Ilkka Helanterä

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.

The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients1

Background. The role of cytomegalovirus (CMV) in chronic kidney allograft rejection remains controversial. The purpose of this study was to examine the impact of CMV infection on histopathologic changes in 6-month protocol biopsy specimens of kidney allografts. Methods. Altogether, 52 renal allograft recipients were studied. CMV infection was diagnosed by CMV antigenemia test, viral cultures from blood and urine, or both. CMV was demonstrated in the biopsy specimens by antigen detection and hybridization in situ. Acute rejections were diagnosed by biopsy histology, and biopsy specimens were graded according to the Banff ’97 classification. Results. CMV infection was diagnosed in 41 patients. The 11 patients in whom CMV infection was not detected were used as controls. Acute rejection was diagnosed in 22 of 41 CMV patients and in 6 of 11 control patients. CMV was demonstrated in the biopsy specimens of 19 of 41 CMV patients. CMV was not associated with increased glomerular, tubular, or interstitial changes. However, the arteriosclerotic changes in small arterioles were significantly increased in the subgroup of patients where CMV was demonstrated in the graft as compared with controls (P <0.01). Analysis of the impact of acute rejection on arteriolar thickening showed that only a positive history of both acute rejection and CMV found in the graft was associated with significantly increased vascular changes compared with CMV-free recipients (P <0.05). Conclusions. Neither CMV nor acute rejection alone was associated with increased vascular or other histopathologic changes in 6-month protocol biopsy specimens of kidney allografts, but a previous history of both acute rejection and the presence of CMV in the graft was associated with increased vascular changes.

Primary CMV Infections Are Common in Kidney Transplant Recipients After 6 Months Valganciclovir Prophylaxis

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.

Viral Impact on Long-term Kidney Graft Function

Acute rejection episodes are an important risk factor for the functional deterioration of solid-organ transplants. With more intense immunosuppressive protocols, the rate of acute rejection episodes has significantly declined in the last decade, but long-term graft function and graft survival are challenged by increasing viral complications. In this article, recent data on the role of adenovirus, polyomavirus BK and JC, cytomegalovirus, human herpesvirus-6 and -7, and parvovirus B19 on the long-term outcome of kidney transplantation are reviewed. An update on the pathophysiology of smoldering viral replication, associated inflammatory damage, and the presumed indirect viral effects is provided, and the implications for diagnostic tests and antiviral intervention are discussed.

Prospective follow-up of primary CMV infections after 6 months of valganciclovir prophylaxis in renal transplant recipients

BACKGROUND The occurrence and clinical course of late primary CMV infections developing after valganciclovir prophylaxis in high-risk renal transplant recipients are poorly described. METHODS Helsinki University Hospital district kidney allograft recipients between January 2004 and March 2007 (N = 175) were prospectively investigated. Patients with D+/R- CMV serostatus and 1-year follow-up were included (N = 25). After 6 months of oral valganciclovir prophylaxis, the patients were monitored for CMV-DNAemia with real-time quantitative plasma PCR at 2-6 weeks interval and if CMV infection was suspected. Infections were treated with i.v. ganciclovir or high-dose valganciclovir, followed by 1-3 months of secondary valganciclovir prophylaxis. RESULTS CMV infection developed in 12/25 patients a mean of 107 days (range 26-330 days) after prophylaxis ended. Two were asymptomatic. In 10 patients symptoms included fever (N = 7), gastrointestinal (N = 5), upper respiratory tract (N = 3) and hepatopathy (N = 2). One patient with infection had prophylaxis terminated after 5 months (leukopenia). The mean viral load at diagnosis was 49 517 (range 490-325 300), and peak viral load was 84 654 (range 1250-527 400) copies/ml. Five infections were treated with valganciclovir and six with i.v. ganciclovir resulting with negative PCR results. One mild infection with low viral load was treated successfully with minimization of immunosuppression. Infection relapse developed in three patients a mean of 31 (range 15-61) days after the end of the therapy. Relapses were treated with valganciclovir. CONCLUSIONS CMV primary infections were common after 6 months of valganciclovir prophylaxis and mostly symptomatic. Relapses commonly occurred. Primary infections seem to be delayed, but were not efficiently prevented by 6 months of prophylaxis.

Demonstration of HHV-6 antigens in biopsies of kidney transplant recipients with cytomegalovirus infection

The activation of human herpesvirus‐6 (HHV‐6) commonly coexists with that of cytomegalovirus (CMV) in organ transplant recipients. No data exist of HHV‐6 in renal allografts, whereas persistent CMV in the kidney associates with poor outcome and histopathologic changes. We examined HHV‐6 and CMV antigens from kidney transplants with previous CMV infection. HHV‐6 and CMV pp65 antigens were demonstrated by monoclonal antibodies and immunohistochemistry from 22 kidney transplants with previous CMV infection. CMV was diagnosed by antigenemia tests and/or viral cultures. HHV‐6 antigens were found in 7/22 biopsies 18–1330 days after CMV infection, in infiltrating leukocytes in six, and in tubular epithelial cells in two patients. CMV infections were treated, and no virus could be detected from urine or blood thereafter, or at the time of the biopsy. Only 1/7 of these biopsies demonstrated also CMV antigens, whereas CMV antigens were found in 6/15 of the biopsies with no HHV‐6. HHV‐6 in the graft was associated with previous acute rejections, but not with any histopathological changes or reduced renal function. In conclusion, HHV‐6 was a common finding in late renal allograft biopsies of patients with previous CMV infection, but its significance remains to be elucidated.

Pretransplant dialysis duration and risk of death after kidney transplantation in the current era.

Background 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. Methods 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. Results 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. Conclusions 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.

Simultaneous BK Polyomavirus (BKPyV)-associated nephropathy and hemorrhagic cystitis after living donor kidney transplantation

BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression.

The risk for end-stage renal disease is increased after burn

OBJECTIVE Acute kidney injury (AKI) commonly complicates burn. Recently, AKI has been suggested to be causally related to chronic end-stage renal disease (ESRD), but controversial data also exist. Our aim was to study the risk of ESRD after burn in a nationwide analysis. METHODS All burn patients undergoing hospitalization between 1998 and 2011 were identified from the National Hospital Discharge Register, and the data were linked with the Finnish Registry for Kidney Diseases, which includes all individuals receiving chronic renal replacement therapy (RRT) in Finland. RESULTS Altogether 41,179 adults were treated at hospitals for burns in Finland between 1998 and 2011. Of these, 86 had a diagnosis of AKI related to the burn. Forty-three burn survivors had ESRD and RRT initiated related to or after the burn. The overall risk for ESRD after burn was increased (standardized incidence ratio, SIR, 2.40, 95% CI 1.73-3.23) compared with the Finnish population. Standardized incidence ratio was 3.11 (95% CI 1.66-5.32) in women and 1.89 (95% CI 1.27-2.69) in men. Of these 43 patients, 38 had a specific non-burn-related diagnosis of ESRD identified in the registry, and ESRD was deemed unlikely to be directly related to the burn. In five patients, the diagnosis of ESRD was unknown cause of renal failure, and causality of the burn with ESRD was evaluated as plausible. CONCLUSION In conclusion, a significantly increased risk of ESRD was recorded after a severe burn. Our results do not support increased incidence of ESRD solely as a consequence of AKI due to burn, but burn may increase the risk of ESRD in patients with pre-existing chronic kidney disease.

Timing and value of protocol biopsies in well‐matched kidney transplant recipients – a clinical and histopathologic analysis

The role and timing of protocol biopsies after kidney transplantation are controversial. We changed our protocol biopsy policy and compared the predictive value of biopsies at different time‐points. Protocol biopsies at 6 months (n = 45) were obtained during 2001–2004, and at 3 and 12 months from 2004 (n = 41). Donor biopsy was available from 70 patients. Histopathologic changes were described with chronic allograft damage index (CADI) and Banff 1997. Follow‐up was for 18 months. Chronic allograft nephropathy (CAN) was present in 12%, 51%, and 34% and borderline or subclinical rejection in 9.8%, 8.9%, and 7.3% of patients at 3, 6, and 12 months. CAN at 6 and 12 months was associated with reduced graft function (P = 0.001). Semiquantitative CADI scores at all time‐points significantly correlated with glomerular filtration rate (GFR) at 18 months. Strongest correlation existed with CADI at 12 months (P < 0.001). Change in CADI between 0–6 and 0–12 months, but not between 0–3 and 3–12 months, correlated with GFR at 18 months (P = 0.03, P = 0.01). Subclinical rejections were rare and chronic changes mild at 3 months. In our well‐matched population, the predictive value of a biopsy at 3 months was inferior to biopsies at 6 or 12 months, both of which were effective in predicting long‐term graft function.