Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Integrated tandem affinity protein purification using the polyhistidine plus extra 4 amino acids (HiP4) tag system.

Peptide tag systems are a robust biophysical and biochemical method that is widely used for protein detection and purification. Here, we developed a novel tag system termed "HiP4" (histidine plus four amino acids) whose epitope sequence comprises only seven amino acids (HHHDYDI) that partially overlap with the conventional 6x histidine tag (6xHis-tag). We produced a monoclonal antibody against the HiP4 tag that can be used in multiple immunoassays with high specificity and affinity. Using this system, we developed a tandem affinity purification (TAP) and mass spectrometry (TAP-MS) system for comprehensive protein interactome analysis. The integrated use of nickel bead purification followed by HiP4 tag immunoprecipitation made it possible to reduce nonspecific binding and improve selectivity, leading to the recovery of previously unrecognized proteins that interact with hepatitis B virus X (HBx) protein or TAR DNA-binding protein 43 (TARDBP or TDP-43). Our results indicate that this system may be viable as a simple and powerful tool for TAP-MS that can achieve low background and high selectivity in comprehensive protein-protein interaction analyses.

The role of latency reversal in HIV cure strategies.

One strategy to eliminate latently infected cells that persist in people with HIV on antiretroviral therapy is to activate virus transcription and virus production to induce virus or immune-mediated cell death. This is called latency reversal. Despite clear activity of multiple latency reversal agents in vitro, clinical trials of latency-reversing agents have not shown significant reduction in latently infected cells. We review new insights into the biology of HIV latency and discuss novel approaches to enhance the efficacy of latency reversal agents.

Autosomal dominant form of type IV collagen nephropathy exists among patients with hereditary nephritis difficult to diagnose clinicopathologically.

AIM: Type IV collagen nephropathies include Alport Syndrome and thin basement membrane nephropathy (TBMN), which are caused by mutations in COL4A3/A4/A5 genes. Recently, reports of patients with heterozygous mutations in COL4A3/A4 have been increasing. The clinical course of these patients has a wide variety, and they are diagnosed as TBMN, autosomal dominant Alport syndrome (ADAS), or familial focal segmental glomerular sclerosis. However, diagnosis, frequency and clinicopathological manifestation of them remains unclear. We tested COL4A3/A4/A5 genes in patients with hereditary nephritis that was difficult to diagnose clinicopathologically, and investigated who should undergo such testing. METHODS: We performed immunostaining for α5 chain of type IV collagen [α5 (IV)] in 27 patients from 21 families who fitted the following criteria: (i) haematuria and proteinuria (± renal dysfunction); (ii) family history of haematuria, proteinuria, and/or renal dysfunction (autosomal dominant inheritance); (iii) no specific glomerulonephritis; and (iv) thinning, splitting, or lamellation of the glomerular basement membrane (GBM) on electron microscopy. Then we performed genetic testing in 19 patients from 16 families who showed normal α5 (IV) patterns. We conducted a retrospective analysis of their clinicopathological findings. RESULTS: Among 16 families, 69% were detected heterozygous mutations in COL4A3/A4, suggesting the diagnosis of TBMN/ADAS. Twenty-one percent of patients developed end stage renal disease. All patients showed thinning of GBM, which was accompanied by splitting or lamellation in seven patients. CONCLUSION: A considerable fraction of patients with hereditary nephritis that is difficult to diagnose clinicopathologically have TBMN/ADAS. It is important to recognize TBMN/ADAS and perform genetic testing in appropriate patients.

The efficacy and safety of anti-interleukin-6 receptor monoclonal blockade in a renal transplant patient with Castleman disease: early post-transplant outcome.

BACKGROUND: Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disease characterized by systemic inflammatory reactions associated with the dysregulated production of interleukin-6 (IL-6). In patients with MCD, renal involvement is uncommon, with only one report published regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to MCD. Recent clinical observations have shown that IL-6 production is implicated in allograft rejection, while IL-6 receptor blockade (with tocilizumab [TCZ]) reduces alloantibody generation and thereby improves graft survival; however, the efficacy and safety of TCZ in MCD patients undergoing KTx is still unknown. CASE PRESENTATION: Herein, we describe the case of a 50-year-old man with MCD who received living-donor KTx for ESRD. Post-operative immunosuppression consisted of a triple-drug regimen (tacrolimus, mycophenolate mofetil and methylprednisolone) with TCZ that was administered intravenously every 2 weeks. At 17 months post-transplantation, the patient remains asymptomatic, and the allograft pathology has shown no evidence of rejection and no development of de novo donor-specific antibody (DSA). CONCLUSIONS: To our knowledge, this is the second reported case of an MCD patient with ESRD who underwent successful KTx. TCZ safely supported the patient during the perioperative period, and this drug may be useful for blocking the generation of donor-specific antibodies and reducing the risk of rejection episodes. KTx in combination with TCZ is thus considered a viable treatment option for ESRD due to MCD.

Kidney transplantation for a patient with refractory childhood-onset ANCA-associated vasculitis.

A 14-year-old Japanese girl was admitted to our institution for the evaluation of renal dysfunction. Her serum creatinine was 1.1 mg/dL, proteinuria was 1.5 g/day, the urine sediment contained numerous erythrocytes per high-power field, and she was positive for myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Proteinuria was first noted at the age of 12 years. Renal biopsy showed crescentic glomerulonephritis with slight immunoglobulin A (IgA) deposition. A diagnosis of ANCA-associated vasculitis was made. Immunosuppressive therapy was initiated, including steroid pulse therapy and intravenous cyclophosphamide pulse therapy, but hemodialysis was required after 6 years. Eight months after the patient became anuric and her MPO-ANCA titer became negative, living-related donor kidney transplantation was done from her mother. ANCA became slightly positive 2 years later, but the patient remains stable without proteinuria or hematuria at 4 years after surgery. This case suggests that kidney transplantation can be performed successfully for a patient with refractory childhood-onset ANCA-associated vasculitis, and that remission of vasculitis associated with ANCA negativity at transplantation may contribute to a better renal prognosis in this patient.

A case of immunoglobulin G4-related kidney disease manifesting after dipeptidyl peptidase-4 inhibitor treatment.

A 68-year-old man with type 2 diabetes mellitus was admitted with decreased renal function. He had high IgG4 (1070 mg/dL) and hypocomplementemia (CH50, 25 U/mL). Kidney biopsy showed tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. Four years later, a second kidney biopsy revealed a new manifestation of membranous nephropathy and tubulointerstitial nephritis with exacerbated fibrosis formation. Six years later, the patient developed bullous pemphigoid, which was thought to be caused by DPP4 inhibitors, so DPP4 inhibitor treatment was discontinued. The use of DPP4 inhibitors correlated with changes in renal function, and the patient was diagnosed with IgG4-related kidney disease related to DPP4 inhibitors.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9 years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7 months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1 h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

Cinacalcet upregulates calcium-sensing receptors of parathyroid glands in hemodialysis patients.

BACKGROUND: Cinacalcet hydrochloride (cinacalcet), a calcimimetic, has been shown to upregulate calcium-sensing receptor (CaSR) expression in parathyroid glands of rats with chronic renal insufficiency. However, the effect of cinacalcet on the reduced CaSR expression in human parathyroid glands remains to be elucidated. METHODS: Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism (SHPT) treated with (n = 10; cinacalcet group) or without (n = 8; conventional group) cinacalcet were examined immunohistochemically with a specific antibody against CaSR. The expression level of CaSR was analyzed semiquantitatively. RESULTS: Compared with normal glands, the immunohistochemical expression of CaSR was decreased significantly in both the cinacalcet and conventional groups. In the cinacalcet group, the expression of CaSR was increased significantly compared with that in the conventional group (1.83 ± 0.14 vs. 0.87 ± 0.15, p < 0.001), even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups. The expression of CaSR was significantly decreased in the larger glands (>500 mg) compared with that in the smaller glands (<500 mg) in both groups; furthermore, it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group. CONCLUSIONS: Our results indicate that cinacalcet upregulates the depressed expression of CaSR in hemodialysis patients with SHPT, and that insufficient expression of CaSR, especially in larger glands with advanced nodular hyperplasia, underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet.

Bone mineral density 5 years after parathyroidectomy in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Whether bone mineral density (BMD) is improved at 5 years after parathyroidectomy (PTx) for secondary hyperparathyroidism (SHPT) remains unknown. OBJECTIVE: To investigate BMD after PTx by dual energy X-ray absorptiometry (DXA). METHODS: BMD was measured at the distal 1/3 of the radius (non-shunt side) and at the lumbar supine (L2-L4, lateral view) before and 5 years after PTx in 35 hemodialysis patients who had undergone surgery from April 1994 to May 2004. The data were analyzed retrospectively. RESULTS: Intact PTH decreased significantly from 1,100 ± 530 (range: 446 - 2,300) pg/ ml before PTx to 75 ± 68 (2 - 251) pg/ml at 5 years after PTx (p < 0.01). Before PTx, the radial BMD and lumbar BMD were both decreased -3.3 ± 1.9 SD and -1.3 ± 2.4 SD compared with the corresponding normal mean T-score, respectively. Radial BMD increased significantly from 0.522 ± 0.113 g/cm2 before PTx to 0.545 ± 0.114 g/cm2 (p = 0.01) at 5 years after PTx, while the T-score improved to -2.8 ± 2.0 SD. In contrast, lumbar BMD showed no significant change between before (0.734 ± 0.202 g/cm2) and 5 years after PTx (0.746 ± 0.199 g/cm2), and neither did the T-score (-1.1 ± 2.3 SD). None of the patients suffered any fractures during follow up. CONCLUSION: These findings indicate that maintaining iPTH at < 300 pg/ml for 5 years after PTx results in an increase of radial BMD in SHPT patients with preoperative BMD levels in the osteoporosis range (below -2.5 SD) according to the WHO, as well as stabilizing lumbar BMD.

Acute renal intracystic hemorrhage in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Renal cyst bleeding is a frequent problem in patients with autosomal dominant polycystic kidney disease (ADPKD). However, information is still limited on its frequency, causative factors, and effects on enlargement of polycystic kidneys in ADPKD. METHODS: We investigated the total volume of acute renal intracystic hemorrhage and its association with total kidney volume (TKV) in a large series of patients with ADPKD on dialysis, referred for renal transcatheter arterial embolization. All patients had undergone CT scan and MRI scan before the procedure. We evaluated factors potentially associated with acute renal intracystic hemorrhage. The association between the  volume of acute renal intracystic hemorrhage and the potential predisposing and associated factors was analysed by univariable and multivariable regressions.  RESULTS: We enrolled 199 patients who underwent renal transcatheter arterial embolization from 2014 to 2018 (107 men, 92 women; mean age 59.1 ± 8.6 years). The median volume of acute renal intracystic hemorrhage was 97.3 ml (interquartile range 36.6-261.7 ml). Multivariable analysis revealed that body weight, kidney stones, systolic blood pressure, and total volume of acute renal intracystic hemorrhage were significantly associated with TKV; age, body mass index, smoking, renal cyst infection, serum alkaline phosphatase, and TKV were significantly associated with the volume of acute renal intracystic hemorrhage ; and sex, age, dialysis vintage, TKV, and total volume of acute renal intracystic hemorrhage were significantly associated with the number of microcoils required to achieve renal  transcatheter arterial embolization. Total volume of acute renal intracystic hemorrhage was significantly associated with TKV (r = 0.15, p = 0.0325) and was greater in younger patients (r= - 0.32, p < 0.0001). Total volume of acute renal intracystic hemorrhage was also correlated with the number of microcoils required for renal transcatheter arterial embolization (r = 0.23, p = 0.0012). CONCLUSION: Acute renal intracystic hemorrhage is frequent among ADPKD patients on dialysis, and total volume of acute renal intracystic hemorrhage significantly associated with  TKV. Total volume of acute renal intracystic hemorrhage  was greater in younger patients with higher renal artery luminal size. These results suggest that renal cyst bleeding and renal artery blood flow may synergistically accelerate the enlargement of polycystic kidneys in ADPKD patients on dialysis.

Changes in Kidney and Liver Volumes in Patients With Autosomal Dominant Polycystic Kidney Disease Before and After Dialysis Initiation.

Objective: To examine the changes in total kidney volume (TKV) and total liver volume (TLV) before and after dialysis initiation in patients with autosomal dominant polycystic kidney disease. Patients and Methods: This was a retrospective, single-center cohort study to investigate the changes in TKV and TLV before and after dialysis initiation, along with influencing factors, using linear mixed models. We enrolled 95 patients with autosomal dominant polycystic kidney disease (85 receiving hemodialysis [HD] and 10 receiving peritoneal dialysis [PD]) who began receiving dialysis at Toranomon Hospital from January 1, 2008, to December 31, 2020. Results: The least squares mean TKV ratio (TKV at each time point/TKV at dialysis initiation) was 63.8% (95% confidence interval [CI], 54.7%-72.9%) at 6 years before dialysis initiation and 95.5% (95% CI, 82.9%-108.2%) at 6 years after dialysis initiation (P<.001). A multivariate linear mixed model analysis revealed that dialysis style (HD or PD) had the strongest effect on changes in TKV (P=.002). The least squares mean TLV ratio was 98.2% (95% CI, 88.4%-108.0%) at 6 years before dialysis initiation and 95.7% (95% CI, 85.2%-106.2%) at 6 years after dialysis initiation (P=.01). Although PD did not have significant effects on changes in TLV (P=.27), the changes in TLV were greater in patients on PD than in those on HD. Conclusion: The TKV increased until dialysis initiation and generally decreased after dialysis initiation. The TLV continued to increase even after dialysis initiation, however, changes in the TLV significantly decreased after dialysis initiation. The increases in TKV and TLV were greater in patients on PD than in those on HD.

Crescentic Glomerulonephritis with Fibrinoid Vasculitis after Administration of Influenza Vaccine.

A 66-year-old man was admitted to our hospital because of a low-grade fever and arthralgia. The symptoms started on the third day after influenza vaccine administration and persisted for two months. Serum creatinine was 1.0 mg/dL; C-reactive protein, 16.1 mg/dL; and myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA), 4,170 IU/mL. A kidney biopsy showed crescentic glomerulonephritis with fibrinoid necrosis of small arteries. Microscopic polyangiitis was diagnosed. After five months of steroid pulse therapy and rituximab administration, the patient entered remission. There have been very few reports of this condition after influenza vaccine administration.

Apolipoprotein E-associated Lipoprotein Glomerulo-tubulopathy.

A 32-year-old man was admitted for the evaluation of proteinuria (5.69 g/day). A light microscopic examination showed markedly dilated glomerular capillary loops with vacuolated areas in many glomeruli, and vacuolated areas were seen on peritubular capillaries in the tubulointerstitium. When electron microscopy specimens prepared by pre-fixation with glutaraldehyde and post-fixation with osmium tetroxide were used for oil red staining, the deposition was confirmed on the affected areas. A genetic analysis of apoE showed that the lipoprotein glomerulopathy was due to apoE-Sendai (Arg145Pro, p.R163P) heterozygosity, which was found in not only the patient but also his mother and twin brother.

Can Takayasu Arteritis Cause Hydronephrosis?

A 74-year-old woman was admitted because of malaise and a low-grade fever. Her C-reactive protein level was 0.96 mg/dL. Computed tomography (CT) revealed diffuse uniform thickening of the arterial wall from the abdominal aorta to the common iliac artery and right hydronephrosis. 18F-fluordesoxyglucose positron emission tomography-CT showed an accumulation in the same area. These findings suggested Takayasu arteritis and retroperitoneal fibrosis as differential diagnoses. Takayasu arteritis is characterized by thickening of the arterial walls, and retroperitoneal fibrosis is characterized by membranous lesions covering the outer surface of the arterial walls. Thus, Takayasu arteritis was deemed the most likely diagnosis. Steroid treatment was effective.

An Inspiring Journey of Hope and Persistence: Life Lessons with Françoise Barré-Sinoussi.

Three early-career female virologists sat down with a distinguished Nobel laureate to discuss two pandemics, 39 years apart [...].

Favorable Short-Term Outcome of Living Donor Kidney Transplantations in Flow Cytometry Crossmatch Positive Cases by Pretransplant Splenectomy: A Case Report.

BACKGROUND: The introduction of rituximab has contributed to successful living donor kidney transplantations in ABO-incompatible recipients and has replaced splenectomy for desensitization. However, several reports still suggest that postoperative splenectomy may be effective in preventing graft failure in patients with acute antibody-mediated kidney transplant rejection (AAMR) in kidney transplantation. Therefore, we aim to assess if preoperative splenectomy also could be an alternative practical choice to avoid AAMR in high-risk rejection cases such as flow cytometry crossmatch (FCXM)-positive cases. MATERIAL AND METHOD: We carried out 4 living donor kidney transplantations in FCXM-positive cases: 3 underwent pretransplant splenectomy, and 1 did not. RESULTS: All 3 cases in whom pretransplant splenectomy was performed were discharged without rejection. On the contrary, in the case where pretransplant splenectomy was not performed, there was graft rejection and additional desensitization therapies were needed. CONCLUSION: While larger clinical studies with longer observation periods are needed, our report suggested that pretransplant splenectomy may lead to successful short-term kidney transplantation outcomes in FCXM-positive cases.

Primary Central Nervous System Post-transplant Lymphoproliferative Disorder Diagnosed by Peripheral Facial Nerve Palsy.

Although primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) causes various symptoms depending on the tumor region, there has been no previous report of PCNS-PTLD in the cerebellopontine angle that was diagnosed due to peripheral facial nerve palsy. We herein report a case involving a 62-year-old man with PCNS-PTLD in the cerebellopontine angle who was diagnosed due to peripheral facial nerve palsy. The reduction of immunosuppressive therapy, whole-brain radiotherapy, intrathecal chemotherapy, and rituximab were effective in treating this patient. Physicians should therefore be mindful that PCNS-PTLD can cause peripheral facial nerve palsy in renal transplant recipients.

Hyperparathyroidism caused by distant pulmonary lesions and parathyromatosis after ethanol injection/parathyroidectomy for secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) treatment includes parathyroidectomy and percutaneous ethanol injection therapy (PEIT), which are invasive procedures. The condition in which benign hyperfunctioning parathyroid tissue is distributed throughout the neck and mediastinum is termed parathyromatosis. Here, we present the case of a 51-year-old woman who began hemodialysis in 1986 due to chronic kidney disease of unknown etiology and developed SHPT in 1999. She underwent 6 rounds of PEIT followed by total a parathyroidectomy with partial forearm autotransplantation. Between 2011 and 2013, surgeons removed several nodules from her pulmonary and cervical regions and the transplanted masses from her forearm; all showed hyperplasia but exhibited no histological evidence of malignancy. Damage to the parathyroid capsule after repeated PEITs may cause local cervical recurrence and pulmonary lesions, although distant lesions are extremely rare in SHPT. This case is of interest due to the possible association between PEIT and parathyromatosis and distal lesions.

Clinicopathological analysis of persistent hypercalcemia and hyperparathyroidism after kidney transplantation in long-term dialysis patients.

Deceased donor kidney transplantation in long-term dialysis patients in Japan has been increasing because of a severe lack of donors. Parathyroid glands of long-term dialysis patients often show qualitative morphological changes from diffuse to nodular hyperplasia. Only a few studies have reported the clinicopathological analysis of persistent hyperparathyroidism after kidney transplantation in long-term (>10 years) dialysis patients. This study on consecutive deceased donor kidney transplantation performed from 2002 to 2010 measured biochemical parameters related to bone and mineral disorders and examined parathyroid tissues in parathyroidectomy cases. Thirty-four subjects (22 males; mean age, 53.8 ± 7.9 years; mean dialysis period, 14.4 ± 4.3 years) were enrolled. Multivariate analysis of potential predictors for the hypercalcemia group at 12 months after transplantation showed that pre-transplantation and early post-transplantation calcium and parathyroid hormone levels were significant determinants. Pathological examination showed that a number of glands showed nodular hyperplasia, even in small glands weighing < 100 mg. In long-term dialysis patients, hyperparathyroidism and hypercalcemia developed at an early stage after transplantation and persisted for a long period (>4 years), with nodular hyperplasia being found even in low-weight parathyroid glands. Pre-transplant high calcium and parathyroid hormone levels were the predictors for the prolonged hypercalcemia. Persistent hyperparathyroidism was considered to be caused by remaining nodular hyperplasia, even if the glands were small. Although the best treatment option is to perform a parathyroidectomy in the waiting period before transplantation, we suggest that it be performed in cases with prolonged hypercalcemia of >6 months after transplantation.