24-h Urinary Protein Excretion Research Articles

Astaxanthin attenuates diabetic kidney injury through upregulation of autophagy in podocytes and pathological crosstalk with mesangial cells

Objectives: Astaxanthin (ATX) is a strong antioxidant drug. This study aimed to investigate the effects of ATX on podocytes in diabetic nephropathy and the underlying renal protective mechanism of ATX, which leads to pathological crosstalk with mesangial cells.Methods: In this study, diabetic rats treated with ATX exhibited reduced 24-h urinary protein excretion and decreased blood glucose and lipid levels compared to vehicle-treated rats. Glomerular mesangial matrix expansion and renal tubular epithelial cell injury were also attenuated in ATX-treated diabetic rats compared to control rats.Results: ATX treatment markedly reduced the α-SMA and collagen IV levels in the kidneys of diabetic rats. Additionally, ATX downregulated autophagy levels. In vitro, compared with normal glucose, high glucose inhibited LC3-II expression and increased p62 expression, whereas ATX treatment reversed these changes. ATX treatment also inhibited α-SMA and collagen IV expression in cultured podocytes. Secreted factors (vascular endothelial growth factor B and transforming growth factor-β) generated by high glucose-induced podocytes downregulated autophagy in human mesangial cells (HMCs); however, this downregulation was upregulated when podocytes were treated with ATX.Conclusions: The current study revealed that ATX attenuates diabetes-induced kidney injury likely through the upregulation of autophagic activity in podocytes and its antifibrotic effects. Crosstalk between podocytes and HMCs can cause renal injury in diabetes, but ATX treatment reversed this phenomenon.

Melittin induces autophagy to alleviate chronic renal failure in 5/6-nephrectomized rats and angiotensin II-induced damage in podocytes.

Chronic renal failure (CRF) is a complex pathological condition that lacks a cure. Certain Chinese medicines, such as melittin, a major component in bee venom, have shown efficacy in treating CRF patients. On the other hand, the mechanisms underlying the therapeutic effects of melittin are unclear. A 5/6 nephrectomy model (5/6 Nx) of renal failure was established on rats for in vivo assays, and mouse podocyte clone 5 (MPC5) mouse podocyte cells were treated with angiotensin II (AngII) to establish an in vitro podocyte damage model. The 24-h urine protein, serum creatinine, and blood urea nitrogen levels were evaluated after one, 2, and 4 weeks. Hematoxylin and eosin staining, Masson staining, and periodic acid-Schiff staining were used to examine the pathological changes in kidney tissues. A cell counting kit 8 assay was used to assess the cell viability. Reverse transcription polymerase chain reaction and Western blot were used to assess the mRNA and protein levels in the cells, respectively. In the rat 5/6 Nx, melittin reduced the 24-h urinary protein excretion and the serum creatinine and blood urea nitrogen levels. Furthermore, the renal pathology was improved in the melittin-treated 5/6 Nx rats. Melittin promoted podocin, nephrin, Beclin 1, and the LC3II/LC3I ratio and inhibited phosphorylated mammalian target of rapamycin (mTOR)/mTOR in 5/6 Nx-induced rats and AngII-induced MPC5 mouse podocyte cells. Moreover, inhibiting autophagy with 3-MA weakened the effects of melittin on podocin, nephrin, and the LC3II/LC3I ratio in podocytes. Melittin may offer protection against kidney injury, probably by regulating podocyte autophagy. These results provide the theoretical basis for applying melittin in CRF therapy.

The correlation of spot urinary protein-to-creatinine ratio with 24-h urinary protein excretion in various glomerulopathies.

Proteinuria is an important and well-known biomarker of many forms of kidney injury. Its quantitation is of particular importance in the diagnosis and management of glomerular diseases. Its quantification can be done by several methods. Among these, the measurement of 24-h urinary protein excretion is the gold standard method. However, it is cumbersome, time-consuming, and inconvenient for patients and is not completely foolproof. Many alternative methods have been tested over time albeit with conflicting results. Among the latter, the measurement of urine protein-to-creatinine ratio (uPCR) in single-voided urinary samples is widely used. The majority of studies found a good correlation between uPCR in single urine samples with 24-h urinary protein estimation, whereas others did not. To investigate the correlation of spot uPCR with 24-h urinary protein estimation in patients suffering from different forms of glomerulopathies at a single large-volume nephrological center in Pakistan. This cross-sectional, observational study was conducted at the Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan from September 2017 to March 2018. All newly presenting adult patients with proteinuria who were being investigated for suspected glomerulonephritis and persistent proteinuria with ages between 18 to 60 years were enrolled. All patients were given detailed advice regarding 24-h urine collection starting at 7:00 AM for total protein and creatinine excretion estimations. A spot urine sample was collected the next day at the time of submission of a 24-h urine sample for measuring uPCR along with a blood sample. The data of patients were collected in a proforma. SPSS version 20.0 was used for statistical analysis. A total of 157 patients were included. Their mean age was 30.45 ± 12.11 years. There were 94 (59.8%) males and 63 (40.2%) females. The mean 24-h urinary protein excretion was 3192.78 ± 1959.79 mg and the mean spot uPCR was 3.16 ± 1.52 in all patients. A weak but significant correlation was observed between spot uPCR and 24-h urinary protein excretion (r = 0.342, P = 0.01) among all patients. On subgroup analysis, a slightly better correlation was found in patients older than 47 years (r = 0.78), and those with body mass index > 25 kg/m2 (r = 0.45). The Bland and Altman's plot analysis comparing the differences between spot uPCR and 24-h protein measurement also showed a wide range of the limits of agreement between the two methods. Overall, the results from this study showed a significant and weakly positive correlation between spot uPCR and 24-h urinary protein estimation in different forms of glomerulopathies. The agreement between the two methods was also poor. Hence, there is a need for careful interpretation of the ratio in an unselected group of patients with kidney disease.

Effective Ayurvedic Management of Steroid Resistant Nephrotic Syndrome - Case Study

Nephrotic syndrome presents with heavy proteinuria (3.5 g Proteins/ 1.73 m2 body surface area/24 hour), dyslipidaemia/ hypercholesterolemia, hypoalbuminema, edema and hypertension. If left untreated or undiagnosed, there is progressive damage to glomeruli causing renal failure. Heavy proteinuria is the most characteristic feature of this syndrome. Several studies have noted that higher the 24-h urine protein excretion, more rapid is the decline in GFR. It may be primary or secondary to other systemic diseases. Case study: This 2 year old male child developed Nephrotic syndrome and was placed on steroids, used to relapse when steroids are withdrawn, and subsequently developed steroid resistance. He was poorly managed by modern line of treatment for last 10 years. The case had developed Cushingoid features due to long term use of steroids. This case was successfully managed by Ayurvedic treatment principles of Deepan-Pachan, Vatalunoman and Mutral chikitsa. Steroids were withdrawn gradually and completely. There was no relapse. He was free of proteinuria. His Cushingoid features disappeared. Edema and Ascites also disappeared. This case study is the example of importance of alternative medicine in treating steroid dependent/resistant cases. When modern treatment has definite limitations to treat such cases, it is ray of hope to thousands of poor sufferers of Steroid resistant Nephrotic syndrome, finding them an effective alternative of Ayurvedic treatment. Keywords: Nephrotic syndrome, Steroid resistance, Ayurvedic management, Dridamula Basti Shotha

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Background: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. Objectives: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. Methods: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. Results: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], −90.90 mg/g, 95% CI, −140.17 to −41.64 mg/g), 24-h urinary protein excretion (WMD, −0.20 g, 95% CI, −0.28 to −0.12 g), estimated glomerular filtration rate (eGFR) (WMD, −1.99 mL/min/1.73 m², 95% CI, −3.28 to −0.70 mL/min/1.73 m²), chronic renal failure events (RR, 0.86, 95% CI, 0.79–0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77–0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73–2.40) and hypotension (RR, 1.80, 95% CI, 1.41–2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56–0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79–1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57–0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02–1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26–25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22–1.22) increased the risk of breast disorders. Conclusions: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Protective effect of paeoniflorin in diabetic nephropathy: A preclinical systematic review revealing the mechanism of action.

Paeoniflorin (PF), the main active glucoside of Paeonia Lactiflora, has many pharmacological activities, such as inhibition of vasodilation, hypoglycemia, and immunomodulation. Although the current evidence has suggested the therapeutic effects of PF on diabetic nephropathy (DN), its potential mechanism of action is still unclear. A systematic review and meta-analysis of the existing literature on paeoniflorin treatment in DN animal models was performed to evaluate the efficacy and mechanism of PF in DN animal models. The risk of bias in each study was judged using the CAMARADES 10-item quality checklist with the number of criteria met varying from 4 / 10 to 7 / 10, with an average of 5.44. From inception to July 2022, We searched eight databases. We used the Cochrane Collaboration's 10-item checklist and RevMan 5.3 software to assess the risk of bias and analyze the data. Three-dimensional dose/time-effect analyses were conducted to examine the dosage/time-response relations between PF and DN. Nine animal studies were systematically reviewed to evaluate the effectiveness of PF in improving animal models of DN. Meta-analysis data and intergroup comparisons indicated that PF slowed the index of mesangial expansion and tubulointerstitial injury, 24-h urinary protein excretion rate, expression of anti-inflammatory mediators (mRNA of MCP-1, TNF-α, iNOS, and IL-1 β), and expression of immune downstream factors (P-IRAK1, TIRF, P-IRF3, MyD88, and NF-κBp-p65). Furthermore, modeling methods, animal species, treatment duration, thickness of tissue sections during the experiment, and experimental procedures were subjected to subgroup analyses. The present study demonstrated that the reno-protective effects of PF were associated with its inhibition on macrophage infiltration, reduction of inflammatory mediators, and immunomodulatory effects. In conclusion, PF can effectively slow down the progression of DN and hold promise as a protective drug for the treatment of DN. Due to the low bioavailability of PF, further studies on renal histology in animals are urgently needed. We therefore recommend an active exploration of the dose and therapeutic time frame of PF in the clinic and in animals. Moreover, it is suggested to actively explore methods to improve the bioavailability of PF to expand the application of PF in the clinic.

Comparison of random urine protein/creatinine ratio with 24-hour urine protein in suspected pre-eclampsia

IntroductionProteinuria is one of the classical criteria for the diagnosis of pre-eclampsia. The gold standard remains the measurement of 24-h urine protein which is time consuming and prone to preanalytical errors. Random urine protein creatinine ratio (UPCR) is endorsed by clinical practice guidelines as a faster alternative. The aim of this study was to evaluate the correlation between the 24-h urine protein excretion and UPCR in the identification of proteinuria in suspected preeclamptic patients. MethodA total of 51 women with suspected pre-eclampsia from the maternal fetal clinic of our institution were retrospectively studied. The correlation between the UPCR in random urine samples and protein excretion in the 24-h urine collection was determined by Deming Regression analysis and Pearson correlation on EP evaluator and SPSS respectively. ResultThere was a significant positive correlation between the numerical values obtained by 24-h urine protein and the UPCR (R = 0.88, P < 0.001). Concordance analysis showed 81.1% positive agreement for proteinuria between methods (>300 mg/24hr and >0.3) and 71.4% negative agreement. The clinical sensitivity and specificity of the UPCR was 74% and 69% respectively. ConclusionOverall, UPCR was well correlated with 24-h urine protein and could be an effective and compliant screening tool to indicate proteinuria in preeclamptic patients.

#2892 CRITICAL ROLE OF SERUM RESPONSE FACTOR IN PODOCYTE EPITHELIAL–MESENCHYMAL TRANSITION OF DIABETIC NEPHROPATHY

Abstract Background and Aims To investigate the expression and function of serum response factor (SRF) in podocyte epithelial–mesenchymal transition (EMT) of diabetic nephropathy (DN). Method Expression of SRF, pSRF, synaptopodin, P-cadherin, ZO-1, α-SMA, FSP-1, fibronectin and collagen-1 were examined in podocytes or renal cortex following high glucose. SRF was upregulated by SRF plasmids and downregulated by CCG-1423 to investigate how SRF influence podocyte EMT in DN. Streptozocin was used to generate DM in rats. Results ① High glucose induced EMT and SRF upregulation in podocytes (Figure 1). High glucose suppressed synaptopodin and ZO-1 expression, and induced SRF, pSRF collagen-1, FSP-1 and α-SMA expression. SRF transferred from cytoplasm to nuclei obviously and the level of SRF was also increased in podocytes after high glucose treatment. ② SRF overexpression mediated EMT, migration and barrier dysfunction of podocytes (Figure 2). Overexpression of exogenous SRF reduced epithelial synaptopodin expression, and increased collagen-1, FSP-1, α-SMA and Snail expression in podocytes. Transwell chamber migration assay showed that overexpression of SRF significantly upregulated the migration of podocytes across the pores of transwell filters. Albumin filtration assay showed that albumin easily diffused across the monolayer of podocytes transfected with SRF cDNA. ③ Inhibition of SRF preserved phenotypes of podocytes in vitro (Figure 3). CCG-1423 selectively suppressed the expression of pSRF and SRF in podocytes after high glucose stimulation. Besides, simultaneous treatment of podocytes with CCG-1423 also significantly abolished the reduction of synaptopodin expression and the induction of collagen-1, FSP-1, α-SMA and Snail expression. CCG-1423 also reduced the transfer of SRF from cytoplasm to nucleus in podocytes treated with high glucose. ④ The effect of CCG-1423 in diabetic rats (Figure 4–-5). CCG-1423 significantly abrogated the reduction of synaptopodin expression and the induction of SRF, collagen-1, α-SMA and FSP-1 expression in renal cortex tissues. Masson and PAS staining demonstrated that renal glomerular fibrosis was present in DM group, and after 8 weeks treatment with CCG-1423, renal glomerular fibrosis was dramatically ameliorated. In addition, CCG-1423 significantly preserved P-cadherin expression and suppressed α-SMA and FN expression in DN rats. More importantly, CCG-1423 dramatically decreased 24-h urine protein excretion by about 50%, and increased serum albumin, compared with DM group. Conclusion Together, increased SRF activity provokes podocytes EMT and dysfunction in DN. Targeting SRF by small molecule inhibitor may be an attractive therapeutic strategy for DN.

The steroid-sparing effects of a mycophenolate mofetil-based regimen in the management of immunoglobulin A nephropathy in patients with histologically active lesions: A comparison with a control cohort receiving conventional therapy

IntroductionWhile the use of different immunosuppressants has been investigated in immunoglobulin A nephropathy, further investigation is needed to assess the effect of a regimen of mycophenolate mofetil combined with a short course of glucocorticosteroids in the subset of patients with histologically active features. We compared the efficacy and safety of a combined regimen of mycophenolate mofetil and glucocorticosteroids to a conventional regimen of glucocorticosteroids alone in patients with immunoglobulin A nephropathy who have active lesions and major urinary abnormalities.MethodsThis retrospective study involved 30 immunoglobulin A nephropathy patients with active histological lesions, 15 of whom were treated with both mycophenolate mofetil 2 g/day for 6 months and 3 pulses of 15 mg/kg methylprednisolone, followed by a short tapering schedule of oral prednisone. The control group was made up of the remaining 15 clinically- and histologically-matched patients treated with glucocorticosteroids alone according to a validated schedule, i.e., 1 g of methylprednisolone given intravenously for 3 consecutive days, followed by oral prednisone 0.5 mg/kg every other day for 6 months. At diagnosis, all patients had urinary protein excretion > 1 g/24 h and microscopic hematuria.ResultsAt the end of the first year of follow-up (30 patients) and after 5 years (17 patients), there were no differences between the two groups in terms of urinary abnormalities and functional parameters. Both regimens achieved a statistically significant decrease in 24-h urinary protein excretion (p < 0.001) and a reduction of microscopic hematuria. However, the mycophenolate mofetil-based regimen allowed a cumulative sparing dose of 6 g of glucocorticosteroids.ConclusionIn this single center study on immunoglobulin A nephropathy patients with active lesions and major urinary abnormalities and at increased risk of glucocorticosteroid-related complications, a mycophenolate mofetil-based regimen demonstrated similar outcomes in terms of complete response and relapse (at 1 and 5 years) compared to a conventional glucocorticosteroid-based protocol, while achieving a consistent reduction of glucocorticosteroid cumulative dose.Graphical

Sclerostin and TNF-related weak inducer of apoptosis: can they be important in the patients with glomerulonephritis?

Sclerostin is a protein produced by osteocytes, kidneys, and vascular cells and has many effects on kidney and vascular structures. Soluble TNF-related weak inducer of apoptosis is a proinflammatory cytokine that may cause glomerular and tubular injury and increase sclerostin expression. This study aimed to investigate serum sclerostin and soluble TNF-related weak inducer of apoptosis levels in patients with glomerulonephritis and the effects they may be associated with. This cross-sectional study included 93 patients, 63 of whom were glomerulonephritis and 30 were healthy controls. Serum sclerostin, soluble TNF-related weak inducer of apoptosis, and 24-h urinary protein excretion were measured, and pulse wave velocity was calculated for arterial stiffness. Serum sclerostin and soluble TNF-related weak inducer of apoptosis were higher in glomerulonephritis patients than in the control group, and serum sclerostin and soluble TNF-related weak inducer of apoptosis levels were correlated with both proteinuria and pulse wave velocity. In addition, in the regression analysis, serum sclerostin and soluble TNF-related weak inducer of apoptosis levels were found to be independent predictors of proteinuria in patients with glomerulonephritis. This is the first study to show that serum sclerostin and soluble TNF-related weak inducer of apoptosis are elevated in glomerulonephritis patients, and these two markers correlate with arterial stiffness and proteinuria in these patients. Considering the effects of sclerostin and soluble TNF-related weak inducer of apoptosis in patients with glomerulonephritis, we think these mechanisms will be the target of both diagnosis and new therapies.

PS-BPC10-4: THE CLINICOPATHOLOGICAL FINDINGS IN NON-DIABETIC CKD PATIENTS WITH CARDIOVASCULAR AUTONOMIC NEUROPATHY

Background: Cardiovascular autonomic neuropathy (CAN) is common as the process of kidney injury. Coefficient of variation of R-R interval (CVR-R) is one of the most convenient, noninvasive tests of heart rate variability, and is widely used to assess cardiac autonomic nerve function. However, the clinical and pathological findings in non-diabetic CKD patients with CAN has not been fully elucidated. This current study investigated the characteristics of non-diabetic CKD patients with CAN diagnosed by CVR-R. Method: Subjects who underwent percutaneous kidney biopsy and performed CVR-R test at the Jikei University School of Medicine Hospital, Tokyo, Japan were retrospectively examined. Patients with arrhythmia, diabetes, and post transplantation were excluded. CAN was defined using the reference values of CVR-R based on age and sex. The proportion of glomerulosclerosis (GS) and interstitial fibrosis/tubular atrophy (IF/TA) were assessed. The severity of arteriosclerosis was determined by the extent of thickening of the intima: grade0 = intimal thickening&lt; thickness of media grade1 = intimal thickening&gt; thickness of media. Results: Ninety subjects were identified (Age 45.7 ± 14.9 (mean ± SD) years old; Male 56%; heart rate 69 ± 11 /min; eGFR 60.0 ± 29.5 mL/min/1.73m2; 24h-urinary protein excretion 0.55 [0.24–1.30] (median [IQR]) g/day; CVR-R rest 3.7 ± 1.7%; GS 11.6 [3.6–24.8] %, IFTA 20 [10–30] %.) Eleven patients were diagnosed as CAN, with nephrosclerosis [n = 4], acute tubulointerstitial nephritis [n = 2], IgA nephropathy [n = 1], IgA vasculitis [n = 1], membranous nephropathy [n = 1], lupus nephritis [n = 1], and focal segmental glomerular sclerosis [n = 1]. Patients with CAN had a higher triglyceride (P = 0.030) and higher IF/TA(P = 0.005) than those without CAN. The severity of arteriosclerosis increased in patients with CAN. (P = 0.017) Conclusion: These results indicated that that arteriosclerosis and IF/TA were associated with CAN in non-diabetic CKD patients.

Polymorphisms of CARD9 Gene Predict Disease Progression and Renal Survival of Immunoglobulin A Nephropathy

Introduction: A previous genome-wide association study has identified CARD9 (caspase recruitment domain family member 9) as a susceptibility gene for immunoglobulin A nephropathy (IgAN), which encodes an adapter protein and is related to mucosal immunity. This study aimed to investigate the association of CARD9 variants with the clinicopathological phenotypes and prognosis of IgAN. Methods: Eight single nucleotide polymorphisms within CARD9 were genotyped using Sequenom MassARRAY iPLEX for 986 IgAN patients in this study. Logistic and linear regression analyses adjusted for age and gender were performed to evaluate the effects of CARD9 gene polymorphisms on clinicopathological phenotypes. The Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival. Results: The T allele of rs10747047 was strongly associated with higher levels of serum creatinine (p = 0.005) and lower levels of estimated glomerular filtration rate (p = 0.005). The rs10870149-G and rs10870077-C alleles were associated with elevated 24-h urine protein excretion (p = 0.041 and 0.022, respectively) and more serious segmental glomerulosclerosis lesions (p = 0.005 and 0.041, respectively) in IgAN patients. Carriers with the T allele of rs10781533 and the C allele of rs3812552 also presented with severe segmental glomerulosclerosis lesions (p = 0.001 and 0.010, respectively). Additionally, rs10747047-C and rs10870077-C alleles were independently related to the poor prognosis of IgAN patients after adjustments for covariates (TT vs. CC hazard ratio [HR] = 0.138, 95% confidence interval [95% CI] = 0.022–0.871, p = 0.035; GG vs. CC HR = 0.321, 95% CI = 0.123, 0.836, p = 0.020, respectively). Conclusion: CARD9 variants are associated with disease severity and rapid disease progression for IgAN in a Chinese Han population.

Levels of Proteinuria and Renal Pathology in Systemic Lupus Erythematosus Patients.

According to the current guidelines, renal biopsies are performed in systemic lupus erythematosus (SLE) patients for proteinuria of 0.5 g/24 h or higher. Renal pathology may be present in patients with lower-level proteinuria (<0.5 g/24 h). We aimed to review the renal histopathology in SLE patients, with lower levels of proteinuria. In this retrospective study, we retrieved SLE patients' data, including 24-h urinary protein excretion and renal histopathology results. We compared various parameters in different lupus nephritis (LN) classes and in different levels of proteinuria (urinary protein <0.5 g, 0.5 to <1 g, and ≥1 g per 24 h). Out of 476 patients, 274 (57.6%) had proteinuria of <0.5 g, 44 (9.2%) had 0.5 to <1 g, and 158 (33.2%) had ≥1 g per 24 h. SLE patients with proteinuria of <0.5 g/24 h were found to have LN, including the proliferative classes. Of the 299 LN cases confirmed by a renal biopsy, low-level proteinuria (<0.5 g) was found in 39.8% of all LN patients, in 50% of patients with Class III LN, 33.3% of those with Class IV LN, 31.4% of those with Class V LN, and 41.4% of those with other LN classes (II/V, III/V, and IV/V). Overall, 35.9% (87/242) of patients with the proliferative LN classes (III, IV, V, II/V, III/V and IV/V) had low-level proteinuria of <0.5 g/24 h. SLE patients with low-level proteinuria had significant renal pathology. Our study suggests there is a need to perform renal biopsies at lower levels of proteinuria.

The maternal reduced uteroplacental perfusion model of preeclampsia induces sexually dimorphic metabolic responses in rat offspring

BackgroundOffspring born to preeclamptic mothers are prone to obesity, diabetes and hypertension in later life, but still, studies investigating the underlying mechanism are limited. Here, we aimed to investigate the impact of the reduced uteroplacental perfusion (RUPP) rat preeclampsia model on offspring metabolic outcomes.MethodsTimed pregnant Wistar rats underwent RUPP or sham surgeries on day 14 of gestation. Glucometabolic parameters were evaluated on postnatal days (PND), 14 (childhood), and 60 (young adult). In addition, intraperitoneal glucose tolerance test (IPGTT), homeostatic model assessment of insulin resistance (HOMA-IR), immunohistochemical staining for insulin in pancreatic islets, arterial blood pressure and 24-h urine protein (24hUP) excretion were performed at PND60.ResultsMale, but not female, young adult rats (PND60) of RUPP dams exhibited an impaired IPGTT, decreased circulatory insulin and weakened pancreatic insulin immunoreactivity. Compared to the male offspring of the sham group, the body mass of male RUPP offspring significantly caught up after PND42, but it was not sex-specific. RUPP pups also exhibited upregulations in glucagon (only males) and ghrelin (both sexes with a more significant increase in males) during PND14–PND60. However, in sham offspring (both sexes), glucagon levels were downregulated and ghrelin levels unchanged during PND14–PND60. The blood pressure, HOMA-IR and 24hUP values did not alter in RUPP pups.ConclusionsThe overall results suggest that maternal RUPP has negative and sex-specific impacts on insulin, glucagon and ghrelin regulations in offspring and that, as young adults, male RUPP rats may be more prone to develop obesity and diabetes.

The association between hypothyroidism and proteinuria in patients with chronic kidney disease: a cross-sectional study

Hypothyroidism is known to be correlated with kidney function and nephrotic range proteinuria. However, it is uncertain whether non-nephrotic proteinuria is associated with hypothyroidism. This study aimed to evaluate the association of proteinuria and hypothyroidism in chronic kidney disease (CKD) patients. We conducted a cross-sectional study composed of 421 CKD patients in a single hospital with measurements of 24-h urine protein excretion (UP) and thyroid function tests. Spearman correlation analysis revealed that 24-h Cr clearance (24hrCcr) was positively (r = 0.273, p < 0.001) and UP was negatively (r = − 0.207, p < 0.001) correlated with free triiodothyronine. Frequency distribution analysis stratified by CKD stage and UP for hypothyroidism revealed that the prevalence of hypothyroidism was higher among participants with higher CKD stage and nephrotic range proteinuria. Multivariate logistic regression analysis revealed that 24hrCcr and UP were significantly correlated with hypothyroidism (24hrCcr/10 mL/min decrease: odds ratio [OR], 1.29; 95% confidence interval [CI], 1.18–1.41; UP/1 g increase: OR, 1.10; 95% CI, 1.03–1.17). In addition, nephrotic range proteinuria, but not moderate UP (UP: 1.5–3.49 g/day), was significantly correlated with hypothyroidism compared to UP < 0.5 g/day. In summary, decreased kidney function and nephrotic range proteinuria, not non-nephrotic proteinuria, are independently associated with the hypothyroidism.

Sappanone a prevents diabetic kidney disease by inhibiting kidney inflammation and fibrosis via the NF-κB signaling pathway

Background: Low grade of sterile inflammation plays detrimental roles in the progression of diabetic kidney disease (DKD). Sappanone A (SA), a kind of homoisoflavanone isolated from the heartwood of Caesalpinia sappan, exerts anti-inflammatory effects in acute kidney injury. However, whether SA has beneficial effects on diabetic kidney disease remains further exploration. Methods and Results: In the present study, uninephrectomized male mice were treated with Streptozotocin (STZ, 50 mg/kg) for five consecutive days to induce diabetes. Next, the diabetic mice were administered orally with SA (10, 20, or 30 mg/kg) or vehicle once per day. Our results showed that STZ treatment significantly enhanced damage in the kidney, as indicated by an increased ratio of kidney weight/body weight, elevated serum creatinine and blood urea nitrogen (BUN), as well as increased 24-h urinary protein excretion, whereas SA-treated mice exhibited a markedly amelioration in these kidney damages. Furthermore, SA attenuated the pathological changes, alleviated fibrotic molecules transforming growth factor-β1 (TGF-β1) and Collagen-IV (Col-IV) production, decreased inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression in STZ-treated mice. Similarly, in glomerular mesangial cells, SA pretreatment decreased high glucose (HG)-induced proliferation, inflammatory cytokines excretion, and fibrotic molecules expression. Mechanistically, SA decreased the expression of nuclear factor kappa B (NF-κB) and restored the expression of total NF-κB inhibitor alpha (IκBα) both in vivo and in vitro. Conclusion: Our data suggest that SA may prevent diabetes-induced kidney inflammation and fibrosis by inhibiting the NF-κB pathway. Hence, SA can be potential and specific therapeutic value in DKD.

Sacubitril/Valsartan Improves Progression of Early Diabetic Nephropathy in Rats Through Inhibition of NLRP3 Inflammasome Pathway.

PurposeDiabetic nephropathy (DN), a global disease, is the leading cause of end-stage renal disease. There is a lack of specific treatment for this disease, and early intervention in disease progression is essential. In this paper, we used a rat model of early diabetic nephropathy to explore the therapeutic mechanism of sacubitril/valsartan in rats with early diabetic nephropathy.Materials and MethodsRats were grouped into 1 normal group; 2. Model group (DN group): STZ (45 mg/kg/d) induced early diabetic nephropathy rats; 3. Sac group: DN rats + Sac group (orally, 60 mg/kg/d) for 6 weeks. After 6 weeks, the levels of serum albumin (ALB), glucose (GLU), creatinine (Cr), urea nitrogen (BUN) and 24-h urinary protein excretion were measured. In renal tissue homogenates, NLRP3 inflammasome, proinflammatory factors IL1-β and TNF-α, oxidative stress MDA and pro-fibrotic cytokine TGF-β1 were performed. Histological analysis of kidneys by hematoxylin and eosin (HE), PAS and Masson trichrome staining.Results1. Sacubitril/valsartan (Sac) significantly improved renal hypertrophy, proteinuria and serum albumin levels in rats with early diabetic nephropathy (P < 0.001), and decreased GLU, Scr (P<0.001), and BUN levels (P < 0.01).2. Light microscopy of renal tissues showed glomerular hypertrophy and interstitial inflammatory cell infiltration, and mean glomerular area (MGA) and mean glomerular volume (MGV) were crucially increased in early diabetic nephropathy (P < 0.001), and the Sac group showed reduced renal pathology and improved MGA and MGV (P < 0.001).3. Kidney tissue homogenate levels of NLRP3, Caspase-1, IL1-β, TNF-α, MDA and TGF-β1 were critically, increased in DN rats (P < 0.001), and SOD was significantly decreased. All these indicators above were improved after treatment (P < 0.0001).ConclusionNlrp3-inflammasome promote progression of diabetic nephropathy through inflammation, fibrosis and oxidative stress; sacubitril/valsartan ameliorated early diabetes-induced renal damage by inhibiting NLRP3 pathway activation.

Ferulic acid ameliorates renal injury via improving autophagy to inhibit inflammation in diabetic nephropathy mice

Diabetic nephropathy (DN) is one of the most serious microvascular complications following diabetes mellitus (DM). Ferulic acid (FA), a phenolic acid widely found in plants, has multiple pharmacological effects such as anti-oxidation, anti-inflammation and anti-tumor. However, the current research on FA in the field of DN is insufficient. The present study aimed to explore the nephroprotective effect of FA on DN in mice and reveal its underlying mechanism. DN was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6J mice. Animals were randomly divided into four groups (n = 8): Control group, DN group, FA group (200 mg/kg FA, i.g.) and valsartan (VAL) group (12 mg/kg VAL, i.g.). The drug was administered once a day for 8 weeks. Treated with FA, the body weight and fasting blood glucose (FBG) of DN mice were reduced and the renal organ coefficient was significantly optimized. Meanwhile, FA decreased levels of 24-h urine protein excretion (24-h UP) in urine and blood urea nitrogen (BUN), creatinine (Cr) in serum, reduced levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in serum. In addition, FA promoted light chain 3 (LC3) expression markedly, and inhibited the expressions of p62, NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1β (IL-1β) in renal tissues. In conclusion, FA played a positive role in alleviating renal injury in HFD/STZ-induced DN mice by enhancing autophagy and suppressing excessive inflammation.

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study

BackgroundThere is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients. MethodsIn this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion≥2.0g/24h and estimated glomerular filtration rate≥50mL/min/1.73m2. Primary endpoint was rate of complete remission. ResultsAfter 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P=0.7). However, the serum creatinine level from baseline was an increase of 13±13.5μmol/L in the tacrolimus group and a decrease of 8.2±20μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group. ConclusionsTacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

MO108: Paraneoplastic Nephrotic Syndrome in a Man with Breast Cancer

Abstract BACKGROUND Nephrotic syndrome is associated with many solid tumours and haematologic malignancies. Membranous nephropathy (MN) is the most commonly reported paraneoplastic glomerulonephritis; about 10% (rate 5–20%) of adults with MN have been reported to have a malignancy [1]. Less frequently, minimal change disease, focal segmental glomerular sclerosis, membranoproliferative and crescentic glomerulonephritis, IgA nephropathy [1] and thrombotic microangiopathy [2] have been associated with cancer. Differentiating primary from secondary glomerular disease in patients with malignancy can be difficult. The probability of a secondary form is higher when the appearance of proteinuria or nephrotic syndrome precedes by few months or develops within a year of cancer diagnosis. The suspicion of paraneoplastic nephropathy is even stronger when tumour remission is associated by significant fall in proteinuria and when recurrence of malignancy is followed by the development of clinical glomerular disease. Solid tumour most commonly associated with glomerular diseases (mainly MN) is lung cancer, followed by prostate and colorectal cancer. Paraneoplastic glomerular diseases are rarely linked to breast cancer. In two reviews, breast cancer was reported only in 3% (5 out of 159 patients) [1] and 8% (6 out of 85 patients) of patients with MN and solid tumours. Breast cancer is the most common malignancy in women, while it is a rare disease in men. Male breast cancers account for less than 1% of all diagnosed cases, and the mean age is usually over 60 years [1]. METHODS We report the case of a breast cancer in a man associated with a paraneoplastic nephrotic syndrome. A 76-year-old man was managed at our renal department since 2016 for chronic kidney disease. He was overweight and affected by non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease. Since 2016 to December 2020, he had stable renal function with serum creatinine levels ranging from 2.5 to 3.0 mg/dL and a normal urinary protein excretion rate (100–150 mg/24 h). In March 2021, the patient developed a right periareolar breast swelling, pain and erythema with yellowish nipple discharge. In the same period, a full-blown nephrotic syndrome with heavy proteinuria (8 g/24 h) was observed, and serum creatinine increased to 3.5–4.0 mg/dL. Immunological blood tests were negative, including anti-PLA2R and anti-THSD7A antibodies. A kidney biopsy could not be performed due to bilateral renal cysts. Mammogram examination and ultrasound imaging revealed ductal ectasia and microscopic calcifications at the site of right breast lesion, so a diagnosis of cancer was made. RESULTS In September 2021, the patient underwent radical right mastectomy and histopathological examination confirmed early-stage breast cancer (pT1a, pN0, Mx R0, ER 100%, PgR 0, Ki67 5%, CerbB2 neg). In the following month, the 24-h urinary protein excretion markedly reduced to 1.4 g and the nephrotic syndrome resolved completely, confirming its secondary origin. CONCLUSIONS Paraneoplastic nephrotic syndrome is a rare complication of cancer. Its recognition and detection of an undiagnosed malignancy could be life-saving. To our knowledge, this is the first case reported in literature of paraneoplastic nephrotic syndrome in a man affected by breast cancer.