IgA nephropathy (IgAN) is characterized by the expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly galactose-deficient polymeric IgA1), IgG and C3. Electron-dense deposits are observed in the glomerular mesangial area and glomerular basement membrane. Therefore, this disease is considered to be an immune complex-mediated glomerulonephritis. The detailed observations of electron-dense deposits are of value for the evaluation of the disease activity. The evidence- and lumped-system-based histological classification can identify the magnitude of the risk of disease progression and is useful for predicting long-term renal outcome in this disease. A study of IgAN patients showed that the number of angiotensin-II-positive cells was correlated with mast cells containing both tryptase and chymase and containing only tryptase in the interstitial lesions with the most severe pathological changes. Hypercomplementemia occurs in the progression of IgAN and is controlled by an increase of complement regulatory proteins. The measurement of urinary levels of membrane attack complex and factor H and extraglomerular C3 deposition could be useful indicators of renal injury in patients with IgAN. Development of glomerulosclerosis in IgAN patients is associated with podocytopenia and the alteration of the podocyte components, i.e. podocalyxin and dendrin. It appears that the number of urinary podocytes and levels of urinary podocalyxin are useful for predicting histological changes in IgAN patients. A positive correlation was observed between acute extracapillary changes and the number of dendrin-positive nuclei per glomerulus in patients with IgAN. It is concluded that there are many immunopathological predictors of prognosis, including genetic background, in this disease. Thus, the early diagnostic screening of prognosis predictors and subsequent intervention are important for the good prognosis in this disease.

Glomerulonephritis (GN) remains a major cause of morbidity and mortality in chronic kidney disease (CKD). Our study aimed to investigate the prevalence of anemia, abnormal serum intact parathyroid hormone (iPTH), calcium, and phosphorus in a Chinese patient population with primary GN. Medical histories and laboratory test results were collected from 2,924 patients with primary GN hospitalized in Ruijin Hospital of Shanghai between January 2003 and August 2009. The leading cause of CKD was primary glomerular diseases, which were responsible for up to 53.5% of all cases. IgA nephropathy was the most common cause, accounting for 38.7%, followed by focal segmental glomerulosclerosis (FSGS). The anemia rate of GN patients in early stages of CKD (stages 1-2 and 3) was 16-36%, and rapidly accelerated to 65.8 and 80.2% in advanced CKD stage 4 and stage 5, respectively. There was no significant decline observed in the level of serum calcium in patients with CKD stages 1-4 (p > 0.05). However, in patients with CKD stage 5 the prevalence of hypocalcaemia increased significantly (13.7%, p = 0.000). The prevalence of hyperphosphatemia did not significantly increase in patients with CKD stages 1-3 (p < 0.05), but was much higher in patients with CKD stages 4 and 5 (p = 0.001 and p = 0.021, respectively) and showed a negative correlation with renal function. Serum iPTH levels did not increase significantly in GN patients with CKD stages 1-2. The median iPTH levels were 54.7, 88.6, and 289.2 pg/ml (p = 0.000) for CKD stages 3-5, respectively, all of which showed negative correlation with renal function. The proportion of vitamin D insufficiency and deficiency increased to 29.3 and 11.2%, respectively, as the glomerular filtration rate fell below 15 ml/min/1.73 m(2). Primary glomerular disease remains the major cause of CKD in China, and complications such as anemia and metabolic bone disease are frequently present in GN patients.

The prevalence of chronic kidney disease (CKD) is reported to be 10.8-11.8% of the Chinese population. With economic development and longer life expectancy, the spectrum of CKD etiology has kept changing. Primary glomerular diseases (PGD) are still the most common renal diseases in China. To investigate the changing pattern of PGD in China, we retrospectively analyzed consecutive native renal biopsies performed in our hospital from 1997 to 2011. The patients were grouped according to a 3-year interval, 1997-1999 (period 1), 2000-2002 (period 2), 2003-2005 (period 3), 2006-2008 (period 4), 2009-2011 (period 5), and divided into three age groups (<20, 20-59, and ≥60 years old). 8,909 qualified cases were enrolled in this study. Among 8,909 specimens, 6,337 (71.13%) were diagnosed as PGD, while this prevalence decreased significantly from 77.61% in 1997-1999 to 66.73% in 2006-2008. IgA nephropathy (IgAN) was the most common PGD (36.66%), without any significant difference in the 5 periods (p = 0.185). IgAN was the most common PGD both in patients between the 20- to 59-year-old group (45.58%) and <20-year-old group (19.29%) as well. Membranous nephropathy (MN) was the most frequently found PGD in patients at age ≥60 years (39.64%). The frequency of MN was increased significantly from 6.48% in 1997-1999 to 22.79% in 2009-2011 (p < 0.001). The proportion of elderly patients increased significantly from 3.18% in 1997-1999 to 15.21% in 2009-2011 (p < 0.001). The prevalence of endocapillary proliferative glomerulonephritis (EnPGN) has decreased since 1997. PGD has remained the most common renal disease in China, although with a descending trend. The spectrum of PGD is different in different age groups. The frequency of EnPGN has decreased significantly, while that of MN has increased significantly.

Glomerular injury can be caused by numerous insults including hemodynamics, infections and immunity, hereditary and metabolic diseases, and toxicity. Basic and translational experimental studies in combination with clinical research in patients with renal disease have advanced our understanding of the etiology and pathogenesis of many forms of glomerulonephritis. This new knowledge has facilitated classification and treatment and has contributed to a better outcome of patients with renal disease. Since renal disease almost without exception leads to systemic cardiovascular complications, these advances are also of general health interest. Here, we shall briefly review general principles in the pathology of glomerular injury and discuss recent developments in the study of podocytopathies; membranous glomerulopathy; ANCA-associated vasculitis; C3 glomerulopathies and the role of complement in endothelial injury; and the prognostic value of the renal biopsy in predicting long-term outcome in lupus nephritis, vasculitis and IgA nephropathy.

Background:

In a previous proteomic study, we detected increased expression of nephronectin in the glomeruli from patients with diabetic nephropathy (DN). The aim of the present study was to clarify the usefulness of determining glomerular expression of nephronectin in kidney disease.

Methods:

We performed immunohistochemical staining for nephronectin in renal biopsy specimens from patients with a variety of kidney diseases (n = 190). The percentage of nephronectin-positive areas in the glomeruli was analyzed using an image analyzer.

Results:

Nephronectin immunoreactivity was clearly, strongly positive in the mesangial expansion and nodular lesions of DN (n = 18), whereas nephronectin immunoreactivity was negative in IgA glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis, membranous glomerulonephritis, minor glomerular abnormalities, crescentic glomerulonephritis, and other kidney diseases, such as amyloidosis and light chain deposition disease. Nephronectin was stained weakly in sclerotic lesions, such as focal segmental glomerulosclerosis and hypertensive nephropathy. The percentage of nephronectin-positive areas in the glomeruli from DN patients [15.1 ± 4.7% (n = 18)] was significantly higher than that for other kidney diseases [5.5 ± 3.6% (n = 172)] (p < 0.001). In multiple regression analyses, fasting plasma glucose and hemoglobin A1c were significantly associated with the increase in the percentage of nephronectin-positive areas in the glomeruli (β = 0.23, p < 0.001 and β = 0.16, p = 0.045, respectively).

Conclusions:

The expression of nephronectin was sufficient to discriminate DN from other kidney diseases with mesangial matrix expansion and nodular lesions. We consider that nephronectin staining could be helpful in the diagnosis of DN.

The glomerulonephritis (GN) are responsible for a significant amount of end stage renal disease. They may be secondary to another disease or idiopathic. When a secondary etiology has been excluded, it is called primary glomerulonephritis (PGN). Glomerular damage may have different presentations and there are many way to classify them. It is thus difficult for the non-specialist to understand the terminology used. This article is a summary of the most frequently encountered PGN such as: IgA nephropathy, membranous GN, idiopathic nephrotic syndrome, extracapillary and membranoproliferative GN. A brief description is given for each one of the PGN including epidemiology, semiology, histology and a pathophysiology explanation.

BACKGROUND:

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, leading to renal failure in 15% to 40% of cases. IgAN is diagnosed by renal biopsy, an invasive method that is not risk-free. We used blood and urine peptide profiles as a noninvasive method of linking IgAN-associated changes with histological lesions by Oxford classification.

METHODS:

We prospectively studied 19 patients with biopsy-proven IgAN and 14 healthy subjects from 2006 to 2009, excluding subjects with crescentic glomerulonephritis and collecting clinical and biochemical data at the time of diagnosis and during follow-up (24 months). Histological lesions were evaluated by Oxford classification. Proteomic analysis was performed by combining magnetic bead (MB) technology and mass spectrometry (MALDI-TOF MS) to obtain peptide profiles. Doubling of serum creatinine was considered a variable of poor renal prognosis.

RESULTS:

We identified 55 peptides---13 in serum, 26 in plasma, and 16 in urine---that differentiated IgAN patients from healthy subjects. A significant association was noted between serum/plasma and urine peptides and histological findings---ie, tubulointerstitial damage, segmental glomerulosclerosis, and endocapillary injury.We also identified 3 peptides---corresponding to bradykinin, uromodulin, and alpha-1-antitrypsin---that were associated with severity of lesions, such as tubulointerstitial damage and segmental glomerulosclerosis.Moreover, blood peptides with m/z 2953, 5337, 9287, and 9289 and urine peptides with m/z 1769, 1898, 1913, 1945, 2491, 2756, 2977, 3004, 3389, and 4752 correlated significantly with poor renal function.

CONCLUSIONS:

In patients with IgAN, the use of noninvasive approaches, such as blood and urine proteomics, can provide valuable information beyond that of standard diagnostic techniques, allowing us to identify blood and urine peptide profiles that are associated with poor histological lesions in IgAN patients.

Chronic kidney disease (CKD) represents a major challenge to public healthcare. Traditional clinical biomarkers of renal function (blood urea nitrogen and serum creatinine) are not sensitive or specific enough and only increase significantly after the presence of substantial CKD. Therefore, more sensitive biomarkers of CKD are needed. CKD-specific biomarkers at an early disease stage and early diagnosis of specific renal diseases would enable improved therapeutic treatment and reduced the personal and financial burdens. The goal of metabolomics is to identify non-targeted, global small-molecule metabolite profiles of complex samples, such as biofluids and tissues. This method offers the potential for a holistic approach to clinical medicine, as well as improvements in disease diagnoses and the understanding of pathological mechanisms. This review article presents an overview of the recent developments in the field of metabolomics, followed by an in-depth discussion of its application to the study of CKD (primary, chronic glomerulonephritis such as IgA nephropathy; secondary, chronic renal injury such as diabetic nephropathy; chronic renal failure including end-stage kidney disease with and without undergoing replacement therapies, etc), including metabolomic analytical technologies, chemometrics, and metabolomics in experimental and clinical research. We describe the current status of the identification of metabolic biomarkers in CKD. Several markers have been confirmed across multiple studies to detect CKD earlier than traditional clinical chemical and histopathological methods. The application of metabolomics in CKD studies provides researchers the opportunity to gain new insights into metabolic profiling and pathophysiological mechanisms. Particular challenges in the field are presented and placed within the context of future applications of metabolomic approaches to the studies of CKD.

High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compound from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been determined. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic analysis in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathology in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addition, Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS production in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice.

PURPOSE OF REVIEW:

This review summarizes recent key findings relating to the role of the complement system in renal pathology.

RECENT FINDINGS:

There is increasing association of genetic variations in complement and complement control proteins with renal disease. Genome-wide association studies have shown that polymorphisms at the complement factor H-related gene locus are associated with susceptibility to IgA nephropathy and systemic lupus erythematosus (SLE). Rare mutations in these genes are associated with familial forms of C3 glomerulopathy. Mutations in other complement genes have been associated with C3 glomerulopathy and hemolytic uremic syndrome. There are now several reports of the use of anti-C5 antibody therapy in renal disease. Preclinical studies have shown the utility of targeted inhibition of C3 activation in models of lupus glomerulonephritis and ischemia reperfusion injury.

SUMMARY:

Complement activation or dysregulation is important in a range of renal pathology and new therapeutic strategies are being developed which may allow rational therapy for these diseases.