Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease, is a diverse clinical entity that occurs after podocyte injury. Although numerous studies have suggested molecular pathways responsible for the development of FSGS, many still remain unknown about its pathogenic mechanisms. Two important pathways were predicted as candidates for the pathogenesis of FSGS in our previous in silico analysis, whom we aim to confirm experimentally in the present study. Methods: The expression levels of 4 enzyme genes that are representative of "chondroitin sulfate degradation" and "eicosanoid metabolism" pathways were investigated in the urinary sediments of biopsy-proven FSGS patients and healthy subjects using real-time polymerase chain reaction (RT-PCR). These target genes were arylsulfatase, hexosaminidase, cyclooxygenase-2 (COX-2), and prostaglandin I2 synthase. The patients were sub-divided into 2 groups based on the range of proteinuria and glomerular filtration rate and were compared for variation in the expression of target genes. Correlation of target genes with clinical and pathological characteristics of the disease was calculated and receiver operating characteristic (ROC) analysis was performed. Results: A combined panel of arylsulfatase, hexosaminidase, and COX-2 improved the diagnosis of FSGS by 76%. Hexosaminidase was correlated with the level of proteinuria, while COX-2 was correlated with interstitial inflammation and serum creatinine level in the disease group. Conclusion: Our data supported the implication of these target genes and pathways in the pathogenesis of FSGS. In addition, these genes can be considered as non-invasive biomarkers for FSGS.

Diabetes remains an important health issue as more patients with chronic and uncontrolled diabetes develop diabetic nephropathy (DN), which classically presents with proteinuria followed by a progressive decrease in renal function. However, an increasing proportion of DN patients have a decline in kidney function and vascular complications without proteinuria, known as non-proteinuric DN (NP-DN). Despite the increased incidence of NP-DN, few clinical or experimental studies have thoroughly investigated the pathophysiological mechanisms and targeted treatment for this form of DN. In this review, we will examine the differences between conventional DN and NP-DN and consider potential pathophysiological mechanisms, diagnostic markers, and treatment for both DN and NP-DN. The investigation of the pathophysiology of NP-DN should provide additional insight into the cardiovascular factors influencing renal function and disease and provide novel treatments for the vascular complications seen in diabetic patients.

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H₂O₂ could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H₂O₂. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

Sulodexide is a heterogeneous group of sulfated glycosaminoglycans (GAGs) that is mainly composed of low-molecular-weight heparin. Clinical studies have demonstrated that sulodexide is capable of reducing urinary albumin excretion rates in patients with type 1 and type 2 diabetes, suggesting that sulodexide has renal protection. However, this efficacy remains inconclusive. In this article, we used meta-analysis to summarize the clinical results of all prospective clinical studies in order to determine the clinical efficacy and safety of sulodexide in diabetic patients with nephropathy. Overall, sulodexide therapy was associated with a significant reduction in urinary protein excretion. In the sulodexide group, 220 (17.7%) achieved at least a 50% decrease in albumin excretion rate compared with only 141 (11.5%) in the placebo. The odds ratio comparing proportions of patients with therapeutic success between the sulodexide and placebo groups was 3.28 (95% confidence interval, 1.34-8.06; P=0.01). These data suggest a renoprotective benefit of sulodexide in patients with diabetes and micro- and macroalbuminuria, which will provide important information for clinical use of this drug as a potential modality for diabetic nephropathy, specifically, the prevention of end-stage renal disease that is often caused by diabetes.

The endothelial glycocalyx has a profound influence at the vascular wall on the transmission of shear stress, on the maintenance of a selective permeability barrier and a low hydraulic conductivity, and on attenuating firm adhesion of blood leukocytes and platelets. Major constituents of the glycocalyx, including syndecans, heparan sulphates and hyaluronan, are shed from the endothelial surface under various acute and chronic clinical conditions, the best characterized being ischaemia and hypoxia, sepsis and inflammation, atherosclerosis, diabetes, renal disease and haemorrhagic viral infections. Damage has also been detected by in vivo microscopic techniques. Matrix metalloproteases may shed syndecans and heparanase, released from activated mast cells, cleaves heparan sulphates from core proteins. According to new data, not only hyaluronidase but also the serine proteases thrombin, elastase, proteinase 3 and plasminogen, as well as cathepsin B lead to loss of hyaluronan from the endothelial surface layer, suggesting a wide array of potentially destructive conditions. Appropriately, pharmacological agents such as inhibitors of inflammation, antithrombin and inhibitors of metalloproteases display potential to attenuate shedding of the glycocalyx in various experimental models. Also, plasma components, especially albumin, stabilize the glycocalyx and contribute to the endothelial surface layer. Though symptoms of the above listed diseases and conditions correlate with sequelae expected from disturbance of the endothelial glycocalyx (oedema, inflammation, leukocyte and platelet adhesion, low reflow), therapeutic studies to prove a causal connection have yet to be designed. With respect to studies on humans, some clinical evidence exists for benefits from application of sulodexide, a preparation delivering precursors of the glycocalyx constituent heparan sulphate. At present, the simplest option for protecting the glycocalyx seems to be to ensure an adequate level of albumin. However, also in this case, definite proof of causality needs to be delivered.

The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.

Sulodexide (SDX), a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is a blend of two glycosaminoglycan (GAG) entities, namely a fast-moving heparin (HP) fraction and a dermatan sulfate (DS; 20%) component. The compound is unique among HP-like substances in that it is biologically active by both the parenteral and oral routes. A main feature of the agent is to undergo extensive absorption by the vascular endothelium. For this reason, in preclinical studies, SDX administered parenterally displays an antithrombotic action similar to that of HPs but associated with fewer alterations of the blood clotting mechanisms and tests, thus being much less conducive to bleeding risk than HPs. When given orally, SDX is associated with minimal changes in classic coagulation tests, but maintains a number of important effects on the structure and function of endothelial cells (EC), and the intercellular matrix. These activities include prevention or restoration of the integrity and permeability of EC, counteraction versus chemical, toxic or metabolic EC injury, regulation of EC-blood cell interactions, inhibition of microvascular inflammatory and proliferative changes, and other similar effects, thus allowing oral SDX to be considered as an endothelial-protecting agent. The best available clinical evidence of the efficacy of SDX administered orally with or without an initial parenteral phase is the following: alleviation of symptoms in chronic venous disease and especially acceleration of healing of venous leg ulcers; prevention of cardiovascular events in survivors after acute myocardial infarction; marked improvement of intermittent claudication in patients with peripheral occlusive arterial disease; and abatement of proteinuria in patients with diabetic nephropathy that may contribute to the amelioration or stabilization of kidney function. Although further clinical trials are warranted, SDX is presently widely accepted in many countries as an effective and safe long-term, endothelial-protecting drug.