Diabetic MedicineVolume 37, Issue 12 p. 1961-1961 Issue InformationFree Access Table of Contents 2 First published: 13 November 2020 https://doi.org/10.1111/dme.14035AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume37, Issue12December 2020Pages 1961-1961 RelatedInformation

Aims Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. Methods This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. Results Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. Conclusions Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

A 62-year-old man visited our hospital with a mild sore throat, high-grade fever, and clavicular pain. Seven years earlier, he had been diagnosed with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. His clavicles were tender and remarkably swollen. Also noted was marked pitting edema in the lower extremities and pustulosis on the palms and soles of the feet. Laboratory studies on admission showed an elevated white cell count (23,400/μl) and serum C-reactive protein level (24.4 mg/dl). Urinalysis revealed proteinuria (2+) and occult blood (3+) with numerous dysmorphic red blood cells and hyalin casts. The patient was diagnosed with recurrence of his SAPHO syndrome and started on oral glucocorticoid therapy. By day 9 after admission, he had gained 16 kg in body weight, and his proteinuria (6.4 g/day) and serum creatinine level (2.3 mg/dl) were elevated. Renal biopsy revealed mesangial proliferative glomerulonephritis with deposition of IgA and C3 in the mesangial area and along the capillary walls. The patient was diagnosed with IgA nephropathy accompanied by nephrotic syndrome. With oral prednisolone therapy, his fever, clavicular pain, and proteinuria were gradually relieved. The clinical course in this case suggests the onset of nephrotic syndrome with IgA nephropathy was associated with the recurrence of the patient’s SAPHO. To our knowledge, this is the first reported case of SAPHO-associated IgA nephropathy.

Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (≥19.6 pg/ml) and the lowest eGFR tertile (<30 ml/min per 1.73 m(2)). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD.

Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF(165) isoform in both kidney and liver under the control of the human alpha-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.

BACKGROUND:Fractalkine (Fkn) is a chemokine that affects cells expressing its receptor, CX3CR1, including CD16-positive (CD16+) monocytes/macrophages (CD16+ Mos). The relationship of levels of glomerular Fkn expression and infiltration by CD16+ Mos with the severity and diversity of glomerular lesions in human lupus nephritis is not known.STUDY DESIGN:Retrospective cross-sectional analysis of variables observed in biopsy specimens.SETTINGS & PARTICIPANTS:88 patients with systemic lupus erythematosus.PREDICTOR:Histological class and severity of lupus nephritis according to the International Society of Nephrology/Renal Pathology Society and clinicopathologic factors.OUTCOMES:Outcome variables are assays related to the degree of glomerular Fkn expression and CD16+ Mo infiltration.MEASUREMENTS:Immunohistological grading of Fkn staining, number of CD16+ Mos, and messenger RNA levels of Fkn and CD16 in glomeruli.RESULTS:Patients with proliferative lupus nephritis (class III and IV glomeruli) showed significantly greater glomerular Fkn expression and CD16+ Mo counts than those with other classes. Infiltrating CD16+ Mos within glomeruli expressed CX3CR1. Moreover, glomerular Fkn expression significantly correlated with the histopathologic activity index and CD16+ Mo counts, and CD16+ Mo counts significantly correlated with serum levels of blood urea nitrogen, complement (CH50), and anti-DNA antibody; estimated glomerular filtration rate; and urinary protein excretion. Glucocorticoid therapy had a tendency to decrease both glomerular Fkn expression and CD16+ Mo counts.LIMITATIONS:Only frozen biopsy specimens (from 49 patients) were analyzed for the evaluation of glomerular Fkn expression.CONCLUSION:Disease activity and proliferative glomerular lupus nephritis lesions are associated with the glomerular Fkn expression and CD16+ Mo accumulation.

A 49-year-old woman with a history of chronic hepatitis C virus infection and Hashimoto disease was admitted to our hospital because of proteinuria, hematuria, purpura, and edema in the lower extremities. Laboratory data on admission revealed proteinuria (0.2 g/day), microscopic hematuria (3+) with RBC casts, renal dysfunction(serum creatinine 1.4 mg/dl), positive anti nuclear antigen (x640, speckled type), hypocoplementemia, mixed cryoglobulinemia (type III), and hepatitis C virus infection (AST 45 IU/l, ALT 33 IU/l). MPO-ANCA level was found to be high (356 EU). In renal biopsy, most glomeruli showed crescentic formation with the weak deposition of IgG, IgM, and C3 in the mesangial area and along the capillary wall. She was diagnosed as having systemic vasculitis associated with MPO ANCA. Methylprednisolone pulse therapy followed by oral prednisolone (40 mg/day) effectively normalized MPO ANCA level. It has been reported that ANCA is found in patients with HCV-associated mixed cryoglobulinemia. Therefore, in chronic hepatitis C patients with systemic vasculitis, we should consider the possibility of ANCA-related microscopic polyangiitis and make a correct diagnosis by renal biopsy.

BACKGROUND:Crescent formation in glomeruli means an acute active lesion that develops a rapidly progressive course. Therapies using pulse methylprednisolone, oral corticosteroids, and cyclophosphamide are recommended, but no agreement has been reached on the optimal therapy. There have been no controlled trials, because of the severity of this condition and because withholding treatment would become an ethical issue.METHODS:We evaluated the safety and efficacy of deoxyspergualin (DSG), an immunosuppressant, in a multicenter, prospective trial of 44 patients with crescent formation in over 10% of glomeruli, who were randomly placed into groups that received daily doses of 0.1 mg/kg (n = 21) and 0.2 mg/kg (n = 23) of DSG, given by a 1-h infusion for 4 weeks, and who were then monitored for 3 months. All patients received DSG in this open-label prospective study. We evaluated the levels of urinary protein and hematuria, and examined renal function after the DSG treatment.RESULTS:Urinary protein significantly decreased with each dose after starting the DSG administration and this efficacy was sustained for 2 months after the discontinuation of DSG. In the groups receiving 0.1 mg/kg and 0.2 mg/kg, mean urinary protein levels were 2.1 g/day and 2.3 g/day at the initiation of the DSG administration, 1.4 g/day and 1.6 g/day at week 4, and 1.5 g/day and 1.3 g/day at week 12, respectively. Hematuria was markedly improved by a dose of 0.2 mg/kg and was not exacerbated following the termination of DSG. Exacerbation of renal dysfunction, as measured by creatinine clearance, serum creatinine, and blood urea nitrogen was prevented by both doses of DSG. The most common adverse reaction was reversible neutropenia.CONCLUSIONS:Short-term treatment with DSG may be effective and tolerated in patients suffering from nephropathies with crescent formation.

We report a case of hypokalemic nephropathy associated with primary Sjögren's syndrome (SS). The patient presented with profound and persistent hypokalemia secondary to distal renal tubular acidosis (RTA). A renal biopsy exhibited tubular degeneration, marked interstitial fibrosis and intense macrophage infiltration. Hypokalemia has been reported to induce macrophage infiltration in experimental animal models but not in humans. This is the first report of intense tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy associated with SS.

BACKGROUND There is little direct evidence that fibroblasts are involved in the progression of the renal interstitial fibrosis in human glomerulonephritis. With the availability of a new specific marker for fibroblasts, we determined the presence of fibroblasts in kidneys with IgA nephropathy (IgAN) and correlated their numbers with various clinical parameters. In particular, we also prospectively asked if the number of fibroblasts in the renal interstitium correlates with prognosis. METHODS Cells positive for fibroblast-specific protein 1 (FSP1) were localized in renal biopsy specimens using immunohistochemistry with anti-FSP1 antibody. Clinical features were analyzed by one-way analysis of variance (ANOVA) with the Bonferroni correction. To assess the prognostic impact of the number of FSP1+ fibroblasts on renal survival in 142 patients with normal serum creatinine, the relationship between covariates to renal survival were evaluated univariately using the log-rank test and multivariately using Cox proportional hazards. RESULTS Fibroblasts identified by their expression of FSP1 accumulate in areas showing severe interstitial fibrosis. Some tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) in fibrotic areas also express FSP1. Numbers of FSP1+ fibroblasts directly correlate with serum creatinine (r = 0.74, P < 0.0001) and inversely correlate with estimated creatinine clearance (r = -0.54, P < 0.0001), and by multivariate analysis, the clinical factors influencing renal survival are urinary protein excretion [> or = 1.0 g/day, relative risk (RR) = 4.20, P= 0.032], hypertension (RR 5.85, P = 0.0027), and > or = 20 FSP1+ fibroblasts per high power field (HPF) (RR 7.39, P = 0.0015). Staining for FSP1+ fibroblasts is largely nonoverlapping with alpha-smooth muscle actin+ (alpha-SMA) cells in the interstitium. CONCLUSION The target protein FSP1 identifies human fibroblasts and tubular epithelium undergoing EMT, and distinguishes them from the diaspora of alpha-SMA+ vascular smooth muscle cells. FSP1+ fibroblasts are critically related to the progression of IgAN; consequently, staining FSP1 in renal biopsy specimens provides a valuable histologic index of progression.

A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years’ treatment.

We report a case of 47-year-old man with subclavian steal phenomenon (SSP). He affected chronic renal failure and received an upper extremity arteriovenous fistula creation for hemodialysis. Angiography showed SSP from right vertebral artery to left subclavian artery (SA), and mild stenosis of left SA. We consider that the course of SSP was synergetic effect of mild SA stenosis and hemodynamic effect due to arteriovenous access creation.

BACKGROUND:To clarify whether vascular endothelial adhesion molecules in glomeruli might contribute to the severity and diversity of glomerular lesions in lupus nephritis, their expression in lupus models was analyzed.METHODS:The expression levels of E- and P-selectin and vascular cell adhesion molecule-1 (VCAM-1) in glomeruli of different histopathologic grades of MRL/MpJ-lpr/lpr (MRL/lpr) lupus mice was studied using laser-capture microdissection of the glomeruli, followed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. The glomerular lesions in SCID mice injected with the 2B11.3 and 7B6.8 clones, which are derived from an MRL/lpr mouse and induce endocapillary proliferative and wire loop type of glomerular lesions, respectively, were analyzed. To investigate the effect of a soluble form of E-selectin (sE-selectin) on the development of glomerular lesions, sE-selectin-producing L cells were prepared by transfection of the cDNA encoding sE-selectin and injected into SCID mice.RESULTS:The glomeruli in MRL/lpr mice showed increased expression of these adhesion molecules, corresponding to the severity of the glomerular lesions. The endocapillary proliferative type lesions in SCID mice induced by the 2B11.3 clone showed significantly increased expression of the adhesion molecules, especially E-selectin and P-selectin, but the wire loop type lesion induced by the 7B6.8 clone expressed only VCAM-1. Formation of the endocapillary proliferative type lesions induced by the 2B11.3 clone was markedly prevented in association with elevation of the serum level of sE-selectin produced by the tansfected L cells.CONCLUSION:The severity and diversity of the histopathology of lupus nephritis are partially associated with the expression of vascular endothelial adhesion molecules in glomeruli.

BACKGROUND Idiopathic membranous nephropathy (IMN) is a representative form of refractory nephrotic syndrome in Japan. Although IMN is thought to run a more benign course in Japanese than in the Caucasian population, risk factors and appropriate treatment are controversial issues. METHODS The research group supported by a grant for "Progressive Renal Disease" from the Ministry of Health, Labor and Welfare, Japan, carried out a national survey of patients with IMN and nephrotic syndrome. Of 1066 nephrotic patients with histopathologically proven IMN registered from 1975 to 1993 in 85 institutions, 949 patients were studied. RESULTS The overall renal survival rates were 95.8%, 90.3%, 81.1%, and 60.5% at 5, 10, 15, and 20 years after diagnosis, respectively. When clinical and histopathologic features at onset of nephrotic syndrome were evaluated by multivariate analysis, male gender, old age (> or =60 years), high serum creatinine concentration (> or =1.5 mg/dL), and the development of tubulointerstitial lesions (> or =20% of the biopsy sample area) were significant predictors of progression to end-stage renal disease (ESRD). The renal survival rate in patients on steroid therapy was significantly higher than in patients on supportive therapy alone. Patients achieving a remission showed a significant reduction of risk for progression. CONCLUSION IMN is a disease with a comparatively good prognosis in Japan even when it is associated with nephrotic syndrome. Steroid therapy, which has not been recommended for IMN in most review articles, seems to be useful at least for Japanese patients. In particular, a remission from heavy proteinuria likely results in a favorable outcome.

64-year-old man, who came to us with diarrhea, presented with ectodermal changes such as hyperpigmentation, alopecia, and onychatrophy, and was affected by polyposis in the colorectum and stomach. The polyps were histologically consistent with those in Cronkhite-Canada syndrome (CCS). Interestingly, the patient also had colon cancer, as well as portal thrombosis and a high concentration of antinuclear antibody. Treatment with prednisolone ameliorated the symptoms and the gastrointestinal polyposis, while the cancer was successfully treated with a hemicolectomy. Six months after the surgery, the patient developed nephropathy, with nephrotic-range proteinuria, without recurrence of the cancer. The biopsied renal specimen showed membranous glomerulonephritis. This is a rare case of CCS associated with various complications such as colon cancer, portal vein thrombosis, a high titer of antinuclear antibodies, and membranous glomerulonephritis. Although the pathogenesis of CCS is essentially unknown, these complications might have been indicative of an underlying immunological abnormality.

When a 63-year-old man was hospitalized with nephrotic syndrome due to focal segmental glomerulosclerosis, a mediastinal mass was discovered. A biopsy specimen obtained by mediastinoscopy showed findings compatible with the plasma cell type of Castleman's disease. Fever, anemia, and anti-nuclear antibody were present. Serum concentrations of gamma globulin, acute phase proteins, and, most strikingly, interleukin-6 (IL-6) were elevated. Methylprednisolone pulse therapy resulted in no clinical improvement. Pathologic examination of the resected thymic tumor showed a squamous cell carcinoma immunoreactive for IL-6. To our knowledge, this case represents the first reported IL-6-producing thymic squamous cell carcinoma associated with Castleman's disease and nephrotic syndrome.

We describe a 76-year-old Japanese woman with primary systemic amyloidosis who presented with angina pectoris associated with ST-segment and T-wave abnormalities resulting from intramyocardial coronary artery amyloidosis. The patient was admitted to our hospital because of dyspnea and pretibial edema 7 years after the diagnosis of variant angina. A diagnosis of primary systemic amyloidosis (AL amyloid protein) was made after examination of gastric and endomyocardial biopsy specimens. The patient died of progressive, uncontrolled heart failure 3 months later. An autopsy study demonstrated only mild-to-moderate atherosclerosis in the epicardial coronary arteries. However, histological examination of the heart revealed diffuse stenoses and obstructions in the intramural coronary arteries by amyloid deposits. This patient had small-vessel coronary disease with ST-segment changes and angina caused by cardiac amyloidosis. A correct diagnosis of ischemic heart disease due to primary amyloidosis is important for estimation of the prognosis and for appropriate management.