Severe Proteinuria Research Articles

PS-B08-13: PLASMIN INHIBITION ALLEVIATES HYPERTENSION AND PODOCYTE INJURY IN DAHL SALT-SENSITIVE RATS

Objective: The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in blood pressure regulation, and the γ subunit is activated by extracellular serine proteases. In proteinuric renal diseases, plasmin filtered through injured glomeruli proteolytically activates γENaC. In addition, filtered plasmin directly causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed severe hypertension and proteinuria together with γENaC activation, and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remains unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as glomerular injury and the effects of plasmin inhibitors in DS rats. Design and method: Five-week-old male DS rats were divided into normal-salt (NS) diet, HS diet, and HS + plasmin inhibitors [tranexamic acid (TA, 2 mg/mL TA in drinking water) and synthetic plasmin inhibitor YO-2 (4 mg/kg/day, intraperitoneal injection)] groups. After systolic blood pressure measurement and 24-h urine collection over time for 5 weeks, the rats were sacrificed for biochemical examination. Results: The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and γENaC in the kidney, which were not attenuated by TA. On the other hand, YO-2 mitigated both hypertension and proteinuria [SBP (mmHg): NS, 130.8 ± 7.5; HS, 209.0 ± 14.2; HS+YO-2, 183.8 ± 8.4; Urinary protein (mg/day): NS, 15.4 ± 3.2; HS 259.0 ± 129.3; HS+YO-2, 94.5 ± 31.5]. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by reducing glomerular apoptotic cells. Furthermore, YO-2 suppressed the upregulation of protease-activated receptor-1 and phosphorylated ERK1/2 as well as mRNA expression of inflammatory and pro-fibrotic cytokines in the kidney. Conclusion: These results indicate that plasmin plays important roles in the development of salt-sensitive hypertension and glomerular injuries in a rat model of hypertension, and suggest that plasmin inhibition could be a potential therapeutic strategy against salt-sensitive hypertension.

PS-BPR03-2: A RARE CASE OF TAKAYASU ARTERITIS INDUCED RENOVASCULAR HYPERTENSION IN A PATIENT WITH CROHN DISEASE

Takayasu arteritis (TA) is chronic inflammatory arteritis affecting large vessels, predominantly the aorta and its main branches. Vascular inflammation occurs wall thickening, fibrosis and stenosis. Arterial stenosis due to TA often causes secondary hypertension. Crohn disease (CD) is chronic granulomatous, inflammatory gastrointestinal disease, It can cause various extraintestinal complications. A few case reports and small case series reported complications of TA and CD. In recently, there are several reports that TA are revealed in patients treated with anti-tumor necrosis factor - alpha antibody for CD. We report a 18 years old male in whom TA was manifested mainly by severe hypertension and proteinuria after infliximab administration for CD. He was diagnosed with CD at the age of 17. He had a great fever and high CRP levels (6.55 mg/dl), and endoscopic examination revealed multiple longitudinal ulcers in the large intestine and ileum. Although, he was treated with adalimumab and 5 -aminosalicylic acid, fever and CRP levels did not improve, Infliximab was administered. Following infliximab administration, his laboratory data revealed renal impairment (blood urea nitrogen level: 13 mg/dl, creatinine level: 1.28 mg/dl), proteinuria (10.0 g/gCr) and he had severe hypertension (about 190/100 mmHg). Both, his plasma aldosterone concentration (PAC) (RIA) and plasma renin activity (PRA) were significantly high (PAC: 798 pg/ml. PRA: 66.2 ng/ml/hr). In addition, magnetic resonance angiography and radioisotope renogram findings revealed stenoses of the right renal artery. Although, a simple CT scan performed 5 months earlier showed no abnormalities in both kidney, contrast-enhanced CT revealed stenoses of the right renal artery, superior mesenteric artery, right renal atrophy, and left renal enlargement. The 99mTc-DTPA Renography reveled severe right renal dysfunction (GFR 14.67/61.21 ml/min). Based on these findings, patient was diagnosed with TA induced renovascular hypertension complicated with CD, and oral administration of prednisolone from 1 mg/kg/day and antihypertensive drugs (amlodipine, doxazosin, and spironolactone) was started. After 14 days treatment, his blood pressure was about 170/90 mmHg. Finally, losartan was administered, his blood pressure was reduced to 120∼150/70∼90 mmHg, and no changes in his serum creatinine levels was observed. We report with a review of the literature.

Use of sodium-glucose cotransporter 2 inhibitors in Alberta adults with chronic kidney disease: a cross-sectional study identifying care gaps to inform knowledge translation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have important kidney and cardiovascular benefits in adults with chronic kidney disease. Among adults with diabetes, we characterized the prevalence of chronic kidney disease eligible for SGLT2 inhibitor treatment, based on definitions of eligibility from trials and diabetes guidelines, and assessed the predictors of SGLT2 inhibitor use. We conducted a cross-sectional study using linked administrative data from Alberta Health in adults with diabetes (2002-2019). Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2 with severe or greater proteinuria (trial-based definition); or eGFR less than 60 mL/min/1.73 m2 or moderate or greater proteinuria regardless of eGFR (diabetes guideline-based definition). Predictors (sociodemographic characteristics, comorbidities and health care utilization) of SGLT2 inhibitor use were identified using logistic regression. Of 446 315 adults with diabetes, 76 630 (17.2%, guideline-based definition; 12 867 [2.9%], trial-based definition) had chronic kidney disease eligible for SGLT2 inhibitor treatment. A total of 7.1% used SGLT2 inhibitors. Older age, lower hemoglobin A1c (HbA1c) levels, female sex, lower neighbourhood income, rural residence and hospital admission were among variables associated with nonuse of SGLT2 inhibitors (adjusted odds ratios [ORs] from 0.13 [age ≥ 85 yr] to 0.92 [rural residence], p < 0.05). Family physician visits were associated with higher SGLT2 inhibitor use (adjusted OR 4.01, p < 0.001 for > 4 visits/yr). Considering all adults, both with and without diabetes, 162 012 individuals with chronic kidney disease (5% of all Alberta adults) may benefit from treatment with SGLT2 inhibitors. Many adults with chronic kidney disease would derive heart and kidney benefits from treatment with SGLT2 inhibitors but had low SGLT2 inhibitor use as of 2019. Efforts will be needed to address lower use of SGLT2 inhibitors among female, older and lower-income adults, and to enhance primary care and promote awareness of the benefits of SGLT2 inhibitors independent of glycemic control.

S-38-7: CONTINUOUS NON-MUTAGENIC DNA DAMAGE IN PODOCYTES ACTIVATES PATHOGENIC MEMORY T CELLS THROUGH ALTERED DNA METHYLATION

Objective: Chronic kidney disease (CKD) is a common cause of hypertension and a complication of uncontrolled hypertension. Recent epigenome-wide studies suggested the association of altered DNA methylation in blood cells with kidney function. However, the mechanism and pathological significance has remained to be adequately elucidated. Design and method: To investigate the significance of DNA double-strand breaks (DSBs) in podocytes, we generated podocyte-specific I-PpoI-expressing mice (podocin-Cre ROSA26-STOP- I-PpoI, referred as I-PpoI-mice). I-PpoI is a homing endonuclease which causes non-mutagenic DSBs. Results: I-PpoI-mice showed severe albuminuria at 6 weeks of age and developed nephrotic syndrome. The mice died because of renal failure around 24 weeks of age following rapid deterioration of renal function. MeDIP-seq analysis using isolated podocytes revealed that 5219 DMRs were identified, and 5212 hypermethylated DMRs were detected in I-PpoI mice. No significant correlation between DNA methylation levels and the distance from I-PpoI cutting sites was observed. Single-cell RNA seq analysis using renal cortex revealed a marked expansion of immune cells, especially CD8+ T cells exhibited a KLRG1low IL-7Rhigh memory precursor effector cell phenotype, with high expression of NKG2D receptors in I-PpoI-mice. The expression of murine NKG2D ligands, which are upregulated by DNA damages, increased in I-PpoI-mice podocytes. In addition, the expression of human NKG2D ligands, MICB, in glomeruli was upregulated in patients with various kidney diseases including hypertensive nephropathy. Whole T cell depletion prevented exacerbation of albuminuria and attenuated glomerulosclerosis and fibrosis in I-PpoI mice, and similar results was obtained by NKG2D blocking. Me-DIP seq analysis using peripheral blood cells, which revealed hypermethylated DMRs in I-PpoI mice were enriched in binding sites for the STAT1 transcription factor. I-PpoI-mice showed a significant increase in CD44high memory/activated phenotype cells of peripheral CD8+ T cell populations, which was similar phenotype of STAT1 knockout mice. The chimeric WT mice with bone marrow (BM) cells of I-PpoI-mice exhibited an increase in albuminuria temporarily, whereas the chimeric I-PpoI-mice with BM cells of WT mice prevented renal fibrosis and renal death. Conclusions: Continuous non-mutagenic DSBs altered DNA methylation regardless of the distance from the primary DSB sites podocytes. Podocyte DNA DSBs also altered methylome of blood cells, including CD8+ T cells, leading sustained changes in immune microenvironment of the kidney and also BM. These results suggest the altered immune microenvironment in the kidney may be a therapeutic target preventing exacerbating glomerulosclerosis and renal fibrosis following podocyte DNA damage in CKD.

ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease

BackgroundHyperglycemia and dyslipidemia are two major characteristics of diabetes. In this study, the effects of glomerular cholesterol accumulation primarily due to ABCA1 deficiency on glomerular endothelial injury in diabetic kidney disease (DKD) and the possible mechanisms were investigated. MethodsThe effects of ABCA1 deficiency on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 deficiency in glomerular endothelial cells (DM-ABCA1−/− mice) and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro. ResultsABCA1 deficiency in glomerular endothelial cells exacerbated renal lipid deposition and kidney injuries in type 2 diabetic mice and manifested as increased creatinine levels, more severe proteinuria, mesangial matrix expansion and fusion of foot processes, and more pronounced renal inflammatory injury and cell death. In HRGECs cultured under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposition of cellular cholesterol, contributed to inflammation and apoptosis, damaged the endothelial glycocalyx barrier, and induced endoplasmic reticulum stress (ERS). Conversely, ABCA1 overexpression enhancing cholesterol efflux or inhibition of ERS in vitro, significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol. ConclusionsThese findings establish a pathogenic role of ABCA1 deficiency in glomerular endothelium injury and dysfunction and imply that ABCA1 may represent a potential effective therapeutic target for early diabetic kidney disease.

Albuminuria post-liver transplant is a predictor of kidney disease progression and mortality.

BACKGROUND: Albuminuria is a marker of chronic kidney disease (CKD) associated with an increased risk of end-stage kidney disease (ESKD) and mortality in the general population, but it is uncertain whether the same association exists in liver transplant (LT) recipients. This study examined the association between albuminuria and kidney failure and mortality in LT recipients.METHODS: Retrospective cohort study of 294 adults who received a LT between January 1, 1989, and December 31, 2011, in British Columbia, Canada. Cox multivariable regression was used to determine the association between ACR and a primary combined outcome of mortality, doubling of serum creatinine, or ESKD; and a secondary outcome of a decrease in estimated glomerular filtration rate (eGFR) ≥30%. RESULTS: At baseline, mean eGFR was 67 (SD 20.9) mL/min/1.73 m2, and 10% had severe albuminuria (ACR >30 mg/mmol). The primary outcome occurred in 20.4% (60) of patients and was associated with ACR >30 mg/mmol (HR 2.77, 95% CI 1.28-6.04; P = 0.01). A decline in eGFR ≥30% occurred in 21.8% (64) of patients, and was associated with ACR >30 mg/mmol (HR 4.77, 95% CI 2.31-9.86; P < 0.0001). CONCLUSIONS: Severe albuminuria (ACR >30 mg/mmol) was associated with an increased risk of loss of kidney function and mortality after LT. Prospective studies are needed to determine if specific interventions directed at reducing albuminuria can improve long-term outcomes in LT recipients.

An 8-month-old boy with infantile nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy.

We present a case of nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy. The patient was an 8-month-old male infant who presented with severe proteinuria and hypertension. He was treated with prednisolone (PSL) for nephrotic syndrome; however, remission was not achieved within 4weeks. He was diagnosed with steroid-resistant nephrotic syndrome and underwent kidney biopsy. Pathological examination revealed membranous nephropathy with IgG deposits on both the glomerular basement membrane (GBM) and the tubular basement membrane (TBM). He was treated with cyclosporine (CsA) in addition to PSL and achieved complete remission. However, frequent relapses occurred after the discontinuation or tapering of immunosuppressants. Two years after treatment initiation, a second biopsy was performed and showed worsening of the disease, which required treatment with several immunosuppressants to achieve complete remission. After that, we performed additional immunostaining for semaphorin 3B, which confirmed the diagnosis of semaphorin 3B-associated membranous nephropathy. Although extremely rare in infantile cases, semaphorin 3B-associated membranous nephropathy should be considered in the differential diagnosis, as strong treatment with immunosuppressants might be needed. In addition, mycophenolate mofetil showed an effective clinical response in this case, indicating that it can be considered for future treatment strategies.

Risk Factors for Early Onset of Proteinuria in Patients Receiving Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma

Introduction: Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC. Methods: Sixty-four patients with Child-Pugh scores of 5–7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated. Results: The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579–9.180; p = 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614–24.010; p = 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133–6.194; p = 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr). Conclusion: Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.

Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2.

The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury. Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence. Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development. Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine. Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.

A retrospective study on the characteristics of renal pathological grades in HSPN children with mild to moderate proteinuria.

To investigate the characteristics of renal pathological grades in Henoch-Schönlein purpura nephritis (HSPN) children with mild to moderate proteinuria and the correlation between pathological grade and severity of proteinuria among this population. HSPN children who were presented with mild (150 mg <24 h urinary protein <25 mg/kg) to moderate (25 mg/kg ≤24 h urinary protein <50 mg/kg) proteinuria and performed renal biopsy without steroid ± immunosuppressant treatment in the Second Xiangya Hospital between January 2010 and March 2021 were involved. We retrospectively analyzed the correlation between age, disease course, degree of proteinuria, type of immunoglobulin deposits, C3 deposits in glomeruli and renal pathological grade. (1) 72 HSPN children including 46 boys and 26 girls were included, with a mean age of onset of 9.01 ± 2.65 years old. The majority of these patients (62.5%) had a disease course between 1 week to 1 month. 51 patients presented with mild proteinuria and 21 patients with moderate proteinuria. (2) Renal biopsy results showed that ISKDC Grade IIIa were both predominant in mild proteinuria group (25, 49%) and moderate proteinuria group (11, 52.4%). 32 patients had grade II (44.4%), 2 had grade IIIb (2.8%), 1 had grade IV (1.4%), and 1 had grade VI (1.4%). There was no correlation between age, disease course and renal pathological grade (p > 0.05). (3) In patients with mild proteinuria (n = 51), 27 (52.9%) HSPN children had a pathological grade ≥ grade III. In patients with moderate proteinuria (n = 21), 13 (61.9%) HSPN children had grade ≥ III. There was no significant difference in the proportion of renal pathological grade between the 2 groups (p > 0.05). (4) There was no significant correlation between glomerular C3 deposits or immunoglobulin deposit types and renal pathological grade (p = 0.776 and p = 0.056 respectively). In HSPN children with mild to moderate proteinuria, longer disease course or heavier urinary protein level is not completely parallel with higher renal pathological grade. ISKDC grade IIIa is the most common pathological grade. Clinicians should pay great attention to the renal injury in patients with mild to moderate proteinuria.

A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis

BackgroundMultiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury.Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described.Case presentationWe present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis.During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected.ConclusionsThis case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment.

Correlation between Degree of HT with Degree of Albuminuria in Non-dialysis Chronic Kidney Disease Patients at Hypertension Kidney Polyclinic Dr. Soetomo General Hospital

Background: Hypertension (HT) in chronic kidney disease (CKD) occurs through increased activity Renin Angiotensin Aldosterone System (RAAS). According ISH 2020, degree of HT is divided into grade 1 and 2. Uncontrolled HT cause damage glomerular capillaries, thereby affecting presence of albuminuria. According KDIGO 2013, degree of albuminuria is divided into mild, moderate, and severe. Albuminuria that lasts more than 3 months indicates CKD. Until now, research on correlation between degree of HT with degree of albuminuria is still limited. This study aims to determine correlation between degree of HT with degree of albuminuria in non-dialysis CKD patients at Hypertension Kidney Polyclinic Dr. Soetomo General Hospital. Methods: Analytical observational study with cross sectional design using medical records of non-dialysis CKD patients at Hypertension Kidney Polyclinic Dr. Soetomo General Hospital for period of May-October 2021, according to inclusion and exclusion criteria. Correlation test using spearman test. Results: There were 75 study subjects with male (61.3%), age 46-65 years old (42.7%), comorbidities other than HT were DM (32%), HT duration <5 years (58.7% ), controlled HT (66.7%), taking 1 anti-HT (74.7%), ARB (26.7%), severe albuminuria (50.7%). This study showed no correlation between degree of HT with degree of albuminuria (p-value=0.982). Conclusion: There is no correlation between degree of HT with degree of albuminuria in non-dialysis CKD patients at Hypertension Kidney Polyclinic Dr. Soetomo General Hospital.

Monoclonal Gammopathy of Undetermined Significance and Risk of Chronic Kidney Disease: Results of the Population-Based Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Background: Monoclonal gammopathy of undetermined significance (MGUS) and chronic kidney disease (CKD) are common conditions. When monoclonal gammopathy causes CKD it is referred to as monoclonal gammopathy of renal significance (MGRS) and a kidney biopsy is required to confirm the diagnosis. Because of this, some have speculated that MGRS may be severely underdiagnosed and have recommended considering a kidney biopsy in all individuals with MGUS who have microscopic hematuria, proteinuria, or declining estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m2. If MGRS were more common than previously thought, the prevalence of CKD in persons with MGUS would be expected to be higher than persons without MGUS. We aimed to compare the prevalence of CKD in individuals with and without MGUS in a large, prospective, screened, population-based cohort. Furthermore, we aimed to assess possible association between M protein concentration and kidney function. Methods: A total of 75,422 participants in the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS with serum protein electrophoresis (SPEP), serum free light chains (FLC), and immunofixation (IFE). All previous clinical laboratory samples were obtained, including serum creatinine (SCr), urine albumin/creatinine ratio (ACR) and urinalysis. CKD was defined as SCr-based eGFR of <60 mL/min/1.73m2, or proteinuria or hematuria, present for >90 days. Participants diagnosed with lymphoproliferative disorders or without data on kidney function were excluded. Power analysis demonstrated that this sample size yielded 90% power to detect a 1.5% absolute difference in the prevalence of CKD in persons with and without MGUS. Prevalence of CKD was evaluated using multivariable logistic regression adjusted for age, sex and MGUS status. The association between eGFR and M protein concentration was assessed with linear regression for continuous eGFR and ordinal logistic regression for CKD categories. All models included age and M protein concentration as four knot restricted cubic splines. Sensitivity analyses were performed where CKD was defined solely by persistently lowered eGFR and as a combination of persistently lowered eGFR, proteinuria, and hematuria. Results: A total of 69,120 participants had SCr measurements and 34,294 had urine studies available. MGUS was present in 4,547 (6.6%) participants, of which 2,242 (49.3%) were non-IgM; 703 (15.5%) were IgM; 1,295 (28.5%) were light chain (LC-MGUS); and 307 (6.7%) were biclonal MGUS. A total of 6,680 (9.7%) participants had CKD defined either as eGFR <60 mL/min/1.73 m2 (N=5,915) or persistent proteinuria or hematuria (N=693), or were receiving treatment for end-stage kidney disease (N=74). Participants with MGUS were significantly older (median [IQR] age 69 [60-76] vs 60 [52-69] years) and more predominantly male (55% vs 41%) compared with participants without MGUS. After adjusting for age and sex, no significant association was found between heavy chain MGUS and CKD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.95-1.17). This also remained true for subgroups of non-IgM MGUS, IgM MGUS, and biclonal MGUS (Table). Participants with LC-MGUS were less likely to have CKD than participants without MGUS (OR 0.39, 95% CI 0.31-0.49, p <0.001). Sensitivity analyses of CKD definition yielded similar results. M protein concentration had a small negative correlation with eGFR (r= -0.08, p<0.001) but when stratified by age and sex category no significant correlation remained. No significant association was found between M protein concentration and worse eGFR category on ordinal logistic regression model adjusted for nonlinear age and sex (OR 1.01, 95% CI, 0.28-3.66). No significant correlation was found between M protein concentration and severity of proteinuria assessed with urine ACR. Conclusion: In this nationwide prospective population-based screening study of nearly 70,000 individuals, we found no association between MGUS and CKD, regardless of whether CKD was defined based on eGFR, urinary findings, or both. Furthermore, we found no association between M protein concentration and eGFR or severity of albuminuria. We conclude that in the absence of multiple myeloma, the results of SPEP, IFE, and serum FLC measurements are of little value in the evaluation of CKD. Furthermore, our results are not consistent with substantial underdiagnosis of MGRS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Case of successful use of sarilumab in secondary renal amyloidosis in a patient with rheumatoid arthritis

Clinical observation of the successful use of the interleukin 6 (IL6) inhibitor sarilumab in secondary renal amyloidosis in a patient with active seropositive rheumatoid arthritis, is presented. This complication was confirmed by biopsy of rectum. The presented clinical example demonstrates a fairly rapid, within five years from the onset of the disease, the development of secondary renal amyolidosis with the formation of a persistent nephrotic syndrome that is resistant to therapy with cyclophosphamide and rituximab. Prescription of the IL6 inhibitor tocilizumab contributed to a decrease in the clinical and laboratory activity of the underlying disease, a decrease in the severity of daily proteinuria, but did not allow to achieve the full effect. The use of another IL6 inhibitor – sarilumab, led to a complete regression of nephrotic syndrome with normalization of general urine analysis, biochemical blood tests – total protein, albumin, total cholesterol, against the background of stable clinical and laboratory remission of rheumatoid arthritis.

Effects of high fat diet-induced obesity on pathophysiology, immune cells, and therapeutic efficacy in systemic lupus erythematosus

Prior studies have suggested a strong link between obesity and autoimmune diseases. This study aimed to evaluate the effects of high fat diet (HFD)-induced obesity on the disease pathogenesis, immune cell infiltration, and therapeutic efficacy in systemic lupus erythematosus (SLE). Treatment with methylprednisolone significantly increased the survival in the control diet group, but not in the HFD group. An HFD significantly increased the incidence of severe proteinuria and glucose intolerance. Regardless of the diet, treatment with methylprednisolone significantly decreased the serum levels of anti-dsDNA antibodies, IL-2, IL-10, and interferon γ-induced protein 10 (IP-10), and improved the renal pathology scores. Treatment with methylprednisolone significantly lowered the serum levels of IL-6, MCP-1, and TNF-α in the control diet group, but not in the HFD group. HFD significantly increased the proportions of CD45+ and M1 cells and significantly decreased the proportion of M2 cells in white adipose tissue; methylprednisolone treatment significantly rescued this effect. In the HFD group, methylprednisolone treatment significantly decreased the M1:M2 and increased the Foxp3+:RORγt+ cell in the spleen compared with the untreated group. These data improve our understanding of the effect of HFD on the therapeutic efficacy of corticosteroids in SLE treatment, which could have clinical implications.

An Alternative Therapy for Membranous Glomerulonephritis: A Case Report

Membranous Glomerulonephritis (GMN) is an autoimmune disease whose etiology has not been defined with precisión, When there is no association with another disease which ocurrs in two thirds of the cases is considered to be idiopathic. It is the most common cause of Nephrotic Syndrome in Adults, primary caucasic and over 60 years of age. It is regarded as a non inflammatory Glomerulonephritis, concept with which I am not completely in agreement because I think as other researchers have taught than in GMN [1] the Complement system contributes to various Glomerulophaties by causing cellular damage by both an inflammation-dependant and inflammation-independent ways. Here I discuss a case of a woman who developed an idiopathic GMN presented with a nephrotic síndrome with severe protracted proteinuria also I describe her initial treatment and the changes that I made and discuss her follow up for 7 years, and current medical status.

The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats.

Salt-sensitive hypertension is associated with poor clinical outcomes. The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in sodium reabsorption and blood pressure regulation, in which its γ subunit is activated by extracellular serine proteases. In proteinuric nephropathies, plasmin filtered through injured glomeruli reportedly activates γENaC in the distal nephron and causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed hypertension and proteinuria along with γENaC activation and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remained unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as podocyte injury and the effects of plasmin inhibitors in DS rats. Five-week-old DS rats were divided into normal-salt diet, HS diet, and HS+plasmin inhibitor (either tranexamic acid [TA] or synthetic plasmin inhibitor YO-2) groups. After blood pressure measurement and 24 h urine collection over 5 weeks, rats were sacrificed for biochemical analyses. The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and γENaC in the kidney, which was significantly attenuated by YO-2 but not TA. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by inhibiting apoptosis and inflammatory/profibrotic cytokines. YO-2 also suppressed upregulation of protease-activated receptor-1 and phosphorylated ERK1/2. These results indicate an important role of plasmin in the development of salt-sensitive hypertension and related podocyte injury, suggesting plasmin inhibition as a potential therapeutic strategy.

The associations between renal disease severity and exposure to organophosphate flame retardants in patients with chronic kidney disease

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032–3.005) per log μg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065–3.086) per log μg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228–0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937–0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants.

Correlation Between Quantitative Anti-dsDNA Levels with Severity of Proteinuria in Systemic Lupus Erythematosus Patients

ObjectiveTo evaluate the correlation of quantitative anti-dsDNA level with proteinuria levels in patients with lupus nephritis in a tertiary care hospital. Study designIn this prospective cross-sectional study, 76 patients of newly diagnosed SLE coming to Fatima Memorial Hospital were included in the study period between January 2020 to June 2020. Demographic data such as age, gender, lupus manifestations such as serositis, arthritis, mucocutaneous disease, and neuropsychiatric manifestations were recorded. Quantitative anti-dsDNA was measured by enzyme-linked immunosorbent assay and proteinuria was estimated by 24h urinary protein collection. Data was analyzed by SPSS 23. Association between categorical variables was assessed using chi-square test. For comparison of categorical independent and continuous dependent variable t-test or Mann–Whitney U test was applied. ResultsThe median age of the cohort was 29 (with inter quartile range – IQR – of 13) years. The female gender comprised of 68 (89.4%) of the cohort population. The median anti-dsDNA level was 54.9 (183.6 IQR) IU, and baseline proteinuria of the cohort was 520mg/dL (1.49 IQR). There was a significant association of anti-dsDNA level with systemic features such as arthritis (p=<0.01), serositis (p=<0.01) and, Raynaud's phenomenon (p=<0.01). NPSLE and mucocutaneous features did not show statistically significant association (p=0.91 and 0.14 respectively). Baseline anti-dsDNA showed a statistically significant correlation with baseline proteinuria levels (p=<0.01). ConclusionQuantitative anti-dsDNA is directly correlated with nephritis measured as proteinuria, and can be detected even before organ involvement. Hence, it can determine disease course and guide early treatment.

Correlation Between Quantitative Anti-dsDNA Levels with Severity of Proteinuria in Systemic Lupus Erythematosus Patients

To evaluate the correlation of quantitative anti-dsDNA level with proteinuria levels in patients with lupus nephritis in a tertiary care hospital. In this prospective cross-sectional study, 76 patients of newly diagnosed SLE coming to Fatima Memorial Hospital were included in the study period between January 2020 to June 2020. Demographic data such as age, gender, lupus manifestations such as serositis, arthritis, mucocutaneous disease, and neuropsychiatric manifestations were recorded. Quantitative anti-dsDNA was measured by enzyme-linked immunosorbent assay and proteinuria was estimated by 24 h urinary protein collection. Data was analyzed by SPSS 23. Association between categorical variables was assessed using chi-square test. For comparison of categorical independent and continuous dependent variable t -test or Mann–Whitney U test was applied. The median age of the cohort was 29 (with inter quartile range – IQR – of 13) years. The female gender comprised of 68 (89.4%) of the cohort population. The median anti-dsDNA level was 54.9 (183.6 IQR) IU, and baseline proteinuria of the cohort was 520 mg/dL (1.49 IQR). There was a significant association of anti-dsDNA level with systemic features such as arthritis ( p = <0.01), serositis ( p = <0.01) and, Raynaud's phenomenon ( p = <0.01). NPSLE and mucocutaneous features did not show statistically significant association ( p = 0.91 and 0.14 respectively). Baseline anti-dsDNA showed a statistically significant correlation with baseline proteinuria levels ( p = <0.01). Quantitative anti-dsDNA is directly correlated with nephritis measured as proteinuria, and can be detected even before organ involvement. Hence, it can determine disease course and guide early treatment. Evaluar la correlación del nivel cuantitativo de anti-dsDNA con los niveles de proteinuria en pacientes con nefritis lúpica en un hospital de tercer nivel. En este estudio transversal prospectivo se incluyeron 76 pacientes de LES recién diagnosticados que acudieron al Fatima Memorial Hospital en el período de estudio entre enero de 2020 y junio de 2020. Se registraron datos demográficos como edad, sexo, manifestaciones de lupus como serositis, artritis, enfermedad mucocutánea y manifestaciones neuropsiquiátricas. El anti-dsDNA cuantitativo se midió mediante un ensayo inmunoabsorbente ligado a enzimas y la proteinuria se estimó mediante la recogida de proteínas en orina de 24 horas. Los datos fueron analizados por SPSS 23. La asociación entre variables categóricas se evaluó mediante la prueba de χ 2 . Para la comparación de variable dependiente continua e independiente categórica se aplicó la prueba t o la prueba u de Mann Whitney. La mediana de edad de la cohorte fue de 29 años (con rango intercuartil – IQR – de 13). El género femenino comprendía 68 (89,4%) de la población de la cohorte. El nivel medio de anti-dsDNA fue 54,9 (183,6 IQR) UI, y la proteinuria basal de la cohorte fue de 520 mg/dL (1,49 IQR). Hubo una asociación significativa del nivel de anti-dsDNA con características sistémicas como artritis (p = <0,01), serositis (p = <0,01) y fenómeno de Raynaud (p = <0,01). El NPSLE y características mucocutáneas no mostraron asociación estadísticamente significativa (p = 0,91 y 0,14, respectivamente). El anti-dsDNA basal mostró una correlación estadísticamente significativa con los niveles basales de proteinuria (p = <0,01). El anti-dsDNA cuantitativo se correlaciona directamente con la nefritis medida como proteinuria y puede detectarse incluso antes de la afectación de órganos; por lo tanto, puede determinar el curso de la enfermedad y orientar el tratamiento temprano.