Assessment of Tumor Markers in Renal Transplant Recipients.

Background/Aim: Malignant tumors are diagnosed using various methods, including diagnostic imaging methods. The measurement of tumor markers is commonly used because of its noninvasiveness and convenience. Furthermore, it is known that the excretion and metabolism of some tumor markers are affected by impaired renal function. In the present study, we investigated the effect of improved renal function on pre-and post-transplantation changes in tumor marker levels [carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and prostate-specific antigen (PSA)] in renal transplant recipients. Patients and Methods: A total of 116 renal transplant recipients, who had not been diagnosed with malignancies between January 2012 and December 2019, were included, and tumor markers were investigated. Results: CEA showed a significant decrease after kidney transplantation, regardless of the dialysis type (3.6→2.6 ng/ml, p<0.001), while other tumor markers showed a significant increase (AFP: 3.6→3.7 ng/ml; CA19-9: 16.2→19.5 U/ml; PSA: 0.95→1.05 ng/ml; all p<0.05). Pre- and postoperative eGFR ratios and postoperative liver function were identified as factors influencing the postoperative CEA and CA19-9 values, while PSA was influenced by the duration of dialysis. No statistically significant factors were found for AFP levels. Conclusion: Caution should be exercised when investigating tumor markers in patients with renal dysfunction, as tumor marker levels may vary depending on the pathophysiology of each patient.

Excess 25-hydroxyvitamin D3 exacerbates tubulointerstitial injury in mice by modulating macrophage phenotype.

Vitamin D hydroxylated at carbon 25 (25(OH)D) is generally recognized as a precursor of active vitamin D. Despite its low affinity for the vitamin D receptor (VDR), both deficient and excessive 25(OH)D levels are associated with poor clinical outcomes. Here we studied direct effects of 25(OH)D3 on the kidney using 25(OH)D-1α-hydroxylase (CYP27B1) knockout mice. The effects of 25(OH)D3 on unilateral ureteral obstruction were analyzed as proximal tubular cells and macrophages are two major cell types that take up 25(OH)D and contribute to the pathogenesis of kidney injury. Excess 25(OH)D3 in obstructed mice worsened oxidative stress and tubulointerstitial fibrosis, whereas moderate levels of 25(OH)D3 had no effects. The exacerbating effects of excess 25(OH)D3 were abolished in CYP27B1/VDR double-knockout mice and in macrophage-depleted CYP27B1 knockout mice. Excess 25(OH)D3 upregulated both M1 marker (TNF-α) and M2 marker (TGF-ß1) levels of kidney-infiltrating macrophages. In vitro analyses verified that excess 25(OH)D3 directly upregulated TNF-α and TGF-ß1 in cultured macrophages but not in tubular cells. TNF-α and 25(OH)D3 cooperatively induced oxidative stress by upregulating iNOS in tubular cells. Aggravated tubulointerstitial fibrosis in mice with excess 25(OH)D3 indicated that macrophage-derived TGF-ß1 also had a key role in the pathogenesis of surplus 25(OH)D3. Thus, excess 25(OH)D3 worsens tubulointerstitial injury by modulating macrophage phenotype.

[Merkel cell carcinoma of the ear lobe complicated with nephrosis syndrome and malignant lymphoma: a case report].

Here we report a rare case of Merkel cell carcinoma complicated with nephrosis and malignant lymphoma. A 79-year-old male, who had undergone rectectomy due to colorectal cancer about 10 years previously, was diagnosed as Merkel cell carcinoma of the left ear lobe with lymph node metastases. Tumor resection and lymph node dissection were performed. A year later, follow-up PET-CT revealed a small hot spot at the ileocecum without apparent tumor formation based on examination by colonoscopy. The patient received 56 Gy of radiation. Two months later, he developed new-onset nephrosis followed by renal failure, and was referred to our hospital (Cr 4.26 mg/dL, UA 13.5 mg/dL, Alb 2.1 g/dL). Further examination negated the possibility of vasculitis, collagen disease, or myeloma kidney. Since his renal function continued to decline, causing uremic symptoms, he was hospitalized and underwent hemodialysis soon after referral. Abdominal CT scan revealed an ileocecal mass with multiple abdominal lymphadenopathy, which was later diagnosed as diffuse large B-cell lymphoma (stage IV) by tumor biopsy. Corticosteroid therapy (prednisolone 60 mg/day) was soon initiated with no response. Local skin redness and blister formation at the left shoulder emerged gradually, which strongly suggested a local recurrence of Merkel cell carcinoma. Despite the use of rituximab, the patient's general condition deteriorated without any sign of recovery. Three months after the start of dialysis, we discontinued dialysis therapy due to his poor health status, and eventually he died of cachexia. Autopsy revealed triple cancers: rectal cancer, Merkel cell carcinoma, and malignant lymphoma. In addition to the case report, we will summarize and discuss former similar case reports in the literature.

Lenalidomide and Dexamethasone for a Patient of POEMS Syndrome Presenting with Massive Ascites.

POEMS syndrome is a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. POEMS syndrome is a rare cause of refractory ascites. We report the case of a patient with POEMS syndrome presenting with massive ascites who was treated with very-low-dose lenalidomide and dexamethasone. A 57-year-old Japanese man was admitted to our hospital with pleural effusion, massive ascites, and leg edema. The diagnosis of POEMS syndrome was made based on the combination of the following findings: peripheral neuropathy, organomegaly, endocrinopathy, serum monoclonal protein elevation, skin changes, plasma VEGF elevation, and evidence of extravascular volume overload. Renal dysfunction induced by biopsy-proven renal involvement of POEMS syndrome was observed. Massive ascites of the patient dramatically diminished with long-time treatment of very-low-dose lenalidomide and dexamethasone. Lenalidomide seems to be a very promising therapy for POEMS syndrome presenting with extravascular volume overload such as edema, pleural effusion, and ascites. Very-low-dose lenalidomide might be effective especially for the patients with POEMS-related nephropathy.

Human herpesvirus 6 open reading frame U14 protein and cellular p53 interact with each other and are contained in the virion.

A mass spectroscopic analysis of proteins from human herpesvirus 6 (HHV-6)-infected cells showed that the HHV-6 U14 protein coimmunoprecipitated with the tumor suppressor p53. The binding of U14 to p53 was verified by coimmunoprecipitation experiments in both Molt-3 cells infected with HHV-6 and 293 cells cotransfected with U14 and p53 expression vectors. Indirect immunofluorescence assays (IFAs) showed that by 18 h postinfection (hpi) U14 localized to the dot-like structures observed in both the nucleus and cytoplasm where p53 was partly accumulated. Despite Northern blotting evidence that U14 follows late kinetics, the U14 protein was detected immediately after infection (at 3 hpi) by IFA. In addition, by Western blotting, U14 was detected at 0 hpi or in the presence of cycloheximide which completely abolished the expression of IE1 protein. In addition to U14, p53 was detected at 0 hpi although it was not detected in mock-infected cells. Furthermore, both U14 and p53 were clearly detected in the viral particles by Western blotting and immunoelectron microscopy, supporting the idea that U14 and p53 are incorporated into virions. Our study provides the first evidence of the incorporation of cellular p53 into viral particles and suggests that p53 may play an important role in viral infection.

Intracellular processing of human herpesvirus 6 glycoproteins Q1 and Q2 into tetrameric complexes expressed on the viral envelope.

Human herpesvirus 6 (HHV-6) glycoproteins H and L (gH and gL, respectively) and the 80-kDa form of glycoprotein Q (gQ-80K) form a heterotrimeric complex that is found on the viral envelope and that is a viral ligand for human CD46. Besides gQ-80K, the gQ gene encodes an additional product whose mature molecular mass is 37 kDa (gQ-37K) and which is derived from a different transcript. Therefore, we designated gQ-80K as gQ1 and gQ-37K as gQ2. We show here that gQ2 also interacts with the gH-gL-gQ1 complex in HHV-6-infected cells and in virions. To examine how these components interact in HHV-6-infected cells, we performed pulse-chase studies. The results demonstrated that gQ2-34K, which is endo-beta-N-acetylglucosaminidase H sensitive and which is the precursor form of gQ2-37K, associates with gQ1-74K, which is the precursor form of gQ1-80K, within 30 min of the pulse period. After a 1-h chase, these precursor forms had associated with the gH-gL dimer. Interestingly, an anti-gH monoclonal antibody coimmunoprecipitated mainly gQ1-80K and gQ2-37K, with little gQ1-74K or gQ2-34K. These results indicate that although gQ2-34K and gQ1-74K interact in the endoplasmic reticulum, the gH-gL-gQ1-80K-gQ2-37K heterotetrameric complex arises in the post-endoplasmic reticulum compartment. The mature complex is subsequently incorporated into viral particles.

Discovery of a second form of tripartite complex containing gH-gL of human herpesvirus 6 and observations on CD46.

The human herpesvirus 6 (HHV-6) glycoprotein H (gH)-glycoprotein L (gL) complex associates with glycoprotein Q (gQ) (Y. Mori, P. Akkapaiboon, X. Yang, and K. Yamanishi, J. Virol. 77:2452-2458, 2003), and the gH-gL-gQ complex interacts with human CD46 (Y. Mori, X. Yang, P. Akkapaiboon, T. Okuno, and K. Yamanishi, J. Virol. 77:4992-4999, 2003). Here, we show that the HHV-6 U47 gene, which is a positional homolog of the human cytomegalovirus glycoprotein O (gO) gene, encodes a third component of the HHV-6 gH-gL-containing envelope complex. A monoclonal antibody (MAb) against the amino terminus of HHV-6 gO reacted in immunoblots with protein species migrating at 120 to 130 kDa and 74 to 80 kDa in lysates of HHV-6-infected cells and with a 74- to 80-kDa protein species in purified virions. The 80-kDa form of gO was coimmunoprecipitated with an anti-gH MAb, but an anti-gQ MAb, which coimmunoprecipitated gH, did not coprecipitate gO. Furthermore, the gH-gL-gO complex did not bind to human CD46, indicating that the complex was not a ligand for CD46. These findings suggested that the viral envelope contains at least two kinds of tripartite complexes, gH-gL-gQ and gH-gL-gO, and that the gH-gL-gO complex may play a role different from that of gH-gL-gQ during viral infection. This is the first report of two kinds of gH-gL complexes on the viral envelope in a member of the herpesvirus family.