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Renal AND Proteinuria [keywords]
- Induction monotherapy with sirolimus has selected beneficial effects on glomerular and tubulointersititial injury in nephrotoxic serum nephritis. [Journal Article]
- Int J Nephrol Renovasc Dis 2014.:303-13.
The study aimed to test the hypothesis that therapeutic treatment with a mammalian target of rapamycin complex 1 inhibitor reduces renal cell proliferation and attenuates glomerular and tubulointerstitial injury in the early phase of nephrotoxic serum nephritis (NSN) in rats.Male Wistar-Kyoto rats received a single tail-vein injection of sheep anti-rat glomerular basement membrane serum (day 0) and were treated with vehicle or sirolimus (0.25 mg/kg/day by subcutaneous injection) from day 1 until day 14.Treatment with sirolimus attenuated kidney enlargement by 41% (P<0.05), improved endogenous creatinine clearance by 50% (P<0.05), and reduced glomerular and tubulointerstitial cell proliferation by 53% and 70%, respectively, (P<0.05 compared to vehicle) in rats with NSN. In glomeruli, sirolimus reduced segmental fibrinoid necrosis by 69%, autologous rat immunoglobulin G deposition, glomerular capillary tuft enlargement, and periglomerular myofibroblast (α-smooth muscle actin-positive cells) accumulation (all P<0.05) but did not significantly affect glomerular crescent formation (P=0.15), macrophage accumulation (P=0.25), or the progression of proteinuria. In contrast, sirolimus preserved tubulointerstitial structure and attenuated all markers of injury (interstitial ED-1- and α-smooth muscle actin-positive cells and tubular vimentin expression; all P<0.05). By immunohistochemistry and Western blot analysis, sirolimus reduced the glomerular and tubulointerstitial expression of phosphorylated (Ser 235/236) S6-ribosomal protein (P<0.05).Induction monotherapy with sirolimus suppressed target of rapamycin complex 1 activation, renal cell proliferation, and injury during the early stages of rodent NSN, but the degree of histological protection was more consistent in the tubulointerstitium than the glomerular compartment.
- Mutual Antagonism of Wilms' Tumor 1 and β-Catenin Dictates Podocyte Health and Disease. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Jul 28.
Activation of β-catenin, the intracellular mediator of canonical Wnt signaling, has a critical role in mediating podocyte injury and proteinuria. However, the underlying mechanisms remain poorly understood. Here, we show that β-catenin triggers ubiquitin-mediated protein degradation of Wilms' tumor 1 (WT1) and functionally antagonizes its action. In mice injected with adriamycin, WT1 protein was progressively lost in glomerular podocytes at 1, 3, and 5 weeks after injection. Notably, loss of WT1 apparently did not result from podocyte depletion but was closely associated with upregulation of β-catenin. This change in WT1/β-catenin ratio was accompanied by loss of podocyte-specific nephrin, podocalyxin, and synaptopodin and acquisition of mesenchymal markers Snail1, α-smooth muscle actin, and fibroblast-specific protein 1. In vitro, overexpression of β-catenin induced WT1 protein degradation through the ubiquitin proteasomal pathway, which was blocked by MG-132. WT1 and β-catenin also competed for binding to common transcriptional coactivator CREB-binding protein and mutually repressed the expression of their respective target genes. In glomerular miniorgan culture, activation of β-catenin by Wnt3a repressed WT1 and its target gene expression. In vivo, blockade of Wnt/β-catenin signaling by endogenous antagonist Klotho induced WT1 and restored podocyte integrity in adriamycin nephropathy. These results show that β-catenin specifically targets WT1 for ubiquitin-mediated degradation, leading to podocyte dedifferentiation and mesenchymal transition. Our data also suggest that WT1 and β-catenin have opposing roles in podocyte biology, and that the ratio of their expression levels dictates the state of podocyte health and disease in vivo.
- Rhophilin-1 Is a Key Regulator of the Podocyte Cytoskeleton and Is Essential for Glomerular Filtration. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Jul 28.
Rhophilin-1 is a Rho GTPase-interacting protein, the biologic function of which is largely unknown. Here, we identify and describe the functional role of Rhophilin-1 as a novel podocyte-specific protein of the kidney glomerulus. Rhophilin-1 knockout mice were phenotypically normal at birth but developed albuminuria at about 2 weeks of age. Kidneys from severely albuminuric mice revealed widespread podocyte foot process effacement, thickening of the glomerular basement membrane, and FSGS-like lesions. The absence of any overt changes in the expression of podocyte proteins at the onset of proteinuria suggested that the primary cause of podocyte abnormalities in Rhpn1-null mice was the result of cell-autonomous, Rhophilin-1-dependent signaling events. In culture, Rhophilin-1 was detected at the plasma membrane leading edge of primary podocytes, where it elicited remodeling of the actin cytoskeleton network. This effect of Rhophilin-1 on actin cytoskeleton organization associated with inhibitory effects on Rho-dependent phosphorylation of the myosin regulatory light chain and stress fiber formation. Conversely, phosphorylation of myosin regulatory light chain increased in podocyte foot processes of Rhpn1(-/-) mice, implicating altered actinomyosin contractility in foot process effacement and compromised filtration capacity. Targeted deletion of RhoA in podocytes of Rhophilin-1 knockout mice exacerbated the renal injury. Taken together, our results indicate that Rhophilin-1 is essential for the integrity of the glomerular filtration barrier and that this protein is a key determinant of podocyte cytoskeleton architecture.
- The relation between treatment and prognosis of childhood membranoproliferative glomerulonephritis. [JOURNAL ARTICLE]
- Ren Fail 2014 Jul 28.:1-5.
Abstract Background: The prognostic factors, the outcome and the most favorable treatment regimen are not entirely known for children with membranoproliferative glomerulonephritis (MPGN). MPGN is a rarely observed disease more prevalent in adolescents, so we aimed to review the clinical and histological properties, treatments and the outcome of our patients who were diagnosed as MPGN. Methods: Fifty-one children - diagnosed with MPGN - were selected from biopsy records in Dr. Sami Ulus Maternity and Children's Hospital Pediatric Nephrology Department from January 1999 to January 2011. A retrospective analysis was made of 33 regularly followed children. Results: Thirty-three patients were identified, 13 female and 20 male. Their age groups at presentation ranged from 4 to 15 years. The following duration was 26-144 months (mean 74). Following the initial treatment, 20 (60%) patients achieved complete remission. Six patients with nephrotic syndrome and one with non-nephrotic proteinuria showed partial remission. The condition of one patient with nephrotic syndrome was unchanged with the persisting symptoms. The one patient with nephrotic syndrome and four others with non-nephrotic proteinuria did not respond to initial treatment as their renal functions decreased gradually. Conclusion: We concluded that only degree of tubulointerstitial damage on the initial biopsy is determinative for prognosis of childhood MPGN. If the patient receives high doses of steroid therapy in the early stages, their treatment is more likely to be successful. The effect of immunosuppressive treatment on MPGN is not clear.
- Renal histologic changes and the outcome in patients with diabetic nephropathy. [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2014 Jul 25.
The progression of diabetic nephropathy (DN) is frequently determined by clinical parameters; however, the predictive value of histologic lesions remains largely unknown. Our aim was to evaluate the relationship between histologic changes and renal outcome in patients with type 2 diabetes mellitus (T2DM).A total of 396 patients with T2DM and biopsy-proven DN who received follow-up for at least 1 year were recruited. The severity of different histologic lesions was assessed using the pathologic classification established by the Renal Pathology Society. Renal outcomes were defined by progression to end-stage renal disease and doubling of serum creatinine. The influence of histologic findings on renal outcomes was assessed using univariate and multivariate Cox regression.A univariate Cox regression showed that the severity of glomerular and interstitial lesions had a significant impact on renal outcomes (P < 0.001). Scores of vascular lesions demonstrated no association with renal outcomes (P > 0.05). A multivariate COX analysis demonstrated that the glomerular classes and scores of interstitial fibrosis and tubular atrophy were significantly associated with renal outcomes when adjusting for baseline proteinuria, mean arterial pressure and estimated glomerular filtration rate (P < 0.05). The glomerular and interstitial lesions correlated significantly among each other. However, in several patients, the severity of interstitial lesions did not correlate with glomerular lesions.These findings indicated that the severity of glomerular and interstitial lesions were significantly associated with renal outcomes in patients with DN, whereas the vascular indexes did not have any impact on renal outcomes.
- Prediction of membranous nephropathy recurrence after transplantation by monitoring of anti-PLA2R1 (M-type phospholipase A2 receptor) autoantibodies: a case series of 15 patients. [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2014 Jul 25.
The predictive value of anti-M-type phospholipase A2 receptor (PLA2R1) autoantibodies for membranous nephropathy (MN) recurrence after renal transplantation remains controversial.Our aim was to monitor anti-PLA2R1 IgG4 activity using a sensitive enzyme-linked immunosorbent assay in 15 kidney transplant recipients with MN, and to test the correlation between antibody titres and MN recurrence.Five patients never exhibited anti-PLA2R1 antibodies, and one of them relapsed. Ten patients (67%) had IgG4 anti-PLA2R1 antibodies at the time of transplantation and during follow-up. The presence of IgG4 anti-PLA2R1 antibodies at the time of kidney transplantation does not imply MN recurrence (P = 0.600, n = 15). However, a positive IgG4 anti-PLA2R1 activity during follow-up (>Month 6) was a significant risk factor for MN relapse (P = 0.0048, n = 10). Indeed, four patients had persistent IgG4 anti-PLA2R1 activity after transplantation and relapsed. Among them, one was successfully treated with rituximab. Another had persistently high IgG4 anti-PLA2R1 activity and exhibited a histological relapse but no proteinuria while on treatment with renin-angiotensin system inhibitors. In contrast, the six other patients who did not relapse exhibited a decrease of their IgG4 anti-PLA2R1 activity following transplant immunosuppression, including two with proteinuria due to biopsy-proven differential diagnoses. A weak transplant immunosuppressive regimen was also a risk factor of MN recurrence (P = 0.0048, n = 10). Indeed, the six patients who received both an induction therapy and a combined treatment with calcineurin inhibitors/mycophenolate exhibited a decrease of IgG4 anti-PLA2R1 activity and did not relapse, while the four patients who did not receive this strong immunosuppressive treatment association had persistently high IgG4 anti-PLA2R1 activity and relapsed.The monitoring of IgG4 anti-PLA2R1 titres during follow-up helps to predict MN recurrence, and a strong immunosuppressive treatment of anti-PLA2R1 positive patients may prevent recurrence.
- Patient-related barriers to hypertension control in a Nigerian population. [Journal Article]
- Int J Gen Med 2014.:345-53.
Hypertension control is a challenge globally. Barriers to optimal control exist at the patient, physician, and health system levels. Patient-related barriers in our environment are not clear. The aim of this study was to identify patient-related barriers to control of hypertension among adults with hypertension in a semiurban community in South-East Nigeria.This was a cross-sectional descriptive study of patients with a diagnosis of hypertension and on antihypertensive medication.A total of 252 participants were included in the survey, and comprised 143 males (56.7%) and 109 females (43.3%). The mean age of the participants was 56.6±12.7 years, with a diagnosis of hypertension for a mean duration of 6.1±3.3 years. Among these patients, 32.9% had controlled blood pressure, while 39.3% and 27.8%, respectively, had stage 1 and stage 2 hypertension according to the Seventh Report of the Joint National Committee on Prevention, Detection and Evaluation of High Blood Pressure. Only 23.4% knew the consequences of poor blood pressure control and 64% were expecting a cure from treatment even when the cause of hypertension was not known. Furthermore, 68.7% showed low adherence to medication, the reported reasons for which included forgetfulness (61.2%), financial constraints (56.6%), high pill burden (22.5%), side effects of medication (17.3%), and low measured blood pressure (12.1%). Finally, knowledge and practice of the lifestyle modifications necessary for blood pressure control was inadequate among the participants.Poor knowledge regarding hypertension, unrealistic expectations of treatment, poor adherence with medication, unawareness of lifestyle modification, and failure to apply these were identified as patient-related barriers to blood pressure control in this study.
- A slight increase within the normal range of serum uric acid and the decline in renal function: associations in a community-based population. [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2014 Jul 24.
Hyperuricemia is a risk factor for adverse renal outcomes in patients with chronic kidney disease. This study investigated the effect of uric acid on renal function in a community-based population.We used a nationwide database of 165 847 subjects (aged 29-74, male 40%) who participated in the annual 'Specific Health Check and Guidance in Japan' checkup between 2008 and 2010; we examined the relationship between serum uric acid levels at baseline and 2-year change in the estimated glomerular filtration rate (eGFR) obtained by using the Japanese equation.After adjusting for possible confounders, the eGFR change was inversely correlated with uric acid at baseline. In the multivariable analysis, the decline in eGFR was significantly more rapid in subjects with the slight increase in uric acid (males ≥5.7 mg/dL, females ≥4.4 mg/dL), and the risk for incidental renal insufficiency (eGFR <60 mL/min/1.73 m(2)) was increased at uric acid of ≥6.3 mg/dL in males and ≥5.5 mg/dL in females, compared with the lowest quintile. The multiple linear regression analysis revealed that the effect of uric acid on eGFR changes was significant, especially in females, those with proteinuria and diabetes and those without alcohol consumption.This study showed that serum uric acid is independently associated with a more rapid decline of eGFR and incident renal insufficiency, and that a slight increase within the normal range of serum uric acid might be a risk for renal damage in the general population.
- The Epithelial Sodium Channel γ-Subunit Is Processed Proteolytically in Human Kidney. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Jul 24.
The epithelial sodium channel (ENaC) of the kidney is necessary for extracellular volume homeostasis and normal arterial BP. Activity of ENaC is enhanced by proteolytic cleavage of the γ-subunit and putative release of a 43-amino acid inhibitory tract from the γ-subunit ectodomain. We hypothesized that proteolytic processing of γENaC occurs in the human kidney under physiologic conditions and that proteinuria contributes to aberrant proteolytic activation. Here, we used monoclonal antibodies (mAbs) with specificity to the human 43-mer inhibitory tract (N and C termini, mAbinhibit, and mAb4C11) and the neoepitope generated after proteolytic cleavage at the prostasin/kallikrein cleavage site (K181-V182 and mAbprostasin) to examine human nephrectomy specimens. By immunoblotting, kidney cortex homogenate from patients treated with angiotensin II type 1 receptor antagonists (n=6) or angiotensin-converting enzyme inhibitors (n=6) exhibited no significant difference in the amount of full-length or furin-cleaved γENaC or the furin-cleaved-to-full-length ratio of γENaC compared with homogenate from patients on no medication (n=5). Patients treated with diuretics (n=4) displayed higher abundance of full-length and furin-cleaved γENaC, with no significant change in the furin-cleaved-to-full-length γENaC ratio. In patients with proteinuria (n=6), the inhibitory tract was detected only in full-length γENaC by mAbinhibit. Prostasin/kallikrein-cleaved γENaC was detected consistently only in tissue from patients with proteinuria and observed in collecting ducts. In conclusion, human kidney γENaC is subject to proteolytic cleavage, yielding fragments compatible with furin cleavage, and proteinuria is associated with cleavage at the putative prostasin/kallikrein site and removal of the inhibitory tract within γENaC.
- TNF-α G308A Gene Polymorphism Has an Impact on Renal Function, Microvascular Permeability, Organ Involvement and Severity of Preeclampsia. [JOURNAL ARTICLE]
- Gynecol Obstet Invest 2014 Jul 22.
Background/Aims: Preeclampsia (PE) is a life-threatening complication of pregnancy that is associated with a high rate of maternal and perinatal morbidity and/or mortality worldwide. If untreated, it can progress to eclampsia, which can result in the death of the mother, the fetus or both. The etiology of PE is still uncertain; however, recently the role of the immune system has gained in importance. The role of tumor necrosis factor-α (TNF-α), a cytokine involved in inflammation processes, has been widely investigated in obstetric disorders. The aims of the present study were to investigate the effect of TNF-α gene G308A (rs1800629) polymorphism on disease risk, renal function, microvascular permeability, endothelial cell dysfunction and organ involvement in women with PE. Methods: Initially, 102 3rd-trimester pregnant women (preeclamptic cases and healthy controls) with singleton pregnancy were invited for participation, of which 76 were genotyped for TNF-α G308A polymorphism and evaluated for plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), fibronectin and TNF-α, which were tested for correlations with the profile of PE. The odds ratio (OR) and 95% confidence intervals obtained from unconditional logistic regression were used to test the association between the TNF-α polymorphism and PE risk. For continuous variables, we applied Student's t test and, for categorical variables, the Pearson χ(2) or Fisher's exact test. The two-way ANOVA test with Bonferroni correction was used in multivariate analyses. Results: The A allele was more frequent in cases than controls (22.4 vs. 13.2%), which increased disease risk (OR = 2.73). Maternal serum levels of TNF-α, sVCAM-1 and fibronectin were significantly increased in cases (855.8 ± 385.1 pg/ml, 1,243 ± 671 ng/ml, 0.308 ± 0.231 g/l, respectively) compared to controls (301.1 ± 156.1 pg/ml, 651 ± 250 ng/ml, 0.218 ± 0.101 g/l, respectively; p < 0.0001, p < 0.0001 and p = 0.031, respectively), and these levels showed an increasing trend with the mutant allele genotype. Moderate and severe proteinuria was higher in rs1800629 allele A subjects compared to G/G carriers (53.8 vs. 14.3% (p < 0.05) and 13.0 vs. 4.7% (p < 0.01), respectively). The adverse effect of rs1800629 allele A on renal function was confirmed by increased plasma creatine levels, urinary protein excretion and lower tubular resorption rate in preeclamptic patients. Moreover, rs1800629 allele A preeclamptic carriers showed higher serum levels of fibronectin and sVCAM-1 compared to G/G homozygotes. Conclusion: This study reveals a possible association between clinical and laboratory manifestations of PE and the TNF-α gene G308A (rs1800629) polymorphism. © 2014 S. Karger AG, Basel.