Search

The eligibility for kidney donation and long-term post-donation renal prognosis of patients with Gitelman syndrome (GS) are unknown. We herein report a 44-year-old woman with GS who donated her kidney for transplant. A gene sequence analysis revealed compound heterozygous mutations of T180K and L858H in the SLC12A3 gene. Since transplantation, the renal function and serum potassium and magnesium levels of the donor and recipient have remained stable for seven years with careful monitoring and supplementation. Patients with asymptomatic GS who have no complications can be considered eligible to donate their kidney for transplant with proper monitoring after transplantation.

Patients with atypical hemolytic uremic syndrome (aHUS) associated with a C3 p.Ile1157Thr mutation show a relatively high renal survival and low mortality rates, but renal histopathological findings after recurrence have been rarely reported. A 30-year-old man with a C3 p.Ile1157Thr mutation experienced a third recurrence of thrombotic microangiopathies with neurological and gastrointestinal disorders. A renal biopsy performed during the recovery phase of acute kidney injury revealed collapsed glomeruli and arteriolar vacuolization. Approximately 10% of glomeruli were globally sclerotic, despite the absence of arterio-/arteriolo-sclerosis. These findings suggest substantial progression of irreversible injuries in multiple organs, including kidneys, which occurs in aHUS patients with repeated thrombotic microangiopathies.

Hypercalcemia is usually secondary to one etiology, although two coexisting etiologies can rarely cause hypercalcemia. Here, we report a 47-year-old woman with hypercalcemia caused by comorbid parathyroid adenoma and pulmonary tuberculosis. Primary hyperparathyroidism is the most common cause of hypercalcemia. Tuberculosis is a rare cause of hypercalcemia, but Japan continues to have an intermediate tuberculosis burden. Therefore, tuberculosis should be considered as a cause of hypercalcemia in Japan. Patients with tuberculosis are often asymptomatic, making the diagnosis difficult. In the previous cases in which these diseases coexisted, one disease was diagnosed after treatment of the other. In our case, the very high 1,25-dihydroxyvitamin D level (162 pg/mL) helped us to diagnose asymptomatic tuberculosis and both diseases were diagnosed promptly. It is necessary to consider comorbidities, including tuberculosis in a case with a very high 1,25-dihydroxyvitamin D level. We report a valuable case in which the early diagnosis and treatment of tuberculosis and primary hyperparathyroidism prevented the spread of tuberculosis.

We report a case of graft intolerance syndrome in which transplant nephrectomy was performed 11 years after kidney transplantation. A 46-year-old man was admitted to our hospital in February 2018 with a mild fever, left lower abdominal pain, and gross hematuria with enlargement of the transplanted kidney. Urinary tract infection was ruled out. Because the symptoms developed after the immunosuppressants had been stopped after kidney graft loss, graft intolerance syndrome was suspected. He had lost his graft in 2016 and had stopped all immunosuppressants since January of 2017. Immunosuppressive therapy was intensified, and steroid half-pulse therapy was added for 3 days. After the steroid pulse therapy, the C-reactive protein (CRP) decreased from 6.47 mg/dL to 0.76 mg/dL, but there was little improvement in the symptoms, and the CRP then increased to 4.44 mg/dL. Transplant nephrectomy was performed in March 2018. Postoperatively, the symptoms disappeared without the administration of immunosuppressants, and the CRP decreased. Pathologically, the resected kidney graft showed persistent active allograft rejection with severe endarteritis, transplant glomerulopathy, and diffuse interstitial fibrosis. Massive thrombi occluded the large arteries, and there was extensive hemorrhagic cortical necrosis. Transplant nephrectomy is uncommon in patients >6 months after transplantation. However, even if more time has passed since transplantation, as in this case, transplant nephrectomy may be a valid option in some cases of severe graft intolerance syndrome.

Vascular lesions related to allograft rejection have a big impact on graft survival. As such, investigation of these lesions is important to understand the pathophysiology of rejection and its management. We report a case of kidney transplant graftectomy by severe mixed-type rejection with acute and chronic active vascular lesions caused by non-adherence to immunosuppressive treatment. The patient presented is a 29-year-old male who received a kidney transplantation in July 2011 (ABO compatible) from his father. He then did not come to the hospital for 3 months prior to his admission and also made his own decision to stop his medication regimen. On October 2013, the patient came to the hospital with dyspnea, nausea, and vomiting and had significant renal dysfunction (serum Cr 30.4 mg/dL, BUN 191 mg/dL). A kidney graft biopsy showed cortical necrosis with severe interstitial hemorrhage and thrombotic microangiopathy (TMA). Despite steroid pulse therapy, kidney graft function did not recover, and the patient underwent a subsequent graft resection. The resected kidney graft displayed various vascular lesions from the renal artery to the interlobular arteries and arterioles including endarteritis, TMA, fibrinoid necrosis, and transplant arteriopathy. This case shows the detailed pathological findings of the vascular lesions in the entire artery tree of kidney allograft, and the pathophysiology is discussed.

Background Sebaceous carcinoma is a rare but progressive malignant skin cancer, and the incidence is approximately five times higher in post-transplant patients than in people who have not received kidney transplants. Sebaceous carcinoma is sometimes found concurrently with visceral cancers and a genetic abnormality, Muir–Torre syndrome. We report the case of a female kidney transplant recipient with sebaceous carcinoma concurrent with colon cancer 10 years after transplantation. Case presentation A 43-year-old woman was admitted due to a rapidly progressive tumor on her head. Histologically, the tumor was diagnosed as sebaceous carcinoma. We diagnosed her with Muir–Torre syndrome based on the following evidence: 1) high prevalence of microsatellite instability in gene locus assay, 2) absence of mismatch repair proteins in the sebaceous carcinoma on immunohistochemical analysis, and 3) a genetic mutation of 1226_1227delAG in the MSH2 exon 7 in the lesion detected by DNA sequencing analysis. Several reports have shown an association between immunosuppressive agents and latent Muir–Torre syndrome progression. Therefore, the progression of colon cancer in this case originated from her genetic mutation for Muir–Torre syndrome and long-term use of immunosuppressive agents. Conclusion This case report not only highlights the importance of adequate diagnosis and therapy for Muir–Torre syndrome, but also suggests the further prevention of the development of malignant tumors in kidney transplant recipients. Physicians should be mindful that sebaceous carcinoma in kidney transplant recipients is highly concurrent with Muir–Torre syndrome.

BackgroundPosttransplant anemia (PTA) is associated with the progression of kidney disease and mortality in kidney transplant recipients. Although the main causes of PTA are recipient factors, donor factors have not been fully investigated. In this study we investigated the association of donor pathological findings with the incidence of PTA in kidney transplant recipients after 3 years of transplantation.MethodsWe conducted a retrospective cohort study at a single university hospital. A total of 50 consecutive adult recipients and donors were enrolled. To assess the structure of interstitial lesions, immunohistochemical staining of interstitial fibrosis and fibroblasts were assessed in 0-h biopsies for quantitative analysis.ResultsThe incidence of PTA in this cohort was 30%. The mean hemoglobin (Hb) was 11.6 ± 0.8 g/dL in patients with PTA and 14.3 ± 1.5 g/dL in patients without PTA. An inverse association was observed in biopsies between interstitial fibrosis area and interstitial fibroblast area (P ConclusionsThe presence of interstitial fibroblasts in donor kidneys may play an important role in predicting the incidence of PTA.

Background A decrease in absolute numbers (abs.) of circulating dendritic cells (DCs) and recruitment into target organs has been reported, but whether the level of proteinuria associates with circulating DC abs. has not been clarified. Methods We conducted a cross-sectional study of 210 patients with kidney disease aged 21–96 years who were admitted to our hospital for kidney biopsy in 2007–2010. For accuracy, the level of proteinuria was thoroughly measured by 24-h urine collection from patients in their admitted condition. The abs. of total DCs (tDCs), myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) was measured by three-color fluorescence-activated cell sorting (FACS). Patients were divided into four groups based upon the quartile of each DC abs. and one-way ANOVA, and multivariable-adjusted regression analyses were performed. Results Quantile analysis showed that the level of daily proteinuria decreased with increasing blood mDC abs., with mean proteinuria levels (g/day) of 2.45, 1.68, 1.68, 1.10 for those in mDC abs. quartiles ≤ 445

Increasing evidence suggests that individuals with low nephron number have an increased lifetime risk of renal insufficiency, thereby emphasizing the importance of evaluating total nephron number in each individual. In recent years, new methods have been described for estimating human total nephron number using a combination of image analysis and renal biopsy, though the reproducibility and accuracy of these methods remain uncertain. This study estimated total nephron number in healthy Japanese subjects using such a method. Implantation biopsies from 44 living kidney donors were analyzed. Using pre-donation contrast CT angiograms, transplantation donor kidneys were three-dimensionally reconstructed, and total renal cortical volume was estimated. Total nephron number was estimated based on glomerular density in biopsy specimens and total renal cortical volume. The obtained results were analyzed in relation to clinical variables and compared with those of a previously reported Japanese autopsy study. The estimated non-sclerotic and total numbers of glomeruli in this cohort were 650,000 ± 220,000 and 710,000 ± 220,000 (mean ± SD) per kidney. Non-sclerotic glomerular number ranged from 280,000 to 1,220,000 per kidney (4.4-fold) and correlated directly with eGFR (r = 0.328, p = 0.030) and inversely with age (r = − 0.355, p = 0.018). The estimated total nephron number obtained in the present study was 25% less than that reported in American living kidney donors obtained using the same procedure and similar to that obtained in a previous Japanese autopsy study using the disector/fractionator method. These results confirm the feasibility of a combined CT angiography and biopsy-based method to estimate total nephron number in humans.

BACKGROUND: Podocyte depletion, low nephron number, aging, and hypertension are associated with glomerulosclerosis and CKD. However, the relationship between podometrics and nephron number has not previously been examined. METHODS: To investigate podometrics and nephron number in healthy Japanese individuals, a population characterized by a relatively low nephron number, we immunostained single paraffin sections from 30 Japanese living-kidney donors (median age, 57 years) with podocyte-specific markers and analyzed images obtained with confocal microscopy. We used model-based stereology to estimate podometrics, and a combined enhanced–computed tomography/biopsy-specimen stereology method to estimate nephron number. RESULTS: The median number of nonsclerotic nephrons per kidney was 659,000 (interquartile range [IQR], 564,000–825,000). The median podocyte number and podocyte density were 518 (IQR, 428–601) per tuft and 219 (IQR, 180–253) per 10(6) μm(3), respectively; these values are similar to those previously reported for other races. Total podocyte number per kidney (obtained by multiplying the individual number of nonsclerotic glomeruli by podocyte number per glomerulus) was 376 million (IQR, 259–449 million) and ranged 7.4-fold between donors. On average, these healthy kidneys lost 5.63 million podocytes per kidney per year, with most of this loss associated with glomerular loss resulting from global glomerulosclerosis, rather than podocyte loss from healthy glomeruli. Hypertension was associated with lower podocyte density and larger podocyte volume, independent of age. CONCLUSIONS: Estimation of the number of nephrons, podocytes, and other podometric parameters in individual kidneys provides new insights into the relationships between these parameters, age, and hypertension in the kidney. This approach might be of considerable value in evaluating the kidney in health and disease.

Background: Recurrence of IgA nephropathy (IgAN) in the transplanted kidney is associated with graft survival, but no specific treatment is available. Tonsillectomy (TE) reportedly arrests the progression of IgAN in the native kidney. Thus, we conducted a single-center retrospective cohort study to evaluate the effect of TE prior to IgAN recurrence. Methods: Of the 36 patients with biopsy-proven IgAN who underwent kidney transplantation, 27 were included in this study. Nine patients underwent TE at 1 year after kidney transplantation (group 1), and the remaining 18 did not undergo TE (group 2). Results: The rate of histological IgAN recurrence was significantly lower in group 1 than in group 2 (11.1 vs. 55.6%, log-rank p = 0.046). In addition, half of the recurrent patients in group 2 exhibited active lesions, compared to none in group 1. Serum Gd-IgA1 levels decreased after TE in group 1, whereas they remained stable or increased slightly in group 2. In the recurrent cases, IgA and Gd-IgA1 were found in the germinal center in addition to the mantle zone of tonsils. Finally, mesangial IgA and Gd-IgA1 immunoreactivity was reduced after TE in some cases. Conclusion: Our data suggest that TE at 1 year after kidney transplantation might be associated with the reduced rate of histological IgAN recurrence. TE arrested or reduced serum Gd-IgA1 and mesangial Gd-IgA1 immunoreactivity. Therefore, we generated a hypothesis that serum Gd-IgA1 derived from the tonsils may play a pivotal role in the pathogenesis of IgAN. Based on these findings, we need to conduct verification in a prospective randomized controlled trial.

High protein intake can increase glomerular filtration rate (GFR) in response to excretory overload, which may exacerbate the progression of kidney disease. However, the direct association between glomerular hemodynamic response at the single-nephron level and dietary protein intake has not been fully elucidated in humans. In the present study, we evaluated nutritional indices associated with single-nephron GFR (SNGFR) calculated based on corrected creatinine clearance (SNGFRCr). We retrospectively identified 43 living kidney donors who underwent enhanced computed tomography and kidney biopsy at the time of donation at Jikei University Hospital in Tokyo from 2007 to 2018. Total nephron number was estimated with imaging-derived cortical volume and morphometry-derived glomerular density. SNGFRCr was calculated by dividing the corrected creatinine clearance by the number of non-sclerosed glomeruli (NglomNSG). The mean (&plusmn, standard deviation) NglomNSG/kidney and SNGFRCr were 685,000 &plusmn, 242,000 and 61.0 &plusmn, 23.9 nL/min, respectively. SNGFRCr was directly associated with estimated protein intake/ideal body weight (p = 0.005) but not with body mass index, mean arterial pressure, albumin, or sodium intake. These findings indicate that greater protein intake may increase SNGFR and lead to glomerular hyperfiltration.

The regulation of food intake is one of the major research areas in the study of metabolic syndromes such as obesity. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behaviour. However, our understanding of neural function under physiological conditions is still limited. Immediate early genes, such as activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), are useful markers of neuronal activity. Here, we investigated the role of Arc/Arg3.1 gene-expressing neurons in the hypothalamus after refeeding using the targeted recombination in active populations method. We identified refeeding-responsive prodynorphin/cholecystokinin neurons in the dorsomedial hypothalamus that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of these neurons decreased food intake and promoted positive valence. Our findings provide insight into the role of newly identified hedonic neurons in the process of feeding-induced satiety.

The immunoglobulin (Ig) D type is a rare variant of multiple myeloma (MM), that accounts for 1-2% of all cases. Compared to the more common types of MM, IgD MM is known to have more severe symptoms at presentation, and a poorer prognosis. A woman was admitted to our hospital for severe acute kidney disease and disorder (AKD) and back pain, and was started on hemodialysis. The renal biopsy revealed light chain cast nephropathy. She was diagnosed with IgD-λ MM based on Bence-Jones protein expression and high IgD serum levels, and started bortezomib therapy with plasma exchange (PE). After three sessions of PE, the serum free light chain levels decreased by 92%, and she was withdrawn from dialysis. The patient underwent autologous transplantation and is still in remission, demonstrating the benefits of a bortezomib-based regimen in combination with PE for IgD MM with AKD.

AIM Arteriolar hyalinosis (AH) is a common lesion in allograft biopsies taken following kidney transplantation. Recent studies have shown that severe AH may predict transplant outcomes and provide information about previous exposure to certain drugs, such as calcineurin inhibitors (CNI). However, the incidence of AH as a direct result of diabetic nephropathy (DN) after kidney transplantation has not been fully evaluated. This study aimed to assess the impact of primary DN on the development of AH lesions in patients who underwent kidney transplantation. METHODS Eighty-three patients who underwent living-donor kidney transplantation between April 2005 and June 2015 were enrolled in this study. A total of 33 patients had DN prior to transplantation. Allograft biopsies were scored according to the Banff classification, and the relationship between the individual histological lesions and clinical baseline data was assessed. RESULTS At early biopsy (3-12 months), there were no differences in the rates of AH lesions between the DN group and the non-DN group (ah ≥ 1: 37% vs. 41.3%, P = 0.719; aah ≥ 1: 14.8% vs. 6.5%; P = 0.453). However, there were significant differences between the groups in biopsies taken more than 3 years after the transplant (ah ≥ 2: 83.3% vs. 36.8%, P = 0.013; aah ≥ 2: 66.7% vs. 21.1%, P = 0.011). Multivariable analysis showed that both the length of time after transplantation and the presence of DN were independent risk factors for ah ≥ 2 (odds ratio [OR]: 2.55, 95% confidence interval [CI]: 1.47-19.54, P = 0.011) and aah ≥ 2 (OR: 7.55, 95% CI: 1.49-38.33, P = 0.015). CONCLUSION This is the first report showing that the presence of primary DN disease contributes to the development of severe AH late in the course after kidney allografts.

The extent of recurrence of original kidney disease after kidney transplantation has been underestimated for several reasons. First, the duration of observation varies among studies. Second, the criteria used to schedule protocol and episode biopsies differ among institutions. And third, diagnostic modalities used for early detection of recurrent original kidney disease also vary. Thus, rates of graft loss attributable to a recurrence of original kidney disease vary among institutions and are often underestimated. However, the recurrence of original disease is often thought to be less important than chronic rejection followed by loss of a functioning allograft. It is important to note that recent data have shown that in patients with certain limited primary kidney diseases (e.g., membranous proliferative glomerulonephritis [MPGN], IgA nephritis [IgAN], focal segmental glomerulonephritis [FSGS], and membranous nephropathy [MN]), the predominant (60%) cause of graft loss is the recurrence of original kidney disease. In addition, the rate of 5-year graft survival in patients with recurrent original kidney disease averages 45%. Thus, research must address the recurrence of original kidney disease. Here we focus on this recurrence and discuss diagnoses, preventive strategies, treatments, and future research directions.

AIM De novo membranous nephropathy (dnMN) contributes to graft failure, but the pathophysiology of the disease remains poorly understood. We defined cases exhibiting granular Immunoglobulin G (IgG) immunofluorescence staining but lacking dense deposits on electron microscopy as being of 'dnMN stage 0'; we studied the associated clinicopathological features. METHODS We studied 4653 allograft biopsy specimens (from 1747 cases treated in the Department of Urology, Tokyo Women's Medical University) and found 42 cases of allograft membranous nephropathy, of which 28 (1.6%) were diagnosed as dnMN. Of these, five cases (0.06%) fulfilled the criteria for dnMN stage 0. RESULTS All five cases were diagnosed based on biopsies indicating increased serum levels of creatinine. Proteinuria status varied from negative to 2+. The median period from transplantation to allograft biopsy was 4068 days. Four of the five cases exhibited suspicious antibody-mediated rejection together with dnMN. The glomerular capillaries of all cases were C4d-positive, as were the peritubular capillaries of three of the four ABO-compatible transplants. In terms of IgG subclass, IgG1 and IgG3 predominated in all cases, and phospholipase A2 receptor status (evaluated via immunoreactivity) was negative in all cases. We examined two cases by immunoelectron microscopy using anti-IgG and anti-C4d antibodies. We found subendothelial and intramembranous deposits expressing both IgG and C4d, corresponding to positivity in immunofluorescence analysis. CONCLUSION We confirmed the existence of dnMN stage 0 by focusing on granular IgG immunofluorescence positivity.

Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient.

Introduction Alterations in glomerular filtration can considerably influence the dynamics and functions of the Bowman capsule. Despite the potentially important role in maintaining normal renal functions, few studies have focused on Bowman capsule volume in normal human kidneys. Methods We analyzed specimens from biopsies performed 1 hour after kidney transplantation from living donors without apparent renal disease. The measurements of all cross-sectional areas of the Bowman capsules and glomerular capillaries were used to estimate the mean Bowman capsule volume (BV) and glomerular capillary volume (GV) in each subject. The G/B ratio was defined as the ratio of GV to BV. The morphometric findings were examined in relation to the clinical findings in donors just before kidney transplantation. Results We analyzed 37 adults with a mean creatinine clearance of 111 ml/min. The mean BV and GV of these subjects were 6.10 ± 2.46 × 106 μm3 and 3.83 ± 1.52 × 106 μm3, respectively. Both the BV and GV varied up to 6-fold and were significantly higher in elderly, obese, or hypertensive subjects in comparison to nonelderly, nonobese, or normotensive subjects, whereas the renal function of each subgroup was similar. The G/B ratio (0.63 ± 0.05) was unaffected, and BV and GV were strongly correlated regardless of these clinical factors (r = 0.980 [95% confidence interval = 0.961−0.990], P Conclusion In the normal adult kidney, there may be an optimal BV to GV ratio for maintaining effective filtration in a variety of clinical situations, including advanced age, obesity, and hypertension.

Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR) has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL) therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection.

Background Previously, we explored the histopathologic characteristics of medullary ray injury (MRI) inducing interstitial fibrosis and tubular atrophy (IF/TA) to determine its etiologies, which include calcineurin inhibitor (CNI) toxicity and urologic complications. However, we did not examine the effects of these etiologies on long-term kidney allograft prognosis, because biopsy timing differed among cases. Aim We examined the influence of early MRI on kidney allograft prognosis using protocol biopsies taken within a 3-month time frame. Methods We defined early MRI as tubular degeneration with interstitial edema or mild fibrosis localized to the medullary ray. We divided 53 protocol biopsies into 2 groups, with and without early MRI. Early MRI+ cases with isometric vacuolization were classified as CNI toxicity; those with Tamm-Horsfall protein in the interstitium and a thyroidlike appearance were classified as urinary tract system abnormalities; remaining cases were classified as “others.” We compared changes in serum levels of creatinine (sCr) over 3 years and fibrosis extent at 1 year. Results The sCr levels were significantly higher in the MRI+ group than the MRI− group at 3 years ( P = .024). Examining the 3 MRI+ subgroups, only the MRI+ urinary tract system abnormalities group had significantly high sCr levels compared to the MRI− group ( P = .019). The MRI+ group showed significant signs of IF/TA at 1 year. Conclusions Early MRI after kidney transplantation was significantly more likely to develop IF/TA at 1 year and had higher sCr levels at 3 years. In such cases, intervention might preserve graft function over the long term.

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism., The ventromedial hypothalamus regulates systemic glucose metabolism. Here the authors show that cytosolic phospholipase A2 mediated phospholipid metabolism contributes to this regulation in healthy animals but exert deteriorating effects on glucose homeostasis under high-fat-diet feeding.

The pathogenesis of glomerular hypertension-mediated FSGS and its histological variations in humans remains unknown. A 47-year-old man developed nephrotic syndrome, renal dysfunction, and malignant hypertension 2 years after donating a kidney to his son. The donor’s remnant kidney developed renal mass at an upper pole which was fed by an aberrant artery that branched from the root of the renal artery. Furthermore, the main non-aberrant renal artery demonstrated severe stenosis that caused renovascular hypertension, resulting in malignant hypertension. Upon radiological examinations, a tumorous mass was detected. Because of progressive renal dysfunction, nephrectomy was performed. The kidney revealed a diffuse distribution of complex FSGS lesions, i.e., a random combination of cellular/collapsing FSGS and glomerular thrombotic microangiopathy, confined to the renal mass, whereas such lesions were absent in the non-mass portion. This indicated that severe glomerular hypertension alone caused FSGS with TMA features. Heterogeneous FSGS lesions let us surmise that glomerular hypertension promoted simultaneous damages in endothelial cells and podocytes, which synergistically progressed to glomerulosclerosis. This unique case uncovers causal relationships between unusual glomerular hypertension and severe forms of FSGS that was possibly caused by the disruption of homeostasis sustained by podocytes and endothelial cells.

Myeloma cast nephropathy is a major complication of multiple myeloma. Recent evidence has demonstrated that the earlier induction of bortezomib-based chemotherapy with plasma exchange (PE) provides better results for kidney function and patient survival. Due to its non-selectivity, PE with albumin replacement carries the risk of fibrinogen loss, leading to bleeding. We herein report a case of successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy and selective PE. A 61-year-old woman who had a 20-year history of type II diabetes mellitus was admitted to our hospital for the evaluation of hypercalcemia, severe kidney dysfunction, and anemia. Subsequent bone marrow evaluation and renal biopsy revealed that she had multiple myeloma (IgG-κ) and myeloma cast nephropathy. Ten days after admission, bortezomib-based chemotherapy with selective PE achieved rapid and thorough free light-chain (FLC) reduction; within a month, her kidney function had been recovered (creatinine level, 1.2 mg/dl). Her serum fibrinogen level was not reduced, and no bleeding complication occurred. Five months later, autologous hematopoietic stem-cell transplantation was performed successfully, and the patient’s kidney function was stable (creatinine level, 1.1 mg/dl) thereafter. This case report demonstrates the importance of early induction therapy with bortezomib-based chemotherapy and PE in a patient with myeloma cast nephropathy, which is especially applicable in patients aged

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal

A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection.

We report a case of recurrent Henoch-Schonlein purpura nephritis (HSPN) treated successfully with a tonsillectomy and steroid pulse therapy in a kidney transplant patient. A 29-year-old woman was admitted to our hospital for an episode biopsy; she had a serum creatinine (S-Cr) of 1.0 mg/dL and 1.34 g/day proteinuria 26 months after kidney transplantation. Histological examination revealed increased amounts of mesangial matrix and mesangial hypercellularity with IgA deposition. Of note, one glomerulus showed focal endocapillary proliferation and tuft necrosis. We diagnosed active recurrent HSPN. Considering both the histological findings and refractory clinical course of the native kidney, she was treated for 3 consecutive days with steroid pulse therapy and a tonsillectomy. The patient's proteinuria decreased gradually to less than 150 mg/day 6 months later. A second biopsy 6 years after kidney transplantation showed an excellent response to treatment and revealed a marked reduction in both the mesangial matrix and mesangial hypercellularity, with trace IgA deposition. We conclude that a tonsillectomy and steroid pulse therapy appeared to be useful in this patient with active recurrent HSPN. This paper is the first to report a tonsillectomy and steroid pulse therapy as a therapeutic option for active recurrent HSPN. Further studies are needed to elucidate the efficacy and mechanisms of tonsillectomy with recurrent HSPN in kidney transplant patients.

Background Patients with Alport syndrome (AS) develop progressive kidney dysfunction due to a hereditary type IV collagen deficiency. Survival of the kidney allograft in patients with AS is reportedly excellent because AS does not recur. However, several studies have implied that the type IV collagen in the GBM originates from podocytes recruited from the recipient’s bone marrow-derived cells, suggesting the possibility of AS recurrence. Limited data are available regarding AS recurrence and graft survival in the Japanese population; the vast majority were obtained from living related kidney transplantation (LRKTx). Methods In this retrospective study, twenty-one patients with AS were compared with 41 matched patients without AS from 1984 to 2015 at two centers using propensity scores. Nineteen of the 21 patients with AS underwent LRKTx. The mean post-transplant follow-up period was 83 months in the AS group and 110 months in the control group. Histopathological AS recurrence was assessed by immunoreactivity of α5 (type IV collagen) antibody and electron microscopy. Results The graft survival rate was equivalent between patients with and without AS (86.7% vs. 77.1% and 69.3% vs. 64.2% at 5 and 10 years; p = 0.16, log-rank test). Immunoreactivity to α5 antibody showed strong linear positivity with no focal defect in six patients. Electron microscopy showed no GBM abnormalities in two patients who were exhibiting long-term kidney allograft survival. Conclusions We confirmed that α5 and the GBM structure were histopathologically maintained in the long term after kidney transplantation. The patient and graft survival rates were equivalent between Japanese patients with and without AS.

Background Several reports on patients with diabetes mellitus (DM) treated by peritoneal dialysis (PD) have shown a higher risk of PD-associated peritonitis compared to non-DM (NDM) patients. The aim of this study was to investigate the incidence of PD-associated peritonitis in DM patients. Methods We divided all patients who received PD at a single center between January 1980 and December 2012 into three groups according to era: Period 1 (n = 43, 1980–1993); Period 2 (n = 123, 1994–2004); and Period 3 (n = 207, 2005–2012). We investigated incidences of PD-associated peritonitis between patients with and without DM. Results In Periods 1 and 2, incidence of PD-associated peritonitis was higher in the DM group than in the NDM group (P

Background Both prevention and treatment of recurrent immunoglobulin A nephropathy (IgAN) in kidney transplant recipients are important since recurrent IgAN seems to affect long-term graft survival. We present here a case of recurrent IgAN that was successfully treated using steroid pulse therapy plus tonsillectomy 10 years after kidney transplantation. Case presentation A 46-year-old male was admitted for an episode biopsy with a serum creatinine level of 1.8 mg/dl and proteinuria (0.7 g/day). Histological features showed recurrent IgAN (only focal segmental mesangial proliferation) and severe arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity, with limited interstitial fibrosis and tubular atrophy (5%) (IF/TA) 8 years after transplantation. Sodium restriction and conversion from cyclosporine to tacrolimus successfully reduced his proteinuria to the level of 0.15 g/day. However, 2 years later, his proteinuria increased again (1.0 g/day) and a second episode biopsy showed global mesangial proliferation with glomerular endocapillary and extracapillary proliferation accompanied by progressive IF/TA (20%). The steroid pulse therapy plus tonsillectomy successfully decreased his proteinuria and he achieved clinical remission 3 years after this treatment. Conclusion This case, presented with a review of relevant literature, demonstrates the difficulty and importance of the treatment of recurrent IgAN and calcineurin inhibitor arteriolopathy, especially in long-term kidney allograft management.

Peritoneal dialysis-associated peritonitis (PD-associated peritonitis) could influence the outcome of PD patients, including technique survival. Although the use of the twin-bag system has decreased the incidence of peritonitis, the effects of biocompatible PD solutions are controversial. Additionally, since both infection-causing microorganisms and antimicrobial therapies have changed over time, the duration of treatment of peritonitis (the duration of peritonitis) seems to have changed. The study included 527 patients who received PD between January 1980 and December 2012 at a single center. We divided patients undergoing PD into three groups according to the type of PD system used, namely single-bag and conventional PD solutions (S+C group, N = 145), twin-bag and conventional PD solutions (T+C group, N = 171) and twin-bag and biocompatible PD solutions (T+B group, N = 211), and analyzed PD-associated peritonitis incidences. Incidences of PD-associated peritonitis (times per patient-months) and peritonitis-free time were 1/59.4, 1/70.6 and 1/103.1, and 52, 97, and 100 months for the S+C, T+C and T+B groups, respectively. The duration of peritonitis, has thus, become dramatically shorter in recent years. Streptococcus sp. were associated with shortest and fungi with longest durations of peritonitis. Staphylococcus sp. and Pseudomonas aeruginosa were predominant in the S+C group. The twin-bag system has made a greater contribution to reductions in PD-associated peritonitis than biocompatible PD solutions. Furthermore, changes in microorganisms, antimicrobial therapies, patient education and improved PD system devices have presumably affected the reduction in the duration of peritonitis.

Background Previous studies have shown that a donor/recipient body weight mismatch affects long-term graft survival and graft function after kidney transplantation. However, the mechanisms are not fully understood. Aim To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation with the donor/recipient body weight ratio. Methods We examined allograft biopsy specimens from 10 recipients with stable kidney function, with body weight mismatch (donor/recipient body weight ratio [D/R BWR]

We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases.

Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI.

Background Both immunological and non-immunological etiologies affect graft function after kidney transplantation, including acute rejection, calcineurin inhibitor toxicity, and a recurrence of glomerulonephritis. Glomerular enlargement or glomerular sclerosis due to glomerular hyperfiltration related to increased renal blood flow is another cause. Although the glomerular volume in baseline biopsies predicts late allograft function, the relationship between allograft function and the annual changes in glomerular volume after kidney transplantation are unclear. Aim We investigated changes in glomerular volume after kidney transplantation and their clinicopathological relationship. Methods We enrolled 23 patients with stable kidney function without an episode of rejection or any complication resulting in a functional decrease in the graft. We measured glomerular volume (GV) using the Weibel–Gomez method and glomerular density (GD) using 0,1 h biopsy samples as baseline controls and 1 yr biopsy samples and investigated the association between the changes in them and clinical parameters, including graft function, proteinuria, and renal hemodynamic markers, including effective renal plasma flow (ERPF) and filtration fraction (FF). The ERPF was calculated from a 99mTc-mercaptoacetyltriglycine (MAG3) renogram. Results The GV and ERPF increased significantly 1 yr after kidney transplantation. In contrast, proteinuria decreased significantly and Δproteinuria (1 yr – 1 month after transplantation) was correlated with ΔGV (P

We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.

We report a case of acute vascular rejection occurring during antituberculosis therapy in a patient who had received a kidney transplant. A 29 year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.5 mg/dL 1 year after primary kidney transplantation. Histological examination yielded no evidence of rejection but a routine chest CT scan revealed typical lung tuberculosis and his serum was positive for QFT. We commenced antituberculosis therapy, including rifampicin, on June 29 2012. We paid close attention to the weekly trough tacrolimus (TAC) level but the S-Cr concentration increased to 3.7 mg/dL on October 16 2012, and he was admitted for biopsy. Histological examination revealed, first, a diffuse aggressive infiltration of tubulointerstitial inflammatory cells accompanied by severe tubulitis and mild intimal arteritis and, second, peritubular capillary infiltration by inflammatory cells (including neutrophils). Laboratory data revealed that our patient did not express donor-specific antibody and the peritubular capillaries did not exhibit C4d immunoreactivity. Upon consideration of both histological and laboratory findings, we diagnosed acute vascular rejection of Banff 2007 class ACR IIA. We commenced 3-day sessions of intravenous steroid pulse therapy twice weekly and adjusted the trough TAC level to 5–8 ng/mL by varying the TAC dose. We next performed an allograft biopsy and found no evidence of rejection (the S-Cr level was 2.7 mg/dL on April 1 2013). The present case report demonstrates the difficulties associated with management of TAC-based regimens in kidney transplant patients undergoing antituberculosis therapy. We also review the relevant literature.

We report the successful management of BK virus nephropathy (BKVN) using therapeutic drug monitoring (TDM) of mycophenolic acid (MPA). A 40-year-old woman was admitted for a protocol biopsy 3 months following primary kidney transplantation. Histological features were distributed in mainly two sections: the corticomedullary junction and cortical area. In the former, massive interstitial mononuclear cell infiltration and mild to moderate tubulitis with nuclear inclusion bodies were found. SV40 staining was positive in the injured tubules. These findings were compatible with BKVN. In the latter, focal interstitial inflammation and severe tubulitis without cytopathic changes were identified outside of SV40-positive areas. Based on the histological findings, we diagnosed BKVN and we also suspected of the complication with acute T-cell-mediated rejection. We started steroid pulse therapy and reduced the dosage of immunosuppressive therapy under careful monitoring, using not only a trough level of tacrolimus but also a 12-h area under the curve (AUC0-12 ) of MPA. After the treatment, the patient maintained kidney function. This case report demonstrates the usefulness of MPA AUC0-12 for more accurate adjustment of immunosuppressive therapy and the difficulty of pathological differentiation of BKVN and acute cellular rejection.

Encapsulating peritoneal sclerosis (EPS) is a serious complication that occurs in patients with long-term peritoneal dialysis (PD). Investigation of risk factors that contribute to EPS in patients on long-term PD therapy is needed. In a retrospective, observational study, data were collected for 107 patients treated with PD therapy for more than 5 years. Fifty cases of EPS were compared with 57 cases of non-EPS. To evaluate the impact of PD-associated peritonitis in EPS, univariate and multivariate logistic regression models were applied. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis were included as explanatory variables in addition to previously reported risk factors. D/P Cr and serum β2MG levels in the EPS and non-EPS groups were: 0.82 ± 0.10 and 0.67 ± 0.12 (P < 0.01), and 33.8 ± 8.54 and 29.2 ± 8.18 mg/L (P < 0.01), respectively. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis was 68% and 42% (P < 0.01), 1.80 ± 2.19 and 0.75 ± 1.07 times (P < 0.01), and 18.1 ± 15.3 and 10.2 ± 4.90 days (P < 0.01), in the EPS and non-EPS groups, respectively. Furthermore, multivariate logistic regression models demonstrated that both D/P Cr and the duration of peritonitis were independently associated with EPS (P < 0.01 and P < 0.05, respectively). In patients on long-term PD therapy, D/P Cr and the duration of peritonitis are independently associated with EPS. Earlier treatment to promote an early recovery from PD-associated peritonitis could be critical in preventing EPS.

The low sensitivity of C4d immunoreactivity in peritubular capillaries (PTCs) hinders its use in the diagnosis of chronic active antibody-mediated rejection (CAAMR). C4d-negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial-associated transcripts (ENDATs). We previously showed that the ENDAT caveolin-1 (CAV-1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV-1 immunoreactivity in PTCs in kidney transplant patients. Ninety-eight kidney transplant recipients were included in this study. The prognostic value of CAV-1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV-1 and pathologische Anatomie Leiden endothelium (PAL-E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV-1/PAL-E

IgA vasculitis, a rare condition resulting in end-stage renal disease, is a small-vessel vasculitis that affects the kidney in 49–83 % of adults. The reported recurrence rate of IgA vasculitis in renal transplant recipients is 11.5–60 %, leading to graft loss in 0–50 % of these patients. However, limited data are available on recurrence and graft loss after renal transplantation. We evaluated renal transplant recipients seen from 1987 to 2015 at the Jikei University School of Medicine and the Department of Urology, Tokyo Women’s Medical University. Using a 1:2 match, 21 patients with IgA vasculitis and 42 controls were selected. The mean post-transplant follow-up was 121 ± 69 months for IgA vasculitis and 147 ± 66 months for the controls. The 15-year patient survival was 100 % in IgA vasculitis and 97.6 % in the controls (p = 0.22). The 5-, 10-, and 15-year graft survival rates were 95.2, 90.5, and 81 % in IgA vasculitis and 100, 90.5, and 88.1 % in the controls, respectively (p = 0.63). The recurrence rate was 28.6 % (6 of 21 cases) and half of them (3 of 6 cases) showed histological activity (ISKDC III). We treated them with methylprednisolone pulse therapy and/or tonsillectomy. None of the recurrence cases lost the allograft. The long-term patient and graft survival of IgA vasculitis in renal transplantation were comparable with the previous reports. The recurrence rate was 28.6 %, but none of the recurrent cases showed allograft loss in this study. We speculate that methylprednisolone pulse therapy and/or tonsillectomy prevent the progression of recurrent IgA vasculitis.

A 41-year-old male patient was admitted to our hospital due to massive proteinuria and hematuria. His 24-hour urinary protein excretion and the number of urinary erythrocytes were 3.91 g/day and 50-99/high-power field, respectively. A renal biopsy showed a severe pathological pattern of immunoglobulin A nephropathy (IgAN) that involved marked endocapillary proliferation and segmental sclerosis (Oxford-MEST score: M0, E1, S1, T0). Because he had nephrotic-level proteinuria with severe pathological findings, which are tonsillectomy and corticosteroid pulse therapy-resistant characteristics, he received mizoribine for a long period as part of the combination therapy using corticosteroid, tonsillectomy, dipyridamole, warfarin and renin-angiotensin-aldosterone system blockers. Twelve months after the beginning of treatment, his urinary findings were normal. In this report, we describe the pathological findings and successful treatment course, and discuss the potential effects of long-term coadministration of mizoribine for adult IgAN treatment.

AIM The transcription factor c-Jun is a major component of the activator protein-1 complex involved in renal physiological events, such as inflammation and fibrosis. We recently demonstrated c-Jun activation in peritubular capillary (PC) endothelial cells and infiltrating cells in acute antibody-mediated rejection after kidney transplantation. However, the clinicopathological role of PC endothelial c-Jun activation has remained undetermined. MATERIAL AND METHOD We investigated endothelial c-Jun activation in PC using phosphorylated c-Jun (p-c-Jun) immunohistochemical staining in 21 cases of chronic active antibody-mediated rejection (CAMR), 14 cases of interstitial fibrosis and tubular atrophy (IF/TA) lacking specific etiology, and 8 normal control subjects (NC). RESULTS In CAMR cases, swollen PC endothelial cells showed strong p-c-Jun staining. More p-c-Jun-positive endothelial cells in PC were observed in CAMR than in IF/TA and NC subjects (p < 0.01). These findings were significantly correlated with reduced PC (rs = -0.78, p = 0.0005), the "ci + ct" score of the Banff classification (rs = 0.81, p = 0.0003) and serum creatinine level (rs = 0.48, p = 0.03). CONCLUSION Endothelial c-Jun activation in PC may contribute to PC loss, interstitial fibrosis and late allograft deterioration in CAMR. These data suggest that c-Jun is an appropriate therapeutic target of CAMR.

Here, we report the successful treatment of a 38-yr-old Japanese man diagnosed with recurrent immunoglobulin A nephropathy (IgAN) with chronic active antibody-mediated rejection (CAAMR), three yr after undergoing living-related donor kidney transplantation. Immediately after transplantation, the allograft function was well maintained with a serum creatinine (S-Cr) level of

c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.

Non-immune injury leading to interstitial fibrosis and tubular atrophy (IF/TA) in renal allografts has various etiologies, but pathological means of verification have yet to be developed. Medullary ray injury (MRI) is a pathological feature of many non-immune injuries inducing IF/TA and pathological determination of calcineurin inhibitor (CNI) toxicity proceeding to striped fibrosis. We investigated the contribution of CNI toxicity to MRI and other non-immune etiologies related to IF/TA. In this study MRI is defined as fibrosis and inflammation localized exclusively to the medullary ray. Thirty-six protocol biopsies showing MRI were analyzed and classified histopathologically as following: MRI related to CNI toxicity; chronic obstruction or reflux nephropathy; and acute or chronic pyelonephritis. The etiology of MRI was CNI toxicity (n= 16, 44.4%), chronic obstruction (n= 13, 36.1%), acute or chronic pyelonephritis (n= 2, 5.6%), and other (n= 5, 13.9%). We performed cystography in seven cases of MRI related to chronic obstruction or reflux nephropathy and six cases showing vesicoureteral reflux. The ci+ct score showed significant progression after one year in 30 of the 36 cases (1.53 ± 1.04 vs. 3.03 ± 1.13, P < 0.01). MRI has various etiologies and may also predict changes in urological complications. The classification of MRI may be useful to determine the non-immune etiology leading to IF/TA.