The impact of antiviral therapy for HCV on kidney disease: a systematic review and meta-analysis

BackgroundControversy persists about the role of hepatitis C as a risk factor for developing kidney disease in the general population. Some authors have evaluated the effect of antiviral therapy for HCV on the risk of kidney disease.Study Aims and DesignA systematic review of the published medical literature was performed to assess whether antiviral therapy for HCV has an independent impact on kidney survival in the adult general population. A random effects model was used to generate an overall estimate of the risk of kidney disease after anti-HCV therapy across the published studies. Meta-regression and stratified analysis were also carried out.ResultsFifteen studies were eligible (n = 356, 285 patients) and separate meta-analyses were conducted according to the outcome. Pooling studies based on viral responses (n = 7; 34,763 individual patients) demonstrated a relationship between sustained viral response and lower frequency of kidney disease; the overall estimate for adjusted risk of kidney disease was 2.50 (95% CI, 1.41; 4.41) (p = 0.0016) and between-study heterogeneity was found (p-value by Q test = 0.004). Aggregation of studies comparing treated vs untreated cohorts (n = 8, n = 333,312 patients) revealed an association between anti-HCV therapy and lower risk of kidney disease. The overall estimate for adjusted risk of kidney disease across the eight studies was 0.39 (95% CI, 0.25; 0.612) (p = 0.0001). Meta-regression showed that the effectiveness of antiviral therapy in reducing the frequency of kidney disease diminishes as cirrhosis (p = 0.02) and HBV infection (p = 0.0001) increase among HCV-infected individuals.ConclusionsAntiviral therapy for HCV lowers the risk of kidney disease among HCV-infected individuals. Studies to understand the mechanisms underlying this association are ongoing.     

Soluble and membranous endothelial protein C receptor in systemic lupus erythematosus patients: Relation to nephritis

Aim of the work

To investigate the role of endothelial protein C receptor (EPCR) (membrane and soluble forms) as a biomarker of lupus nephritis (LN) in systemic lupus erythematosus (SLE) patients and to study its relation to the prognosis and response to treatment.

FIBRILLARY GLOMERULONEPHRITIS – A REPORT OF TWO CASES

Two patients with an uncommon form of glomerulonephritis are described. The main clinical features were hematuria and proteinuria associated with normal renal function. The glomerular lesions consisted of mesangial hypercellularity and capillary wall thickening. Immunofluorescence was positive for IgG and C3 in both cases. Widespread deposition of microfibrils (mean diameters 17.0 nm and 18.4 nm) within mesangial areas and capillary basement membranes was seen on electron microscopy. Congo red staining for amyloid was negative. In both patients there was no evidence of underlying disease or extra-glomerular involvement and hence the disorder appeared to represent a primary glomerulonephritis.     

The Clinicopathologic Significance of Endothelial Tubuloreticular Inclusions in Glomerular Diseases

Abstract

Background: The presence of tubuloreticular inclusions (TRIs) in endothelial cells (ECs) always evokes suspicion of an association with underlying viral infections or autoimmune diseases. However, other underlying diseases can be associated with TRI expression. Since identification of the underlying disease is of primary consideration for management of glomerulonephritis (GN), it is important to clarify the clinical significance of TRI expression.

Methods: The authors studied 104 renal biopsy cases having TRI. They investigated their clinicopathological profiles and focused on potential connections with underlying diseases.

Results: Among 104 renal biopsy cases, 62 cases (59.6%) were associated with lupus nephritis (LN) and 20 cases (19.2%) were associated with a viral infection (hepatitis B virus (13), hepatits C virus (4), and human immunodeficiency virus (3)). Other underlying disease groups included membranous GN (MGN) (7), IgA nephropathy (7), Henoch-Schoenlein purpura (HSP) nephritis (2), and others (6). The incidence of TRIs in both LN and viral infections was significantly higher than for other diseases (p?<?0.0001). Among 7 MGN cases, 2 cases were diabetes, 1 case was associated with lung cancer, another case with antineutrophilic cytoplasmic antibody (ANCA), and the others showed no evidence of systemic disease. On immunofluorescence (IF) study, 2 MGN cases, 2 IgA nephropathy cases, and 1 HSP nephritis case showed C1q deposition, with no evidence of SLE.

Conclusions: TRIs were identified in MGN and other glomerular diseases, including IgA nephropathy and HSP nephritis. However, a diagnosis of LN should be considered because TRIs associated with a full-house IF pattern are usually found in LN.     

Value of Electron Microscopy in the Diagnosis of Glomerular Diseases

To evaluate the contribution of electron microscopy to the final diagnosis of glomerulopathies, the authors established a prospective study during the first semester of 2006. A total of 52 kidney biopsies were performed with 3 samples for light microscopy, immunofluorescence, and electron microscopy. Among these renal biopsies, only 20 were examined with electron microscopy because the diagnosis made on the basis of conventional methods had remained unclear or doubtful. In 18 cases, electron microscopy was undertaken for the investigation of primary kidney disease. The 2 remaining cases were transplant biopsies. In this series of 20 patients, there were 3 children with an average age of 9 years and 17 adults with an average age of 35.5 years. Fifteen patients (75%) were nephrotic. The study revealed that electron microscopy was essential for diagnosis in 8 cases (40%) and was helpful in 12 cases (60%). In conclusion, the results showed that the ultrastructural study provides essential or helpful information in many cases of glomerular diseases, and therefore electron microscopy should be considered an important tool of diagnostic renal pathology. As was recommended, it is important to reserve renal tissue for ultrastructural study unless electron microscopy can be routinely used in all biopsies. Thus, this technique could be performed wherever a renal biopsy has to be ultrastructurally evaluated.     

Cell Interposition in Glomerular Capillary Walls in Cryoglobulinemic Glomerulonephritis (CRYGN). Ultrastructural Investigation of 23 Cases

The present report describes ultrastructural findings on twenty-three cases of CRYGN showing membranoproliferative pattern under light microscopy. Attention was paid to the presence of double contoured peripheral basement membranes and to the characteristics of the interposed cells. The latter, according to the well known characteristics of membranoproliferative GN, are thought to be mesangial in nature. In fact, mesangial cells were found in 8 cases only, always associated with monocytes. Only monocytes were recorded in 12 cases, whereas in other 3 cases double contours were not connected to cell interposition.

Despite similarities under light microscopy, CRYGN is therefore rather different from idiopathic membranoproliferative GN because of the prevalence of exudative changes, mainly due to monocyte infiltration, over proliferative lesions.     

Podocyte loss involves MDM2‐driven mitotic catastrophe

Podocyte apoptosis as a pathway of podocyte loss is often suspected but rarely detected. To study podocyte apoptosis versus inflammatory forms of podocyte death in vivo, we targeted murine double minute (MDM)‐2 for three reasons. First, MDM2 inhibits p53‐dependent apoptosis; second, MDM2 facilitates NF‐κB signalling; and third, podocytes show strong MDM2 expression. We hypothesized that blocking MDM2 during glomerular injury may trigger p53‐mediated podocyte apoptosis, proteinuria, and glomerulosclerosis. Unexpectedly, MDM2 blockade in early adriamycin nephropathy of Balb/c mice had the opposite effect and reduced intra‐renal cytokine and chemokine expression, glomerular macrophage and T‐cell counts, and plasma creatinine and blood urea nitrogen levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not trigger podocyte death but induced G2/M arrest to prevent aberrant nuclear divisions and detachment of dying aneuploid podocytes, a feature of mitotic catastrophe in vitro and in vivo. Consistent with these observations, 12 of 164 consecutive human renal biopsies revealed features of podocyte mitotic catastrophe but only in glomerular disorders with proteinuria. Furthermore, delayed MDM2 blockade reduced plasma creatinine levels, blood urea nitrogen, tubular atrophy, interstitial leukocyte numbers, and cytokine expression as well as interstitial fibrosis. Together, MDM2‐mediated mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 forces podocytes to complete the cell cycle, which in the absence of cytokinesis leads to podocyte aneuploidy, mitotic catastrophe, and loss by detachment. MDM2 blockade with nutlin‐3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Parasites alter the pathological phenotype of lupus nephritis

Abstract

Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites. DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-γ. In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN. MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN. Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera. T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-γ were comparable between infected and uninfected MR/lpr mice. Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis.     

Serum anti-phospolipase A2 receptor antibodies and glomerular IgG4 in the diagnosis of membranous nephropathy

Objective To discuss the relationship between serum anti-Phosphalipase A2 receptor (PLA2R) antibodies and glomerular IgG4 subclass in patients with membranous nephropathy and evaluate the diagnostic value of the two markers. Methods Patients diagnosed as membranous nephropathy from October 2011 to April 2014 in Peking Union Medical College Hospital were included and divided into IMN and SMN groups accoding to their clinical diagnosis. Serum anti-PLA2R antibodies and glomerular IgG subclasses were both detected by indirect immunofluorescence assay. Receiver operator characteristic curves were used to evaluate the diagnostic efficiency of anti-PLA2R antibodies and glomerular IgG4. Results Prevalence of serum anti-PLA2R antibodies of IMN patients was 69.5% (41/59); prevalence of MLN patients was 4.8% (1/21). Within the IMN group, thirty-five patients showed positive results of both serum anti-PLA2R antibodies and glomerular IgG4; Six patients were positive for serum anti-PLA2R antibodies but negative for glomerular IgG4; Seventeen patients were positive for glomerular IgG4 but negative for serum anti-PLA2R antibodies; one patient was negative for both tests. The sensitivity of serum anti-PLA2R antibody was 69.5% and the specificity was 95.2%; the sensitivity of glomerular IgG4 was 89.8% and the specificity was 52.3%. The sensitivity of the combined marker consisting of serum anti-PLA2R antibody and glomerular IgG4 was 59.3% and the specificity was 100%. Four out of the six patients secondary to HBV infection, one out of the three patients secondary to Sjögren syndrome, one out of the three patients secondary to malignant tumor showed positive results of serum anti-PLA2R antibodies. Conclusions Serum anti-PLA2R antibodies were of high prevalence among IMN patients; the prevalence among SMN patients varied with etiologies. Results of serum anti-PLA2R antibodies and glomerular IgG4 were helpful to rule out secondary etiologies in the diagnosis of membrnous nephropathy.     

Clinical and pathological features of young patients with idiopathic membranous nephropathy in 20 cases

Objective To investigate the clinical and pathological features of idiopathic membranous nephropathy (IMN) in young patients. Methods Clinical data of 20 young patients, 16 to 44 years, who were diagnosed as IMN admitted to the Zhejiang Provincial People's Hospital from January 2013 to December 2014 were retrospectively analyzed, comparing to 55 mid-aged patients who were diagnosed as IMN during the same period in the hospital. Clinical and pathological features of above mentioned patients were analyzed. Results Young patients with IMN accounted for 26.7% of IMN patients. Compared to mid-aged patients, young patients with IMN had lower proportion of hypertension (P=0.003), lower blood glucose level (P=0.010), higher estimated glomerular filtration rate (eGFR) and low-density lipoprotein (LDL) (P=0.012, P=0.038), and lower levels of T3 and T4 (P=0.030, P=0.034). Furthermore, there were less sclerosis glomeruli (P＜0.001), hyaline change of arteriole (P=0.040) and arteriolar wall thickening (P＜0.0001), lower positive ratios of IgA (P=0.008), and more without renal tubulointerstitial lesions (P=0.018) in young patients. There were no statistically significant differences between these two groups in other index. Conclusions Compared to mid-aged patients, young patients with IMN have better blood pressure and blood glucose level, higher glomerular filtration rate and LDL. Moreover, thyroid function is significantly affected, meanwhile the lesions of glomerular, interstitial and vascular are mild in young patients.