The impact on graft survival of interstitial inflammation in borderline change of allograft kidneys.

AIM: In kidney transplantation cases, borderline change (BL) can lead to a progressive course. However, factors related to outcome and the progress of BL are not well defined. In this study, we focused specifically on interstitial inflammation as a factor influencing outcome after diagnosis of BL. METHODS: We followed 252 recipients who underwent renal transplantation between 1998 to 2012 at our hospital. Of those, we retrospectively studied 40 diagnosed with BL from allograft biopsy findings, and then classified them as BL1 and BL2 according to the level of interstitial inflammation (i) (BL1: i < 10%, BL2: i ≥ 10%). RESULTS: There were 21 BL1 and 19 BL2 cases, of whom 7 developed rejection during the follow-up period. There were no significant differences for graft survival rate and the rate leading to acute rejection between the 2 groups (P = 0.44, P = 0.69). Univariate analysis showed that the grade of interstitial inflammation was not a significant risk factor for developing acute rejection (P = 0.816). CONCLUSION: Our results show that the level of interstitial inflammation does not have an effect on a progressive BL course.

A Case of Acute Kidney Injury Caused by Myoglobin Cast Nephropathy With Sars-Cov-2 Infection in a Living-Donor Kidney Transplant Recipient.

When COVID-19 affects patients with risk factors such as chronic kidney disease or on immunosuppressive drugs, they often rapidly become seriously ill. We describe a 50-year-old man who was affected with SARS-CoV-2 and had undergone an ABO-compatible living-donor kidney transplantation from his father 14 years ago because of end-stage renal failure due to hypertensive nephrosclerosis. He had continued on immunosuppressive drugs and completed vaccination twice (9 months ago and 6 months ago) with messenger RNA (mRNA) vaccines against SARS-CoV-2. However, he was temporarily on a mechanical ventilator due to respiratory failure and hemodialysis due to acute kidney injury (AKI). He was finally weaned from the ventilator and hemodialysis by taking steroid and antiviral drugs. Echo-guided renal biopsy revealed myoglobin cast nephropathy. We experienced 14 outpatients after living-donor kidney transplantation infected with SARS-CoV-2, but only this case developed AKI.

Immunohistochemical features of BK virus nephropathy in renal transplant recipients.

BK virus nephropathy (BKVN) is one of the factors that reduces renal graft function after transplantation. However, BKVN and rejection present similar pathological findings, as both are accompanied by cellular infiltration to the interstitium and tubulitis, thus they are difficult to distinguish for diagnosis and medical treatment. In the present study, we examined immunohistochemical pathological features of BKVN in four cases treated in our hospital from 2007 to 2010. Common immunohistological finding is that tubulitis in these cases was primarily EMA and 34ßE12-positive and existed predominantly from the collecting duct to the distal convoluted tubule. The majority of infected cells existed in EMA and 34ßE12-positive tubules, which were also located mainly from the collecting duct to the distal tubule. In addition, a large number of SV40-positive infected cells were similarly seen. Dylon staining clearly revealed eosinophils. We concluded that the main pathological features of BKVN are the presence of tubulitis and infected cells predominantly from the collecting duct to distal tubule and the appearance of eosinophils.

Recurrence of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Deposits with a Striated Ultrastructure.

A 64-year-old man with nephrotic syndrome was admitted to another hospital where his renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) with monoclonal immunoglobulin (Ig) G, subclass 1, κ light chain (IgG1κ) deposition on immunofluorescence (IF). Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) was suspected due to monoclonal IgG1κ deposits and the absence of hematological abnormalities. However, the typical PGNMID phenotype was not observed by electron microscopy. Instead, an organized and striated muscle-like structure was observed in the subendothelial space. Since a 2-year treatment with immunosuppressants did not improve his proteinuria, a second biopsy was performed at our hospital. It showed an MPGN-like phenotype; however, monoclonal Ig deposits on IF were no longer observed. One year after the second biopsy, he developed ESRD. Thus, he underwent living kidney transplantation from his wife. Allograft biopsy was performed as proteinuria was observed 3 months after transplantation, which again showed an MPGN-like phenotype with monoclonal IgG1κ deposits. The observed electron-dense deposits were similar to those in the native biopsies. Accordingly, the patient was diagnosed with recurrent MPGN. Adding methylprednisolone pulse therapy to conventional immunosuppressants did not improve the patient's renal function or proteinuria. He died of Legionella pneumonia 8 months after transplantation. Considering the patient's histological findings of MPGN with monoclonal IgG1κ deposits and early recurrence of glomerulonephritis after transplantation, he was diagnosed with PGNMID with novel electron-dense deposits.

Single-Needle Intensive Granulocyte and Monocyte Adsorptive Apheresis Is Suitable for Elderly Patients With Active Ulcerative Colitis Taking no Corticosteroids or Biologics.

Twice-weekly intensive granulocyte/monocyte adsorptive apheresis is effective and safe for ulcerative colitis, but maintaining two blood access routes is problematic. We previously reported that intensive granulocyte/monocyte adsorptive apheresis using a single needle in ulcerative colitis is effective and safe. We hypothesized that the efficacy and safety of single-needle intensive granulocyte/monocyte adsorptive apheresis for ulcerative colitis would especially benefit the elderly. We enrolled 17 elderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis, 27 elderly ulcerative colitis patients to receive double-needle intensive granulocyte/monocyte adsorptive apheresis, and 52 nonelderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis. Remission and mucosal healing rates after treatment did not differ significantly between elderly ulcerative colitis patients receiving single-needle apheresis and the other two groups. In addition, no serious adverse effects, including blood clots, were observed in single-needle intensive granulocyte/monocyte adsorptive apheresis patients. Single-needle intensive granulocyte/monocyte adsorptive apheresis might be a novel alternative therapeutic option for elderly ulcerative colitis patients before considering corticosteroids.

[A case report of BK virus nephropathy after an ABO-incompatible living kidney transplantation].

We present a case of 29-year-old female who underwent an ABO-incompatible living kidney transplantation from her father. The serum creatinine (s-Cr) level of this patient was stabilized about 1.1-1.2 mg/dl during the first 3 months after the transplantation. Thereafter, the function of allograft was deteriorated gradually. A biopsy performed on post-transplant day (PTD) 520 to evaluate a rise in creatinine revealed an interstitial nephritis and chronic renal allograft nephropathy. The renal function worsened persistently, although we increased the dosage of immunosuppressant subsequently. The following biopsy performed on PTD 630 showed a suspicion of BK virus nephropathy, with a mass of tubular epithelial nuclear inclusions and an interstitial nephritis. The diagnosis of BK virus nephropathy was confirmed on the immunohistochemistry staining using anti-SV40 antibody and PCR analysis. Despite reducing the immunosuppressants, the function of the allograft worsened progressively and was lost on PTD 912.

Renal transplantations from parents to siblings with autosomal recessive Alport syndrome caused by a rearrangement in an intronic antisense Alu element in the COL4A3 gene led to different outcomes.

Two siblings with autosomal recessive Alport syndrome (ARAS) obtained renal transplants from their consanguineous parents. Their COL4A3 mRNA transcripts were disrupted by a 139 bp intronic sequence between exon 48 and 49, which was derived from an antisense Alu element in this intron. The new amino acid sequence from the cryptic exon was terminated by a stop codon at the 1511th codon, resulting in the loss of 76 % α3(IV)NC1. This is the first case report of kidney transplantations between ARAS-homozygous siblings and their heterozygous parents. The brother experienced acute rejection just after transplantation and post-transplantation anti-glomerular basement membrane (GBM) nephritis, whereas the sister has experienced no problems to date. The anti-GBM nephritis could have resulted from the acute rejection. The COL4A3 gene heterozygous mutated parents, who are possibly at risk for thin basement membrane disease, have maintained their renal functions without urinary abnormalities after renal transplantation to date.

Association of treatment with 15-deoxyspergualin and BK virus nephropathy in kidney allograft recipients.

OBJECTIVE: BK virus nephropathy (BKVN) has been proposed as an important cause of allograft dysfunction and loss in kidney allograft recipient over the last decade. Intense immunosuppression and tubular injury have been shown to promote the replication of polyomavirus. 15-deoxyspergualin (DSG), an effective immunosuppressive agent, is used as a rescue drug for acute rejection in clinical renal transplantation in Japan. To determine whether DSG is a risk factor for BKVN and outline the relationship among BKVN, DSG, and other risk factors, we analyzed 88 patients who received living-related renal transplantation between January 1999 and April 2003. METHODS: A total of 114 biopsy specimens from 88 living-related kidney transplantation recipients (performed between January 1999 to April 2003) were retrospectively analyzed. Patients received immunosuppression therapy based on calcineurin inhibitors and corticosteroid [tacrolimus (TAC) 33 and cyclosporin (CyA) 55]. Additionally, mycophenolate mofeteil (MMF) was used in 21 patients; DSG was used in seven patients; and anti-CD3 monoclonal antibody was used in 16 patients. We analyzed the degree of donor/recipient human leucocyte antigen (HLA) compatibility assessed by the number of HLA-A, -B, and -DR-mismatched antigens in 88 patients. The diagnosis of BKVN was made by the light microscopic examination and a positive immunohistochemical staining of anti-40 antibody in biopsy specimens. Patients were divided into two groups of group A (mild histological change) and group B (moderate or severe histological change) to determine the risk factors in different histological staging. The clinical course of two typical patients in different histological stage is described briefly to outline the risk factors of BKVN. RESULTS: We identified seven cases of BKVN (8.0%) from 88 transplanted patients. Significantly higher incidence of combination regimen consisting of TAC and MMF in BKVN group was noticed compared with non-BKVN group (57.1% vs. 9.9%; p = 0.003). BKVN was associated with a significantly higher incidence of DSG administration compared with non-BKVN group (57.1% vs. 3.7%; p

Incidence of positive C4d deposition in long-term survival cases over 10 yr after renal transplantation.

BACKGROUND: The incidence of positive C4d deposition in peritubular capillaries (PTC) in long-term survival cases remains controversial. Some incidences of positive C4d deposition in PTC in cases of long-term survival less than 10 yr have been reported. We retrospectively examined the incidence of positive C4d deposition in long-term survival cases over 10 yr after renal transplantation and the histological and clinical characteristics of the positive C4d staining cases. METHODS: We examined 14 protocol biopsy cases performed at Osaka University Hospital between March 2004 and March 2005. The average interval between the operation and the day of biopsy was 15.4 yr. Histological diagnosis was made in accordance with the Banff 97 classification. Paraffin-embedded tissue was stained with polyclonal anti-C4d antibody. Detection of donor-specific antibody (DSA) was determined by flow cytometric assay. The cases were divided according to C4d positivity. RESULTS: Three of 14 cases (21.4%) were C4d positive and belonged to the C4d+/DSA+ group, while 11 cases were of the C4d-/DSA- group. There were no significant differences between the two groups in serum creatinine (sCr) or proteinuria at the time of biopsy. A trend towards decreasing rate of the inverse of sCr (1/sCr) in the C4d+/DSA+ group was noted. In the C4d+/DSA+ group, three transplant glomerulopathy (TGP) were identified. On the other hand, TGP were identified in six of 11 cases of the C4d-/DSA- group. We investigated the relevance of typical chronic rejection (CR) features and the positivity of C4d. No significant differences were observed between the CR features and C4d depositions in PTC (p = 0.26). CONCLUSION: In long-term survival cases with positive C4d, a trend towards decreasing rate of 1/sCr was revealed, but their histological characteristic features was not recognized.

Prevalence, characteristics, and outcome of BK virus nephropathy in Japanese renal transplant patients: analysis in protocol and episode biopsies.

BACKGROUND: BK virus nephropathy (BKN) is recognized as a cause of graft loss in renal transplant patients. This may be related to the introduction of new and potent immunosuppressive regimens. In Japan, our experience regarding its prevalence, clinical significance, and outcome is still limited. In this study, our primary purpose is to outline the prevalence, outcome, and clinical characteristics of BKN as observed at Osaka University Hospital. METHODS: We retrospectively analyzed 112 biopsy specimens from 87 renal transplant patients. All transplantations were from living donors. Of the 112 biopsy specimens, 71 were from protocol biopsies and 41 were from episode biopsies. Calcineurin inhibitors and corticosteroid were used in all patients (tacrolimus 32 and cyclosporin 55). In addition, azathioprine was used in 43 patients, mizoribine was used in 24 patients, and mycophenolate mofetil was used in 20 patients. BKN was diagnosed by light microscopic examination and a positive immunohistochemical staining of anti-SV40 antibody in a biopsy specimen. In order to investigate the outcome and potential risk factors of patients with different histological staging, we divided the patients into groups A (mild histological change) and B (moderate or severe histological change). RESULTS: Of the 87 patients, six were diagnosed with BKN. There were no significant differences between BKN patients and non-BKN patients, except for the number of patients with graft loss (p < 0.001). Of the six BKN patients, three were in group A, and three were in group B. We recognized a significant difference between group A and group B in terms of anti-rejection treatment including glucocorticoid, tacrolimus trough levels of over 8 ng/mL, episode of acute rejection within 1-month post-transplantation, and the time period between transplantation and BKN diagnosis. CONCLUSIONS: This is the first report of BKN in Japanese renal allograft recipients. In our hospital, the prevalence, risk factors, and outcome were similar to those previously for non-Japanese recipients.

Analysis of allograft biopsy specimens from long-term surviving patients with stable renal function: predictive value of long-term graft prognosis.

Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 +/- 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection (P = 0.0193) and CAN (P = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.

Differential diagnosis of kidney transplant rejection and cyclosporin/tacrolimus nephropathy using urine cytology.

A total of 9000 urine samples from 69 kidney transplant recipients were studied for differential diagnoses of transplant rejection and cyclosporin/tacrolimus toxicity. New-Sternheimer and Papanicolaou staining were used to differentiate cells in urine. We also employed an immunocytochemical technique for further identification of exfoliated cells. With New-Sternheimer and Papanicolaou staining, the predominance of proximal tubular cells was useful to differentiate cyclosporin/tacrolimus toxicity from acute rejection in cases of increased serum creatinine level. During rejection episodes, an increased number of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase of CD2-, CD4- CD8-, CD25- and HLA-DR-positive cells with rejection. However, there was no relationship between Banff criteria rejection grade and the increase of mononuclear cells.

Correlation between the Banff 97 classification of renal allograft biopsies and clinical outcome.

The 1997 fourth Banff meeting revised the consensus for describing transplant biopsies. We have conducted a retrospective analysis of biopsies correlated between the Banff 97 classification and clinical outcome. The patients ( n=149), who had a total of 404 biopsy-proven rejections, were assessed and the biopsies taken from these patients were re-examined and classified according to the Banff 97 classification. Morphological changes in the glomeruli (g), interstitium (i), tubules(t), and arterial vessels (v) were scored. Severity of acute rejection was statistically associated with unresponsiveness to anti-rejection treatment ( P<0.0001) and predicted an increased risk of graft failure ( P<0.05). Each quantitative criterion (g, i, t, and v) was also statistically associated with unresponsiveness to anti-rejection treatment. Mean serum creatinine levels were significantly higher in the groups graded Banff 97 type I-III after 1 and 2 years of follow-up. The Banff 97 classification correlated with reversibility of rejection episodes and long-term graft survival.