Kidney disease is a worldwide public health problem. The prevalence of end-stage renal disease (ESRD), a final outcome of kidney disease, has increased progressively in the past decades and has emerged as a great burden to the healthcare system in China. Glomerulonephritis is still the most common cause of ESRD in China. However, the prevalence of diabetes and hypertension are increasing dramatically. There are modifiable risk factors for the development of progressive renal dysfunction. The challenge is to identify the disease and deliver effective therapies at the right time with the right tools. In the last two years, Chinese nephrologists have done a lot of basic and clinical work and have advanced our knowledge in this field. The focus of this review will be on selected topics where substantial progress in our understanding has been made, especially in the fields of IgA nephropathy (IgAN), lupus nephritis, diabetic nephropathy and aristolochic acid nephropathy (AAN). Existing problems are identified and future development potential is also discussed.
IgAN is a worldwide disease and was first reported by Berger in 1968. In China, the study of this disease began in the 1980s. IgAN was the most common chronic kidney disease (CKD) and the primary cause of chronic renal failure (CRF) in China. The incidence of IgAN reported in China is 45.3% of primary glomerular diseases confirmed by biopsy.
IgAN is considered to be a multifactorial disease, whose pathogenesis involves genetic and environmental factors. Megsin (SERPINB7), which is predominantly expressed in glomerular mesangium, is upregulated in IgAN.1 A genetic study of 423 Chinese patients with biopsy-proven IgAN revealed that Megsin 2093C and 2180T alleles were transmitted from heterozygous parents to patients significantly more often than expected. The results suggested that the genetic variation in Megsin conferred susceptibility to IgAN in the Chinese population.2 Other recent Chinese reports showed that the genotype frequency of Fcgr3b heterozygote NA1/NA23 and polymorphisms of the C1GALT1 gene4 were associated with the genetic susceptibility to IgAN in the Chinese population. However, the polymorphisms of transferrin receptor (TFRC) in the 424G/A and -5184C/T sites were not correlated with susceptibility to IgAN.5
IgAN is characterized by mesangial deposition of polymeric IgA1 (pIgA1), yet the pathogenetic mechanism remains unresolved. It was reported that differently charged IgA1 from IgAN patients has a different glycosylation profile. Leung et al6 demonstrated an unusual glycosylation and sialylation pattern of anionic pIgA1 in IgAN which might have an important effect on its pathogenesis. Glycosylation of IgA1 molecules could significantly affect the binding of IgA1 on human mesangial cells.7 As an important producer of IgA, CD19+CD5+ B cells play a prominent role in IgA deposition in the mesangium and the pathogenesis of primary IgAN.8 Through direct and indirect pathways, IgA1 from IgAN patients might accelerate progression of IgAN by inducing the apoptosis of podocytes.9 The expression of glomerular epithelial protein 1 (GLEPP1), a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte, might be a useful marker of podocyte injury in IgAN.10
Several genes are reported to be relevant with the progression of IgAN. A study in 1147 Chinese subjects revealed that there was no association between the VNTR polymorphism of the MUC20 gene and clinical manifestations in IgAN patients at the time of renal biopsy.11 However, IgAN patients with SL/LL genotypes and NA1/NA2 heterozygosity at Fcgr3b were risk factors for progression of IgAN in the Chinese.3 Cao et al12 suggested that HLA-DRB1 polymorphisms were related to the occurrence and disease progression of pIgA1 patients in Han Chinese, with HLA-DRB1*140501 being a susceptible allele and HLA-DRB1*070101 a resistant allele. HLA-DRB1*030101 might serve as a predictor of disease progression and renal damage of pIgAN in Han Chinese. Further studies are warranted to explore the immunological mechanisms for the genotype-phenotype relationship.
There are many proven indicators, such as impaired renal function, severe proteinuria, hypertension, glomerulosclerosis and interstitial fibrosis, which can predict an unfavorable outcome of IgAN.13 Similarly, in Chinese IgAN, patients with renal impairment, hypertension and advanced histological involvement had the highest risk for disease progression.14 Hematuria, microalbuminuria, tubulointerstitial lesions and alpha 2,6 sialic acid (SA) level of serum IgA1 are useful markers to identify those patients at high risk for renal progression.15,16 A retrospective study showed that proteinuria, elevated serum creatinine, glomerulosclerosis, crescent formation and interstitial fibrosis were independent risk factors in Chinese patients with IgAN.17 The levels of serum IgA, aberrant glycosylation of serum IgA1 and GLEPP1 expression were closely associated with pathological phenotypes and might be predictors of clinical and pathological severity.10,16,18
Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and the most common form of secondary renal disease diagnosed by renal biopsy in China. Until recently, the treatment of LN mainly rested on three drugs: corticosteroids, cyclophosphamide (CTX) and azathioprine. However, newer agents have been introduced in the last few years, such as mycophenolate mofetil (MMF), rapamycin and leflunomide. Current progress in LN treatment in China focuses on exploring new therapeutic methods to improve its remission and survival rates.
MMF is a relatively new immunosupressor which selectively inhibits proliferating T and B lymphocytes by inhibiting purine nucleotide synthesis and depleting the cells of guanosine triphosphate. It has been used in various autoimmune diseases and proven to be effective and have fewer side effects. So far, MMF may be an alternative to CTX for induction and maintenance therapy of patients with proliferative LN and has been widely used in Chinese patients.
The first randomized clinical trial of MMF for the treatment of proliferative LN was performed in China. Forty-two patients with diffuse proliferative LN were randomized to MMF at a dose of 2 g/d for 12 months or CTX for 6 months, followed by prednisolone and azathioprine for another 6 months. There was no difference in complete or partial remission rates between the two groups. The rates of relapse in the MMF and CTX groups were similar, while the prevalence of side effects was significantly lower in the MMF group. Tang et al20 conducted a 12-month retrospective, controlled study to compare the effects, relapse ratio and outcomes between MMF and pulse intravenous CTX for the induction therapy in patients with crescentic LN. They found a higher complete remission ratio, lower relapse ratio and more infrequent side effects in the MMF group than in the CTX group. A 24-week prospective multicentre study in 213 Chinese patients with active LN showed that MMF combined with prednisolone was an effective and well-tolerated induction treatment for patients with active LN and for controlling SLE systemic activity.21
More recently, Bao et al22 proposed “multitarget therapy in the treatment of diffuse proliferative LN”. In this prospective study, 40 patients with class V+IV LN were randomly assigned to induction therapy with tacrolimus, steroids and a low dose of MMF (multitarget therapy) or intravenous cyclophosphamide (IVCY). An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy than with IVCY. Most adverse events were less frequent in the multitarget therapy group. They concluded that multitarget therapy was superior to IVCY for inducing complete remission of class V+IV LN and was well tolerated. In an open-label trial, Wang et al23 compared MMF with monthly intravenous injection (i.v.) CTX as induction therapy for class IV LN with renal noninflammatory necrotizing vasculopathy (NNV). Their results revealed that MMF was more effective than i.v. CTX in inducing complete remission of LN with NNV and had a more favorable safety profile. However, a short follow-up and a small number of patients were its limitation.
Overall, after a meta-analysis of randomized controlled trials, MMF has higher efficacy in inducing remission in severe LN than pulsed intravenous therapy with CTX. Compared with azathioprine, MMF is also an alternative for maintenance therapy of severe LN without significant difference in the prognosis or safety.24 Before it can be adopted as the new standard induction therapy for LN, however, more data are needed. The ongoing ASPREVA Lupus Management Study is a global effort to make clear the precise dosage and duration for the administration of MMF in induction or maintenance therapy of severe LN.25
Leflunomide, a selective inhibitor of T cell proliferation and has pronounced antiinflammatory activity through inhibiting nuclear factor-κB (NF-κB) and tumor necrosis factor-α, and has been approved for the treatment of rheumatoid arthritis.26 Recent reports showed that orally administered leflunomide was effective in induction therapy of patients with biopsy-proven proliferative LN comparable to that of intravenous CTX and was generally well-tolerated.27,28 Another Chinese clinical trial also confirmed that leflunomide was effective in the therapy of proliferative LN.29
Rapamycin, a macrolide antibiotic, is known to have potent immunosuppressive activity.30 It suppresses the proliferation and clonal expansion of interleukin-2-stimulated T cells through the inhibition of mammalian target of rapamycin (mTOR), a 70-kD S6 protein kinase necessary for cell-cycle progression.31 The main clinical application of rapamycin is for the prevention of acute rejection in solid organ transplant recipients.32 Recent studies revealed its efficacy in preventing the development and attenuating the severity of established LN in NZB/WF1 mice. The beneficial effects of rapamycin were mediated, at least in part, through inhibition of lymphoproliferation, reduced monocyte chemoattractant protein (MCP)-1, RANTES expression and decreased inflammatory cell infiltration in the kidney. These observations suggested that rapamycin could be of therapeutic value in the treatment of human LN.33
Diabetic nephropathy is a leading cause of end-stage renal failure, which can account for disabilities and high mortality rates in patients with diabetes. The rising prevalence of young onset diabetes, which is closely associated with obesity and genetic factors, as well as the increased propensity to develop kidney disease, is a special challenge in the management of Chinese diabetic patients. In the light of economic advancement, urbanization and changes of lifestyle (such as diet and physical activity) that have taken place in China, it is estimated that the number of diabetic patients in China will increase from 20.8 million in 2000 to 42.3 million in 2030.34 If there are no early diagnosis and intervention strategies for diabetes and impaired glucose tolerance, a tremendous increased burden caused by diabetes will ensue in China.
Nowadays, therapeutic options such as strict blood pressure and/or glycemic control are effective for preventing the progression of diabetic nephropathy, but the number of diabetic patients on hemodialysis is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed.
Previously it was shown that treatment with MMF attenuated renal inflammation and reduced renal injury in a model of diabetes. However, the mechanism involved in the renoprotective effects of MMF in experimental diabetes has not been clearly delineated. MMF ameliorated early renal injury via the inhibition of oxidative stress, reduction of T cells and macrophage infiltration and the expression of chemokines/cytokines such as intercellular adhesion molecule 1 (ICAM-1), MCP-1 and transforming growth factor-beta1 (TGF-β1) in diabetic nephropathy.35–37 MMF can decrease urinary albumin excretion, which might be at least partly correlated with up-regulated expression of nephrin and podocin in the glomeruli of diabetic rats.38 Meanwhile, MMF might have renoprotective effects in early stage of diabetic nephropathy through preventing podocyte loss.37
The combined effects of MMF and ACEI/ARB in diabetic nephropathy are controversial. For example, in streptozotocin (STZ)-induced diabetes mellitus model the combination of valsartan and MMF might protect the kidney from injury by up-regulating the expression of TNF-related apoptosis inducing ligand (TRAIL).39
Another study supported the observation that a combination of enalapril and MMF conferred superiority over monotherapy in renoprotection,40 a mechanism which might be at least partly correlated with synergistic suppression of increased macrophage recruitment and over-expression of MCP-1 and TGF-β1 in renal tissue in diabetic rats. However, Zhang et al37 reported that the combined therapy of valsartan and MMF did not show any superiority over monotherapies for renal protection.
Treatment of diabetic nephropathy with thiazolidinediones (TZDs) is believed to prevent glomerular injury. In diabetic rats, rosiglitazone protected the glomerulus by its role in reducing reactive oxygen species, NF-κB activation and MCP-1 expression in the early phase of diabetic nephropathy.41 Rosiglitazone also protected the kidney from renal injury from advanced glycation end products (AGEs), which might be associated with the suppression of plasminogen activator inhibitor (PAI)-1 expression through peroxisome proliferator-activated receptor (PPAR)-dependent and independent mechanisms. It is also reported that pioglitazone treatment had curative effects on diabetic nephropathy by attenuating the decrease of glomerular MMP-2 and the increase of collagen IV degradation.43 Renoprotection conferred by pioglitazone combined with losartan was superior to that conferred by losartan alone in subjects with type 2 diabetic nephropathy. The combination was generally well tolerated.
Rapamycin treatment could prevent the early renal structural changes of diabetes in experimental rats, and thus halted the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.45 But it still needs further study.
ARISTOLOCHIC ACID NEPHROPATHY
The concept of Chinese herb nephropathy (CHN) was proposed in 1990s. CHN, first reported by Vanherweghem et al46 in a group of young patients with ESRD who had followed the same slimming regimen that included an Aristolochia species containing aristolochic acid (AA) in Belgium in 1993. It is a rapidly progressive renal interstitial fibrosis associated with a high risk of urothelial cancer.46,47 The observed nephropathy now is called AAN.48 There are approximately 40 different species herbs containing different levels of AA, a few of which are frequently used in the clinic, such as Fructus aristolochiae, slender dutchmanspipe root, and dutchmanspipe vine. In recent years, several Western countries and some Eastern countries have prohibited the use of herbs containing AA and other related compounds. These actions will no doubt reduce the incidence of AAN.
The major characteristic of AAN is a progressive tubulointerstitial nephropathy, but the pathophysiological mechanisms by which AA induces renal interstitial fibrosis are still largely unknown. In an in vitro study, high doses of aristolochic acid I (AAI), which is the main effective content in AA, could directly lead to the death of mouse primary renal tubular epithelial cells (RTECs) within short time. However low doses of AAI for a long duration might induce renal tubulointerstitial fibrosis through its conductive epithelial to mesenchymal transition, and TGF-β1/Smad7 signaling is involved in this process.49 Mitochondrial permeability transition (MPT) plays a critical role in the pathogenesis of renal tubular epithelial cell injury induced by AAI.50 In in vivo experiments, AA can induce the injury of the renal tubules, impair cell regeneration and inhibit the expression of bone morphogenetic protein-7 (BMP-7) mRNA in renal tissue.51 Yang et al52 explored the possible mechanisms responsible for the inability of plerosis and the tendency towards fibrosis in AA-induced acute tubular necrosis (AA-ATN). The strong ability for RTECs repair after acute injury was severely diminished, which was partly due to reduced epidermal growth factor (EGF) expression and anti-fibrosis mechanisms might also be impaired in AA-ATN.
Increasing evidences have shown that the microvasculature might play a critically important role in progressive renal disease. In a rat model of AAN, loss of peritubular capillaries and hypoxia increased the area of tubulointerstitial fibrosis by up-regulating the expression of hypoxia inducible factor-1 alpha (HIF-1α), indicating ischemia and hypoxia were the important causes of severe tubulointerstitial fibrosis in AAN rats.53 Wen et al54 also reported that ischemic injury contributed to the pathogenesis of AAN. The exact mechanism may be associated with increased HIF-1α protein expression, decreased vascular endothelial growth factor (VEGF) protein expression, and an imbalance of vasoactive substances (such as endothelin-1 and nitric oxide) after acute kidney injury induced by AA.
The experiment on the prevention of AAN is rare. Recently, Wang et al55 provided in vitro evidence that recombinant human erythropoietin mediated renoprotective effects against AA injury in renal tubular cells by ameliorating the damage to cytoskeleton, reducing the number of apoptotic cells and promoting cell regeneration. In chronic AAN, Hirsutella sinensis could inhibit the production of TGF-β1, connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase (TIMP)-1 and PAI-1, which alleviated renal interstitial fibrosis and improved renal function. Sun et al57 revealed that prostaglandin E1 (PGE1) could slow the progression of renal failure and increase hemoglobin levels in AAN patients. But the mechanism is still unclear.
Although some progress has been made in China in the basic science and clinical workings of kidney disease in the last two years, there are still many problems we should mention. Despite the fact that CKD is a progressive disease that impairs kidney function, most people in China know little or nothing about CKD and are unaware of the risks if the disease is undiagnosed and untreated. The majority of people with CKD are asyptomatic until kidney function is severely and irreversibly impaired. Most Chinese with CKD, even severe CKD, are unaware they have kidney disease. In China many new CKD cases are diagnosed with elevated serum creatinine. Therefore, education programs for the Chinese and for CKD patients should be strengthened and an annual check of those at risk is essential.
Lack of awareness of the CKD epidemic has had significant repercussions. The incomplete study of the CKD epidemic has been discussed in another review paper.58 A study on the incidence and prevalence nationwide in China should be launched to facilitate early prevention of CKD by controlling diabetes, hypertension, hyperlipidemia and treat mild or moderate CKD as early as possible. Early intervention can reduce CKD progression, cardiovascular risk and improve the quality of life. The challenge is to identify people with, or at risk of developing CKD and determine who needs intervention to minimize cardiovascular risk and to determine what intervention should be used.
The percentage of CKD patients who achieved their treatment goal was low and few patients started renal replacement therapy in time. A good CKD management program to advance the care of patients with CKD should be developed that includes initiation of therapy to slow the progression of kidney failure, effective treatment of CKD complications and a smooth transition to renal replacement therapy when needed without the high associated clinical morbidity and costs.
One more thing that requires our attention is that until now, kidney impairment induced by Chinese herbal medicine has not attracted enough attention among Chinese people. A more effective diagnosis monitoring and screening system has to be set up to catch the patients at an early stage. The diagnosis, pathogenesis and prevention of nephropathy induced by AA are still unclear. Therefore, we should realize its harmfulness and reinforce basic and clinical researches.
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