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Fibronectin glomerulopathy (FNG) is a rare, autosomal dominant renal disease with massive mesangial, and subendothelial fibronectin deposits. It presents proteinuria, often in the nephrotic range in the third to fourth decade, and slow progression to end-stage renal disease. The risk of recurrent disease in renal allograft is uncertain. A Japanese female with end-stage renal disease because of unknown origin received a renal transplant and was referred with proteinuria and mild deterioration of renal function four months after transplantation. Five allograft biopsies were underwent from one h to 12 months after the transplantation, including a biopsy 19 d after the transplantation, which revealed dense deposits suggesting fibronectin. A biopsy 134 d after the transplantation showed a feature of lobular glomerulonephritis corresponding FNG. The diagnosis was confirmed by IST4 positive and IST9 negative immunostaining together with typical fibrillary dense deposits in the mesangium and subendothelial spaces in electron microscopy. This is the first report of recurrent FNG in Japan.

The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody-mediated rejection (ABMR) in Banff classification since 2003. However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d-negative ABMR has been more focused in renal allograft pathology. The aim of this study was to make certain of C4d staining for ABMR that was diagnosed by clinical and morphological findings. C4d staining was employed by immunofluorescence. This study included 14 patients with acute ABMR and 16 with chronic active ABMR. Eight of acute ABMR were ABO-blood-type-incompatible renal transplantation (ABOinRTx) pre-treated by DFPP and splenectomy or rituximub. In acute ABMR after ABOinRTx, C4d staining along peritubular capillary (PTC) was positive in five of them (62.5%). Only one graft biopsy of five acute ABMR with donor-specific antibody (DSA) showed C4d positive. We assembled 16 graft biopsies showing typical transplant glomerulopathy and thickened PTC basement membrane with peritubular capillaritis as a suspicious pathological chronic active ABMR. Four of eight DSA-positive patients were C4d negative in PTC; however, three of four DSA-positive and C4d-negative patients in PTC chronic active ABMR were C4d positive in only glomerular capillaries. C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings.

Calcineurin inhibitors (CNI) have been commonly used as pivotal immunosuppressive agents to renal transplant recipients and have contributed significantly to improving short-term allograft survival. However, long-term administration of CNI may cause an adverse effect on kidney function, known as chronic nephrotoxicity. Chronic CNI nephrotoxicity (CNI-NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI-specific arteriolar hyaline deposition from non-specific arteriolar hyalinosis. We studied whether arteriolar vacuolization represents an early lesion of aah as a predictor of CNI-NT. We retrospectively studied the 79 patients under treatment with a CNI immunosuppressant, who underwent living-related renal transplantation (RTx) from January 2007 to March 2009. We examined serial protocol graft biopsies at one h, one, six, and 12 months after RTx. We classified histological findings into two groups on the basis of aah lesion (with or without aah) in serial biopsies for 12 months. Arteriolar vacuolization was more frequently observed in the aah group than in the non-aah group with a significant difference. Arteriolar vacuolization was found even in the one-h biopsy specimens, indicating a non-specific histopathological finding. But in the aah group, arteriolar vacuolization tended to be more frequently observed later on. Aah can be a predictor of CNI-NT.

The Banff 2007 classification allows chronic rejection to be differentiated based on clinicopathological characteristics evidenced by two independent immunologic mechanisms; chronic active antibody-mediated rejection and chronic active T-lymphocyte mediated rejection. However, several incompletely understood issues concerning chronic active antibody-mediated rejection remain. Chronic active antibody-mediated rejection is characterized by C4d deposition in the capillary basement membrane(PTC), the presence of circulating anti-donor antibodies(DSA), and morphologic evidence of chronic tissue injury such as glomerular double contours compatible with transplant glomerulopathy (TPG), PTC basement membrane multilayering, interstitial fibrosis/tubular atrophy, and fibrous arterial intimal thickening. PTC basement membrane multilayering correlates highly with TPG, and most of TPG have evidence of either C4d-positive staining or DSA. However, the proposed criteria do not apply to all situations of chronic active antibody-mediated rejection. C4d is not a magic marker for antibody-mediated rejection. C4d staining is not always highly sensitive for detecting antibody-mediated rejection. Multi-institutional studies should be conducted to better understand the clinicopathological context of chronic antibody-mediated rejection. These studies should include well-designed serial protocol biopsies with evaluation by electron microscopy, C4d staining performed on frozen sections, and assessment using sensitive DSA detection methods.

Recurrence of glomerulonephritis (GN) is one of the major risk factors of long-surviving renal graft dysfunction. Cryoglobulinemic glomerulonephritis of hepatitis-C virus (HCV)-negative patient is a rare cause of end-stage renal disease. There is little case report of recurrent cryoglobulinemic glomerulonephritis in negative HCV recipients after renal transplantation. We represent a renal allograft recipient of an interesting recurrent cryoglobulinemic glomerulonephritis. The patient was diagnosed with mixed cryoglobulinemic glomerulonephritis by kidney biopsy at the age of 32 . He had no HCV, HBV nor liver dysfunction. He received immunosuppressive therapy, however, was introduced to hemodialysis treatment after 13 yr. He received a cadaveric renal transplantation at the age of 50, and immunosuppressive treatment was started with ciclosporin, prednisolone and mycophenolate mofetil (MMF). Four yr after transplantation, he developed fever and purpura of lower limbs. His serum creatinine level did not increase, however, proteinuria, hematuria, hypocomplementemia, positive rheumatoid factor and mixed cryoglobulinemia were noted. Detailed analysis failed to reveal the composition of mixed cryoglobulinemia. The renal allograft biopsy showed membranoproliferative-type GN with monocyte and polynuclear leukocyte accumulation of capillary loops and small cellular crescent. Immunofluorescent study showed C3, IgG and IgM deposition of mesangial and capillary pattern. Regardless of steroid pulse therapy, hypocomplementemia and positive rheumatoid factor did not improve. Ten yr after transplantation, he was affected by cellulitis and sepsis. Afterward, rising of serum creatinine and nephrotic range proteinuria developed. The allograft biopsy revealed advanced cryoglobulinemic glomerulonephritis with characteristic vascular lesions. Electron microscopy showed organized subendothelial deposits compatible with cryoglobulinemic glomerulonephritis and proteinaceous thrombus in arteriole.

Live kidney donors are supposed to have no clinical kidney disease. Here, we present a unique case of subclinical membranous nephropathy (MN) from a living donor, who had urinalysis-free stable kidney function pre- and post-transplant. A 39-yr-old Asian woman received a second kidney graft from her spouse whose urinalysis and blood chemistry were stable and normal. Her intraoperative one-h core biopsy revealed thick glomerular basement membrane (GBM) and a bubbly type appearance, compatible with stage II MN on Churg's classification. According to two other protocol biopsies, GBM thickening persisted until month six post-transplant. Interestingly, both the donor and the recipient had stable kidney function without overt proteinuria at each monthly visit until one yr post-transplant. Taken together, we speculate that "silent" MN may exist in certain healthy individuals, who present only with histopathologically compatible MN and no other findings.

The pathogenesis of antibody-mediated rejection has been investigated, but the precise mechanism of chronic glomerular rejection remains unclear. We have followed the clinicopathological course of a patient with pre-existing anti-donor antibody only detected by flow-cytometry crossmatch for over 3 years. Glomerular endothelial injuries and peculiar glomerular lesions were noted in biopsy specimen of postoperative year 3; however, both typical chronic vascular rejection lesions and peritubular capillary multilayered lesions were not revealed We consider that the presence of weak anti-donor antibody leading early onset of acute humoral rejection played a role in the pathogenesis of early onset of chronic transplant glomerulopathy.

A 53-yr-old woman with end-stage renal disease was admitted for renal transplantation (RTX). About a decade ago, she had presented with urinary abnormalities. Monoclonal IgA lambda was detected. Renal biopsy showed nodular glomerulosclerosis, and an immunohistochemical study for lambda was negative. Fibrillary glomerulonephritis was suggested as the most likely diagnosis. RTX was successfully performed, and graft function was stable for the first half year. Graft biopsy was performed at one yr post-transplant. Glomeruli showed nodular lesion similar to native kidney biopsy findings. Immunofluorescence microscopy (IF) indicated strong lambda staining along the glomerular basement membrane, the tubular basement membrane (TBM), and the peritubular capillary. The diagnosis of recurrent light chain deposition disease (LCDD) was confirmed. A series of biopsies are available to conduct studies on the recurrent process of LCDD. Light microscopy showed no remarkable changes up to six months post-RTX. However, the IF study revealed evident granular depositions of lambda along the TBM only at the one-h biopsy. Typical IF staining pattern of lambda and EDD compatible with LCDD were noted after six months post-transplant. This is the first case report that elucidated the details of the recurrent process of LCDD at one yr after the operation.

Calcineurin inhibitors (CNI) have been commonly used as pivotal immunosuppressive agents to renal transplant recipients and have contributed significantly to improving short-term allograft survival. However, long-term administration of CNI may cause an adverse effect on kidney function, known as chronic nephrotoxicity. Chronic CNI nephrotoxicity (CNI-NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI-specific arteriolar hyaline deposition from non-specific arteriolar hyalinosis. We studied whether arteriolar vacuolization represents an early lesion of aah as a predictor of CNI-NT. We retrospectively studied the 79 patients under treatment with a CNI immunosuppressant, who underwent living-related renal transplantation (RTx) from January 2007 to March 2009. We examined serial protocol graft biopsies at one h, one, six, and 12 months after RTx. We classified histological findings into two groups on the basis of aah lesion (with or without aah) in serial biopsies for 12 months. Arteriolar vacuolization was more frequently observed in the aah group than in the non-aah group with a significant difference. Arteriolar vacuolization was found even in the one-h biopsy specimens, indicating a non-specific histopathological finding. But in the aah group, arteriolar vacuolization tended to be more frequently observed later on. Aah can be a predictor of CNI-NT.

The Banff 2007 classification allows chronic rejection to be differentiated based on clinicopathological characteristics evidenced by two independent immunologic mechanisms; chronic active antibody-mediated rejection and chronic active T-lymphocyte mediated rejection. However, several incompletely understood issues concerning chronic active antibody-mediated rejection remain. Chronic active antibody-mediated rejection is characterized by C4d deposition in the capillary basement membrane(PTC), the presence of circulating anti-donor antibodies(DSA), and morphologic evidence of chronic tissue injury such as glomerular double contours compatible with transplant glomerulopathy (TPG), PTC basement membrane multilayering, interstitial fibrosis/tubular atrophy, and fibrous arterial intimal thickening. PTC basement membrane multilayering correlates highly with TPG, and most of TPG have evidence of either C4d-positive staining or DSA. However, the proposed criteria do not apply to all situations of chronic active antibody-mediated rejection. C4d is not a magic marker for antibody-mediated rejection. C4d staining is not always highly sensitive for detecting antibody-mediated rejection. Multi-institutional studies should be conducted to better understand the clinicopathological context of chronic antibody-mediated rejection. These studies should include well-designed serial protocol biopsies with evaluation by electron microscopy, C4d staining performed on frozen sections, and assessment using sensitive DSA detection methods.

Recurrence of glomerulonephritis (GN) is one of the major risk factors of long-surviving renal graft dysfunction. Cryoglobulinemic glomerulonephritis of hepatitis-C virus (HCV)-negative patient is a rare cause of end-stage renal disease. There is little case report of recurrent cryoglobulinemic glomerulonephritis in negative HCV recipients after renal transplantation. We represent a renal allograft recipient of an interesting recurrent cryoglobulinemic glomerulonephritis. The patient was diagnosed with mixed cryoglobulinemic glomerulonephritis by kidney biopsy at the age of 32 . He had no HCV, HBV nor liver dysfunction. He received immunosuppressive therapy, however, was introduced to hemodialysis treatment after 13 yr. He received a cadaveric renal transplantation at the age of 50, and immunosuppressive treatment was started with ciclosporin, prednisolone and mycophenolate mofetil (MMF). Four yr after transplantation, he developed fever and purpura of lower limbs. His serum creatinine level did not increase, however, proteinuria, hematuria, hypocomplementemia, positive rheumatoid factor and mixed cryoglobulinemia were noted. Detailed analysis failed to reveal the composition of mixed cryoglobulinemia. The renal allograft biopsy showed membranoproliferative-type GN with monocyte and polynuclear leukocyte accumulation of capillary loops and small cellular crescent. Immunofluorescent study showed C3, IgG and IgM deposition of mesangial and capillary pattern. Regardless of steroid pulse therapy, hypocomplementemia and positive rheumatoid factor did not improve. Ten yr after transplantation, he was affected by cellulitis and sepsis. Afterward, rising of serum creatinine and nephrotic range proteinuria developed. The allograft biopsy revealed advanced cryoglobulinemic glomerulonephritis with characteristic vascular lesions. Electron microscopy showed organized subendothelial deposits compatible with cryoglobulinemic glomerulonephritis and proteinaceous thrombus in arteriole.

We report clinical and histopathologic findings of a case of acute rejection with adenovirus infection after kidney transplantation. A 63-yr-old woman with end-stage renal disease caused by lupus nephritis received an ABO-incompatible living kidney transplantation from her husband. On the 7th post-operative day (POD), she had fever, hematuria, and bladder irritation. Although she was treated with an antibiotic, the symptoms were not improved. We diagnosed adenovirus infection as positive with the urine shell vial method and blood PCR analysis. Cyclophosphamide was interrupted and immunoglobulin therapy was performed. However, urine output decreased and serum creatinine levels increased. An episode biopsy was performed on POD 20. We diagnosed acute antibody-mediated rejection. She was treated with plasma exchange for acute rejection and antiviral drug (rivabirin) for active adenovirus infection. However, the renal graft dysfunction was deemed irreversible and the renal graft was removed on POD 34. The graftectomy specimen showed acute rejection and acute tubular necrosis with adenovirus infection.

The pathogenesis of antibody-mediated rejection has been investigated, but the precise mechanism of chronic glomerular rejection remains unclear. We have followed the clinicopathological course of a patient with pre-existing anti-donor antibody only detected by flow-cytometry crossmatch for over 3 years. Glomerular endothelial injuries and peculiar glomerular lesions were noted in biopsy specimen of postoperative year 3; however, both typical chronic vascular rejection lesions and peritubular capillary multilayered lesions were not revealed. We consider that the presence of weak anti-donor antibody leading early onset of acute humoral rejection played a role in the pathogenesis of early onset of chronic transplant glomerulopathy.