations between January 2007 and February 2011 followed up at Helsinki University Hospital nephrology clinic, 136 were screened for BKV viremia by quantitative analysis of BKV DNA in plasma. PyVAN was diagnosed by biopsy histopathology and SV40 T-antigen detection. BKV viremia or PyVAN were treated by reducing immunosuppression.
BKV viremia was detected in 12 (9%) patients. PyVAN was diagnosed in six patients (4%). In the six patients with no PyVAN, four had low-level viremia (<10 000 copies/mL) of short duration (<2 months), one had high-level viremia, and one had sustained low-level viremia. After reduction of immunosuppression, all except one patient were able to clear viremia. No grafts were lost due to PyVAN.
Even in a low-risk population, BKV viremia and PyVAN occur, highlighting the importance of monitoring viral loads. Reduction of immunosuppression was successful, and no grafts were lost due to PyVAN.
[Show abstract][Hide abstract] ABSTRACT: Congenital obstructive uropathy can lead to end stage renal disease. Progression to end stage renal disease in childhood is well described but long-term prognosis in adulthood has not been thoroughly investigated. In this study we evaluated the risk of end stage renal disease in patients with posterior urethral valves.
During 1953 to 2003 a total of 200 male patients were treated for posterior urethral valves at our institution and of these 193 could be followed for renal outcome. Followup data on patients treated with dialysis or kidney transplantation were collected from patient records and the Finnish Kidney Transplantation Registry, and data on deceased patients were collected from hospital records and the Finnish Population Register Centre.
Median patient age at evaluation was 31 years (range 6 to 69). Of the 193 patients followed 44 (22.8%) had progression to end stage renal disease. According to a Kaplan-Meier analysis the lifetime risk of end stage renal disease was 28.5% (SE 3.8%). No patient had end stage renal disease after the age of 34 years. The lowest serum creatinine value during postoperative year 1 was associated with speed of progression to end stage renal disease. Early presentation, pneumothorax, bilateral vesicoureteral reflux and recurrent urinary tract infections after the abolition of urethral obstruction were associated with an increased risk of end stage renal disease at followup.
Congenital obstructive uropathy can lead to end stage renal disease during childhood or young adulthood. However, the risk of end stage renal disease seems to decrease eventually. Poor kidney function at presentation is associated with worse renal prognosis.
The Journal of urology 12/2011; 186(6):2392-6. DOI:10.1016/j.juro.2011.07.109 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) and complicates kidney transplant outcome. We studied whether donor neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for acute kidney injury, could predict DGF after transplantation.
We included 99 consecutive, deceased donors and their 176 kidney recipients. For NGAL detection, donor serum and urine samples were collected before the donor operation. The samples were analyzed using a commercial enzyme-linked immunosorbent assay kit (serum) and the ARCHITECT method (urine).
Mean donor serum NGAL (S-NGAL) concentration was 218 ng/mL (range 27 to 658, standard deviation (SD) 145.1) and mean donor urine NGAL (U-NGAL) concentration was 18 ng/mL (range 0 to 177, SD 27.1). Donor S-NGAL and U-NGAL concentrations correlated directly with donor plasma creatinine levels and indirectly with estimated glomerular filtration rate (eGFR) calculated using the modification of diet in renal disease equation for glomerular filtration rate. In transplantations with high (greater than the mean) donor U-NGAL concentrations, prolonged DGF lasting longer than 14 days occurred more often than in transplantations with low (less than the mean) U-NGAL concentration (23% vs. 11%, P = 0.028), and 1-year graft survival was worse (90.3% vs. 97.4%, P = 0.048). High U-NGAL concentration was also associated with significantly more histological changes in the donor kidney biopsies than the low U-NGAL concentration. In a multivariate analysis, U-NGAL, expanded criteria donor status and eGFR emerged as independent risk factors for prolonged DGF. U-NGAL concentration failed to predict DGF on the basis of receiver operating characteristic curve analysis.
This first report on S-NGAL and U-NGAL levels in deceased donors shows that donor U-NGAL, but not donor S-NGAL, measurements give added value when evaluating the suitability of a potential deceased kidney donor.
[Show abstract][Hide abstract] ABSTRACT: Different donor parameters and baseline biopsy have been used to assess the quality of donor organs. There is, however, no consensus which risk factors and chronic changes in the donor kidney can be accepted for transplantation. The study included 481 deceased organ donors and their 829 kidney recipients transplanted during 1995-2005. The biopsies were re-evaluated according to the Banff 97 classification. The prognostic significance of donor risk factors and Chronic Allograft Damage Index (CADI) was analyzed. We propose a new donor risk score, calculated as the count of positive risk factors from a defined set of factors in the medical history of the donor. This donor risk score predicts histological quality of the kidney, graft function, and survival. Transplantations from donors with donor risk score >4 had significantly decreased graft survival compared to those with donor risk scores 0-4; the five-yr death-censored graft survivals were 83% vs. 93%, respectively. High donor CADI score (>3) was associated with worse graft function and survival. Three-yr glomerular filtration rate declined from 82 to 49 mL/min with donor CADI increase from 0 to ≥4. Our results show that high donor risk score and CADI value reflect low functional reserve and risk for poor graft outcome.
[Show abstract][Hide abstract] ABSTRACT: 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.
Kidney International 01/2011; 79(1):89-98. DOI:10.1038/ki.2010.351 · 8.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Medical Virology 11/2010; 82(11):1940-9. DOI:10.1002/jmv.21894 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prolonging cytomegalovirus (CMV) prophylaxis in CMV seronegative recipients of a kidney from CMV seropositive donor (D+/R–) may reduce the incidence of late infections. We analyzed late-onset primary CMV infections after 6 months valganciclovir prophylaxis.
Data from all CMV D+/R– kidney transplant recipients between January 2004 and December 2008 at our center were analyzed. Patients with a functioning graft at 6 months after transplantation who received 6 months of valganciclovir prophylaxis 900 mg once daily were included (N = 127). CMV was diagnosed with quantitative PCR. Prophylaxis was completed in 119 patients. Prophylaxis was stopped at 3–5 months due to leukopenia or gastrointestinal side effects in eight patients. Late-onset primary CMV infection developed in 47/127 (37%) patients median 244 days after transplantation (range 150–655) and median 67 days after the cessation of prophylaxis (range 1–475). Four infections were asymptomatic. In others, symptoms included fever (N = 28), gastrointestinal symptoms (nausea, vomiting, diarrhea) (N = 24), respiratory tract symptoms (N = 12), and hepatopathy (N = 6). Median peak viral load was 13500 copies/mL (range 400–2 831 000). Recurrent CMV infection developed in 9/47 (19%) patients. No significant risk factors for CMV infection were identified.
Symptomatic primary CMV infections were commonly detected also after prolonged valganciclovir prophylaxis.
American Journal of Transplantation 09/2010; 10(9):2026-32. DOI:10.1111/j.1600-6143.2010.03225.x · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the treatment of end-stage renal disease, kidney transplantation is the best and most cost-effective alternative with regard to both prognosis and quality of life. Problems arise from the disproportion between the number of available allografts and the patients waiting for the transplantation. There are few absolute contraindications to kidney transplantation. In the assessment of the eligibility for transplantation of patients on dialysis the most important factors include cardiovascular diseases, cancer diseases, other diseases affecting operability and life expectancy, age, excess weight and possible infections.
[Show abstract][Hide abstract] ABSTRACT: Skin cancers are the most frequent malignancies in organ transplant recipients (OTRs). Squamous cell carcinomas (SCCs) occur 65-250 times more frequently in OTRs and tend to be aggressive in behavior. Because matrix metalloproteinases (MMPs) have a central role in tumorigenesis and invasion, we investigated the epithelial and stromal MMP and tissue inhibitor of MMP (TIMP) expression profile in SCCs of immunosuppressed (IS) compared with immunocompetent (IC) patients to determine if differences could explain the more aggressive behavior of SCCs in OTRs.
Matched pairs from 20 SCCs of IS and IC patients were studied using immunohistochemistry for MMP-1, MMP-7, MMP-8, MMP-9, MMP-13 and MMP-26 and TIMP-1 and TIMP-3.
Among all MMPs studied, only staining for MMP-26 was significantly more intense in cancer cells of the post-transplant group compared with the IC group (p = 0.01), whereas MMP-9 expression was more abundant in stromal macrophages surrounding SCCs of IC patients (p = 0.02). MMP-26 expression in cancer cells (p = 0.04) and that of MMP-9 in neutrophils (p = 0.005) were more abundant in SCCs of patients using cyclosporine.
We conclude that MMP-26 and MMP-9 may contribute to the more aggressive behavior of SCCs in OTRs.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non-immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs-10, -12 and -21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs-10 and -21 to SCC development in the FVB/N-Tg(KRT5-Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen's disease and timed back skin biopsies of mice with selective inhibition of Rel/NF-kappaB signalling were performed. Semiquantitatively assessed stromal MMP-10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell-derived MMP-10, -12 and -21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP-21 more abundantly. MMP-10 expression was observed already in Bowen's disease while MMP-21 was absent. MMP-10 and -21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP-10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host-response reaction to skin cancer. MMP-21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.