Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway

BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Effects of Matrine on Adenine-Induced Chronic Tubulointerstitial Fibrosis in Rats

Aim ,To study the mechanism relative to therapeutic effects of matrine on adenine-induced renal interstitial fibrosis in rats. Methods Sixty male Wistar rats were selected and randomly divided into 3 groups： normal control group （NCG） consisted of 8 rats, adenine treated group （ATG） 28 rats, and matrine treated group （MTG） 24 rats. Each rat in ATG and MTG was gavaged with adenine （250 mg·kg^-1·d^-1 ） for 21 d. After gavage with adenine for one week, each rat in MTG was administered intraperitoneally matrine（20 mg·kg^-1·d^-1 ） in vehicle （ 1 mL of 0.9% sodium chloride） daily. On days 14, 21, and 28, the serum levels of urea nitrogen, creatinine, and IL-6 were determined and the rat kidneys of ATG, MTG and NCGwere examined pathologically. Radioimmunoassay for serum IL- 6 immunohistochemical staining for TGF-β1 expression in the kidney and semiquantitative analysis were performed. HE staining for semiquantitative analysis of tubulointerstitial injury. Results The serum levels of urea nitrogen and creatinine in MTG were lower as compare to ATG （ P 〈 0.05 ） whereas serum IL- 6 and renal TGF-β1 expression levels were significantly lower than those in ATG （P 〈0.05 ）, but all these indexes were higher than those in NCG （P 〈 0.01 ）. In MTG, the index of tubulointerstitial lesion was lower than that in ATG （P 〈 0.05 ）. Conclusion Matrine inhibits the renal tubulointerstial fibrosis in the adenine-induced rat model by suppressing serum level of IL-6 and expression of TGF-β1 in the tubulointerstitium.

Effects and Mechanism of Irbesartan on Tubulointerstitial fibrosis in 5/6 Nephrectomized Rats

Tubulointerstitial fibrosis(TIF)is a common pathological feature of end-stage kidney disease.Previous studies showed that upregulation of TGFβ1 notably contributed to the chronic renal injury and irbesartan halted the development of TIF in rats with 5/6 renal mass reduction.This study was to investigate the effects of irbesartan on chronic TIF and the mechanism involved TGFβ1 in the rodent model of chronic renal failure involving 5/6 nephrectomy.The results showed that irbesartan significantly attenuated th...

Expression of Connective Tissue Growth Factor in Renal Tubulointerstitial Fibrosis in Rats and Its Pathogenic Role

Summary： In order to explore the role of connective tissue growth factor （CTGF） in the pathogenesis of renal tubulointerstitial fibrosis, 48 Wistar rats were randomly divided into sham-operated and unilateral ureteral obstruction （UUO） group. On the postoperative day 1, 3, 7 and 14, the rats were killed and the kidneys were removed. The renal tubulointerstitial injury index was evaluated according to the MASSON staining. The mRNA levels of CTGF, transforming growth factor β1 （TGF-β1）. collagen [ （col I ）, and plasminogen activator inhibitor-1 （PAI 1） were detected using rexerse transcriptional-polymerase chain reaction （RT PCR）. Immunohistochemistry was performed to evaluale the protein expression of the above factors, and the relations among them were analyzed. Quantitative expression of CTGF protein in the kidneys was also assessed using Western blot. The results showed that TGF-β1 mRNA level was increased at first day after UUO, followed by a marked elevation of CTGF mRNA level, which began to increase 3 days after UUO （P〈0.01）. With the progression of the disease, the mRNA expression of CTGF, col I and PAI-1 was increased progressively. Immunohistochemistry revealed that the CTGF protein expression was significantly increased in fibrotic areas and tubular epithelial cells 3 days after UUO. On the post-UUO day 7, the protein level of CTGF was positively related to the renal tubulointerstitial injury index （r =0.62, P〈0.01）, the expression of TGF-β1 （r=0.85, P〈0.01）, colI （r=0.78, P〈0.01）, and PAI-1（r=0.76, P〈0.01）. Upon Western blot analysis, CTGF protein expression began to increase 3 days after UUO, and appeared progressively throughout the time course （P〈0.01, as compared with sham-operated group）. It is concluded that CTGF can be induced by TGF-β and mediate various profibrotic actions of this cytokine, such as increasing extracellular matrix （ECM） synthesis and decreasing ECM degradation. The increased expression of CTGF may play a crucial role in the development and progression of tubulointerstitial fibrosis.

Successful treatment of tubulointerstitial nephritis in immunoglobulin G4-related disease with rituximab: A case report

BACKGROUND Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition that consisted of disorders that share particular clinical,serologic and pathologic properties.The common presentation of disease includes tumor-like swelling of involved organs and the histopathological findings are a lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells,and a variable degree of fibrosis that has a characteristic "storiform" pattern in biopsy specimens of tumorlike masses.Major presentations of this disease,which often affects more than one organ,include autoimmune pancreatitis,salivary gland disease (sialadenitis),orbital disease and retroperitoneal fibrosis.The steroid treatment is essential for the treatment of the disease however,other immunosuppressive drugs including cyclophosphamide or rituximab could be an option in resistant cases.CASE SUMMARY Herein,we reported a 34-year-old woman whom previously had diagnosed with asthma,rheumatoid arthritis and Sj?gren’s syndrome (SS) referred our nephrology department due to acute kidney failure development at the last rheumatology visit.After kidney biopsy she has been diagnosed with IgG4-RD and tubuluointerstitial nephritis.She had been accepted resistant to steroid,mycophenolate mofetil,methotrexate and azathioprine therapies due to receiving in last two years.She refused to receive cyclophosphamide due to potential gonadotoxicity of the drug.Thus,rituximab therapy was considered.She received 1000 mg infusion,15 d apart and 6 mo later it has been administered same protocol.After one year from the last rituximab dose serum creatinine decreased from 4.4 mg/dL to 1.6 mg/dL,erythrocyte sedimentation rate decreased from 109 mm/h to 13 mm/h [reference range (RR) 0-20],and Creactive protein decreased from 55.6 mg/L to 5 mg/L (RR 0–6).All pathologic lymph nodes and masses were also disappeared.CONCLUSION Patients with IgG4-RD usually misdiagnosed with rheumatologic diseases including systemic lupus erythematous or SS and also they were screened for the presence of malignancy.Rituximab could be an important treatment option in cases with steroid resistant tubulointerstitial nephritis in IgG4-RD.

C5b-9 does not mediate tubulointerstitial injury in experimental acute glomerular disease characterized by selective proteinuria

AIM： To determine whether complement membrane attack complex （C5b-9） has a pathogenic role in tubuloin-terstitial injury in a renal disease model characterized by acute highly selective proteinuria. METHODS： Protein-overload nephropathy （PON） was induced in adult female Piebald-Viral-Glaxo rats with or without complement C6 defciency （C6- and C6＋） by daily intraperitoneal injections of bovine serum albumin （BSA, 2 g/d）, and examined on days 2, 4 and 8.RESULTS： Groups with PON developed equivalent levels of heavy proteinuria within 24 h of BSA injection. In C6＋ rats with PON, the tubulointerstitial expression of C5b-9 was increased and localized predominantly to the basolateral surface of tubular epithelial cells （TECs）, whereas it was undetectable in C6- animals. TEC proliferation （as assessed by the number of BrdU＋cells） increased by more than 50-fold in PON, peaking on day 2 and declining on days 4 to 8. There was a trend for a reduction in the number of BrdU＋ TECs on day 4 in the C6- PON group （ P = 0.10 compared to C6＋） but not at any other time-point. Kidney enlargement, TEC apoptosis （TUNEL＋ cells） and markers of tubular injury （tubule dilatation, loss of TEC height, protein cast formation） were not altered by C6 deficiency in PON. Interstitial monocyte （ED-1＋ cell） accumulation was partially reduced in C6- animals with PON on day 4 （ P = 0.01） but there was no change in myofbroblast accumulation. CONCLUSION： These data suggest that C5b-9 does not mediate tubulointerstitial injury in acute glomerular diseases characterized by selective proteinuria.

Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report

BACKGROUND Autosomal dominant tubulointerstitial kidney disease(ADTKD)is a progressive chronic disease that is inherited in an autosomal dominant fashion.Symptoms include hyperuricemia,gout,interstitial nephritis,renal cysts,and progressive renal damage that can lead to end-stage renal disease.Mutations in the uromodulin gene(UMOD)characterize the ADTKD-UMOD clinical subtype of this disease.To date,>100 UMOD mutations have been identified.Early diagnosis of ADTKD-UMOD is important to treat the disease,slow down disease progression,and facilitate the identification of potentially affected family members.CASE SUMMARY We report a 40-year-old man harboring a novel heterozygous missense mutation in UMOD(c.554G>T;p.Arg185Leu).The patient had hyperuricemia,gout,and chronic kidney disease.The same mutation was detected in his daughter,aunt and cousin.CONCLUSION A single nucleotide substitution in exon 3 of UMOD was responsible for the heterozygous missense mutation(c.554G>T,p.Arg185Leu).

Identification of genes related to tubulointerstitial injury in type 2 diabetic nephropathy based on bioinformatics and machine learning

Objective:To explore the genes related to renal tubulointerstitial injury in DN and to elucidate their underlying mechanism by using bioinformatics multi-chip joint analysis and machine learning technology,so as to provide new ideas for the diagnosis and treatment of DN.Methods:Four gene expression datasets of DN tubulointerstitial tissues were retrieved from the GEO database.GSE30122,GSE47185 and GSE99340 were used as the combined microarray datasets,and GSE104954 was used as the independent verification datasets.The differentially expressed genes(DEGs)were identified by R language,and Gene Ontology(GO)enrichment,KEGG pathway enrichment,Gene Set Enrichment Analysis(GSEA)and Immune Cell Infiltration Analysis were performed.Furthermore,LASSO regression,SVM-RFE and RF machine learning algorithm were used to screen core genes,while external validation and Receiver Operating Curve(ROC)analysis as well as the model of prediction nomogram were performed.Finally,the influence of the clinical characteristics of DN patients was explored by Nephroseq.Results:A total of 107 DEGs were obtained,enrichment analysis revealed that the tubulointerstitial injury in DN was mainly involved in adaptive immune response,lymphocyte mediated immunity,regulation of immune effector process and immune-inflammatory pathways such as staphylococcus aureus infection,complement and coagulation cascades,phagosomes,and Th1 and Th2 cell differentiation.In addition,cell adhesion molecule,cytokine-cytokine receptor interaction and ECM-receptor interaction pathways were also significantly enriched.Memory resting CD4 T cells,γδ毮T cells,resting mast cells and neutrophil cells were up-regulated,while CD8 T cells were down-regulated.Machine learning identified MARCKSL1,CX3CR1,FSTL1,AGR2,GADD45B as core genes with good diagnostic and predictive efficacy.Conclusion:The key pathological mechanism of tubulointerstitial injury in DN is immune disorder,inflammatory reaction,cytokine action and extracellular matrix deposition.Moreover,MARCKSL1,CX3CR1,FSTL1 may be the potential biomarkers for the diagnosis and prediction of DN.

A Case of Acute Renal Failure Associated with IgG4-Related Disease Presenting Both Tubulointerstitial Nephritis and Retroperitoneal Fibrosis

We report a case of IgG4-related disease presenting both tubulointerstitial nephritis and retroperitoneal fibrosis causing acute renal failure in a 63-year-old male. He was admitted to our hospital because of acute renal failure requiring emergent hemodialysis. Computed tomography showed a soft-tissue density mass with an irregular border in the retroperitoneum. The mass involved bilateral ureters and had caused acute renal failure by bilateral hydronephrosis. Because of a history of uveitis and high IgG4 levels, we considered a diagnosis of retroperitoneal fibrosis, IgG4-related disease. Kidney biopsy revealed IgG4-related kidney disease with interstitial nephritis. After relief of urinary obstruction by inserting ureteral catheters into the bilateral ureters, renal function recovered.

Effect of Adhesion Molecule P-selectin and Dendritic Cells on Tubulointerstitial Lesions in IgA Nephropathy

To observe the expression of P-selectin and the localization of dendritic cells (DCs) in human kidney with IgA nephropathy, and to evaluate their function in human renal tubulointerstitial lesions and renal dysfunction, 45 biopsy specimens of patients with IgA nephropathy were divided into 3 groups according to the degree of renal tubulointerstitial lesions: i. e. mild group ( n =29), moderate group ( n =10), severe group ( n =6). Ten normal renal tissues severed as control. The expression of P-selectin was analysed by immunohistochemistry. CD1a +CD80 +DCs were investigated by double immunostaining method and the images were analyzed with Axioplan 2 microscopy. The experimental results showed that (1) P-selectin was not expressed in normal controls, but presented mainly in renal tubular epithelial cells, which was greater in severe group than mild and moderate groups. The expression of P-selectin was associated with the degree of renal tubulointerstitial lesions. (2) CD1a +CD80 +DCs were hardly observed in nomal renal tissues, but in renal tissues of patients with IgA nephropathy, CD1a +CD80 +DCs were mostly found in renal tubulointerstitium. Also the distribution area, number and density of CD1a +CD80 +DCs in severe group was much more than other groups, which was associated with the degree of renal tubulointerstitial lesions and the lever of serum creatine. The distribution of CD1a +CD80 +DCs was associated with the expression of P-selectin in patient′s renal tubulointerstitium. The present study demonstrated that P-selectin and DCs might play an important role in renal tubulointerstitial lesions of IgA nephropathy, and DCs recruited into the renal tissues with IgA nephropathy might be mediated by P-selectin.

Tubulointerstitial Nephritis Complicated with Primary Sjogren’s Syndrome under Treatment for Type 2 Diabetes Mellitus

Tubulointerstitial nephritis complicated by primary Sj?gren’s syndrome in a patient under treatment for type 2 diabetes mellitus was diagnosed in the early stage of the disease by renal biopsy. The symptoms of primary Sj?gren’s syndrome, such as thirst and polydipsia, were masked by the characteristic symptoms of type 2 diabetes mellitus. An association between sicca symptoms and diabetes mellitus (types 1 and 2) has been previously reported. Hence, it is possible that there are common underlying immunological mechanisms between primary Sj?gren’s syndrome and diabetes mellitus of both types. Intervention with steroids in a timely manner appears to have prevented or slowed the progression of re- nal impairment.

Epithelial to mesenchymal transition in the progression of tubulointerstitial fibrosis

Objective To review the mechanisms of epithelial to mesenchymal transition （EMT） and its role in the progression of tubulointerstitial fibrosis. Data sources The data used in this review were obtained mainly from the studies of EMT reported from 2000-2006. Study selection Relevant articles on studies of EMT in tubulointerstitial fibrosis were selected. Data were mainly extracted from the 45 articles listed in the reference section of this review. Results The process of EMT has gained wide recognition as candidate mechanism in progression of chronic fibrotic disorders. New markers were identified and facilitate the observation of EMT. EMT is regulated by many factors through activation of kinase-dependent signaling cascades. Recent findings suggest that EMT is a reversible process, which can be controlled by factors for their epithelial inducing activities. Conclusion Remarkable progresses of EMT research have been made recently. Preventing or reversing EMT is a promising strategy against renal fibrosis.

Yishen Jiangzhuo Granules(益肾降浊冲剂) Affect Tubulointerstitial Fibrosis via A Mitochondrion-Mediated Apoptotic Pathway

Objective： To investigate the effect of Yishen Jiangzhuo Granules （益肾降浊冲剂 , YSJZG） on mitochondrial injury and regeneration and renal tubular epithelial cell apoptosis in chronic renal failure （CRF） rats and explore its mechanism from molecular pathology, gene, protein levels, and relative pathway. Methods： The CRF rat model was established using 5/6 nephrectomy. Sixty rats were randomly divided into six groups： sham-operation group, model （CRF） group, Niaoduqing Granules （尿毒清颗粒）-treated group [5 g/（kg.day）], low-, moderate-, and high-dose [L-YSJZG, M-YSJZG, H-YSJZG at 3, 6, and 9 g/（kg-day）] YSJZG-treated group （n=10 each）. The levels of serum creatinine （Scr）, blood urea nitrogen （BUN）, and 24-h urine protein were assessed after 10 weeks of treatment. The tubulointerstitial injury and collagen deposition were evaluated using periodic acid-schiff stain and Masson staining. Renal tubular epithelial cell apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, mitochondrial injury was observed using an electron microscope, and superoxide dismutase （SOD）, glutathione （GSH） and malondialdehyde （MDA） levels were assessed using chromometry. Transforming growth factor- 1 β（TGF-β 1） expression was assessed using immunohistochemistry. The expressions of Bax, Bcl-2, peroxisome proliferator-activated receptor γ coactivator-1 α （PGC-1α）, mitochondrial transcription factor A （Tfam）, mitogen-activated protein kinases （MAPK） phosphorylation were evaluated by Western blot. Results： YSJZG decreased the 24-h urine protein, BUN, Scr, remnant kidney weight-to-body weight ratio, renal tubular injury, deposition of collagen, and the apoptosis of renal tubular epithelial cells in a dose-dependent manner. YSJZG dose-dependently restored the number and structure of mitochondria and the expression of Tfam and PCG-1 α, up-regulated the expression of Bcl-2, and inhibited the expression of Bax. YSJZG also dose-dependently inhibited TGF- 13 1 expression, increased SOD and GSH activity, decreased the MDA level, and inhibited p38MAPK and pERK1/2 phosphorylation （all P〈0.01）. Conclusion： YSJZG improved the renal function in rats with CRF and inhibited the progression of tubulointerstitial fibrosis by dose-dependently alleviating mitochondrial injury, restoring the expression of Tfam and PCG-1α , and inhibiting renal tubular epithelial cell apoptosis through inhibiting activation of reactive oxygen species-MAPK signaling.

Jujuboside A ameliorates tubulointerstitial fibrosis in diabetic mice through down-regulating the YY1/TGF-β1 signaling pathway

Diabetic nephropathy(DN)is one of the most common complications of diabetes mellitus,which is characterized in renal tubulointerstitial fibrosis(TIF).The current study was designed to investigate the protective effect of Jujuboside A(Ju A)on TIF in type 2 diabetes(T2DM)mice,and explore its underlying anti-fibrosis mechanism.A mouse T2DM model was established using high fat diet(HFD)feeding combined with intraperitoneal injection of streptozotocin(STZ).Then,diabetic mice were treated with Ju A(10,20 and 40 mg·kg^(−1)·d^(−1),i.g.)for 12 weeks.Results showed that administration of Ju A not only down-regulated fasting blood glucose(FBG)levels,but also improved hyperlipidemia and renal function in diabetic mice.Moreover,the reduced ECM accumulation was observed in the renal cortex of Ju A treated diabetic mice,while the TIF progression was also attenuated by Ju A through blocking the epithelial-to-mesenchymal transition(EMT)of renal tubular epithelial cells(RTECs).Further mechanism studies showed that Ju A treatment effectively down-regulated the protein expression and subsequent nuclear translocation of Yin Yang 1(YY1)in the renal cortex of diabetic mice,and reduced the levels of transforming growth factor-β1(TGF-β1)in the serum and renal cortex of Ju A treated mice.According to in vitro studies,the up-regulated YY1/TGF-β1 signaling pathway was restored by Ju A in high glucose(HG)cultured HK-2 cells.Taken together,these findings demonstrated that Ju A can ameliorate the TIF of DN through down-regulating the YY1/TGF-β1 signaling pathway.

Clinicopathological features and renal outcomes of Ig A nephropathy with acute tubulointerstitial nephropathy

Objective To evaluate the clinicopathological characteristicsand outcomes of IgA nephropathy ( IgAN)with acute tubulointerstitial nephropathy ( ATIN ).Methods Patients who were diagnosed as IgAN with ATIN and IgAN without ATIN by renal biopsy in PekingUniversity First Hospital were enrolled. Seventy four casesof IgAN with ATIN and 74 cases of IgAN withoutATIN were enrolled based on stratified sampling (chosenby 1∶ 1). The two groups were well matched with age,gender,follow-up time,mesangial hypercellularity(M),endocapillary hypercellularity(E),segmental glomerulosclerosis( S ),tubular atrophy /interstitial fibrosis ( T )and cellular /fibrocellular crescent(C). The clinicopathologicalcharacteristics and outcomes of the two groupswere retrospectively analyzed.

Repetitive administration of cultured human CD34+cells improve adenine-induced kidney injury in mice

BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease(CKD).AIM To examine the efficacy of cultured human CD34+cells with enhanced proliferating potential in kidney injury in mice.METHODS Human umbilical cord blood(UCB)-derived CD34+cells were incubated for one week in vasculogenic conditioning medium.Vasculogenic culture significantly increased the number of CD34+cells and their ability to form endothelial progenitor cell colony-forming units.Adenineinduced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice,and cultured human UCB-CD34+cells were administered at a dose of 1×106/mouse on days 7,14,and 21 after the start of adenine diet.RESULTS Repetitive administration of cultured UCB-CD34+cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group.Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group(P<0.01).Microvasculature integrity was significantly preserved(P<0.01)and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group(P<0.001).CONCLUSION Early intervention using human cultured CD34+cells significantly improved the progression of tubulointerstitial kidney injury.Repetitive administration of cultured human UCB-CD34+cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.

Renal Involvement in Sarcoidosis

Introduction: Sarcoidosis is a granulomatous systemic disease. Renal damage is rare but it can evolve to chronic renal failure (CRF). The aim of our work is to describe the clinical, paraclinical, histological and evolutionary profile of renal involvement during sarcoidosis and to identify the progression factors leading to CRF. Materials and Methods: This is a retrospective descriptive study from January 2009 to December 2022. We collected the medical records of patients with sarcoidosis and renal involvement. To study the progression factors leading to CRF we identified two groups of patients: the group with normal renal function and the group that developed CRF. Results: We included in our study 17 patients with renal sarcoidosis. Their mean age was 45 ± 14.7 years and the sex ratio was 0.4. Renal involvement is revealing of sarcoidosis in 76% of cases. Renal failure was diagnosed in 88% of patients. Proteinuria was positive in 76.5% of cases, leukocyturia in 59% of patients and hematuria in 41% of patients. Renal biopsy was performed in 15 patients showing tubulointerstitial nephropathy in all biopsies. Epithelioid and gigan-to-cellular granuloma without caseous necrosis was found in 46% of cases. Associated glomerular involvement such as segmental and focal hyalinosis was found in 2 patients. Corticosteroid therapy was initiated in 88% of patients for a median duration of 15 months. Normalization of renal function was achieved in 41% of patients, while 59%, i.e. 10 patients, retained a CRF, including 2 who were on dialysis. We showed a statistically significant relationship between the evolution towards CRF and the presence of interstitial fibrosis > 25%. Conclusion: Despite its rarity, renal involvement can be revealing of sarcoidosis, which can condition the prognosis and lead to CRF. Its detection allows an early diagnosis and treatment.

Systemic Capillary Leak Syndrome Secondary to COVID-19 Infection: Case Report

Introduction: Systemic capillary leak syndrome (SCLS) is an increasingly recognized rare syndrome. Its diagnosis is suggested by the occurrence of edema with arterial hypotension, hemoconcentration, and paradoxical hypoalbuminemia. SCLS can be idiopathic (Clarkson syndrome) or secondary. Secondary SCLS (SSCLS) is mainly triggered by infections (especially viruses), drugs (antitumor therapy), malignancies, and inflammatory diseases. We report a case of systemic capillary leak syndrome secondary to the COVID-19 infection. Observation: A 74-year-old chronic smoker with no particular history was initially admitted to the intensive care unit (ICU) with a picture of respiratory distress secondary to a COVID-19 infection with favorable evolution, hence his transfer to the emergency services. On Day 8 of hospitalization, following the installation of arterial hypotension, not responding to filling, associated with hypoalbuminemia, and generalized edematous syndrome, and in the absence of any other explanation for this clinical picture, a SCLS secondary to COVID-19 infection was suggested. On the balance sheet, after the discovery of acute renal failure, serum creatinine went from 7.9 mg/l to 16.6 mg/l with microalbuminuria at 420 mg/24h and leukocyturia at 20 elements/mm3 without germ-evoked tubulointerstitial nephritis (TIN) secondary to a viral infection with COVID-19. The evolution was marked by the spontaneous regression of the edema and the normalization of the blood pressure figures. Discussion: The classic triad combining hypotension, hemoconcentration, and hypoalbuminemia suggests the diagnosis of SCLS once all other causes of shock have been ruled out. Hemoconcentration is less constant in SSCLS than in ISCLS. This is the case with our patient. The exact pathophysiological process of SCLS is largely unknown. Viral infections are the most common infectious cause of SCLS. The kidneys are the second-most common organs affected by the SARS-Cov-2 coronavirus infection. The presence of nephritis can be used as an indicator of SCLS, which can be a predictor of serious complications such as fluid overload, respiratory failure, and the need for ICU admission. Conclusion: In the event of COVID-19 infection, the appearance of hypotension and hypoalbuminemia with the gradual onset of generalized edema should suggest SCLS. The establishment of close monitoring is mandatory, given the risk of fatal evolution. Fortunately, for our patient, the evolution was favorable.

Immunoglobulin G4-related kidney diseases: An updated review

This review will encompass definition, pathogenesis, renal clinical manifestations and treatment of immunoglobulin G4-related diseases( IgG4-RDs). IgG4-RD is a recently recognized clinical entity that often involves multiple organs and is characterized by high levels of serum immunoglobulins G4, dense infiltration of IgG4+ cells and storiform fibrosis. Cellular immunity, particularly T-cell mediated immunity, has been implicated in the pathogenesis of IgG4-RDs. The most frequent renal manifestations of IgG4-RD are IgG4-related tubulointerstitial nephritis, membranous glomerulopathy and obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis. IgG4-RD diagnosis should be based on specific histopathological findings, confirmed by tissue immunostaining, typical radiological findings and an appropriate clinical context. The first line treatment is the steroids with two warnings: Steroid resistance and relapse after discontinuation. In the case of steroid resistance, B cell depleting agents as rituximab represent the secondline treatment. In the case of relapse after discontinuation, steroid treatment may be associated with steroid sparing agents. Since the disease has been only recently identified, more prospective, long-term studies are needed to an improved understanding and a more correct and safe treatment.

Late and Reversible Kidney-Lung Failure after Intra-Bladder BCG Therapy

We observed a 76-year-old man who presented “acute kidney-lung failure” 9 months after intravesical Bacillus Calmette-Guérin (BCG) adjuvant treatment for a T1 bladder cancer. He had inflammatory infiltration on chest radiography and required dialysis for acute renal failure. A percutaneous renal biopsy was performed and revealed tubulointerstitial nephritis with a moderate eosinophilic infiltrate without granulomatous lesion. After a few days, an open lung biopsy was also done due to respiratory deterioration. The anatomopathologic specimen demonstrated moderate fibrosis with lympho-neutrophilic infiltration and few aspecific granulomatous lesions without caseous necrosis. Sarcoidosis was suspected and high dose oral methylprednisolone was started. Three weeks later, Mycobacterium bovis was identified by Polymerase Chain Reaction on open lung biopsy. He responded well to steroids and tuberculostatic tri-therapy. After one month of immunosuppressive treatment, renal function was resolved and hemodialysis could be discontinued. Despite the frequent use of adjuvant BCG immunotherapy, systemic complications such as hepatitis, pneumonitis, spondylodiscitis or multiorgan failure are rare (<1%). Hematogenous dissemination which occurs a few weeks after traumatic instillations is usually suspected but not demonstrated because of absence of mycobacterium in histological specimen. Our case differs from those previously reported by the simultaneous presence of acid-fast bacilli highlighted on lung samples. We discuss the pathophysiology of BCG complications, the use of prophylactic or therapeutic treatment and recommend guidelines to prevent such complications.