BK & JC Polyoma Viruses Cause Kidney Transplant Rejection

Active BK polymoma virus infection has been conclusively linked to transplant interstitial nephritis and kidney transplant rejection. Cytomegalovirus, Epstein-Barr virus, and other viruses are also known to be involved.

Human polyoma virus infection of renal allografts: histopathological diagnosis, clinical significance, and literature review. O Pappa, AJ Demetris, RB Raikow, PS Randhawa. Mod Pathol 1996 Feb;9(2):105-109. Review.

Pappa - Mod Pathol 1996 abstract / PubMed

Human polyoma virus-associated interstitial nephritis in the allograft kidney. PS Randhawa, S Finkelstein, V Scantlebury, R Shapiro, C Vivas, M Jordan, MM Picken, AJ Demetris. Transplantation 1999 Jan 15;67(1):103-109. 22 cases. "The clinical features mimicked acute rejection (n=19), chronic rejection with incidental diagnosis at nephrectomy (n=2), or drug toxicity (n=1). Histology showed homogenous intranuclear inclusions. In situ hybridization showed BK virus (BKV) to be the predominant species, but polymerase chain reaction documented JC virus co-infection in one of five cases so tested."

Randhawa - Transplantation 1999 abstract / PubMed

Post-transplantation polyomavirus infections. S Boubenider, C Hiesse, S Marchand, A Hafi, F Kriaa, B Charpentier. J Nephrol 1999 Jan-Feb;12(1):24-29. Review.

Boubenider - J Nephrol 1999 abstract / PubMed

Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. I Binet, V Nickeleit, HH Hirsch, O Prince, P Dalquen, F Gudat, MJ Mihatsch, G Thiel. Transplantation 1999 Mar 27;67(6):918-922. Graft loss occurred in 4 of 5 cases, among 70 total kidney transplants.

Binet - Transplantation 1999 abstract / PubMed

Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease. V Nickeleit, HH Hirsch, IF Binet, F Gudat, O Prince, P Dalquen, G Thiel, MJ Mihatsch. J Am Soc Nephrol 1999 May;10(5):1080-1089. 5 cases. "All patients were excreting PV-infected cells in the urine. PV infection was associated with 40% graft loss (2 of 5) and a serum creatinine of 484+/-326 micromol/L (mean +/- SD; 11 mo post-Tx). Tx control groups showed PV-infected cells in the urine in 5%."

Nickeleit / J Am Soc Nephrol 1999 full article

Human polyoma virus in renal allograft biopsies: morphological findings and correlation with urine cytology. CR Drachenberg, CO Beskow, CB Cangro, PM Bourquin, A Simsir, J Fink, MR Weir, DK Klassen, ST Bartlett, JC Papadimitriou. Hum Pathol 1999 Aug;30(8):970-977. 361 renal transplant patients. "PV was identified in 1.8% biopsy specimens (1.9% of patients). PV interstitial nephritis showed the typical viral cytopathic changes in tubular epithelial cells associated with marked tubular damage and a disproportionately mild degree of tubulitis. There was no difference in the incidence of PV in the urine of patients with acutely deteriorating versus stable renal function (18% and 19%, respectively); however, urines with large numbers of infected cells (> 10/cytospin) and inflammatory changes in the sediments corresponded invariably to patients with acute allograft dysfunction (8 of 8), and in most cases to biopsy specimens showing PV interstitial nephritis (7 of 8)."

Drachenberg - Hum Pathol 1999 abstract / PubMed

Diagnosis and management of BK polyomavirus interstitial nephritis in renal transplant patients. DN Howell, SR Smith, DW Butterly, PS Klassen, HR Kligman, JL Burchette, SE Miller. Transplantation 1999 Nov 15;68(9):1279-1288. 7 patients with polyomavirus nephritis out of 240 renal transplants. "Patients with polyomavirus infection shared several clinical features, including ureteral obstruction (5/7 patients), lymphocele (3/7), bacterial urinary tract infection (3/7), hematuria (3/7), cytomegalovirus infection (3/7), and immunosuppression with mycophenolate mofetil (6/7). All patients experienced elevations in serum creatinine, which stabilized or decreased in four patients with altered or decreased immunosuppression."

Howell - Transplantation 1999 abstract / PubMed

BK virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game. V Nickeleit, HH Hirsch, M Zeiler, F Gudat, O Prince, G Thiel, MJ Mihatsch. Nephrol Dial Transplant 2000 Mar;15(3):324-332. Review of treatment of 11 patients.

Nickeleit / Nephrol Dial Transplant 2000 full article

Testing for polyomavirus type BK DNA in plasma to identify renal allograft recipients with viral nephropathy. V Nickeleit, T Klimkait, IF Binet, P Dalquen, V Del Zenero, G Thiel, MJ Mihatsch, HH Hirsch. N Engl J Med 2000 May 4;342(18):1309-1315. 9 patients with BK virus nephropathy. "BK virus DNA was initially undetectable but was detected 16 to 33 weeks before nephropathy became clinically evident and was confirmed by biopsy. Tests for BK virus DNA in plasma became negative and the nephropathy resolved after the doses of immunosuppressive drugs were decreased in two patients and after removal of the renal allograft in three patients. BK virus DNA was found in the plasma of only 2 of the 41 renal-allograft recipients who had no signs of nephropathy and in none of the patients with HIV-1 infection."

Nickeleit / NEJM 2000 full article

Human polyomavirus BKV and renal disease. KV Shah. Nephrol Dial Transplant 2000;15(6):754-755. Review article.

Shah / Nephrol Dial Transplant 2000 full article

New perspectives: Late complications after transplantation. D Snydman. Medscape News re XVIII International Congress of the Transplantation Society, 2000 Aug 27. "It has long been known that infections have various effects on the kidney allograft. Infection affects the kidney in 5 distinct ways. Direct effect -- parenchymal infection (ie, polyomavirus); Indirect effect -- systemic response to infection such as immune complex formation or thrombotic microngiopathy (eg, hepatitis C virus [HCV] infection); Potentiation of rejection (ie, cytomegalovirus [CMV] infection); infiltration of kidney with neoplastic cells (ie, Epstein-Barr virus [EBV] infection); Toxic or allergic response to antimicrobial agents." A CME credit article. (Link died http://www.medscape.com/medscape/cno/2000/ICTS/Story.cfm?story_id=1592.)

Steroid-resistant kidney transplant rejection: diagnosis and treatment. HA Bock. J Am Soc Nephrol 2001 Feb;12 Suppl 17:S48-S52. Review.

Bock / J Am Soc Nephrol 2001 full article

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis. M Ahuja, EP Cohen, AM Dayer, B Kampalath, CC Chang, BA Bresnahan, S Hariharan. Transplantation 2001 Apr 15;71(7):896-899. 10 cases. "The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5-40%) compared with 6% (range, 0-10%) in those with acute rejection (P=0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2-15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15-30%) in those patients who had acute rejection (P=0.0159)."

Ahuja - Transplantation 2001 abstract / PubMed

JC VIRUS INFECTION IN ALLOGRAFT KIDNEYS: Analysis by Polymerase Chain Reaction and Immunohistochemistry. P Randhawa, F Baksh, N Aoki, D Tschirhart, aS Finkelstein. Transplantation 2001 May 15;71(9):1300-1303. "JCV DNA was found in 7 (36.8%) of 19 allograft kidney biopsy specimens with viral nephropathy and 0 (0%) of 19 native or allograft biopsy specimens without viral nephropathy."

Randhawa - Transplantation 2001 abstract / PubMed

An Association between BK Virus Replication in Bone Marrow and Cytopenia in Kidney-Transplant Recipients. E Pambrun, C Mengelle, G Fillola, P Laharrague, L Esposito, I Cardeau-Desangles, A Del Bello, J Izopet, L Rostaing, N Kamar. J Transplant 2014;2014:252914 - 2014 Apr 29. "At least one virus was detected in the bone marrow of 25/72 patients (35%), that is, parvovirus B19 alone (n = 8), parvovirus plus Epstein-Barr virus (EBV) (n = 3), cytomegalovirus (n = 4), EBV (n = 2), BKV alone (n = 7), and BKV plus EBV (n = 1). Three of the eight patients who had BKV replication within the bone marrow had no detectable BKV replication in the blood. Neutropenia was observed in all patients with BKV replication in the bone marrow, and blockade of granulocyte maturation was observed. Hematological disorders disappeared in all patients after doses of immunosuppressants were reduced." "Parvovirus B19 infection is a classic cause of anemia, and cytomegalovirus (CMV) is well known to suppress bone-marrow function."

Pambrun - J Transplant 2014 full article / PubMed Central
Pambrun / J Transplant 2014 full article

Polyomaviruses in other transplant patients

Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. AY Leung, CK Suen, AK Lie, RH Liang, KY Yuen, YL Kwong. Blood 2001 Sep 15;98(6):1971-1978. "BK viruria was quantitatively related to the occurrence of HC after BMT" in 50 patients.

Leung / Blood 2001 full article

Reactivation of polyomaviruses in normal subjects

Age-Related Urinary Excretion of BK Polyomavirus by Non-immunocompromised Individuals. S Zhong, HY Zheng, M Suzuki,Q Chen, H Ikegaya, N Aoki, S Usuku, N Kobayashi, S Nukuzuma, Y Yasuda, N Kuniyoshi, Y Yogo, T Kitamura. J Clin Microbiol 2007 Jan;45(1):193-198. In 9 age groups of 50 healthy volunteers or non-immunocompromised patients, "The rate of BK viruria was relatively low in subjects aged <30 years old, but gradually increased with age in subjects >/=30 years old. However, BK viruria was less frequent than JC viruria in adults. The detected BKV isolates were classified into subtypes and detection rates for individual subtypes were compared among age groups; this analysis showed that viruria of subtypes I (the most prevalent subtype) and IV (the second most prevalent subtype) occurred more frequently in older subjects."

Zhong - J Clin Microbiol 2007 abstract / PubMed

Cytomegalovirus Complicates Organ Transplants

The clinical significance of cytomegaloviral inclusions in the allograft kidney. R Kashrap, R Shapiro, M Jordan, PS Randhawa. Transplantation 1999 Jan 15;67(1):98-103. 10 patients, 9 of whom had previous episodes of acute rejection, and five lost grafts. "CMV inclusions in renal allograft biopsies typically occur after treatment for rejection. Ganciclovir eradicates replicative virus, but graft outcome is determined by coexisting acute rejection and chronic allograft nephropathy. Graft loss primarily attributable to CMV was not observed."

Kashyap - Transplantation 1999 abstract / PubMed

The expansion of CD4+CD28- T cells in patients with chronic kidney graft rejection. A Pawlik, M Florczak, M Masiuk, G Dutkiewicz, B Machalinski, J Rozanski, L Domanski, B Gawronska-Szklarz. Transplant Proc 2003 Dec;35(8):2902-2904. 20 healthy individuals, 20 patients after renal transplantation with stable graft function, and 20 with chronic graft rejection. In patients with stable graft function, the median frequency of CD4+CD28- T cells was 3.1% and was significantly higher in comparison to the control group (1.4%) (P <.01).The highest subset CD4+CD28- cells was detected in patients with chronic graft rejection (10.65%). The amount of CD4+CD28- cells was significantly higher in this group in comparison to patients with stable graft function (P <.01)."

Pawlik - Transplant Proc 2003 abstract / PubMed

[Re CD4(+)CD28(-) T cells] Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

van Leeuwen / J Immunol 2004 full article

Cytomegalovirus replication and "herpesvirus burden" as risk factor of cardiovascular events in the first year after renal transplantation. E Gomez, A Laures, JM Baltar, S Melon, B Diez, M de Ona. Transplant Proc 2005 Nov;37(9):3760-3763. "Among 121 renal transplant recipients, 13 presented cardiovascular events, all associated with CMV replication (P = .004)... All patients with these events were seropositive for CMV, HSV, VZV, and EBV, as opposed to 64.8% without them (P = .009)."

Gomez - Transplant Proc 2005 abstract / PubMed

Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease. MG Betjes, NH Litjens, R Zietse. Nephrol Dial Transplant 2007 Nov;22(11):3298-3303. 408 ESRD patients. "The average titre for anti-CMV immunoglobulin G was higher in patients with atherosclerotic disease (100 AU/ml vs 71 AU/ml, P < 0.05). CMV seropositivity was independently associated with an elevated CRP. In addition, patients with the combination of a high CRP and CMV seropositivity showed the highest prevalence of atherosclerotic disease."

Betjes / Nephrol Dial Transplant 2007 full article

Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. MG Betjes, M Huisman, W Weimar, NH Litjens. Kidney Int 2008 Sep;74(6):760-767. "Here we found that this patient population has a significant age-dependent increase of CD4(+)CD28(-) T cells that comprise over half of the circulating CD4 T cells in some. Patients over 50 years of age have a 50-fold higher percentage of CD4(+)CD28(-) T cells compared to seronegative patients and a 5-fold higher percentage when compared to seropositive healthy controls. Stimulation by CMV-antigen or by polyclonal stimulation using PMA and ionomycin showed that CD4(+)CD28(-) cells in patients with end stage renal disease degranulated and secreted interferon gamma thus indicating that they are cytolytic. The average anti-CMV IgG titer displayed a remarkable age-dependent increase only in patients with end stage renal disease. These findings are highly suggestive of repetitive antigenic stimulation of the immune system in patients with end stage disease by subclinical CMV reactivation which might contribute to increased atherosclerotic risk."

Betjes - Kidney Int 2008 abstract / PubMed

Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection. FL Luan, LJ Stuckey, JM Park, D Kaul, D Cibrik, A Ojo. J Am Soc Nephrol 2009 Nov;20(11):2449-2458. 222 seronegative recipients of seropositive kidney and/or pancreas transplants. "Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained."

Luan - J Am Soc Nephrol 2009 full article / PubMed Central
Luan / J Am Soc Nephrol 2009 full article

Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. MG Betjes, EE de Wit, W Weimar, NH Litjens. Nephrol Dial Transplant 2010 Nov;25(11):3640-3646. Prospectively collected data from 240 cytomegalovirus-seropositive stable ESRD patients. "An ~2–3-fold increase in the prevalence of atherosclerotic disease was noted between patients with the highest and lowest number of CD4posCD28null cells. CD8posCD28null T-cell populations were also significantly expanded in cytomegalovirus-seropositive ESRD patients and closely correlated with the number of CD4posCD28null T cells. However, this cell population was not related to an increased prevalence of cardiovascular disease."

Betjes / Nephrol Dial Transplant 2010 full article

Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. M Shimamura, JE Murphy-Ullrich, WJ Britt. PLoS Pathog 2010 Nov 4;6(11):e1001170. "We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome."

Shimamura - PLoS Pathog 2010 full article / PubMed Central
Shimamura / PLoS Pathog 2010 full article

CD4+CD28null cells are expanded and exhibit a cytolytic profile in end-stage renal disease patients on peritoneal dialysis. AK Yadav, V Jha. Nephrol Dial Transplant 2011 May;26(5):1689-1694. 33 dialysis patients without CAD and 20 healthy subjects. "Compared to healthy controls, CD4(+)CD28(null) T cells were significantly expanded in PD patients (10.30 ± 2.03% versus 3.55 ± 0.67%, mean ± SE, P = 0.0007). Perforin and granzyme B expressions were restricted to CD4(+)CD28(null) T cells compared to CD4(+)CD28(+) T cells (<0.0001). A greater proportion of CD4(+)CD28(null) T cells in PD patients expressed these molecules (P = 0.007 and 0.04). hs-CRP level was increased in PD patients (P < 0.0001) but did not correlate with the CD4(+)CD28(null) T-cell frequency. Increasing age correlated with the CD4(+)CD28(null) cells."

Yadav / Nephrol Dial Transplant 2011 full article

Association of circulating fractalkine (CX3CL1) and CX3CR1(+)CD4(+) T cells with common carotid artery intima-media thickness in patients with chronic kidney disease. AK Yadav, A Lal, V Jha. J Atheroscler Thromb 2011;18(11):958-965. 128 patients and 62 healthy controls. "Compared to HC, CKD patients exhibited a 2.5-fold increase in the CD4(+)CX3CR1(+) T cell population (14.8±0.6 vs 5.9±0.34%, p < 0.0001). The expression of CX3CR1 was largely restricted to those CD4(+) cells that lacked CD28 co-stimulatory molecule. Fractalkine (pg/mL) and hsCRP (µg/mL) levels were increased in CKD subjects (510.6±61.6 vs. 239.7±9.67, p =0.003, and 93.8± 5.3 vs. 48.4±6.8, p < 0.0001), as was the CCA-IMT (0.71±0.01 vs. 0.56±0.01 mm, p < 0.0001). There was a significant relationship between CD4(+)CX3CR1(+) T cells and fractalkine levels (r = 0.2, p =0.01). CCA-IMT correlated positively with CX3CR1(+) T cells (r =0.34, p < 0.0001), CD4(+) CX3CR1(+) T cells (r =0.39, p < 0.0001), CD4(+)CD28(null)CX3CR1(+) T cells (r =0.23, p =0.02), fractalkine (r =0.3, p =0.001), age (r =0.33, p < 0.0001) and diabetes (p =0.01). On multiple regression, only CD4(+)CX3CR1(+) T cells and the presence of diabetes continued to show an association with IMT (p < 0.0001 and 0.0029 respectively)."

Yadav / J Atheroscler Thromb 2011 full article landing

Cytotoxic CD4CD28(null) T Lymphocytes, Systemic Inflammation and Atherosclerotic Risk in Patients with Chronic Kidney Disease. AK Yadav, A Lal, V Jha. Nephron Clin Pract 2012 Aug 16;120(4):c185-c193. 128 CKD and 62 control subjects. "The frequency of CD4(+)CD28(null) cells was significantly increased in CKD patients (10.14 ± 0.8 vs. 3.53 ± 0.36, p < 0.0001). The expression of perforin and granzyme B on CD4(+)CD28(null) cells was found to be significantly higher compared to CD4(+)CD28(+) cells (p < 0.0001). A larger proportion of CD4(+)CD28(null) cells obtained from CKD subjects showed the expression of perforin and granzyme B compared to those from healthy controls. CKD patients showed increased CCA-IMT (p < 0.0001). CD4(+)CD28(null) cells were positively correlated with the IMT (r = 0.505, p < 0.0001). CKD subjects showed increased levels of hsCRP, IL-6 and TNF-α. Only the TNF-α level showed a correlation with CD4(+)CD28(null) cells (r = 0.45, p < 0.0001). In vitro treatment with TNF-α but not IL-6 resulted in further downregulation of CD28 on the CD4(+) T cell surface."

Yadav - Nephron Clin Pract 2012 abstract / PubMed

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. EM Hodson, M Ladhani, AC Webster, GF Strippoli, JC Craig. Cochrane Database Syst Rev 2013 Feb 28;2:CD003774. 37 studies (4342 participants). "Prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment significantly reduced the risk for CMV disease (19 studies; RR 0.42, 95% CI 0.34 to 0.52), CMV infection (17 studies; RR 0.61, 95% CI 0.48 to 0.77), and all-cause mortality (17 studies; RR 0.63, 95% CI 0.43 to 0.92) primarily due to reduced mortality from CMV disease (7 studies; RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduced the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but not fungal infection, acute rejection or graft loss.Meta-regression showed no significant difference in the relative benefit of treatment (risk of CMV disease or all-cause mortality) by organ transplanted or CMV serostatus; no conclusions were possible for CMV negative recipients of negative organs... Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. These data suggest that antiviral prophylaxis should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants."

Hodson - Cochrane Database Syst Rev 2013 abstract / PubMed

Cytomegalovirus contributes partly to uremia-associated premature immunological ageing of the T-cell compartment. RW Meijers, NH Litjens, EA de Wit, AW Langerak, A van der Spek, CC Baan, W Weimar, MG Betjes. Clin Exp Immunol 2013 Dec;174(3):424-432. "End-stage renal disease (ESRD) patients have a severely immunologically aged T-cell compartment but also a high prevalence of CMV infection... It appeared that CMV infection did not affect thymic output but reduced RTL [relative telomere length] of CD8+ T cells in ESRD patients. Moreover, increased T-cell differentiation was observed with higher percentages of CD57+ and CD28null CD4+ and CD8+ memory T cells. These CD28null T cells had significantly shorter telomeres compared to CD28+ T cells."

Meijers - Clin Exp Immunol 2013 abstract / PubMed

Heat shock proteins 60 and 70 specific proinflammatory and cytotoxic response of CD4+CD28null cells in chronic kidney disease. AK Yadav, V Kumar, V Jha. Mediators Inflamm 2013;2013:384807. 25 patients and 8 healthy controls. "The basal mRNA expression of IFN-γ, perforin, and granzyme B in CD4(+)CD28(null) cells was higher in subjects with CKD compared to that in HC (P < 0.0001). Subjects with CKD also showed expression of IFN-γ, perforin, and granzyme B in the CD4(+)CD28(+) subset, but this was much weaker than that seen in the CD4(+)CD28(null) population (P < 0.0001). We did not note the expression of these molecules at mRNA or protein level in either subset of CD4 cells in HC. After incubation with HSP60 and HSP70, CD4(+)CD28(null) cells showed increased expression at mRNA (P < 0.001) and protein level (P < 0.001). CD4(+)CD28(+) cells also showed a weak increase in expression. No antigen-specific response was noted in HC."

Yadav - Mediators Inflamm 2013 full article / PubMed Central
Yadav / Mediators Inflamm 2013 full article

Cytomegalovirus & Epstein Barr Virus Serostatus as a predictor of the long term Outcome of Kidney Transplantation. AK Le Page, FE Mackie, SJ McTaggart, S Kennedy. Nephrology (Carlton) 2013 Dec;18(12):813-819. 2566 transplants in Australia. "Serostatus for both viruses was significantly associated with donor and recipient age and recipient smoking status. For both viruses the majority of transplants were in a D+/R+ serostatus setting: 45.3% for CMV and 77.9% for EBV. D/R serostatus for either virus did not have a significant effect on graft or patient survival. We conclude that in the current era of viral prophylaxis and surveillance, long term outcome for the kidney transplant population is unaffected by D/R CMV and EBV serostatus."

Le Page - Nephrology (Carlton) 2013 abstract / PubMed

Human Cytomegalovirus Inhibits Erythropoietin Production. LM Butler, M Dzabic, F Bakker, B Davoudi, H Jeffery, P Religa, K Bojakowski, KC Yaiw, A Rahbar, C Söderberg-Naucler. J Am Soc Nephrol 2014 Aug;25(8):1669-1678. "In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultraviolet-inactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxia-inducible transcription factor (HIF)-1α and HIF2α, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2α mRNA. HIF2α is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2α was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients."

Butler - J Am Soc Nephrol 2014 abstract / PubMed

Reduced Rate of Cardiovascular Death After Cytomegalovirus Prophylaxis in Renal Transplant Recipients. G Opelz, B Döhler. Transplantation 2015 Jun;99(6):1197-1202. 61,927 adult transplant patients, 1990-2012. "Cytomegalovirus prophylaxis was administered in 18%, 75%, 27% and 34% of R-/D- (recipient-negative, donor-negative), R-/D+, R+/D- and R+/D+ transplants, respectively. Only in R-/D+ transplants was CMV prophylaxis associated with significantly improved patient survival versus no prophylaxis (P<0.001). Unexpectedly, in the R-/D+ subgroup, [death with a functioning graft] because of infection was not significantly affected by use of CMV prophylaxis (P=0.16) but death from cardiovascular disease was significantly lower (P<0.001). Cox regression analysis confirmed that the primary impact of CMV prophylaxis on DWFG in R-/D+ transplants was because of reduced cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.51-0.85; P=0.002), an effect restricted to patients aged 40 years or older (hazard ratio, 0.61; 95% confidence interval, 0.46-0.81; P<0.001)."

Opelz & Döhler - Transplantation 2015 abstract / PubMed

Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors. SZ Sahin, H Akalin, A Ersoy, A Yildiz, G Ocakoglu, ED Cetinoglu, OS Dizdar, E Kazak, B Ener. Mycopathologia 2015 Aug;180(1-2):43-50. 32 patients (10.30 %) who developed fungal infection. "The independent risk factors associated with invasive fungal infection episodes were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90-64.73, p < 0.001), cytomegalovirus infection (OR 18.54, 95 % CI 9.01-38.17, p < 0.001), and the presence of diabetes mellitus (OR 6.01, 95 % CI 2.95-12.25, p < 0.001). Mortality was significantly higher among patients with fungal infections than among other patients (53.10 and 17.80 %, respectively; p < 0.001)."

Sahin - Mycopathologia 2015 abstract / PubMed

Effect of Cytomegalovirus Infection on Survival of Older Kidney Transplant Patients (D+/R+): Impact of Valganciclovir Prophylaxis Versus Preemptive Therapy. E Luna, F Caravaca, F Ferreira, N Fernandez, P Martķn, ML Vargas, J Saenz de Santamarķa, G Garcia Pino, L Azevedo, A Muńoz Sanz. Transplant Proc 2016 Nov;48(9):2931-2937. 233 patients. "The incidence of CMV infection in the P group was 32% versus 6% in V group. Patients with CMV viremia showed worse survival values than patients without viremia (log rank P = .031). Five-year survivals were 74% vs 88%, respectively. Cox regression showed that the adjusted effect of CMV infection on overall survival was a significant risk (hazard ratio [HR], 2.07; 95% CI, 1.003-4.29). Patients with CMV viremia showed worse cardiovascular survival than patients without viremia, with 5-year survivals of 79% vs 94%. Cox regression showed that the adjusted effect of CMV infection was a significant risk (HR, 2.62)."

Luna - Transplant Proc 2016 abstract / PubMed

Anti-smoking hate propaganda to deny transplants to smokers

Smokers are more likely to have been infected by both cytomegalovirus and polyomaviruses, for socioeconomic reasons. These infections most likely occurred during childhood, long before they began smoking. These viruses impair graft suvival and cause other complications. Nevertheless, the anti-smoking criminals ignore the role of infection in order to blame smoking. Bertram L. Kasiske and Dagmar Klinger, at the Hennepin County Medical Center in Minneapolis, Minnesota, have perpetrated a fraudulent study purporting to show that smoking negatively affects graft survival, and advocating that smokers should be denied kidney transplants on this grounds. Their study is a fraud because it is based on the anti-smokers' favorite deceit, namely multivariate analysis.

There is no such thing as determining "independent effects of smoking on outcomes" by statistical means. In fact, the paper by Phillips and Smith demonstrates that analyses such as these are merely devices for generating bogus "risk factors" as a result of confounding by infection.

The study by Kasiske and Klinger failed to even mention BKV as a cause of kidney transplant rejection. Furthermore, they jammed together kidney disease of every possible etiology, with differing outcomes, most of which have prevalence which varies by social class (which cannot be adjusted out), and in which infections are known or suspected causes. And, by examining outcomes besides kidney rejection, such as heart disease, they exploited every other kind of confounding by infection as well.

Their pretense that their motive is "to maximize the overall benefit" from transplants is transparently specious. Because they propose to deny transplants on the basis of group generalities instead of according to the prognosis of individual cases, they would actually reduce the overall benefit instead.

Morally, their proposal is as utterly putrid as anything devised in Nazi Germany, because what they really want is to harvest organs from smokers for use in non-smokers, while denying smokers this benefit.

Cigarette smoking in renal transplant recipients. B Kasiske, D Klinger. J Am Soc Nephrol 2000;11(4):753-759.

Kasiske - J Am Soc Nephrol 2000 abstract / PubMed
Kasiske / J Am Soc Nephrol 2000 full article

See Also:

CMV & other infections cause heart disease
CMV Impairs Immunity
CMV and Social Class
HPV is implicated in bladder cancer #Polyomaviruses


cast 12-20-16