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.

Renal shear wave velocity by acoustic radiation force impulse did not reflect advanced renal impairment.

AIM: Acoustic radiation force impulse is a noninvasive method for evaluating tissue elasticity on ultrasound. Renal shear wave velocity measured by this technique has not been fully investigated in patients with renal disease. The aim of the present study was to compare renal shear wave velocity in end-stage renal disease patients and that in patients without chronic kidney disease and to investigate influencing factors. METHODS: Renal shear wave velocities were measured in 59 healthy young subjects (control group), 31 subjects without chronic kidney disease (non-CKD group), and 39 end-stage renal disease patients (ESRD group). Each measurement was performed 10 times at both kidneys, and the mean value of eight of 10 measurements, excluding the maximum and minimum values, was compared. RESULTS: Renal shear wave velocity could be measured in all subjects. Renal shear wave velocity in the control group was higher than in the non-CKD group and in the ESRD group, and no difference was found between the non-CKD group and the ESRD group. Age and depth were negatively correlated to the renal shear wave velocity. In multiple regression analysis, age and depth were independent factors for renal shear wave velocity, while renal impairment was not. There was no difference between the non-CKD group and the ESRD group, even when ages were matched and depth was adjusted. CONCLUSION: Renal shear wave velocity was not associated with advanced renal impairment. However, it reflected alteration of renal aging, and this technique may be useful to detect renal impairment in the earlier stages.

Apoptosis induced by an uromodulin mutant C112Y and its suppression by topiroxostat.

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD that encodes uromodulin. Topiroxostat, a novel non-purine analog, selectively inhibits xanthine oxidase and reduces the serum uric acid levels and the urinary albuminuria. METHODS: Genomic DNA of a patient was extracted from peripheral white blood. Exons and flanking sequences of UMOD were amplified by PCR with primers. Mutation analysis was performed by direct sequencing of the PCR products. The wild-type and mutant uromodulin were expressed in HEK293 cells and analyzed by western blotting, immunoprecipitation, immunofluorescence, and flow cytometry. RESULTS: We identified an FJHN patient who carried a novel UMOD mutation G335A (C112Y). The levels of both cytosolic and secreted C112Y protein were significantly decreased compared with the wild-type, whereas the level of ubiquitination was higher in C112Y than that in the wild type. The half-life of C112Y was shortened and it was restored by a proteasome inhibitor MG132. Immunofluorescence revealed decreased levels of C112Y in the Golgi apparatus and on the plasma membrane. Expression of C112Y induced cellular apoptosis as revealed by flow cytometry. Apoptosis induced by C112Y was suppressed by topiroxostat. CONCLUSION: C112Y causes its protein instability resulting cellular apoptosis which could be suppressed with topiroxostat.

Atypical Anti-Glomerular Basement Membrane Nephritis After the First Dose of the Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine.

Atypical anti-glomerular basement membrane (GBM) nephritis is a slowly progressive characterized by linear deposition of immunoglobulin (Ig) G in the GBM without circulating anti-GBM antibodies or lung involvement. There is no established therapy for this disease, and efficacy of the immunosuppressive treatment is questionable. A few cases of atypical anti-GBM nephritis have been reported after administration of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Classic anti-GBM disease has also been reported after the administration of the second dose of the SARS-CoV-2 vaccine. Herein, we present the case of a SARS-CoV-2 vaccine-induced atypical anti-GBM nephritis that developed after the first dose and was unresponsive to immunosuppressive therapy. A 57-year-old Japanese woman developed edema 11 days after the first dose of the SARS-CoV-2 mRNA vaccine. She developed nephrotic-range proteinuria and microscopic hematuria. Renal biopsy revealed endocapillary proliferative glomerulonephritis with linear IgG deposition. However, electron-dense deposits were not detected on electron microscopy. The patient tested negative for circulating anti-GBM antibodies and was diagnosed with atypical anti-GBM nephritis. Although steroids and mizoribine were administered, the patient's renal function deteriorated. In conclusion, atypical anti-GBM nephritis may have earlier onset than the classic anti-GBM disease. Given its uncertainty of effectiveness, immunosuppressive agents should be carefully used for SARS-CoV-2 mRNA vaccine-induced atypical anti-GBM nephritis.

Rapid three-dimensional analysis of renal biopsy sections by low vacuum scanning electron microscopy.

Renal biopsy paraffin sections were examined by low vacuum scanning electron microscopy (LVSEM) in the backscattered electron (BSE) mode, a novel method for rapid pathological analysis which allowed detailed and efficient three-dimensional observations of glomeruli. Renal samples that had been already diagnosed by light microscopy (LM) as exhibiting IgA nephropathy, minor glomerular abnormalities, and membranous glomerulonephritis (GN) were rapidly processed in the present study. Unstained paraffin sections of biopsy samples on glass slides were deparaffinized, stained with platinum blue (Pt-blue) or periodic acid silver-methenamine (PAM), and directly observed with a LVSEM. Overviews of whole sections and detailed observations of individual glomeruli were immediately performed at arbitrary magnifications between ×50 to ×18,000. Cut surface views and surface views of glomeruli were demonstrated at the same time. On Pt-blue-stained sections, podocytes, endothelia, mesangium, and glomerular basement membranes (GBMs) could be distinguished due to the different yields of BSE signals, and pathological features were investigated in every sample. The abnormal surface appearances of podocytes with foot processes and the varying thicknesses of GBM were revealed three-dimensionally, features difficult to observe under LM and transmission electron microscopy. PAM-positive GBM alterations in membranous GN were distinctly visualized through overlying cells without cell removal under LVSEM at high magnification. Not only prominent spike formation but also slight protrusions were clearly revealed in the side views of GBM. Crater-like or hole-like structures were shown in the en face views of GBM. Accordingly, LVSEM is expected to provide a novel approach to the pathological diagnosis of human glomerular diseases using conventional renal biopsy sections.

Predictive Value of Cortical Thickness Measured by Ultrasonography for Renal Impairment: A Longitudinal Study in Chronic Kidney Disease.

BACKGROUND: Kidney size is associated with renal function, however it is not elucidated whether kidney size is a risk for the progression of chronic kidney disease. The aim of this study was to investigate the predictive value of morphological evaluation of kidney size by ultrasonography for the progression of renal dysfunction. METHODS: Morphological parameters including kidney length, volume, cortical thickness, and medullary thickness were measured by ultrasonography in 87 patients with chronic kidney disease, and adjusted by body size. Renal functions at baseline and after 2 years were measured and the associations of morphological parameters to decline in renal function over 2 years were analyzed. RESULTS: Height-adjusted cortical thickness was correlated to decline in renal function (r = 0.426, p < 0.001). Height-adjusted cortical thickness could predict renal dysfunction with the area under the curve of 0.786, and height-adjusted cortical thickness of 4.0 mm/cm was a cut off value with a sensitivity of 72.5% and a specificity of 80.0% for the risk of a more than 30% decline in renal function or initiation of dialysis. CONCLUSIONS: We provide new insights into the utility of measuring cortical thickness by ultrasonography for predict future renal impairment.

Renal shear wave elastography for the assessment of nephron hypertrophy: a cross-sectional study in chronic kidney disease.

PURPOSE: To investigate the association of renal elasticity to microscopic findings of nephron hypertrophy and nephrosclerosis. METHODS: Patients who underwent renal biopsy were enrolled. Renal elasticity was measured by acoustic radiation force impulse, and nephron size (glomerular volume, non-sclerotic glomerular density, and mean profile tubular area) and nephrosclerosis (globally sclerotic glomeruli and interstitial fibrosis) were estimated. Nephron hypertrophy was indicated by larger glomerular volume, larger tubular area, and lower non-sclerotic glomerular density. Nephrosclerosis was indicated by a higher percentage of globally sclerotic glomeruli and higher severity of fibrosis. RESULTS: Renal elasticity was negatively correlated with glomerular volume (r = - 0.480, P = 0.024) and mean tubular area (r = - 0.469, P = 0.028), but it was not correlated with non-sclerotic glomerular density (r = 0.205, P = 0.359), percentage of globally sclerotic glomeruli (r = 0.057, P = 0.800), and severity of fibrosis (r = 0.014, P = 0.950). In a multiple linear regression analysis, glomerular volume and mean tubular area were independently associated with renal elasticity (std ß = - 0.454, P = 0.015 and std ß = - 0.577, P = 0.007, respectively). CONCLUSION: Renal elasticity was correlated with microstructural findings of nephron hypertrophy. Measuring renal elasticity could help in detecting kidney disease.

Shewanella algae Bacteremia in an End-stage Renal Disease Patient: A Case Report and Review of the Literature.

A 71-year-old man was admitted because of nausea and abdominal pain. He was receiving an erythropoiesis-stimulating agent for anemia and dysregulated iron metabolism due to stage G5 chronic kidney disease. He had a history of raw fish intake and was diagnosed with infectious enterocolitis, which worsened and led to septic shock. Shewanella putrefaciens grew in the blood culture, but Shewanella algae was identified in a 16S rRNA gene sequence analysis. We herein report a case of S. algae bacteremia believed to have been transmitted orally. We also reviewed previous case reports on Shewanella infection in end-stage renal disease patients.

Left Renal Cortical Thickness Measured by Ultrasound Can Predict Early Progression of Chronic Kidney Disease.

AIMS: The kidney becomes atrophic in advanced chronic kidney disease, and renal size and parenchymal volume correlate with renal function. However, alterations in renal parenchymal volume have not been adequately studied in terms of the renal cortex and medulla. We investigated the relationship between the changes in the renal cortex and medulla and renal function. METHODS: Renal ultrasound (US) parameters including renal length, parenchymal thickness, cortical thickness and medullary thickness were assessed in 176 subjects, who were categorized into 4 groups based on the estimated glomerular filtration rate (ml/min/1.73 m2): group 1, ≥ 90; group 2, ≥ 60 but < 90; group 3, ≥ 30 but < 60; and group 4, < 30. Renal US parameters in both kidneys were compared among the 4 groups. RESULTS: We found stepwise associations in renal length, cortical thickness and parenchymal thickness with decreased renal function. Medullary thickness showed no changes among groups 1-3. Multiple linear regression analysis including sex, age and renal US parameters showed that only renal length was an independent predictor of renal function. When analyzed in groups 1-3, cortical thickness was the strongest associated parameter. Lower cortical left/right ratio (left cortical thickness/right cortical thickness) showed a stepwise association with a decrease in renal function. CONCLUSION: Renal length and cortical thickness measured by US were correlated with renal function. In particular, left cortical thickness could help to detect early changes in renal function.

[Case of autosomal dominant polycystic kidney disease presenting hepatic encephalopathy].

We report a 71-year-old woman with autosomal dominant polycystic kidney disease (ADPKD), who presented with hepatic encephalopathy. She was diagnosed as having ADPKD at 61 years of age. Thereafter, her renal function gradually worsened and she was admitted to our hospital because of encephalopathy and end-stage renal failure. The main laboratory findings were as follows: BUN 77 mg/dl; creatinine 9.0 mg/d; ammonia 573 microg/dl. Hepatic encephalopathy was improved after hemodialysis and administration of lactulose. The liver demonstrated multiple cysts on computed tomography. Angiography demonstrated that the peripheral branch of the portal vein was stenotic and a spleno-renal shunt was detected. We considered that portal hypertension was caused by multiple liver cysts, and that hepatic encephalopathy was caused by the spleno-renal shunt. It is generally considered that severe hepatic complications are rare in ADPKD, but this case suggested the need to screen for the development of hepatic lesions in ADPKD.

Influence of Olmesartan on Sirtuin 1 mRNA Expression in 5/6 Nephrectomized Spontaneously Hypertensive Rats.

BACKGROUND: Recent studies revealed that sirtuin 1 (SIRT1) has a relation to the mechanism of transforming growth factor-beta (TGF-beta) mediated apoptosis in glomerular mesangial cells and plays an important role in blood pressure regulation. It has been suggested that SIRT1 contributes to the renoprotective effect of angiotensin receptor blocker (ARB), but this has not yet become clearly recognized. In this study, we examined the relationship between SIRT1 and the therapeutic effect of olmesartan on renal injury in nephrectomized spontaneously hypertensive rats (SHRs). METHODS: Male Wistar rats and 5/6 nephrectomized (5/6Nx) SHRs were assigned to 5 groups as follows: group A, Wistar rats; group B, Wistar rats administered high-dose olmesartan (15 mg/kg/day); group C, 5/6Nx SHRs; group D, 5/6Nx SHRs administered low-dose (3 mg/kg/day) olmesartan; and group E, 5/6Nx SHRs administered high-dose olmesartan. The drugs were administered for 12 weeks. Blood pressure and urinary protein excretion were measured every 4 weeks. Serum creatinine, glomerular sclerosis, SIRT1 mRNA level, TGF-beta mRNA level and klotho mRNA level were measured at the end of the examination. RESULTS: Systolic blood pressure, urinary protein excretion, serum creatinine and glomerular sclerosis in Wistar rats were significantly lower than that of 5/6Nx SHRs. Among 5/6Nx SHRs, high doses of olmesartan significantly decreased urinary protein excretion, serum creatinine and glomerular sclerosis compared to the non-treated and low-dose olmesartan groups. Expression of SIRT1 and klotho mRNA were significantly downregulated in 5/6Nx SHRs; however, olmesartan did not attribute to any change in gene expression. Expression of TGF-beta mRNA was significantly increased in 5/6Nx SHRs, and olmesartan did not affect the level of TGF-beta mRNA expression. CONCLUSION: Expression of SIRT1 is decreased in 5/6Nx SHRs compared to Wistar rats. Olmesartan suppressed glomerular sclerosis, but did not increase the expression of SIRT1, suggesting that the renoprotective effect of olmesartan is independent of the SIRT1 pathway.

The Effects of Olmesartan and Alfacalcidol on Renoprotection and klotho Gene Expression in 5/6 Nephrectomized Spontaneously Hypertensive Rats.

Recently, an angiotensin inhibitor has been shown to upregulate the klotho mRNA level in chronic renal failure. In addition, the administration of vitamin D has been reported to improve the mortality of patients with chronic renal failure. In this study, we examined the effects of an angiotensin inhibitor and/or vitamin D on the progression of chronic renal failure by using male 5/6 nephrectomized (5/6Nx) spontaneously hypertensive rats. Male 5/6Nx spontaneously hypertensive rats were assigned to 4 groups as follows: 5/6Nx group, 5/6Nx rats; Alf group, 5/6Nx rats administered alfacalcidol (0.2 µg/kg/day); Olm group, 5/6Nx rats administered olmesartan (15 mg/kg/day); Alf + Olm group, 5/6Nx rats administered alfacalcidol (0.2 µg/kg/day) and olmesartan (15 mg/kg/day). These drugs were administered for 12 weeks. Systolic blood pressure in the Alf, Olm and Alf + Olm groups were significantly decreased relative to that in the 5/6Nx group during the 12-week experimental period. As a result, all treated groups showed renoprotection based on improvement of the systolic blood pressure, urinary protein excretion and histological renal fibrosis. Combination therapy of alfacalcidol and olmesartan was more effective than either alfacalcidol or olmesartan alone. Expression of klotho mRNA was significantly upregulated in the Alf + Olm group in comparison with in the 5/6Nx group. Serum levels of fibroblast growth factor 23 in the Alf group and the Alf + Olm group were significantly higher than those in the 5/6Nx group and the Olm group. In conclusion, the combination of Olm and Alf inhibited the progression of renal damage in the 5/6Nx group through the strong antihypertensive effect as well as the upregulation of the klotho gene.