Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

Matrix metalloproteinases(MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition(EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition(Endo MT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, hasbeen shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β(TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.

Inflammatory status in chronic renal failure: The role of homocysteinemia and pro-inflammatory cytokines

AIM： To evaluate determinants of infammatory mark-ers in chronic renal failure patients according to the level of glomerular fltration rate. METHODS： One hundred ffty four patients （Age： 44 ± 06 years; male/female： 66/88） with chronic renal fail-ure （CRF） were divided into 6 groups according to the National Kidney Foundation （NKF） classification. They included 28 primary stage renal failure patients （CRF 1）, 28 moderate stage renal failure patients （CRF 2）,28 severe stage renal failure patients （CRF 3）, 18 end-stage renal failure patients （CRF 4）, 40 hemodialysis （HD） patients, and 12 peritoneal dialysis （PD） patients. Tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β）, interleukin-6 （IL-6） and C-reactive protein （CRP） were analyzed by immunosorbent assay kit （ELISA） （Cayman Chemical’s ACETM EIA kit）. Immunoassay methods were used for total homocysteine （tHcy） （fuorescence polarization immunoanalysis HPLC, PerkinEmer 200 series）, transferrin （MININEPHTM human transferin kit： ZK070.R）, ferritin （ADVIA Centaur ） and fbrinogen analysis （ACL 200）. Differences between groups were performed using SPSS 20.0 and data are expressed as the mean ± SD.RESULTS： Results showed that in comparison with CRF 1 group and other groups, TNF-α and IL-6 levels were respectively more elevated in HD （16.38 ± 5.52 pg/mL vs 0.39 ± 0.03 pg/mL, 11.05 ± 3.59 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001） and PD （14.04 ± 3.40 pg/mL vs 0.39 ± 0.03 pg/mL, 10.15 ± 1.66 pg/mL vs 8.20 ± 0.22 pg/mL, P 〈 0.001）. IL-1β levels were increased in HD （9.63 ± 3.50 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） and CRF 4 （7.76 ± 0.66 pg/mL vs 3.24 ± 0.10 pg/mL, P 〈 0.001） patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD （32.27 ± 12.08 μmol/L） and PD （28.37 ± 4.98 μmol/L） patients compared to the other groups of CRF （P 〈 0.001）. The serum CRP level was signifcantly increased in HD （18.17 ± 6.38 mg/L） and PD （17.97 ± 4.85 mg/L） patients compared to the other groups of CRF patients （P 〈 0.001）. The plasma fbrinogen level was more elevated in HD （6.86 ± 1.06 g/L） and CRF 4 （6.05 ± 0.57 g/L） than in the other groups （ P 〈 0.001）. Furthermore; the ferritin level was higher in HD （169.90 ± 62.16 ng/mL） and PD （90.08 ± 22.09 ng/mL） pa-tients compared to the other groups of CRF （P 〈 0.001）. The serum transferrin value was signifcantly decreased especially in PD （1.78 ± 0.21 g/L） compared to the oth-er groups （P 〈 0.001）. We found a negative correlation between glomerular fltration rate （GFR）, TNF-α levels （ r = -0.75, P 〈 0.001）, and tHcy levels （ r = -0.68, P 〈 0.001）. We observed a positive correlation between GFR and transferrin levels （ r = 0.60, P 〈 0.001）. CONCLUSION： CRF was associated with elevated in-flammatory markers. The inflammation was observed at the severe stage of CRF and increases with progres-sion of renal failure.

Searching for a treatment for Alport syndrome using mouse models

Alport syndrome （AS） is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encod-ing the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identifed and the frst Al-port mouse model was developed using a knockout ap-proach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the patho-genesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharma-cological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refnement as research advances. In terms of the pharmacological drugs, angiotensin-con-verting enzyme inhibitors have been shown to be effec-tive in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.

Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules

The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.

Time-dependent viscoelastic properties along rat small intestine

AIM： To measure the time-dependent （viscoelastic） behavior in the change of the small intestinal opening angle and to test how well the behavior could be described by the Kelvin model for a standard linear solid. METHODS： Segments from the duodenum, jejunum, and ileum were harvested from 10 female Wistar rats and the luminal diameter, wall thickness, and opening angle over time （θ（t）） were measured from rings cut from these segments. RESULTS： Morphometric variations were found along the small intestine with an increase in luminal area and a decrease in wall thickness from the duodenum to the ileum. The opening angle obtained after 60 rain was highest in the duodenum （220.8±12.9°）and decreased along the length of the intestine to 143.9±8.9° in the jejunum and 151.4±9.4° in the ileum. The change of opening angle as a function of time, fitted well to the Kelvin model using the equation θ（t）/θo = [1-ηexp （-λt）] after the ring was cut. The computed creep rate λ. did not differ between the segments. Compared to constant calculated from pig aorta and coronary artery, it showed that α agreed well （within 5%）, η was three times larger than that for vascular tissue, and λ ranged ±40% from the value of the pig coronary artery and was a third of the value of pig aorta. CONCLUSION： The change of opening angle over time for all the small intestine segments fits well to the standard linear spring-dashpot model. This viscoelastic constant of the rat small intestine is fairly homogenous along its length. The data obtained from this study add to a base set of biomechanical data on the small intestine and provide a reference state for comparison to other tissues,diseased intestinal tissue or intestinal tissue exposed to drugs or chemicals.

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

Immunoglobulin A （IgA） nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identifed even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 （IgA1） with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a “lanthanic” deposition remains to be clarifed. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarifed.

Primary glomerular diseases in the elderly

Primary glomerular diseases in the elderly population are a frustrating topic due to difficulties in both the diagnosis and decision making about treatment. The most frequent type of primary glomerular disease in elderly is membranous nephropathy; while its counterpart in younger population is Ig A nephropathy. The most frequent cause of nephrotic syndrome in the elderly is also membranous nephropathy. Pauci-immune crescentic glomerulonephritis(GN) rate increases both in elderly and very elderly population. Pauci-immune crescentic GNs should be regarded as urgencies in elderly patients as in their younger counterparts due to potential for causing end-stage renal disease in case of delayed diagnosis and treatment, and also causing mortality due to alveolar hemorrhage in patients with pulmonary involvement. Renal biopsy is the inevitable diagnostic method in the elderly as in all other age groups. Renal biopsy prevents unnecessary treatments and provides prognostic data. So advanced age should not be the sole contraindication for renal biopsy. The course of primary glomerular diseases may differ in the elderly population. Acute kidney injury is more frequent in the course and renal functions may be worse at presentation. These patients are more prone to be hypertensive. The decision about adding immune suppressive therapies to conservative methods should be made considering many factors like co-morbidities, drug side effects and potential drug interactions, risk of infection, patient preference, life expectancy and renal functions at the time of diagnosis.

Reclassification of membranoproliferative glomerulonephritis:Identification of a new GN:C3GN

This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.

Diagnosis and treatment of small intestinal bleeding:Retrospective analysis of 76 cases

AIM: To investigate the causes of small intestinal bleed- ing as well as its diagnosis and therapeutic approaches. METHODS: A retrospective analysis was conducted ac- cording to the clinical records of 76 patients with small intestinal bleeding admitted to our hospital in the past 5 years. RESULTS: In these patients, tumor was the most fre- quent cause of small intestinal bleeding (37/76), fol- lowed by Meckel’s diverticulum (21/76), angiopathy (15/76) and ectopic pancreas (3/76). Of the 76 patients, 21 were diagnosed by digital subtraction angiography, 13 by barium and air double contrast X-ray examination of the small intestine, 11 by 99mTc-sestamibi scintigraphy of the abdominal cavity, 6 by enteroscopy of the small intestine, 21 by laparoscopic laparotomy, and 4 by ex- ploratory laparotomy. Although all the patients received surgical treatment, most of them (68/76) received part enterectomy covering the diseased segment and entero- anastomosis. The follow-up time ranged from 1 year to 5 years. No case had recurrent alimentary tract bleeding or other complications. CONCLUSION: Tumor is the major cause of small in- testinal bleeding followed by Meckel’s diverticulum and angiopathy. The main approaches to definite diagnosis of small intestinal bleeding include digital subtraction an- giography, 99mTc-sestamibi scintigraphy of the abdominal cavity, barium and air double contrast X-ray examina- tion of the small intestine, laparoscopic laparotomy or exploratory laparotomy. Part enterectomy covering the diseased segment and enteroanastomosis are the most effective treatment modalities for small intestinal bleed- ing.

Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients

AIM： To assess the correlation between the serum hep-cidin-25 level and left ventricular mass index.METHODS： This study was a cross-sectional study conducted between March 2009 and April 2010. Demo-graphic and biochemical data, including the serum hep-cidin-25 level, were collected for chronic kidney disease （CKD） patients. Two-dimensional echocardiography was performed to determine the left ventricle mass （LVM）, left ventricular mass index （LVMI）, interventricular septum thickness （IVSd）, left ventricle posterior wall thickness （LVPW）, right ventricular dimension （RVD）, left atrium （LA） and ejection fraction （EF）.RESULTS： A total of 146 patients with stage 1 to 5 CKD were enrolled. Serum hepcidin-25 levels were 16.51 ± 5.2, 17.59 ± 5.32, 17.38 ± 6.47, 19.98 ± 4.98 and 22.03 ± 4.8 ng/mL for stage 1 to 5 CKD patients, respectively. Hepcidin-25 level was independently pre-dicted by the serum ferritin level （β = 0.6, P = 0.002） and the estimated glomerular fltration rate （β = -0.48, P = 0.04）. There were negative correlations between the serum hepcidin level and the LVM and LVMI （ P = 0.04 and P = 0.005, respectively）. Systolic blood pressure （BP） was positively correlated with the LVMI （ P = 0.005）. In the multivariate analysis, a decreased serum hepci-din-25 level was independently associated with a higher LVMI （β = -0.28, 95%CI： -0.48 - -0.02, P = 0.006） after adjusting for body mass index, age and systolic BP.CONCLUSION： A lower serum hepcidin level is associ-ated with a higher LVMI in CKD patients. Low hepcidin levels may be independently correlated with unfavor-able cardiovascular outcomes in this population.

Urgent call for reconsideration of chronic kidney disease

Circulating toxins namely： free radicals, cytokines and metabolic products induce glomerular endothelial dys-function, hemodynamic maladjustment and chronic ischemic state;this leads to tubulointerstitial fbrosis in chronic kidney disease （CKD）. Altered vascular homeo-stasis observed in late stage CKD revealed defective angiogenesis and impaired nitric oxide production ex-plaining therapeutic resistance to vasodilator treatment in late stage CKD. Under current practice, CKD patients are diagnosed and treated at a rather late stage due to the lack of sensitivity of the diagnostic markers avail-able. This suggests the need for an alternative thera-peutic strategy implementing the therapeutic approachat an early stage. This view is supported by the normal or mildly impaired vascular homeostasis observed in early stage CKD. Treatment at this early stage can potentially enhance renal perfusion, correct the renal ischemic state and restore renal function. Thus, this alternative therapeutic approach would effectively pre-vent end-stage renal disease.

Pathogenesis of glomerular haematuria

Haematuria was known as a benign hallmark of some glomerular diseases, but over the last decade, new evidences pointed its negative implications on kidneydisease progression. Cytotoxic effects of oxidative stress induced by hemoglobin, heme, or iron released from red blood cells may account for the tubular injury observed in human biopsy specimens. However, the precise mechanisms responsible for haematuria remain unclear. The presence of red blood cells （RBCs） with irregular contours and shape in the urine indicates RBCs egression from the glomerular capillary into the urinary space. Therefore glomerular haematuria may be a marker of glomerular filtration barrier dysfunction or damage. In this review we describe some key issues regarding epidemiology and pathogenesis of haematuric diseases as well as their renal morphological fndings.

Anti-Helicobacter pylori therapy significantly reduces Helicobacter py/ori-Induced gastric mucosal damage in Mongolian gerbils

AIM: To investigate the effectiveness of 4 d' anti-Helicobacter pylori therapy on the H pylori-infected Mongolian gerbils based on physiological and pathological changes. METHODS: We used 6-wk-old male gerbils orally inoculated with H pylori (ATCC43504, 2×108 CFU/mL). Seven weeks after H pylori inoculation, the animals of study group received 4 d' anti-H pylori triple therapy (H pylori-eradicated group). Seven days later, all animals of the H pylori-eradicated and control groups (H pylori-infected & H pylori-uninfected groups) were sacrificed. We examined gastric mucosal lesions macroscopically, studied gastritis microscopically and determined the stomach weight ratio, myeloperoxidase (MPO) activity and prostaglandin (PG) E2 level. RESULTS: The results showed that both macroscopic and histological gastric damages were significantly less in H pylori-eradicated group than H pylori-infected group. Stomach weight ratio, MPO activity and PGE2 levels were significantly higher in H pylori-infected group than those in the other two groups. CONCLUSION: Four days' anti-H pylori therapy was effective in the improvement of H pylori-induced gastric lesions in Mongolian gerbils.

Double-balloon enteroscopy reliably directs surgical intervention for patients with small intestinal bleeding

AIM: To evaluate preoperative double-balloon enteroscopy for determining bleeding lesions of small intestine, thus directing selective surgical intervention. METHODS: We retrospectively reviewed 56 patients who underwent double-balloon enteroscopy to localize intestinal bleeding prior to surgical intervention, and compared enteroscopic findings with those of intraoperation to determine the accuracy of enteroscopy in identifying and localizing the sites of small intestinal bleeding. RESULTS: Double-balloon enteroscopy was performed in all 56 patients in a 30-mo period. A possible site of blood loss was identified in 54 (96%) patients. Enteroscopy provided accurate localization of the bleeding in 53 (95%) of 56 patients, but failed to disclose the cause of bleeding in 4 (7%). There was one case with negative intraoperative finding (2%). Resection of the affected bowel was carried out except one patient who experienced rebleeding after operation. Gastrointestinal stromal tumor (GIST) was most frequently diagnosed (55%). CONCLUSION: Double-balloon enteroscopy is a safe, reliable modality for determining bleeding lesion of small intestine. This technique can be used to direct selective surgical intervention.

A ruptured large extraluminal ileal gastrointestinal stromal tumor causing hemoperitoneum

We describe an 87-year-old woman with a large ileal gastrointestinal stromal tumor (GIST) causing hemoperitoneum. A CT scan demonstrated a large heterogeneous mass measuring about 13 cm × 11 cm in the pelvis and hemoperitoneum, with a non-uniform enhancement pattern. The mass was diagnosed as a GIST originating from the gastrointestinal tract. She underwent an urgent laparotomy and an ileal GIST with a rupture was found 130 cm from the anal to the Treitz’s ligament. Hemoperitoneum caused by ileal GIST rupture is a rare condition. Bleeding in the large tumor leading to rupture of the capsule might cause hemoperitoneum in the present case.

Duplication cyst of the small intestine found by double-balloon endoscopy:A case report

A 35-year-old man was admitted due to bloody stool and anemia. The bleeding source could not be detected by esophagogastroduodenoscopy or colonoscopy. Double balloon endoscopy (DBE) revealed a diverticulum-like hole in which coagula stuck in the ileum at 1 meter on the oral side from the ileocecal valve. The adjacent mucosa just to the oral side of the hole was elevated like a submucosal tumor. The lesion was considered the source of bleeding and removed surgically. It was determined to be a cyst with an ileal structure on the mesenteric aspect accompanying gastric mucosa. The diagnosis was a duplication cyst of the ileum,which is a rare entity that can cause gastrointestinal bleeding. In the present case,DBE was used to fi nd the hemorrhagic duplication cyst in the ileum.

Regulatory roles of nitric oxide and angiotensin Ⅱ on renal tubular transport

Renal tubules regulate blood pressure and humoral homeostasis. Mediators that play a significant role in regulating the transport of solutes and water include angiotensin Ⅱ （AngⅡ） and nitric oxide （NO）. AngⅡcan signifcantly raise blood pressure via effects on the heart, vasculature, and renal tubules. AngⅡ generally stimulates sodium reabsorption by triggering sodium and fuid retention in almost all segments of renal tu-bules. Stimulation of renal proximal tubule （PT） trans-port is thought to be essential for AngⅡ-mediated hy-pertension. However, AngⅡ has a biphasic effect on in vitro PT transport in mice, rats, and rabbits： stimulation at low concentrations and inhibition at high concentra-tions. On the other hand, NO is generally thought to inhibit renal tubular transport. In PTs, NO seems to be involved in the inhibitory effect of AngⅡ. A recent study reports a surprising fnding： AngⅡ has a mono-phasic stimulatory effect on human PT transport. De-tailed analysis of signalling mechanisms indicates that in contrast to other species, the human NO/guanosine 3’,5’-cyclic monophosphate/extracellular signal-regulat-ed kinase pathway seems to mediate this effect of Ang Ⅱ on PT transport. In this review we will discuss recent progress in understanding the effects of AngⅡ and NO on renal tubular transport.

Collapsing focal segmental glomerulosclerosis: Current concepts

Collapsing focal segmental glomerulosclerosis （cFSGS）, also known as collapsing glomerulopathy is currently classified under the rubric of FSGS. However, its de-fining morphological features are in stark contrast to those observed in most other variants of FSGS. During the early stage of the disease, the lesion is character-ized pathologically by an implosive segmental and/or global collapse of the glomerular capillary tufts, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease. With advancement of the disease, segmental and/or global glomerulosclerosis is also observed in association with the collapsing le-sions. The etiology of this enigmatic disorder is still elusive, but a growing list of diseases/conditions is being reported in association with this morphological pattern of renal parenchymal injury. The pathogenesis of cFSGS involves discreet epithelial cell injury leadingto cell cycle dysregulation and a proliferative cellularphenotype. From the clinical perspective, cFSGS is no-torious for its propensity to affect black people, a highincidence and severity of nephrotic syndrome, markedresistance to empirical therapy, and rapid progressionto end-stage renal disease. The lesion has also beenreported in transplanted kidneys either as recurrent orde novo disease, frequently leading to graft loss. Mostcases have been reported in western countries, but the lesion is also being increasingly recognized in the tropi-cal regions. The recent increase in reporting of cFSGS partly refects a true increase in the incidence and part-ly a detection bias. There is no specifc treatment for the disorder at present. Newer insights into the patho-genesis may lead to the development of targeted and specifc therapy in near future. There is an urgent need to increase awareness of the lesion among pathologists and nephrologists, especially those from developing countries, to ensure accurate diagnosis and appropriate managment. With the accumulation of more and more data, it is hoped that the prevailing confusion about the nosological identity of the lesion will also be resolved in a more logical way.

Primary focal and segmental glomerulosclerosis and soluble factor urokinase-type plasminogen activator receptor

Primary focal and segmental glomerulosclerosis(FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The different available therapeutic approaches are unsuccessful, in part due to partially deciphered heterogeneous and complex pathophysiological mechanisms. Moreover, the term FSGS, even in its primary form, comprises a histological description shared by a number of different causes with completely different molecular pathways of disease. This review focuses on the latest developments regarding the pathophysiology of primary acquired FSGS caused by soluble factor urokinase type plasminogen activator receptor, a circulating permeability factor involved in proteinuria and edema formation, and describes recent advances with potential success in therapy.