Ectopic Production of Parathyroid Hormone and Production of Parathyroid Hormone-related Protein in Dedifferentiated Endometrial Carcinoma Induced Severe Hypercalcemia.

Hypercalcemia is a significant complication in cancer patients, primarily caused by parathyroid hormone-related peptide (PTHrP) and, rarely, by parathyroid hormone (PTH) production from tumors. We report a case of severe hypercalcemia in a woman with uterine cancer who exhibited elevated PTH and PTHrP levels. Surgical intervention revealed dedifferentiated endometrial carcinoma. Postoperatively, PTH and PTHrP levels normalized but subsequently increased due to metastases. A molecular analysis confirmed the expression of the PTH gene and protein within the tumor, indicating ectopic PTH production. In diagnosing and treating cancers, it is necessary to consider not only PTHrP production but also ectopic PTH production.

Arteriolar hyalinization at 0-hour biopsy predicts long-term graft function in deceased kidney transplantation.

OBJECTIVES: Regarding the relationship between donor kidney quality and renal graft function after deceased kidney transplantation (KTx) following donation after cardiac death (DCD), the evaluation timing varies depending on the study. Evaluation of histology and changes in long-term renal graft function is limited. METHODS: A retrospective single-center study included 71 recipients who underwent 0-hour biopsy for KTx from DCD. The recipients were divided into two groups to evaluate factors related to renal graft function (study1). The two groups were categorized as stable graft function and poor graft function with the change of estimated glomerular filtration rate (eGFR) after KTx. The recipients were then divided into four groups to assess whether the factors identified in study1 were related to the change in long-term renal graft function (study2). They were categorized as follows: Improved, Stable, Deteriorated, and Primary non-function with the change of eGFR after KTx. RESULTS: In study1, donor age ≥ 50 years (29.5% vs. 65.2%; p = 0.09), banff arteriolar hyalinosis (ah) score (0.66 ± 0.78 vs. 1.2 ± 1.0; p = 0.018), and presence of glomerulosclerosis (43.2% vs. 76.2%; p = 0.017) were significant risk factors for poor long-term graft function. When the recipients were divided into four groups, the severity of ah correlated well with changes in long-term renal function. CONCLUSIONS: We can predict the shift in long-term renal graft function after KTx from DCD according to the severity of ah by 0-hour biopsy.

A Case of Dabigatran-related Nephropathy Complicated by Tubulointerstitial Nephritis in a Patient with a Normal Renal Function and Undiagnosed IgA Nephropathy.

A 69-year-old woman was referred to our hospital because of an acute kidney injury with macroscopic hematuria. She had been taking dabigatran for atrial flutter for six years. Based on the typical histological findings of her kidney biopsy and her history of dabigatran use with prolonged activated partial thromboplastin time, she was diagnosed with dabigatran-related nephropathy complicated by tubulointerstitial nephritis with IgA nephropathy. After prednisolone therapy, the renal function improved. Direct-acting oral anticoagulants, including dabigatran, may cause anticoagulant-related nephropathy similar to warfarin, even in patients with a normal renal function. Tubulointerstitial nephritis may coexist with dabigatran-related nephropathy, and prednisolone therapy should be considered in such cases. IgA nephropathy has been reported as a background disease, and caution should be exercised when encountering it.

Pathogenic variants of Alport syndrome and monogenic diabetes identified by exome sequencing in a family.

We present a family of two female Alport syndrome patients with a family history of impaired glucose tolerance. Whole exome sequencing identified a novel heterozygous variant of COL4A5 NM_033380.3: c.2636 C > A (p.S879*) and a rare variant of GCK NM_001354800.1: c.1135 G > A (p.A379T) as the causes of Alport syndrome and monogenic diabetes, respectively. Two independent pathogenic variants affected the clinical phenotypes. Clinical next-generation sequencing is helpful for identifying the causes of patients' manifestations.

Histopathological features of kidney and renal prognosis in patients with preeclampsia.

OBJECTIVE: Understanding the long-term prognosis of preeclampsia (PE) is important. Proteinuria and poor renal function persist in some PE patients, but the relationship between their histopathological findings of kidney and renal prognosis is unknown. Our objective was to clarify the relationship between clinicopathological features and renal prognosis in PE patients. STUDY DESIGN: Retrospective observational study. MAIN OUTCOME MEASURES: Seventy patients who had been referred to the Niigata University Hospital between 1977 and 2014 and were diagnosed with PE were classified into unimproved and improved groups. The unimproved group included patients whose serum creatinine level had doubled and/or whose proteinuria had persisted until the end of observation, which included three patients with end-stage kidney disease (ESKD). The improved group included patients whose serum creatinine level did not double and whose proteinuria had disappeared until the last observation. We examined and compared these patients' characteristics, clinical and laboratory findings, and renal histopathological findings from percutaneous kidney biopsies. RESULTS: There were no significant differences in the clinical backgrounds and clinical findings between the two groups during pregnancy. However, light microscopy findings of their kidney biopsies were able to identify significantly more severe duplications of the capillary loop, interstitial cell infiltration, and interstitial fibrosis in the unimproved group. CONCLUSIONS: Histopathological examination of the kidney may be a valid method for predicting the long-term prognosis of renal function and for histological a risk assessment of poor renal recovery in PE patients.

Tubulointerstitial nephritis with monotypic lympho-plasmacytic infiltrates in a patient with primary Sjögren's syndrome accompanied by IgA-type monoclonal gammopathy.

BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

Analysis of the prevalence of systemic de novo thrombotic microangiopathy after ABO-incompatible kidney transplantation and the associated risk factors.

OBJECTIVES: To analyze the prevalence of systemic de novo thrombotic microangiopathy in ABO-incompatible kidney transplantation and risk factors associated with this condition. METHODS: A total of 201 patients who received living-donor kidney transplantation (114 patients with ABO-identical kidney transplantation and 87 patients with ABO-incompatible kidney transplantation) were retrospectively analyzed. Systemic de novo thrombotic microangiopathy was diagnosed clinically according to the presence of thrombocytopenia with microangiopathic hemolytic anemia and pathological findings of thrombotic microangiopathy. Anti-A and anti-B antibodies were purified from human plasma, and these antibodies' bindings to human kidney were investigated in vitro. RESULTS: ABO-incompatible kidney transplantation was a significant risk factor of systemic de novo thrombotic microangiopathy (odds ratio 55.9, 95% CI 1.8-8.9, P < 0.001) after transplantation. Multivariate logistic regression analysis showed that non-use of mycophenolate mofetil, pretreatment immunoglobulin G antibody titer ≥64-fold and pretransplant immunoglobulin M antibody titer ≥16-fold were significant risk factors for systemic de novo thrombotic microangiopathy in ABO-incompatible kidney transplantation. Microvascular inflammation of 1-h post-transplant biopsy could be observed more frequently in thrombotic microangiopathy patients than in non-thrombotic microangiopathy patients. Anti-A and anti-B antibodies purified from human plasma showed a strong in vitro reaction against human kidney when the antibody titer was ≥16-fold. CONCLUSIONS: Antibody titer should be decreased to ≤16-fold until the day of ABO-incompatible kidney transplantation by desensitization therapy including mycophenolate mofetil. The 1-h biopsy results might help to diagnose systemic de novo thrombotic microangiopathy.

Bortezomib Eliminates Plasma Cells From a Renal Graft in Plasma Cell-Rich Acute Rejection.

Plasma cell-rich acute rejection (PCAR) and antibody-mediated rejection (ABMR), for which a standard treatment has not yet been established, are associated with poor graft survival after kidney transplantation. Here, we report a case series of 3 Japanese patients diagnosed with PCAR accompanied by ABMR. Steroid pulse therapy and rabbit antithymocyte globulin, plasma exchange, intravenous immunoglobulin, and rituximab therapies were sequentially performed in the first case. A graft biopsy after each treatment showed that plasma cell infiltration persisted. Five months after the initiation of rejection therapy, the patient was subjected to bortezomib therapy, which led to the partial elimination of plasma cells from the graft. However, the graft function gradually deteriorated, and hemodialysis treatment was warranted. In the other 2 cases, the patients received the same combination of therapy including bortezomib within a short period. Graft biopsies performed subsequently showed a marked decrease in the number of infiltrated plasma cells, and stabilization of renal graft function was achieved in both cases. Bortezomib, which targets plasma cells, is a potent drug that eliminates infiltrated plasma cells from the graft in PCAR. Thus, in addition to conventional therapy comprising plasma exchange, intravenous immunoglobulin, and rituximab against ABMR, bortezomib may be necessary to administer without any delay to control PCAR.

Acute kidney injury in an adult patient with IgA nephropathy and chronic replicative Epstein-Barr virus infection.

Most of the adult population are infected with Epstein-Barr virus (EBV), but as EBV replication is usually under immune system control, the majority of individuals remain asymptomatic. On the other hand, some individuals continuously retain a high EBV antibody titer and a high EBV DNA load in their blood, suggesting a defect of EBV replication control. To date, only a limited number of reports have addressed the relationship between this chronic form of EBV infection and renal involvement. Here, we describe an 80-year-old woman who developed acute kidney injury shortly after an episode of mosquito bites, accompanied by a severe skin rash, which raised a suspicion of chronic EBV infection. She was subsequently diagnosed as having chronic replicative EBV infection. Renal biopsy revealed a diagnosis of IgA nephropathy with crescent formation. Although the relationship between IgA nephropathy and EBV infection has been discussed, no substantial understanding has yet emerged. The patient's characteristic clinical course suggested that the renal failure may have been partly attributable to chronic EBV infection. This case suggests that physicians may need to consider the possibility that chronic EBV infection may affect the clinical course of IgA nephropathy, or exacerbate the disease.

[RESULTS OF TONSILLECTOMY AND STEROID PULSE THERAPY IN 20 CASES OF RECURRENT IgA NEPHROPATHY AFTER KIDNEY TRANSPLANTATION].

(Background) The standard treatment for recurrent immunoglobulin A nephropathy (rIgAN) after kidney transplantation (KTx) has not been established. (Methods) The results of treatment consisting of tonsillectomy and steroid pulse therapy in 20 recipients who were diagnosed as rIgAN were retrospectively analyzed. (Results) The level of proteinuria significantly decreased from 0.84±0.81 g/day to 0.27±0.31 g/day after treatment (P=0.007). Microscopic hematuria disappeared or improved in 58.3% and 66.6% of recipients 6 and 12 months after treatment, respectively. Serum creatinine levels remained stable for 5 years by the treatment, except for 3 cases of graft loss. Sixteen recipients received renal graft biopsies before and after treatment. Mesangial IgA deposition were dramatically decreased in 7 recipients (43.75%). The degree of mesangial hypercellularity, endocapillary hypercellularity, and crescents formation improved in 3 (18.8%), 6 (37.5%), and 4 (25%) recipients after treatment. (Conclusion) Steroid pulse therapy combined with tonsillectomy may be clinically and histopathologically effective treatment for rIgAN after KTx.

Immune-mediated acquired lecithin-cholesterol acyltransferase deficiency: A case report and literature review.

BACKGROUND: Recessive inherited disorder lecithin-cholesterol acyltransferase (LCAT) deficiency causes severe hypocholesterolemia and nephrotic syndrome. Characteristic lipoprotein subfractions have been observed in familial LCAT deficiency (FLD) with renal damage. OBJECTIVE: We described a case of acquired LCAT deficiencies with literature review. METHODS: The lipoprotein profiles examined by gel permeation-high-performance liquid chromatography (GP-HPLC) and native 2-dimensional electrophoresis before and after prednisolone (PSL) treatment. RESULTS: Here we describe the case of a 67-year-old man with severely low levels of cholesterol. The serum LCAT activity was undetectable, and autoantibodies against it were detected. The patient developed nephrotic syndrome at the age of 70 years. Renal biopsy revealed not only membranous glomerulonephritis but also lesions similar to those seen in FLD. We initiated PSL treatment, which resulted in remission of the nephrotic syndrome. In GP-HPLC analysis, lipoprotein profile was similar to that of FLD although lipoprotein X level was low. Acquired LCAT deficiencies are extremely rare with only 7 known cases including ours. Patients with undetectable LCAT activity levels develop nephrotic syndrome that requires PSL treatment; cases whose LCAT activity levels can be determined may also develop nephrotic syndrome, but spontaneously recover. CONCLUSION: Lipoprotein X may play a role in the development of renal impairment in individuals with FLD. However, the effect might be less significant in individuals with acquired LCAT deficiency.

Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management. CASE PRESENTATION: We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive. CONCLUSIONS: The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

Tubulointerstitial nephritis and Fanconi syndrome in a patient with primary Sjögren's syndrome accompanied by antimitochondrial antibodies: A case report and review of the literature.

We describe a 53-year-old woman with primary Sjögren's syndrome and tubulointerstitial nephritis showing distal renal tubular acidosis and Fanconi syndrome. The patient showed high serum IgM levels and positivity for antimitochondrial antibodies, although her liver function was in normal range. According to our literature review, 75% of patients with tubulointerstitial nephritis who were positive for antimitochondrial antibodies showed Fanconi syndrome, suggesting that these antibodies may directly be associated with the pathophysiology of Fanconi syndrome.

[THE USE OF BORTEZOMIB FOR THE TREATMENT OF CHRONIC ANTIBODY MEDIATED REJECTION AFTER KIDNEY TRANSPLANTATION].

(Backgrounds) The efficacy of bortezomib for chronic antibody mediated rejection (CAMR) after kidney transplantation is still obscure. (Materials and methods) CAMR were persisted in 5 recipients who were treated with plasma exchange, low dose of IVIG, steroid pulse therapy, and rituximab. 1.3 mg/m2 of bortezomib was administered on days 1, 4, 8, 11. Serum creatinine (sCr) levels, anti-HLA antibodies, and histology were analyzed. (Results) Stable sCr levels were obtained in 3 out of 5 recipients. No one lost renal graft function during follow-up periods. Anti-HLA class I antibodies were significantly decreased after bortezomib treatment, however anti-HLA class II antibodies were not changed. Histology showed no improvement at 6 months after bortezomib administration. Two recipients whose sCr levels increased during follow-up had already had interstitial fibrosis and tubular atrophy (IF/TA) in histology before bortezomib treatment. (Conclusions) The use of bortezomib after IF/TA could be detected in histology may not contribute to stabilize renal graft function in CAMR.

[LONG-TERM OUTCOME OF PEDIATRIC KIDNEY TRANSPLANTATION: A SINGLE-CENTER EXPERIENCES].

(Background) Long-term care is necessary for normal growth and development of pediatric recipients of kidney transplants. We report on our experience with pediatric kidney transplantation (KTx) during the past 19 years. (Methods) We retrospectively analyzed the data from 26 recipients who received KTx between 1996 and 2014 at Niigata University Hospital (one patient underwent two consecutive KTx during the designated period). All recipients were 16 years old or younger at the time of KTx. (Results) The graft survival rates at 1, 5, and 10 years after transplantation were 96%, 96%, and 88%, respectively. Three recipients lost the renal graft function due to graft thrombosis, antibody mediated rejection and steroid resistant rejection. Drug non-adherence was associated with rejection episodes, which led to the increasing of estimated glomerular filtration rate (eGFR) level. In addition, renal graft function was related to the growth after KTx. Eighteen recipients graduated from high school during follow-up periods and 17 recipients obtained employment. (Conclusion) Interventions promoting adherence should be implemented among pediatric recipients and parents to optimize graft survival and growth after KTx. Successful KTx contributed the high rate of social participation and employment after pediatric KTx.

Tubulointerstitial Nephritis with IgM-Positive Plasma Cells.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis.

The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid). The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.