Pathology after eculizumab in dense deposit disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.     

Do genetic factors play a role in Berger's disease?

The epidemiology of Berger's disease is poorly defined. We know that the disease occurs worldwide and that there may be an increased occurrence in certain ethnic groups. Whether secondary mesangial IgA deposits should be considered part of the same disease process is unknown. The association of certain HLA antigens with the occurrence of Berger's disease has been demonstrated by several groups. The multiple occurrence of Berger's disease or of Berger's disease and Henoch-Schönlein purpura in the same family has been reported. The preliminary results of a French collaborative study show 43 such families. However, these facts do not demonstrate a familial clustering since the multiple occurrence of cases in a family may occur by chance. The study of affected siblings (sib pair method) from different families may be used nevertheless, in order to understand the possible inheritance of the disease. Previously reported data on HLA haplotypes of effected siblings are combined with unpublished cases. There is an excess of HLA-identical siblings but it is possible that there might have been some bias towards publishing HLA-identical pairs. Further systematic studies on a large number of HLA-typed affected sibling pairs are needed before concluding a linkage between HLA and the disease.     

A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency

A 14-year-old girl presented with acute glomerulonephritis. Tests revealed hypocomplementemia and elevated Antistreptolysin-O titers, and renal biopsy revealed endocapillary and mesangial proliferative glomerulonephritis with double contours of the glomerular basement membrane (GBM). Despite methylprednisolone pulse therapy and the administration of oral prednisolone, overt proteinuria and hypocomplementemia persisted. A second renal biopsy 6 months later confirmed the initial diagnosis of dense deposit disease (DDD) based on electron-dense deposits in the GBM. C3 nephritic factor (C3NeF) and a deficiency of complement factor H (CFH) were not evident. A nephritis-associated plasmin receptor (NAPlr), nephritogenic group A streptococcal antigen, and the plasmin activity by in situ zymography were been in both the first and second biopsy specimens. The patient received combined immunomodulatory therapy with prednisolone and mizoribine, and the urinary protein decreased to a mild level at 27 months after disease onset. These findings suggest that persistent glomerular NAPlr deposition may be associated with the pathogenesis of DDD in some patients without the involvement of C3NeF or CFH mutation and that DDD patients of this type may respond to immunomodulatory treatment.     

Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (n = 1) or immune-complex-mediated MPGN type I (n = 2), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients.     

Metabolic syndrome does not always play a critical role in decreased GFR

Background There is a paucity of literature available as to the relationship between different levels of each metabolic syndrome (MetS) component and decreased GFR. In the present study, we aimed to demonstrate whether MetS always plays a critical role in decreased GFR. Methods A cross-sectional study was conducted between February 2010 and September 2012, with 75,468 adults enrolled undergoing measurements of blood pressure as well as tests of blood and urine samples. Univariate and multivariable logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI), and the chi-square test was used for categorical variables and described as a percentage. Results Of the 75,468 participants, 350 (0.5%) subjects met criteria for the decreased GFR, with a mean age of 48.79?±?13.76?years. After adjustment for age, diastolic blood pressure and high-density lipoprotein were inversely related to decreased estimated glomerular filtration rate (eGFR) in multivariable analyses, with an OR (95% CI) of 0.57 (0.39–0.84) and 0.41 (0.24–0.72), respectively. The prevalence rate of CKD in critical group was 0.73% (154 of 21,127) and 0% (0 of 370) in noncritical group. In analysis stratified by the type of MetS components, the differences in noncritical group and the reference group were not statistically significant (χ^2?=^?1.349, p?>?0.05). Conclusions MetS does not always play a critical role in decreased GFR, with different levels of individual components of MetS exerting idiosyncratic effects in decreased eGFR. In fact, patients with abnormal body mass index, high triglycerides, and elevated fasting plasma glucose would not have impact on decreased GFR.     

CXC chemokines play a critical role in liver injury, recovery, and regeneration

Background

Hepatic ischemia/reperfusion (I/R) injury is a principal consideration of trauma, resectional liver surgery, and transplantation. Despite improvements in supportive care, hepatic I/R injury continues to negatively impact patient outcomes because of significant tissue damage and organ dysfunction. CXC chemokines have been implicated as key mediators in the deleterious inflammatory cascade after hepatic I/R and also as important, beneficial regulators of liver recovery and regeneration. As such, their potential to mediate both beneficial and detrimental effects on hepatocytes makes them a key target for therapy. Herein, we provide a review of the inflammatory mechanisms of hepatic I/R injury, with a focus on the divergent functions of CXC chemokines in this response compared with other liver insults, and offer an explanation of this apparent paradox.

Data sources

MEDLINE and PubMed.

Conclusions

CXC chemokines are key mediators of both the inflammatory response to hepatic I/R as well as the recovery from this injury. Their contrasting functions in the regeneration of liver mass after an ischemic insult indicates that therapeutic manipulation of these mediator pathways should differ depending on the surgical milieu.     

C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up

C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.     

Does lead play a role in the development of chronic renal disease?

For many decades lead has been considered to be one of the causes of chronic renal failure. A critical analysis of the available epidemiological studies, however, indicates that the relationship between lead exposure and the development of chronic renal failure is largely circumstantial. Indeed, several aspects remain obscure: relative and absolute risk, risk factors, duration of exposure, pathology and diagnostic criteria. Moreover, methodological problems related to cohort selection (i.e. the 'Healthy worker effect'), study design and definition of renal dysfunction may limit the value of the epidemiological results. Although the available literature suggests that lead may play a direct or contributory role in the development of chronic renal failure it is concluded that additional detailed epidemiological studies are required.     

Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice

Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. To clarify the role of complement in lupus nephritis, MRL/lpr mice were given Crry as a recombinant protein (Crry-Ig) from 12 to 24 wk of age. Control groups were given saline or normal mouse IgG. Sera and urine were collected biweekly. Only 1 of 20 (5%) Crry-Ig-treated mice developed renal failure (BUN > 50 mg/dl) compared with 18 of 38 (47.4%) mice in control groups (P = 0.001). BUN levels at 24 wk were reduced from 68.8 +/- 9.7 mg/dl in control groups to 38.5 +/- 3.9 mg/dl in the Crry-Ig-treated group (P < 0.01). Urinary albumin excretion at 24 wk was also significantly reduced from 5.3 +/- 1.4 mg/mg creatinine in the control groups to 0.5 +/- 0.2 mg/mg creatinine in the Crry-Ig-treated group (P < 0.05). Of the histologic data at 24 wk, there was a significant reduction in scores for glomerulosclerosis and C3d, IgG, IgG3, and IgA staining intensity in glomeruli in complement-inhibited animals. Crry-Ig-treated animals were also protected from vasculitic lesions. Although there was no effect on relevant autoimmune manifestations such as anti-double stranded DNA titers or cryoglobulin IgG3 levels, circulating immune complex levels were markedly higher in complement-inhibited animals. Thus, inhibition of complement activation with Crry-Ig significantly reduces renal disease in MRL/lpr lupus mice. The data support the strategy of using recombinant complement C3 inhibitors to treat human lupus nephritis.     

Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome.

BACKGROUND: Dense deposit disease (DDD) is an uncommon cause of end-stage renal disease (ESRD). As a consequence, information on the outcome of renal transplantation in patients with DDD comes from series with a limited number of patients. METHODS: We present the histological and clinical data of 13 adult patients with DDD, who received their first allograft in our centre in the period between 1983 and 1994. RESULTS: Renal transplant biopsies were performed in 11 patients, at 2.9 months after transplantation (median; range 0.4-13.8 months). The indication for taking the biopsy was in all instances a raised serum creatinine level. Five patients also had a significant proteinuria. In only one patient, light microscopy showed alterations in the capillary walls suggestive of a recurrence of DDD. However, by immunofluorescence or electron microscopy, we found glomerular deposits compatible with a recurrence of DDD in all 11 patients. Three patterns of glomerular C3 deposition were found: globular depositions only in the mesangium; mesangial accumulation with linear deposits in the capillary wall; and prominent linear presence in the capillary wall with only a few mesangial granules. The findings by electron microscopy matched the immunofluorescence results. The linear C3 accumulation in the capillary wall was visible ultrastructurally as electron-dense ribbon-like transformation of the glomerular basement membrane. Mesangial C3 deposits were seen ultrastructurally as local electron-dense deposits in the mesangium. Four patients showed a pronounced glomerular influx of neutrophils, accompanied by crescents in three patients. In these three latter patients, the recurrence of DDD was the only histological lesion. In the other patients, the recurrence was merely a coincidence, the biopsy demonstrating an additional histological lesion (three chronic vascular rejection, two acute rejection, one ischaemic necrosis and two cyclosporin A toxicity). Eight patients with a recurrence of DDD have progressed to ESRD at an average of 14 months (range 0.2-38 months) after transplantation. The recurrence was the sole cause of graft loss in the three patients with crescents. The patients in whom the C3 deposits were confined to the mesangium appeared to have a better prognosis. CONCLUSIONS: The histological recurrence rate of DDD is high. The histological picture is quite diverse, and in most patients abnormalities are only found by immunofluorescence and electron microscopy. Up to one-quarter of the patients with DDD lost their grafts because of a recurrence.     

Levels of complement factor C3 and its activated product, C3a, in operatively salvaged blood

In intra-operative blood salvage the collected blood is exposed to traumatized tissue and a synthetic circuit. Because of this exposure it was expected that the complement system, which is a contact system present in plasma, would be activated in salvaged blood. To determine whether this occurs, the plasma levels of the complement factor C3 and its activated fragment, C3a, were measured in intra-operative salvaged blood before and after washing. Samples were obtained from patients undergoing aortic surgery where intra-operative salvage was used. In the unwashed salvaged blood, the level of C3 fell (mean C3: 0.33 g/L) and the level of C3a increased (mean C3a: 1994 ng/mL) compared with the patient circulating levels of C3 and C3a (mean C3: 0.70 g/L, mean C3a: 855 ng/mL) respectively. Washing of the collected blood reduced the C3a level (mean: 346 ng/mL) to the patient's level and reduced C3 to the lower detection limit of the test (less than 0.2 g/L). The raised level of C3a and the reduced level of C3 confirm that the complement system is activated and imply that other complement factors are also activated.     

Clearances of complement components, C3 proactivator and other serum proteins in chronic membranoproliferative glomerulonephritis (CMPGN).

In chronic membranoproliferative glomerulonephritis (CMPGN) the activation of the complement system through the properdin pathway plays an important role. The clearance of complement components and of the C3-proactivator (C3-PA) have been determined in 18 patients. Hemolytically active C5, C6, C7 and C3-PA were detected in the urine for the first time. The clearances of the complement components did not correlate with the clearances of other serum proteins with similar molecular weights. The specificities of the single complement components in the urine were tested by specific complement inhibitors such as hydrazine, KSCN, and the C4-inactivating factor.     

Adipocyte-derived serum amyloid A3 and hyaluronan play a role in monocyte recruitment and adhesion

Obesity is characterized by adipocyte hypertrophy and macrophage accumulation in adipose tissue. Monocyte chemoattractant protein-1 (MCP-1) plays a role in macrophage recruitment into adipose tissue. However, other adipocyte-derived factors, e.g., hyaluronan and serum amyloid A (SAA), can facilitate monocyte adhesion and chemotaxis, respectively. The objective was to test the potential involvement of these factors in macrophage recruitment. Differentiated 3T3-L1 adipocytes made hypertrophic by growth in high glucose conditions were used to study SAA and hyaluronan regulation in vitro. Two mouse models of obesity were used to study their expression in vivo. Nuclear factor-kappaB was upregulated and peroxisome proliferator-activated receptor (PPAR)gamma was downregulated in hypertrophic 3T3-L1 cells, with increased expression of SAA3 and increased hyaluronan production. Rosiglitazone, a PPARgamma agonist, reversed these changes. Hypertrophic adipocytes demonstrated overexpression of SAA3 and hyaluronan synthase 2 in vitro and in vivo in diet-induced and genetic obesity. SAA and hyaluronan existed as part of a complex matrix that increased the adhesion and retention of monocytes. This complex, purified by binding to a biotinylated hyaluronan binding protein affinity column, also showed monocyte chemotactic activity, which was dependent on the presence of SAA3 and hyaluronan but independent of MCP-1. We hypothesize that adipocyte hypertrophy leads to increased production of SAA and hyaluronan, which act in concert to recruit and retain monocytes, thereby leading to local inflammation in adipose tissue.