Various Types Of Glomerulonephritis Research Articles

Analysis of Various Types of Glomerulonephritis with Crescents at a Single Center

Background The importance of crescent formation in glomerulonephritis has increased. However, detailed analysis of crescentic glomerulonephritis in Asia is scarce. In addition, advances in serological diagnostic techniques (antineutrophil cytoplasmic and antiglomerular basement membrane autoantibodies) and early diagnosis have reduced the number of cases meeting the strict definition of crescentic glomerulonephritis (>50% of glomeruli are crescentic). Therefore, we analyzed the clinicopathological features and renal prognosis of glomerulonephritis cases that exhibited at least one crescentic lesion. Methods We retrospectively evaluated 265 adult patients diagnosed with glomerulonephritis with at least one crescent formation based on the results of renal biopsy. We divided the patients into two groups based on the four types of glomerulonephritis, namely, the immune-complex (type II: IgA nephropathy, IgA vasculitis with nephritis, and lupus nephritis) and pauci-immune (type III: microscopic polyangiitis) groups. Factors affecting renal prognosis (end-stage renal failure requiring renal replacement therapy) were examined in a multivariate analysis using the Cox proportional hazards model. Kaplan–Meier curves and log-rank test were used to analyze and compare time from entry to renal death. Results Renal prognosis differed significantly between the immune-complex and pauci-immune groups. Among the four types of glomerulonephritis, IgA nephropathy was the most prevalent. Multivariate analysis showed that renal function at renal biopsy and the ratio of global sclerosis independently predicted renal prognosis, but the type of glomerulonephritis was not a factor. Conclusions Renal dysfunction at renal biopsy and the ratio of global sclerosis predicted renal prognosis, because it reflects the degree of irreversible renal damage. We also suspect that the formation of at least one crescentic lesion led to the development of these predictive factors, regardless of the type of glomerular disease and degree of crescent formation.

The severity of glomerular endothelial cell injury is associated with infiltrating macrophage heterogeneity in endocapillary proliferative glomerulonephritis

Endocapillary proliferation occurs in various types of glomerulonephritis (GN), with varying prognoses. We examined 42 renal biopsy samples representing endocapillary proliferative lesions from post-streptococcal acute GN (PSAGN), Henoch–Schönlein purpura nephritis (HSPN), and lupus nephritis (LN). In PSAGN, the glomerular capillary network was maintained, although severe lesions displayed dots or short, curved lines, indicating CD34-positive capillaries and suggesting capillary obstruction. Conversely, patients with LN and HSPN displayed obstruction of CD34-positive capillaries with dissociation from the glomerular basement membrane even in mild lesions. According to computer-assisted morphologic analysis, the cell density did not differ between the diseases. However, in PSAGN, the number of capillary loops was significantly increased, with a larger glomerular capillary luminal area than in the other groups. In addition, the number and frequency of CD163-positive cells (M2 macrophages) tended to be higher in PSAGN, while there were no significant differences in the number of CD68-positive (total) macrophages. These results indicate that in PSAGN, endothelial cell damage is less severe, and angiogenesis may be promoted. The severity of endothelial cell injury in each disease may be associated with differences in infiltrating inflammatory cell phenotypes.

Podocentric view of glomerular proteinuria: Focused on cytoskeletal changes and toward promising targeted therapies and challenges

Among renal cells, podocytes (glomerular epithelial cells) are the most critical to prevent plasma proteins from excessive loss by forming their sophisticated foot processes (FP) and slit diaphragms (SD). A general finding in the glomeruli of patients with nephrotic syndrome is the foot processes "effacement" resulted from dysregulated actin cytoskeleton reorganization. Ultrastructural analysis in patients with nephrotic syndrome has demonstrated that such changes tend to be dynamic and can sometimes be reversible. In a more molecular sense, injured podocytes can no longer maintain their tight regulation and "retract" their FP, but not "efface" them. Past studies have revealed multiple exquisite mechanisms and arrays of proteins participating in the regulation of cytoskeletal rearrangement, and these mechanisms serve as potential targets to treat. A major challenge to develop specific therapies is the targeted mechanism has to be crucial and specific enough for podocyte-oriented kidney diseases, and it would be even better to manifest in most of the glomerulonephritis. Studies have shown many approaches targeting different mechanisms, but none of them has been proved to be effective in clinical medicine. Up to the present, Abatacept (Orencia) is the first (and the only) clinical targeted therapy demonstrating limited success. It inhibits the co-stimulatory response of B7-1 (CD80) induced in various types of glomerulonephritis. Future clinical studies have to be expanded to substantiate this highly specific targeted therapy because the Abatacept effect is not generally accepted even within the nephrology community. Nevertheless, there are ongoing searches for specific treatment targeting podocytes through various approaches.

Features of lymphocyte differentiation in ANCA-associated and virus-associated glomerulonephritis in children

Glomerulonephritis is a heterogeneous group of immuno-inflammatory diseases. The purpose of the study: to analyze the subpopulation composition of lymphocytes in children with various types of glomerulonephritis. 50 children aged 1 to 16 years were examined: 1 group — 17 children aged 1 to 16 years with ANCA-associated glomerulonephritis; 2 group — 33 patients aged 2 to 16 years with virus-associated glomerulonephritis. Diagnostics of the subpopulation composition of lymphocytes was performed by flow cytometry using non-flushing technology using a three-color combination of monoclonal antibodies. It was found that the development of ANCA-associated glomerulonephritis is accompanied by signs of immunodeficiency against the background of a relative increase in the content of T-lymphocyte subpopulations. Differentiation of lymphocytes in children with virus-associated glomerulonephritis is ambiguous: the process goes either along the path of activation of antiviral protection, or along the path of development of insufficient antiviral activity of immunocytes. In children with virus-associated glomerulonephritis, a decrease in the level of B-lymphocytes was found, correlating with hypoimmunoglobulinemia A, which is an additional factor in reducing resistance on the mucous membranes. The study of lymphocyte differentiation in the development of glomerulonephritis is important for identifying the main immunological mechanisms involved in the pathogenesis of these diseases.

Clinical correlation and prognostic significance of immunofluorescence in renal biopsies of patients having Glomerulonephritis.

Objective:To correlate the immunofluorescence (IF) findings on renal biopsies of patients of glomerulonephritis (GN) with the clinical course of the disease.Methods:This retrospective descriptive study was done at the Department of Pediatrics Medicine Unit-I, Nishtar Hospital Multan, from January 2008 to January 2019. A total of 387 cases of both gender, aged up to 16 years, diagnosed having GN on the basis of renal biopsies by light microscopy (LM) and IF findings, were included. Outcome as remission, partial remission, no remission with stable kidney disease, no remission with progressive kidney disease and end-stage kidney disease (ESKD) were computed. Chi square test was applied to see the correlation of IF findings and outcome by taking p value less than 0.05 as statistically significant.Results:Focal segmental glomerulosclerosis (FSGS) was found to be the commonest histopathology finding noted in 158 (40.8%) followed by mesangioproliferative GN 74 (19.1%) and membranous nephropathy 42 (10.9%). Complete remission was observed in 145 (37.5%) cases whereas ESKD was seen in 26 (6.7%). Distinct pattern of IF findings were shown when distribution of IF findings were seen with respect to all study variables (p value < 0.001). For outcome, 134 (51.3%) IF negative cases had complete remission while 93 (35.6%) negative IF findings also had partial remission. ESKD was seen among 14 (25.9%) IgM positive and three (33.3%) IgA positive cases.Conclusion:Immunofluorescence proved an important diagnostic tool in reaching the exact diagnosis in various types of GN. Distinct correlation between IF findings and clinical course of various types of GN was observed. IF negative cases had better outcome and was not having progressive course of disease so prognosis remained better than IF positive cases in this study.

Concurrent Kidney Glomerular and Interstitial Lesions Associated with Kimura’s Disease

Background: Kimura disease (KD) is a chronic benign inflammatory disorder that is usually manifested as a deep, subcutaneous mass with or without regional lymphadenopathy in the head and neck region. Various types of glomerulonephritis are associated with KD, including minimal change disease (MCD), membranous glomerulopathy (MN), and immunoglobulin (Ig)A-nephropathy. Kidney interstitial lesion associated with KD is rarely reported. The aim of this study was to expand the spectrum of kidney lesions associated with KD. Methods: From 2007 to 2016, 12 cases of KD with kidney lesions were retrospectively reviewed. Pathological examinations included hematoxylin and eosin staining, periodic acid-schiff staining, periodic acid-methenamine silver staining, and Masson staining, immunofluorescence, and electron microscope analyses. Results: Anatomic sites of subcutaneous involvement included head and neck area, arm, and groin. Most cases had elevated IgE level and peripheral eosinophilia. Nephrotic syndrome was the most common kidney manifestation. Pathological results showed 3 types of glomerulonephritis, including 9 cases of MCD, 2 cases of IgA nephropathy, and 1 case of MN. Of note, 4 MCD cases showed concurrent glomerular and interstitial lesions associated with KD, including 2 distinct patterns: (1) a diffusely eosinophilic and lymphatic infiltration similar to KD lesion developed elsewhere and (2) exclusively eosinophilic infiltration in the interstitium. Eight out of 10 patients were responsive to steroid treatment and had complete remission of proteinuria and recovery of kidney function. Conclusion: Our report suggested that, in addition to glomerulonephritis, interstitial lesions may also be associated with KD. Pathologist should pay special attention to differentiated diagnosis when such pathological changes are identified in patients with subcutaneous mass or cervical lymphadenopathy with concurrent kidney manifestation.

Histopathological study of lupus nephritis with special reference to nonlupus nephritis, focal segmental glomerulosclerosis, interstitial nephritis, and amyloidosis

Context: Lupus nephritis (LN) is the involvement of kidney in systemic lupus erythematosus (SLE) where various types of glomerulonephritis (GN) are seen which affects the therapy also. Aims: To find out the frequency of various types of LN and nonlupus lesion in the kidney of SLE patient. Settings and Design: Retrospective analysis. Subjects and Methods: Total 52 cases of LN were studied between the periods of January 2011 and June 2014. Statistical Analysis Used: Calculation of mean and standard deviation. Results: There was female (76.93%) predominance over males (23.08%). In 63.46%, both ANA and dsDNA antibodies were positive. Only 57.69% patient had typical features of SLE and 17.29% patient had only one clinical manifestation to suggest SLE. In rest cases, renal limited SLE with severe anemia was found. Type IV LN was more common (53.84%) while Type III LN, Type II LN, and Type V LN were seen in equal frequency (9.61% each). In 2 cases, a combination of Type V + IV was found. In 5 cases (9.61%), nonlupus type of lesion was seen. It included 2 cases (3.84%) of amyloidosis and 3 cases of severe chronic tubulointerstitial nephritis with focal segmental glomerulosclerosis (5.76% FSGS). Out of 28 cases of Type IV LN, crescentic GN was found in 10 cases (19.23% CGN). In another 44.44% cases, focal crescents were seen in <40% glomeruli. Conclusions: Thus our study concludes that in LN Type IV is the most common LN and nonlupus related lesions, e.g., amyloidosis, and chronic interstitial nephritis and FSGS can also be found in LN.

Roles of layilin in TNF-α-induced epithelial-mesenchymal transformation of renal tubular epithelial cells

BackgroundTumor necrosis factor (TNF)-α is suggested to induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells that possibly exacerbates renal interstitial fibrosis in glomerulonephritis (GN). We here investigated whether layilin (LAYN), a c-type lectin-homologous protein, was involved in the EMT process. MethodsExpression of LAYN was investigated in kidneys of mice administered with TNF-α and in a clear cell renal carcinoma cell line of KMRC-1 stimulated with TNF-α by quantitative polymerase chain reaction (qPCR) and/or western blotting. Expression of LAYN was assessed immunohistochemically in renal biopsy samples of patients with various types of GN. Changes of EMT markers and cell morphology by TNF-α and transforming growth factor (TGF)-β in LAYN-knocked down KMRC-1 cells were investigated by qPCR and immunocytochemistry. ResultsAdministration of TNF-α increased expression of LAYN in renal tubular epithelia in mice. TNF-α but not TGF-β increased expression of LAYN in KMRC-1 cells. Renal biopsy samples from the patients with GN showed high expression of LAYN in tubular epithelial cells. TNF-α induced up-regulation of vimentin, down-regulation of E-cadherin, and fibroblast-like morphological change in KMRC-1 cells, indicating occurrence of EMT. These changes were not observed in the LAYN-knocked down cells. In contrast, similarly occurred TGF-β-induced EMT was not affected by the LAYN knockdown. ConclusionOur data indicate that LAYN is involved in the TNF-α-induced EMT of renal tubular epithelial cells. LAYN may play roles in the generation of renal interstitial fibrosis in GN via TNF-α-induced EMT.

Hepatitis B virus-related glomerulonephritis: not a predominant cause of proteinuria in korean patients with chronic hepatitis B.

Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN. Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea. Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group. Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV-GN.

Effect of Smad pathway activation on podocyte cell cycle regulation: an immunohistochemical evaluation

Background: Mature podocytes are in cell cycle arrest and their inability to proliferate successfully is a consequence of negative cell-cycle regulators’ expression, such as p57. Phosphorylated smad2/smad3 (pSmad2/3) is an intracellular heteromeric mediator of transforming growth factor beta (TGF-β) signals and, together with co-activators such as P300, regulates gene transcription, including cell cycle regulator proteins. Methods: In order to investigate Smad pathway activation and podocyte cell cycle regulation in glomerular injury, we studied the glomerular immunohistochemical expression of p57, pSmad2/3 and P300 in samples from 67 patients with various types of glomerulonephritis (GN) and 10 normal kidney tissue specimens. Results: pSmad2/3 and p300 expression were found significantly increased in all glomerular cell types in both proliferative and nonproliferative GN, while a significant reduction in p57-positive podocytes was observed when compared to controls. Staining for p57 was found to inversely correlate to pSmad2/3 suggesting that glomerular Smad pathway activation is related to down-regulation of p57 expression in proliferative glomerulonephritis. To our knowledge, this is the first study that indicates a relation between the TGF-beta/Smad signalling pathway and the cell cycle regulatory protein p57 in human GN. Conclusion: The increased pSmad2/3 staining together with the reduced p57 expression found in biopsy specimens with intense interstitial inflammation, indicate a possible relation between interstitial inflammation, glomerular Smad pathway activation and podocyte cell-cycle deregulation.

The influences of larger physical constitutions including obesity on the amount of urine protein excretion in primary glomerulonephritis: research of the Japan Renal Biopsy Registry.

This study aimed to describe the influences of larger physical constitutions including obesity on the amount of urine protein excretion (AUPE) in primary glomerulonephritis. The distinct effects on the AUPE in various types of glomerulonephritis were evaluated. Using the database of the Japan Renal Biopsy Registry (J-RBR) from 2007 to 2010, 4060 cases with primary glomerulonephritis including MCNS, FSGS, MN, MPGN, IgAN, and non-IgA were reviewed. The AUPEs were compared between high and low Body Mass Index (BMI) groups, and larger and smaller body surface area (BSA) groups using the indexes of BMI 25.0 kg/m(2) and BSA 1.73 m(2) in all cases and in each histological group. Multivariable analysis was performed to evaluate the predominant contributors to the AUPE. The larger physical constitution groups (BMI ≥25.0 kg/m(2) or BSA ≥1.73 m(2)) had significantly higher AUPEs in all cases with primary glomerulonephritis. When compared in each histological group, the mean AUPEs were significantly higher in the larger physical constitution groups, excluding the FSGS and non-IgA groups. Multiple regression analysis revealed that the significant contributors to the AUPE were BMI and BSA in MCNS and MN, whereas BMI and BSA were not significant and mean blood pressure and serum creatinine were significant in FSGS and non-IgA. Larger physical constitutions including obesity had a significant impact on the increase in the AUPE in primary glomerulonephritis, especially in MCNS and MN. However, FSGS and non-IgA were distinct for having blood pressure and renal dysfunction as possibly the major causes of proteinuria.

Dengue-associated kidney disease.

A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue is considered a major global health threat by the World Health Organization. Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science have been searched. An RNA virus from the genus Flavivirus, dengue virus is transmitted by Aedes aegypti,the yellow fever mosquito. Dengue is asymptomatic in as many as one half of infected individuals. Dengue fever is an acute febrile illness accompanied by constitutional symptoms. Dengue hemorrhagic fever and dengue shock syndrome are the severe forms of dengue infection.Dengue infection has been associated with a variety of renal disorders. Acute renal failure is a potential complication of severe dengue infection and is typically associated with hypotension, rhabdomyolysis, or hemolysis. Acute renal failure complicates severe dengue infection in 2-5% of the cases and carries a high mortality rate. Proteinuria has been detected in as high as 74% of patients with severe dengue infection. Hematuria has been reported in up to 12.5% of patients. Various types of glomerulonephritis have been reported during or shortly after dengue infection in humans and mouse models of dengue infection. Mesangial proliferation and immune complex deposition are the dominant histologic features of dengue-associated glomerulonephritis. On a rare occasion, dengue infection is associated with systemic autoimmune disorders involving the kidneys. In the vast majority of cases, dengue infection and associated renal disorders are self-limited.

Glomerular disease in patients with infectious processes developing antineutrophil cytoplasmic antibodies.

To identify differences in treatment and outcome of various types of glomerulonephritis developing in the course of infections triggering antineutrophil cytoplasmic antibody (ANCA) formation, we analyzed published reports of 50 patients. Immunosuppressives were added to antibiotics in 22 of 23 patients with pauci-immune glomerulonephritis. Improvement was noted in 85% of 20 patients with information on outcomes. Death rate was 13%. Corticosteroids were added to antibiotics in about 50% of 19 patients with postinfectious glomerulonephritis. Improvement rate was 74%, and death rate was 26%. Two patients with mixed histological features were analyzed under both pauci-immune and post-infectious glomerulonephritis categories. In 9 patients with other renal histology, treatment consisted of antibiotics alone (7 patients), antibiotics plus immunosuppressives (1 patient), or immunosuppressives alone (1 patient). Improvement rate was 67%, permanent renal failure rate was 22%, and death rate was 11%. One patient with antiglomerular basement disease glomerulonephritis required maintenance hemodialysis. Glomerulonephritis developing in patients who became ANCA-positive during the course of an infection is associated with significant mortality. The histological type of the glomerulonephritis guides the choice of treatment. Pauci-immune glomerulonephritis is usually treated with addition of immunosuppressives to antibiotics.

Urinary Fractalkine and Monocyte Chemoattractant Protein-1 as Possible Predictors of Disease Activity of Childhood Glomerulonephritis

Renal biopsy is the gold standard for confirmation of disease severity and diagnosis of glomerulonephritis (GN), but its procedure is invasive with a risk of complications. Thus, a non-invasive monitoring method is desirable especially in pediatric patients. Fractalkine and monocyte chemoattractant protein-1 (MCP-1) are proinflammatory chemokines, and both have been reported to be involved in the pathogenesis of immunocomplex-mediated GN. Recently, it has been reported that urinary fractalkine and MCP-1 may serve as possible predictors of disease activity of adult patients with GN. We, therefore, examined whether urinary levels of fractalkine and MCP-1 correlate with clinical and histologic parameters. Twenty-six consecutive children with various types of GN were enrolled in this study, including lupus nephritis, IgA nephropathy, membranous nephropathy, acute GN, and thin basement membrane disease (served as a non-inflammatory control). Urinary fractalkine and MCP-1 concentrations in the first morning urine samples obtained at the time of renal biopsy were measured by enzyme-linked immunosorbent assay, and standardized for urinary creatinine concentrations. Urinary fractalkine concentration differed significantly among the disease categories. Urinary concentrations of fractalkine and MCP-1 showed a significant positive correlation with the degree of occult blood in urine and a significant inverse correlation with the estimated glomerular filtration rate. Furthermore, the urinary MCP-1 concentration was significantly correlated with histological chronicity indices in patients with lupus nephritis and IgA nephropathy. Measurement of urinary fractalkine and MCP-1 concentrations may be useful as a non-invasive method for predicting the disease activity of GN in children.

Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria

Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-κB signaling is among the most important regulators of proinflammatory signaling. Its role in podocytes, the epithelial cells at the kidney filtration barrier, is poorly understood. Here, we inhibited NF-κB signaling in podocytes by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-specific NEMO-deficient mice (NEMO(pko)) were viable and did not show proteinuria or overt changes in kidney morphology. After induction of glomerulonephritis, both NEMO(pko) and control mice developed significant proteinuria. However, NEMO(pko) mice recovered much faster, showing rapid remission of proteinuria and restoration of podocyte morphology. Interestingly, quantification of infiltrating macrophages, T-lymphocytes, and granulocytes at day 7 revealed no significant difference between wild-type and NEMO(pko). To further investigate the underlying mechanisms, we created a stable NEMO knockdown mouse podocyte cell line. Again, no overt changes in morphology were observed. Translocation of NF-κB to the nucleus after stimulation with TNFα or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNFα or IL-1 was significantly reduced in NEMO-deficient podocytes and in glomerular samples obtained at day 7 after induction of nephrotoxic nephritis. Collectively, these results show that proinflammatory activity of NF-κB in podocytes aggravates proteinuria in experimental glomerulonephritis in mice. Based on these data, it may be speculated that immunosuppressive drugs may not only target professional immune cells but also podocytes directly to convey their beneficial effects in various types of glomerulonephritis.

Glomerulonephritis und Vaskulitis als Ursacheneiner arteriellen Hypertonie

The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required.

Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis

The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.

Kidney Injury Molecule-1 Correlates With Kidney Function in Renal Allograft Recipients

Introduction KIM-1 (kidney injury molecule-1) is responsible for the clearance of debris from damaged renal tubules. KIM-1 can be expressed and excreted in urine within 12 hours after the initial ischemic insult and before regeneration of the epithelium, persisting over time thereafter. Urinary KIM-1 has been reported to be a noninvasive, rapid, sensitive, and reproducible biomarker of experimental nephrotoxic and ischemic acute kidney injury. Renal KIM-1 expression is significantly increased in human kidney tissue among patients with a wide range of kidney diseases, including various types of glomerulonephritis, chronic allograft nephropathy, acute rejection, hypertension, and Wegener's granulomatosis. Both renal and urinary KIM-1 correlate with kidney damage and negatively with renal function, but not with proteinuria. The aim of this study was to assess whether urinary KIM-1 correlated with kidney function in kidney allograft recipients. Methods Serum NGAL, creatinine and estimated glomerular filtration rate (eGFR) were evaluated in 170 kidney allograft recipients on therapy with a calcineurin inhibitor plus mycophenolate mofetil or azathioprine and prednisone as well as in healthy volunteers. KIM-1 was estimated in urine using a commercially available kit. Results Kidney transplant recipients showed significantly higher KIM-1 values than the control group. Normotensive kidney allograft recipients displayed significantly lower NGAL results than hypertensive subjects. Urinary KIM-1 was significantly higher among diabetic than nondiabetic subjects, whereas creatinine did not differ significantly between them. Upon univariate analysis urinary KIM-1 strongly correlated with serum creatinine ( r = .64) and eGFR ( r = −.71), and only weakly with other parameters. Upon multiple regression analysis, the best predictor of urinary KIM-1 was eGFR (beta −0.61), which explained 61% of KIM-1 concentrations. Conclusion Even a successful kidney transplantation is associated with kidney injury as reflected by elevated urinary KIM-1 and lower eGFR. Therefore, KIM-1 needs to be investigated as a potential early marker for impaired renal function/kidney injury, especially in patients with other risk factors for damage such as hypertension or diabetes.

Transcription Factor Sp1 Expression Is Upregulated in Human Glomerulonephritis: Correlation with pSmad2/3 and p300 Expression and Renal Injury

Background. Sp1 is a ubiquitous transcription factor that mediates the fibrogenic factor transforming growth factor beta (TGF-β) signals through cooperation with Smad proteins. The transcriptional coactivator p300 is also suggested to play a role in Smad signal transduction. Methods. We investigated the immunohistochemical expression of Sp1 as well as the expression of pSmad2/3 and the coactivator p300 in 157 renal biopsy specimens from patients with various types of glomerulonephritis (GN). Correlations between immunohistochemical, clinical, and histologic parameters were performed. Results. Sp1 exhibited an increased glomerular and proximal tubular expression in all forms of GN compared to controls. The proximal tubular expression of Sp1 was significantly increased in proliferative GNs (p = 0.025), whereas in secondary GNs, there was a significant increase in the molecule's glomerular expression (p = 0.008). Sp1 correlated positively with pSmad2/3 and p300 expression in proximal tubules (r = 0.241, p = 0.018 and r = 0.244, p = 0.014, respectively), while in proliferative GNs, its expression correlated positively with pSmad2/3 expression in glomeruli (r = 0.32, p = 0.028). Sp1 glomerular and proximal tubular immunostaining correlated positively with serum creatinine levels (r = 0.265, p = 0.02 and r = 0.306, p = 0.006, respectively), while its proximal tubular expression showed a similar correlation with interstitial fibrosis (r = 0.213, p = 0.025). Sp1 was constantly detected in hyperplastic lesions and cellular crescents (each 100%), and very often in micro adhesions (94%) and segmentally or globally sclerotic areas (each 83%). Conclusions. This study documents the upregulation of Sp1 expression in glomeruli and proximal tubules of GN specimens. Our findings suggest a possible cooperation of Sp1 with pSmad2/3 and p300 in mediating renal injury as well as a possible role for this molecule in the pathogenesis and the progression of human GN.

Pharmacokinetic study of mizoribine in child‐onset glomerulonephritis

Mizoribine (MZR) has been successfully used without serious adverse effects in patients with various types of glomerulonephritis, but there are only a few pharmacokinetic studies of MZR. The purpose of the present paper was to report the results of a pharmacokinetic study of MZR in child-onset glomerulonephritis. Nine patients were enrolled. MZR was administered orally at 60-300 mg/day (3.0-8.4 mg/kg bodyweight/day) divided in one or two daily doses. Blood samples were collected 7-10 times before and after drug administration. Urine samples were also collected during the blood sampling periods. Twenty-three concentration curves of MZR were analyzed in the present study. Pharmacokinetic parameters for mizoribine were estimated using concentration-time profiles. The non-parametric Spearman correlation coefficient was calculated to determine significant associations between variables. P < 0.05 was considered significant. The obtained pharmacokinetic values at a dose of 3.36 +/- 1.91 mg/kg bodyweight were as follows: time to peak serum MZR concentration, 2.94 +/- 0.82 h; peak serum MZR concentration, 1.59 +/- 1.16 microg/mL; half-life, 1.96 +/- 0.92 h; area under the serum MZR concentration-time curve from time zero to infinity, 9.36 +/- 6.58 microg h/mL; volume of the distribution of MZR at a steady state, 2.03 +/- 0.80 L/kg; and rate of urinary excretion of MZR, 49.1 +/- 18.7%. The parameters estimated in the present study may be useful for the MZR treatment of patients with child-onset glomerulonephritis.