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It is not known why only some hepatitis C virus (HCV) infected patients develop glomerulonephritis (GN). Therefore, we investigated the role of soluble complement regulators in the development of HCV associated GN. Serum levels of complement 4 binding protein (C4BP) were significantly lower in group 1 (median 70 ng/ml) than in groups 2 (median 88.8 ng/ml) and 3 (median 82.8 ng/ml) with p value of 0.007. The minor allele (allele A) of rs800292 for CFH was significantly higher in group 2 and group 3 (G 54% and A 46%) than in group 1 (G 73% and A 27%), p = 0.04. Low C4BP levels are associated with GN in HCV infected patients. In addition, rs800292 SNP in CFH protects against GN in patients with HCV.

The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality. Delta (Δ) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with ≤-3ml/min/1.73m2/yr were defined as rapid progressors (RP) and those with ΔeGFR between -0.5 and +1ml/min/1.73m2/yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their ΔeGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group. There were 255 SP and 259 RP in the final cohort. Median ΔeGFR was 0.07 vs. -4.7 ml/min/1.73m2/yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1-3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2-6.2; p = 0.014). The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy.

Objectives It is not known why only some hepatitis C virus (HCV) infected patients develop glomerulonephritis (GN). Therefore, we investigated the role of soluble complement regulators in the development of HCV associated GN. Methods Patients with HCV associated GN who were admitted to our nephrology unit between July 2016 and July 2018 were recruited to the study (group 1). Two other age and sex matched groups were studied as control groups: patients with HCV without GN (group 2) and healthy HCV negative volunteers (group 3). There were 26 participants in each of the three groups at the end of the recruitment period. An assay of serum fluid-phase complement regulators was performed using enzyme linked immunosorbent assay technique. Three complement single nucleotide polymorphisms (SNPs) were analyzed using real time polymerase chain reaction (Taqman; thermo fisher scientific): rs2230199 and rs1047286 for complement 3 (C3) and rs800292 for complement factor H (CFH). Results Serum levels of complement 4 binding protein (C4BP) were significantly lower in group 1 (median 70 ng/ml) than in groups 2 (median 88.8 ng/ml) and 3 (median 82.8 ng/ml) with p value of 0.007. The minor allele (allele A) of rs800292 for CFH was significantly higher in group 2 and group 3 (G 54% and A 46%) than in group 1 (G 73% and A 27%), p = 0.04. Conclusions Low C4BP levels are associated with GN in HCV infected patients. In addition, rs800292 SNP in CFH protects against GN in patients with HCV.

The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality. Delta ([DELTA]) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with [less than or equal to]-3ml/min/1.73m.sup.2 /yr were defined as rapid progressors (RP) and those with [DELTA]eGFR between -0.5 and +1ml/min/1.73m.sup.2 /yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their [DELTA]eGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group. There were 255 SP and 259 RP in the final cohort. Median [DELTA]eGFR was 0.07 vs. -4.7 ml/min/1.73m.sup.2 /yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1-3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2-6.2; p = 0.014). The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy.

Polyoma virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients and could be the result of use of potent immunosuppression following transplantation. Because there is no safe and effective anti-viral therapy available presently, screening-based prevention and pre-emptive strategy are recommended. This study, which was conducted at the Nephrology Unit, Internal Medicine Department, Alexandria University, consisted of two phases : Phase 1 was a cross-sectional study and phase 2 was a 6-month follow-up study only for polyoma virus-positive cases. Phase 1 included 75 renal allograft recipients from living donors. Urine cytology for decoy cells and quantitative real-time blood polymerase chain reaction (PCR) for the BK virus (BKV) were performed on all the study patients. Renal biopsy was performed only in patients with deteriorating renal function associated with positive urine cytology. Patients who showed positive urine cytology for decoy cells and / or positive quantitative BKV PCR assay were followed-up for six months. During follow-up, the serum creatinine level, with or without urine cytology for decoy cells, and BKV PCR viral load assay were performed. Among the 75 kidney transplant recipients studied, eight were positive for decoy cells (11 %), three showed viremia by quantitative PCR for BKV (4.1 %), while two others showed nephropathy (2.7 %) in the form of tubulointerstitial nephritis with intra-nuclear inclusions in the tubular cells. Cases with stable renal function and positive decoy cells or viremia cleared the virus spontaneously during follow-up without any intervention. Only one case with biopsyproven nephropathy and deteriorating graft function, with undetectable BKV in blood, lost the graft while another case with viremia died during follow-up due to septicemia. Our study suggests that polyoma virus should be considered as a cause of nephropathy in renal transplant recipients. Further research is required to understand this entity better.

Mast cells (MCs) have been implicated in the pathogenesis of atherosclerosis and tissue fibrosis. However, the role of MC in the development of renal fibrosis has not been fully elucidated. Stem cell factor (SCF; the ligand for MC c-kit receptor) is thought to attract and activate MCs. The intensity of MC infiltration and SCF expression in renal biopsies from 56 patients with different forms of primary and secondary glomerulonephritis and five controls were investigated by immunohistochemistry, using a monoclonal anti-human MC tryptase antibody and a polyclonal antihuman SCF antibody. A large number of MCs were detected in the renal interstitium of the diseased kidneys. Immunostainable SCF was detected in tubular as well as interstitial cells. MC infiltration was significantly higher in glomerulonephritis (16.9 +/- 10.2 cells/field) compared with controls (2.8 +/- 2.1 cells/field, P = 0.03). Similarly, immunostainable SCF was 0.6 +/- 0.3% for controls and 3.3 +/- 2.1% in the glomerulonephritis group (P = 0.02). MC infiltration was highly correlated with SCF expression in diseased kidneys (r = 0.93, P = 0.0001). Double immunostain showed them to colocalize in some interstitial cells. Analysis of MC proliferation [proliferating cell nuclear antigen (PCNA) positivity] and apoptosis (in situ end labeling of DNA) showed these cells to be terminally differentiated. Both MCs and SCF were correlated with interstitial fibrosis (R = 0.71 for MC and R = 0.62 for SCF, P = 0.0001) and interstitial alpha-smooth muscle actin (R = 0.69 for MC and R = 0.60 for SCF P = 0.0001). Using regression analysis, the number of MC infiltration was found to be a very powerful determinant of interstitial fibrosis in the glomerulonephritis group (R2 = 91.4%). MCs as an infiltrating hematopoietic cell and its growth factor (SCF) seem to be up-regulated in glomerulonephritis, and may play a role in the development of renal fibrosis.

Dahl salt sensitive (DS) rats are a paradigm of salt sensitive hypertensive humans. OMA is a dual vasopeptidase inhibitor that inhibits neutral endopeptidase and angiotensin converting enzyme, thus concomitantly preventing degradation of natriuretic and other hypotensive peptides, inhibiting synthesis of angiotensin II and increasing bioavailability of nitric oxide (NO). DS rats have abnormal pressure natriuresis and develop hypertension accompanied by decreased vascular NO synthesis, endothelial dysfunction and cardiovascular injury, when fed high (4%) NaCl diet (HS)(Cir-97). We designed a 12 week study to investigate the effect of OMA (given by gavage 40 mg/kg/day) in DS-hypertensive rats. DS rats were fed (4% NaCl) for 4 weeks and then divided into 3 groups (n=6/group): 1- (HS) was kept on 4% NaCl, 2- (HS+OMA) kept on 4% NaCl and given OMA and 3- (HS/Lo+OMA) kept on 4% NaCl and given OMA; but switched to a 0.5% NaCl diet for the last 4 weeks. A 4th group (NS) was fed 0.5% NaCl for the whole duration of the study. Systolic blood pressure (SBP) was measured every two weeks. At the end of the study, the rats were sacrificed and LV and Aortic (Ao) hypertrophy were calculated. HS developed impaired endothelium dependent relaxation to ACh in aortic rings (ED50, HS 5.42+ 0.4 vs. NS 7.09+ 0.1*) - see table Group NS HS HS+OMA HS/Lo+OMA Mortality % 0% 83% 0% 0% SBP (mmHg) 152 ± 6* 222 ± 8 220 ± 2 139 ±3* LVH (gm/100gBW) 0.18 ± .01* 0.34 ± .02 0.26 ± .01* 0.18 ± .00* Ao Hyp. (mg/cm/100gBW) 3.5 ± .1* 8.0 ± .3 6.2 ± .6* 3.6 ± .1* ED50 (-LogM ACh) 7.09 ± .1* 5.42 ± .4 7.23 ± .2* 8.15 ± .1* *(p<0.05, in comparison to HS). OMA dramatically improved survival, decreased LVH and Ao hypertrophy and normalized endothelial function (ED50) independent of blood pressure. In addition, once switched to 0.5%NaCl(HS/Lo+OMA), OMA normalized blood pressure as well as end-organ injury. These data suggest that in salt sensitive hypertension Omapatrilat improves vascular remodeling, endothelial dysfunction and end-organ injury in-addition to, but independent of its blood pressure lowering effect. We attribute these salutary effect of vasopeptidase inhibition to the restitution of the balance between natriuretic peptides, nitric oxide and the renin angiotensin system.

Studies in humans have shown that pancreatic transplantation not only arrests but can reverse diabetic nephropathy (NEJM '98). Experimentally studies have suggested that in chronic renal failure due to either renal ablation (5/6 Nx) or toxic nephropathy due to puromycin, interruption of the renin angiotensin system (RAS) may not only arrest progression but may in fact reverse glomerular injury (KI '91, '94). Dahl salt sensitive (DS) rats fed high dietary salt develop hypertension and severe renal injury. We designed a 12 week study to evaluate whether the treatment with an angiotensin receptor-1 (AT1-R) blocker {Candesartan (Cande) given by gavage 10 mg/kg/day} may reverse glomerular injury. DS rats were fed 4% NaCl for 6 weeks and then divided into 3 groups: 1- (HS) was sacrificed, 2- (HS/LS) switched to Low salt (0.5% NaCl), 3- (HS/LS+Cande) switched to 0.5% NaCl and treated with Cande. A 4th group was kept on 0.5% NaCl for the duration of the study. Systolic blood pressure (SBP), 24-hr urinary protein excretion (U-Pr) and kidney weight (KW) were measured. Glomerular injury (GIS) was scored semi-quantitatively to assess the severity and the distribution of lesions as previously described (KI '84). Results: (See Table) Groups Time of sacrifice (Weeks) SBP (mmHg) KW (g) U-Pr (mg/24hrs) GIS HS (n=6) 6 223±13 1.7±0.06 130±25 87±14 HS/LS (n=6) 12 202±3 1.7±0.07φ 104±14 #,φ 50±8φ,#,δ HS/LS+Cande (n=6) 12 143±6* 1.5±0.05* 35±10* 20±3* LS (n=6) 12 154±2* 1.4±0.03* 53±2* 10±7* (p < 0.05 ** in comparison to HS φto LS #to HS/LS+Cande δto HS) Thus, reduction of dietary salt (HS/LS) did not significantly reduce SBP or U-Pr, although it modestly reduced GIS. On the other hand, AT1-R blockade (HS/LS+Cande) normalized SBP, U-Pr, and not only arrested, but reversed glomerular injury. Clinically, longitudinal studies with serial renal biopsies should reveal a) whether AT1-R blockade can reverse glomerular injury and b) whether doses beyond those necessary for blood pressure control are required for this effect.

Role of stem cell factor and mast cells in the progression of chronic glomerulonephritides. Mast cells (MCs) have been implicated in the pathogenesis of atherosclerosis and tissue fibrosis. However, the role of MC in the development of renal fibrosis has not been fully elucidated. Stem cell factor (SCF; the ligand for MC c-kit receptor) is thought to attract and activate MCs. The intensity of MC infiltration and SCF expression in renal biopsies from 56 patients with different forms of primary and secondary glomerulonephritis and five controls were investigated by immunohistochemistry, using a monoclonal anti-human MC tryptase antibody and a polyclonal antihuman SCF antibody. A large number of MCs were detected in the renal interstitium of the diseased kidneys. Immunostainable SCF was detected in tubular as well as interstitial cells. MC infiltration was significantly higher in glomerulonephritis (16.9 ± 10.2 cells/field) compared with controls (2.8 ± 2.1 cells/field, P = 0.03). Similarly, immunostainable SCF was 0.6 ± 0.3% for controls and 3.3 ± 2.1% in the glomerulonephritis group (P = 0.02). MC infiltration was highly correlated with SCF expression in diseased kidneys (r = 0.93, P = 0.0001). Double immunostain showed them to colocalize in some interstitial cells. Analysis of MC proliferation [proliferating cell nuclear antigen (PCNA) positivity] and apoptosis (in situ end labeling of DNA) showed these cells to be terminally differentiated. Both MCs and SCF were correlated with interstitial fibrosis (R = 0.71 for MC and R = 0.62 for SCF, P = 0.0001) and interstitial α-smooth muscle actin (R = 0.69 for MC and R = 0.60 for SCF P = 0.0001). Using regression analysis, the number of MC infiltration was found to be a very powerful determinant of interstitial fibrosis in the glomerulonephritis group (R2 = 91.4%). MCs as an infiltrating hematopoietic cell and its growth factor (SCF) seem to be up-regulated in glomerulonephritis, and may play a role in the development of renal fibrosis.