Inflammation Is More Sensitive than Cell Proliferation in Response to Rapamycin Treatment in Polycystic Kidney Disease.

INTRODUCTION: It has been reported that rapamycin inhibited inflammation in renal interstitial diseases. We therefore hypothesized that rapamycin could attenuate inflammation in polycystic kidney disease (PKD). METHODS: Han:SPRD rats were treated with rapamycin by daily gavage from 4 weeks to 12 weeks of age at the dosage of 0.5 mg/kg/day (low dose) or 1 mg/kg/day (high dose). WT9-12 human PKD cells were treated with various concentrations of rapamycin. RESULTS: Two-kidney/total body weight ratio and cystic index in Cy/+ kidneys were significantly reduced with the treatment of low-dose rapamycin and further reduced by the treatment with high-dose rapamycin. However, the renal function of Cy/+ rats was equally improved by the treatment with either low-dose or high-dose rapamycin. The renal cell proliferation was significantly decreased in Cy/+ kidneys with the treatment of low-dose rapamycin and was further decreased with the treatment of high-dose rapamycin as examined by Ki67 staining. The phosphorylation of S6K in cystic kidneys was decreased by low-dose rapamycin and further decreased by high-dose rapamycin. Both low-dose and high-dose rapamycin treatment decreased macrophage infiltration and the expression of complement factor B (CFB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) to a similar level. The expression of CFB, MCP-1, and TNF-α and phosphorylation of S6K were inhibited in WT9-12 cells treated with 10 nm rapamycin at 24 h and 48 h, respectively. Moreover, the phosphorylation of Akt was not increased by 1 nm and 10 nm of rapamycin and enhanced by 1 µm rapamycin treatment. Interestingly, WT9-12 cell proliferation could be inhibited by 1 µm rapamycin. CONCLUSION: Low dose of rapamycin could inhibit inflammation and protect renal function in PKD. Inflammation is more sensitive than cell proliferation in response to rapamycin treatment in PKD.

Activation of GPER1 in macrophages ameliorates UUO-induced renal fibrosis.

Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male unilateral ureteral obstruction (UUO) models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 or M2 phenotypes. The RNA-sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G-1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G-1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage activation. These findings indicate that GPER1 may be a promising therapeutic target for treating renal fibrosis.

Dehydration Accelerates Cytogenesis and Cyst Growth in Pkd1-/- Mice by Regulating Macrophage M2 Polarization.

Adult autosomal dominant polycystic kidney disease (ADPKD) has been shown to be related as a "third hit" to the occurrence of acute or chronic kidney injury. Here, we examined whether dehydration, as a common kidney risk factor, could cause cystogenesis in chronic-onset Pkd1-/- mice by regulating macrophage activation. First, we confirmed that dehydration accelerated cytogenesis in Pkd1-/- mice and that macrophages infiltrated the kidney tissues even earlier than macroscopic cyst formation. Then, microarray analysis suggested that glycolysis pathway may be involved in macrophage activation in Pkd1-/- kidneys under conditions of dehydration. Further, we confirmed glycolysis pathway was activated and lactic acid (L-LA) was overproduced in the Pkd1-/- kidney under conditions of dehydration. We have already proved that L-LA strongly stimulated M2 macrophage polarization and overproduction of polyamine in macrophage in vitro, and in the present study, we further discovered that M2 polarization-induced polyamine production shortened the primary cilia length by disrupting the PC1/PC2 complex. Finally, the activation of L-LA-arginase 1-polyamine pathway contributed to cystogenesis and progressive cyst growth in Pkd1-/- mice recurrently exposed to dehydration.

Macrophages promote heat stress nephropathy in mice via the C3a-C3aR-TNF pathway.

Heat-stress nephropathy (HSN) is associated with recurrent dehydration. However, the mechanisms underlying HSN remain largely unknown. In this study, we evaluated the role of dehydration in HSN and kidney injury in mice. Firstly, we found that complement was strongly activated in the mice that were exposed to dehydration; and among complement components, the interaction between C3a and its receptor, C3aR, was more closely associated with kidney injury. Then two-month-old mice were intraperitoneally injected with 2% dimethyl sulfoxide (DMSO) or the C3aR inhibitor SB290157 during dehydration. DMSO-treated mice exhibited excessive macrophage infiltration, renal cell apoptosis, and kidney fibrosis. In contrast, SB290157-treated mice had no apparent kidney injury. By fluorescence-activated cell sorting (FACS), we found that SB290157 treatment in mice remarkably inhibited macrophage infiltration and suppressed CCR2 expression in macrophages. In addition, C3a binding to C3aR promoted macrophage polarization toward the M1 phenotype and increased the production of TNF-α, which induced renal tubular epithelial cell (RTEC) apoptosis in vivo and in vitro. Interestingly, C3a treatment failed to directly induce TNF-α production and apoptosis in RTECs. However, TNF-α production in response to C3a treatment was significantly elevated when RTECs were cocultured with macrophages, suggesting that macrophages rather than RTECs are the target of C3a-C3aR interaction. At last, we proved that infusion of macrophages which highly expressed TNF-α would significantly deteriorate HSN in TNF-KO mice when they were exposed to recurrent dehydration. This study uncovers a novel mechanism underlying the pathogenesis of HSN, and a potential pathway to prevent kidney injury during dehydration.

Thrombotic thrombocytopenic purpura developed after pegylated interferon treatment for hepatitis B infection.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia. It is related to severe deficiency in ADAMTS13, which is usually acquired via ADAMTS13 autoantibodies or inherited via mutations of the ADAMTS13 gene. The etiology of acquired TTP including HIV infection, pregnancy, autoimmune disease, organ transplantation, drugs, malignancy and so on. Here, we firstly reported a patient diagnosed as acquired TTP after pegylated interferon therapy for hepatitis B and COVID-19 vaccination. CASE PRESENTATION: A 36-year-old male attended to our unit with a five-day history of intermittent hematuria and progressive fatigue on January 5th, 2022. He had a 13 years history of hepatitis B infection and undergone pegylated interferon treatment (which was paused for two months because of COVID-19 vaccination) for nearly 3 years. Laboratory evaluation revealed a haemoglobin level of 61 g/L, platelet count of 11 × 109/L, lactate dehydrogenase 2133 U/L. The direct and indirect Coombs test were both negative. On a peripheral blood smear, there were about 18.8% schistocytes. Meanwhile, the results of ADAMTS 13 activity and antibody were < 5% and 181.34 ng/ml (131.25-646.5), respectively CONCLUSION: This case firstly reported the rare complication of TTP after pegylated interferon treatment for hepatitis B and COVID-19 vaccine injection. This unique sign warrants more attention as an early cue of diagnosis of TTP and be aware of the rarity adverse effect of interferon therapy and COVID-19 vaccination.

Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. METHODS: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+⁣/- cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. RESULTS: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. CONCLUSIONS: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

Pancreatic extracorporeal shock wave lithotripsy for a patient concurrent with autosomal dominant polycystic kidney disease: a case report.

Whether pancreatic extracorporeal shock wave lithotripsy (ESWL) is safe for patients with autosomal dominant polycystic kidney disease (ADPKD) is unclear. A woman in her early 30s was admitted to our hospital because of intermittent upper abdominal pain and recurrent pancreatitis. The imaging results confirmed the diagnosis of pancreatic stones and ADPKD. We performed pancreatic ESWL using a third-generation lithotripter to pulverize the pancreatic stones. A maximum of 5000 shock waves was delivered per therapeutic session. A second session of ESWL was performed the next day. The patient developed no adverse events or complications related to pancreatic ESWL. Three years after treatment, the patient had developed no relapse of pancreatitis or abdominal pain. Shock waves do not lead to complications such as hematuria, cyst rupture, or deterioration of the inner bleeding of renal cysts. Multiple kidney cysts are not a contraindication for pancreatic ESWL.

Icariin attenuates renal interstitial fibrosis through G protein-coupled estrogen receptor in a UUO murine model.

BACKGROUND/AIMS: Icariin plays an antifibrotic role in the unilateral ureteral obstruction (UUO) model; however, its primary mechanism has not been elucidated. G protein-coupled estrogen receptor (GPER) has been shown to be associated with fibrosis and mitochondrial biogenesis. In this study, we aimed to investigate the impact of GPER on renal fibrosis and whether icariin attenuates renal fibrosis dependent on GPER. METHODS: In the in vivo study, 10-week-old mice were subjected to the UUO model followed by UUO with icariin, G-15 (a GPER antagonist), and icariin + G-15. GPER expression, renal fibrosis levels, and mitochondrial alterations were measured and analyzed. In an in vitro study, we examined the antifibrotic effect of icariin on rat renal fibroblasts (NRK-49F) via GPER. RESULTS: Consistent with a previous study, icariin significantly attenuated fibrotic markers and protected the kidneys against mitochondrial injuries in the UUO model. However, G-15 exacerbated renal fibrosis and abolished the protective effect of icariin in the UUO model. Furthermore, antagonizing or knocking down GPER in NRK-49F significantly increased fibrotic markers and eliminated the antifibrotic effect of icariin. CONCLUSIONS: Our findings indicate that (1) GPER inhibition exacerbates renal fibrosis, and (2) icariin exerts antifibrotic effects against renal fibrosis through GPER.

Prognostic analysis of crescentic glomerulonephritis with acute kidney injury: a single-center cohort with 5-year follow-up.

BACKGROUND: Crescentic glomerulonephritis (CrGN) represents a severe form of glomerular injury that results in high rates of renal failure. This study aimed to investigate the influence of potential clinical and pathological factors on renal outcomes of CrGN; and the relationship between 3-month and 5-year follow-up as well. METHODS: The cohort enrolled patients diagnosed of biopsy proven CrGN with acute kidney injury(AKI) from January 1, 2010, to January 1, 2018 in Shanghai Changzheng Hospital and followed up for 5 years. RESULTS: A total of 56 patients were included, among whom 11 patients (19.6%) had type I, 12 (21.4%) had type II, and 33 (58.9%) had type III CrGN. Patients with type II CrGN tended to have a lower crescent score, less renal tubular damage, and lower serum creatinine than the other two types. Three-month cumulative renal survival rates of types I, II, and III CrGN were 45.5%, 66.7%, and 48.5%, respectively. Five-year cumulative renal survival rates of types I, II, and III CrGN were 27.2%, 83.3%, and 36.4%, respectively. The Kappa Consistency Test between 3-month and 5-year outcomes was 0.573(P < 0.001). Cox regression model showed that in-hospital dialysis was an indicative renal survival factor in 3 months (HR 15.670, 95% CI 2.987-82.210, P = 0.001). It also showed that the crescent score had an unfavorable effect for renal survival in 5 years (HR 1.750 95% CI 1.018-3.009, P = 0.043). CONCLUSIONS: Clinical manifestations and outcomes varied by different CrGN types. Three-month outcomes could partially reflect the 5-year outcomes. Severity of crescents was an independent risk factor for renal survival in CrGN.

Comparison of Outcomes between Percutaneous and Surgical Placement of Peritoneal Dialysis Catheters in Uremic Patients: A Meta-Analysis.

BACKGROUND: The optimal technique for inserting peritoneal dialysis catheters in uremic patients remains debated. This meta-analysis aimed to summarize the current evidence evaluating the efficacy and safety of percutaneous insertion methods compared to surgical methods. METHOD: A literature search was performed in the PubMed, EMBASE, Cochrane, and Web of Science databases. The primary outcome was defined as catheter survival. The secondary outcomes were mechanical and infectious complications related to catheter insertion. RESULTS: Twenty studies were finally identified, including 2 randomized controlled trials. The pooled results of catheter survival, overall mechanical complications, and infectious complications were not significant (odds ratio [OR] = 1.10, 95% confidence interval (CI) = 0.76-1.57, p = 0.62; OR = 0.73, 95% CI = 0.48-1.11, p = 0.14; and OR = 0.64, 95% CI = 0.37-1.09, p = 0.14, respectively). Comparison stratified by the blind percutaneous method versus open surgery indicated a lower overall number of mechanical complications (OR = 0.54, 95% CI = 0.31-0.93, I2 = 72%) and malposition rate (OR = 0.56, 95% CI = 0.34-0.90, I2 = 0%). The leakage rate was higher in the blind percutaneous group than in the open surgery group (OR = 2.55, 95% CI = 1.72-3.79, I2 = 0%); the guided percutaneous method achieved a similar leakage risk to the surgical methods. CONCLUSIONS: The blind percutaneous method performed better with fewer overall mechanical complications and less malposition than open surgery. The leakage risk was higher in the blind percutaneous group, while the guided percutaneous placement group showed similar outcomes to the surgical method groups. Percutaneous methods also had a lower infection risk, which needs further evidence to be confirmed.

NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and zebrafish and mouse models.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear-cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease-specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC-specific up-regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1-/- and 786-0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early-onset Pkd1-deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.

Leflunomide plus low-dose prednisone in patients with progressive IgA nephropathy: a multicenter, prospective, randomized, open-labeled, and controlled trial.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide, and the optimal approach to its treatment remains a significant challenge. METHODS: We did a prospective, randomized, open-labeled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment, and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF + prednisone group) or conventionally accepted-dose prednisone [prednisone(alone) group] Our primary outcome was 24-h urine protein excretion (UPE) and secondary outcomes were serum albumin (sALB), serum creatinine (Scr), and eGFR. Safety was evaluated in all patients who received the trial medications. RESULTS: One hundred and eight patients [59 in LEF + prednisone group, 49 in prednisone (alone) group]were enrolled and finished their treatment and follow-up periods. There is no significant difference in the baseline level between the two groups. Compared with baseline, both groups showed a significant decrease in 24-h UPE (p < 0.01) and increase in sALB (p < 0.01), with stable Scr and eGFR throughout the 12-month treatment period. What's more, these effects were sustained through the 12-month follow-up period. However, there was no difference in 24-h UPE, sALB, Scr, and eGFR between the two groups (p > 0.05). At 12 months, a difference in overall response rate, relapsing rate, and incidence of adverse events between the two groups was not significant. CONCLUSIONS: The efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in the treatment of progressive IgAN are comparable.

PKD2 gene variants in Chinese patients with autosomal dominant polycystic kidney disease.

PKD2 gene variants account for 4.5% to 20% of patients with autosomal dominant polycystic kidney disease (ADPKD). Little is known about the clinical characteristics of PKD2 variants in Chinese patients with ADPKD. Herein, we performed a comprehensive search for variants of PKD2 gene in 44 Chinese ADPKD pedigrees and a total of 37 variants were identified. Of these 37 variants, 18 were nonsense variants, 10 frameshift variants, 4 missense variants, and 5 splice site variants. 11/37 variants were detected for the first time. The median age at diagnosis was 30.5 years, and positive family history was detected in 77.27% patients, liver cysts in 68.18%, hypertension in 45.45%, nephrolithiasis in 31.82%, macro-hematuria in 22.73%, and proteinuria in 13.63%. The level of estimated glomerular filtration rate in 8/39 patients were blow 60 ml/min/1.73m2 . 11/17 patients were classified as rapid progression by Mayo Clinic classification. The end stage renal disease (ESRD) events were reported in 9/22 pedigrees, and the presence of nephrolithiasis and macro-hematuria were significantly associated with ESRD in the pedigrees with PKD2 variants. The identified variants and clinical features will facilitate the early diagnosis and prognosis prediction in Chinese ADPKD patients with PKD2 variants.

The Role of Renal Pathology in the Prognosis and Recovery of Community-Acquired Acute Kidney Injury.

OBJECTIVES: The determinants leading to different renal outcomes in community-acquired acute kidney injury (CA-AKI) and the influence of renal histological damage on the prognosis and recovery of CA-AKI are scarcely reported. METHODS: Adult patients with CA-AKI admitted to Shanghai Changzheng Hospital with renal biopsy profiles from January 1, 2010, to December 31, 2018, were enrolled in our cohort. After 3 months of follow-up, clinical outcomes, including patient survival, dialysis requirement during hospitalization and at 3 months, CKD stage 3-5, and renal functional recovery at 3 months, were analyzed, and risk factors were identified. RESULTS: A total of 294 patients with CA-AKI with renal pathology were identified for this cohort. Among 282 patients who survived 3 months after AKI, 59.6% completely recovered, 21.3% partially recovered, 21.3% progressed to stage 3-5 CKD without dialysis, and 17.7% maintained dialysis. Moreover, 70.4% of patients in the cohort presented with de novo intrinsic renal disease, except acute tubular necrosis or acute interstitial nephritis, on renal biopsy. In the multivariate analyses, clinical factors were more related to short-term outcomes and severity of CA-AKI, represented by mortality, in-hospital dialysis, and CRRT requirement, while pathological elements were more involved with CKD progression, including dialysis-dependent or stage 3-5 CKD, and renal function recovery at the 3-month follow-up. The detrimental influence of glomerular and arterial lesions on renal prognosis of CA-AKI was as critical as tubular and interstitial lesions. CONCLUSIONS: Clinical and pathological parameters both contribute to patient and renal outcomes after CA-AKI. The value of renal biopsy should be recognized in prognostic prediction.

p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease.

Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.

Matrix metalloproteinase-7 in platelet-activated macrophages accounts for cardiac remodeling in uremic mice.

Heart failure is the leading cause of mortality in patients with end-stage renal disease, and progressive cardiac remodeling is the key pathological basis of heart failure. However, the mechanism by which uremia-induced cardiac remodeling occurs is not well understood. Here, we showed that platelets were significantly activated in 5/6 nephrectomy-operated mice, and cardiac remodeling in the uremic mice was significantly improved when platelets were effectively depleted. A cardiac fibrosis-related gene expression profile revealed that Mmp7, encoding matrix metalloproteinase-7 (MMP-7), exhibited the greatest degree of downregulation in the hearts of uremic mice with platelets depleted. Using fluorescence-activated cell sorting, we discovered that MMP-7 was mainly expressed in M1 and M4 cardiac macrophages, although it was also extensively expressed in heart tissues. For the upstream therapeutic target, neutralization of platelet factor 4 (PF4) with monoclonal antibody not only significantly suppressed M4 macrophages in vivo, but also notably prevented collagen destruction in heart tissues. For the downstream therapeutic target, the pharmacological inhibition of MMP-7 with selective inhibitor failed to notably affect the platelet status, but significantly reduced heart collagen destruction in mice, a further indication that MMP-7 is a crucial downstream molecular target of platelet activation. In vitro, platelets interacted with macrophages and drove them to upregulate MMP-7 expression via free molecules, especially PF4. Taken together, the data suggest that MMP-7 is a key downstream target of platelet activation during uremia. Thus, MMP-7 is a likely and novel therapeutic target for intervention of cardiac remodeling during uremia.

A 64-year-old woman with raccoon eyes following kidney biopsy: a case report.

BACKGROUND: Raccoon eyes or periorbital ecchymosis is caused by blood tracking into periorbital tissues, which is mostly recognized in injuries of head and neck, basal skull fractures, convexity fractures and facial fractures. It was also reported in systematic disorders, such as multiple myeloma, amyloidosis, Kaposi's sarcoma, migraine and neuroblastoma. However, it is unusual to see a patient showing periorbital purpura after kidney biopsy with no other ecchymosis. Here, we firstly reported this rare symptom after kidney biopsy in a patient who was finally diagnosed as immunoglobulin light chain (AL) amyloidosis. CASE PRESENTATION: A 64-year old woman was admitted to our clinic with 1.5 years history of sub-nephrotic proteinuria and slowly progressive deterioration of renal function. Laboratory -investigations revealed an M-peak in the λ fraction of IgA and concentrations of serum free-light-chain (FLC) were 44.95 mg/L for κ isotype and 173 mg/L for λ isotype. Unexpectedly the patient showed periorbital purpura 24 h later after kidney biopsy with no more other ecchymosis. Renal biopsy showed massively glomerulosclerosis, interstitial fibrosis with positively Congo red staining in mesangial areas. For fluorescent staining, the kidney tissue showed strongly λ light-chain deposition. The fibrils (8-12 nm in diameter) were confirmed by electron micrograph. CONCLUSIONS: This case firstly reported this rare symptom after the kidney biopsy in a patient who was finally diagnosed as AL amyloidosis. And this unique sign of periorbital ecchymosis warrants more attention as an early cue of amyloidosis.

[Clinical practice guidelines for polycystic kidney diseases].

Polycystic kidney disease (PKD) is a group of hereditary kidney diseases caused by genetic mutations. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the two main forms of PKD. The pathological features of PKD include progressive enlargement of renal cysts and destruction of kidney structure, which may eventually lead to end-stage renal disease (ESRD). As a result, the lives of PKD patients can only be sustained by dialysis or kidney transplantation. On the basis of basic research, clinical studies and guidelines issued for PKD at home and abroad, and by combining with the reality of Chinese PKD patients, this guideline has summarized the key points for the genetic counseling and clinical treatment of PKD, with an aim to improve the understanding and standardized diagnosis and treatment for such disorders.

A Sphingosine-1-Phosphate Modulator Ameliorates Polycystic Kidney Disease in Han:SPRD Rats.

BACKGROUND: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized -Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. METHODS: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. RESULTS: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. CONCLUSION: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.

The role of the complement factor B-arginase-polyamine molecular axis in uremia-induced cardiac remodeling in mice.

The role of complement system in heart diseases is controversial. Besides, the mechanisms by which complement components participate in cardiac remodeling (CR) and heart failure during uremia are unclear. In this study, 5/6 nephrectomy was performed to adult mice to establish the uremic model and CR deteriorated over the course of uremia. Although complement pathways were not further activated over the course of the disease, soluble complement factor B (CFB) was upregulated at post-nephrectomy day 90 (PNx90) compared with PNx30. Further, CFB notably deteriorated CR in uremic mice but this effect was reversed by depletion of macrophages with liposomal clodronate. In vivo and in vitro CFB upregulated arginase 1 (ARG1) expression, increased ARG1 enzymatic activity, and stimulated the syntheses of ornithine, leading to polyamine overproduction in macrophages. Putrescine, an important polyamine, promoted cardiac fibroblast proliferation and collagen production, resulting in progressive CR. In vivo the inhibition of ARG1 activity with Nω -hydroxyl-l-arginine remarkably improved the general survival rates, inhibited the infiltration of cardiac fibroblasts, and alleviated progression of CR in uremic mice. Taken together, the CFB-ARG1-putrescine axis is related to progression of CR and ARG1 hyperactivity in macrophages may provide a novel therapeutic target against the heart injury in uremia.