The Comparison Spondin 2 Levels in Primary Glomerular Diseases.

Acquired glomerular lesions in patients with Down syndrome

Given the reported efficacy of mycophenolate mofetil (MMF) in the treatment of glomerular diseases, we question whether MMF can reduce the rate of renal allograft loss due to glomerular disease recurrence compared to azathioprine (AZA) as adjunctive therapy to cyclosporine (CSA)-based immunosuppression. This is a retrospective study based on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database designed to compare the Kaplan-Meier rates of graft loss due to disease recurrence stratified by primary renal diagnoses between recipients receiving CSA+AZA versus CSA+MMF. Recipients of primary kidney transplants (both deceased donor and living, related and unrelated) renal transplants performed between 1 January 1988 and 31 December 2007 with the primary renal diagnosis of IgA nephropathy (IgAN), membranous glomerulonephropathy (MGN), membranoproliferative glomerulonephropathy (MPGN), lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) with a functioning allograft at discharge were included. Seven thousand eight hundred and twenty-six recipients of primary deceased donor kidney transplants (DDKT) [CSA + AZA: IgAN (890), MGN (380), MPGN (193), LN (1324), FSGS (1314) and CSA+MMF: IgAN (855), MGN (614), MPGN (116), LN (715), FSGS (1425)] and 5498 recipients of living donor kidney transplants (LDKT) [CSA+AZA: IgAN (694), MGN (229), MPGN (100), LN (592), FSGS (654) and CSA+MMF: IgAN (1066), MGN (435), MPGN (89), LN (530), FSGS (1109)] were included in the analysis. At 10-year follow-up (mean duration was 5.6 to 6.7±1.8 years in DDKT and 6.2 to 7.4±1.7 years in LDKT), mean times of transplantation (era of transplantation) were: 1992±1.6 years and 2002±1.9 years for the CSA+AZA and CSA+MMF groups, respectively. There was no statistically significant difference in the Kaplan-Meier rates of graft loss due to disease recurrence of any glomerular disease studied between the CSA+AZA and CSA+MMF groups in either DDKT or LDKT recipients. Chi-square analysis revealed no statistically significant difference between the two immunosuppressive regimen groups in terms of age, gender and ethnic background. The OPTN/UNOS database revealed no difference in the rates of renal allograft loss due to disease recurrence of IgAN, MGN, MPGN, LN and FSGS among recipients receiving either CSA+AZA or CSA+MMF maintenance immunosuppressive therapy at 10-year follow-up.

Glomerular diseases are an important cause of chronic renal failure in developing countries. The spectrum of diseases causing nephrotic syndrome is changing globally in the last few decades. The aim of this prospective study was to look at this spectrum at a tertiary care center in North India and to analyze the changing trends over the last five decades. Patients in the age group 18-60 years with nephrotic syndrome were consecutively included in the study. Renal biopsies were performed in all patients and were subjected to light microscopy, immunofluorescence (IF) and electron microscopy (EM). While the IF was performed in 78% of cases, EM was available in one-fourth of cases. During 2002-2007, 364 patients (60.2% males) were included in the study. The mean age was 31.5 years. Primary glomerular diseases accounted for 89% of cases while lupus nephritis was the most common secondary glomerular disease. Focal segmental glomerulosclerosis (FSGS) accounted for 30.6% of primary glomerular diseases making it the most common cause of nephrotic syndrome. It was followed by membranous glomerulonephritis (MGN) in 24.4%, mesangiocapillary glomerulonephritis in 17.9% and minimal change disease in 14.8%. In the age group >40 years, MGN was the most common lesion (32.5%) followed by FSGS (27.7%). Over the last five decades, there was a nearly five-fold increase in the incidence of FSGS, 3-fold increase in MGN and a 10-fold reduction in diffuse proliferative glomerulonephritis while there was no major change in incidence of other diseases. The biopsy diagnosis of FSGS has increased considerably in last few decades and it is now the most common cause of nephrotic syndrome in adults in North India. MGN is the most common lesion in patients over 40 years of age.

Our study aimed to obtain a comprehensive insight into the etiology of nephrotic syndrome in our patient population. We analyzed medical records of 290 patients with diagnosis of nephrotic syndrome as defined by International Study of Kidney Disease in Children (ISKDC), between January 1987 and December 2000, at the Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar. Primary glomerular disease was found to be the most prevalent, accounting for 91.73% of all glomerular diseases. Among primary glomerular diseases, minimal change disease (MCD) was the most common histological lesion (43.79%). Most patients presented within 3 months duration (61.4%) and the most common symptom was puffiness of face (98.45%) followed by pedal edema (91%). Focal segmental glomerulosclerosis (FSGS) was the second most common lesion (16.89%) followed by membranous glomerulonephritis (GN) (13.4%) and membranoproliferative GN (11.72%). Amongst secondary glomerular diseases, diabetes mellitus was the most prevalent (4.48%), followed by lupus nephritis (3.1%). In conclusion, primary glomerular diseases constituted the most common group encountered and the prevalence of MCD was quite high with males, children and young adults. FSGS was associated with a high prevalence of end-stage renal disease (ESRD; 26.53%), hypertension (71.42%) and hematuria (81.63%).

Objective To analyze the common clinical and pathological types of elderly patients after renal biopsy in Guangxi. Methods By means of enrolling 373 elderly patients (aged ≥ 60 years) who had undergone renal biopsy in the First Affiliated Hospital of Guangxi Medical University from August 2012 to August 2015, and collecting the data of gender, age, nationality, clinical diagnosis, kidney pathological diagnosis, etc, the renal disease spectrum of elderly patients were retrospectively analyzed with the SPSS13.0 software. And statistical descriptions were made for the categorical variables with frequency and percentage. Results The most common clinical syndrome in elderly patients after renal biopsy was nephrotic syndrome (NS, 50.1%), followed by acute kidney injury (AKI, 28.7%) and chronic nephritis syndrome (15.5%). In the elderly patients after renal biopsy, primary glomerular diseases accounted for 67.8%, and secondary glomerular diseases accounted for 26.8%. In primary glomerular diseases, idiopathic membranous nephropathy (IMN, 71.9%) was the leading renal histopathological type, followed by minimal change disease (MCD, 9.9%) and focal segmental glomerulosclerosis (FSGS, 7.9%). In the secondary glomerular diseases, the most common type was ANCA-associated vasculitis (AAV, 31.0%), followed by lupus nephritis (20.0%) and diabetic nephropathy (12%). In the NS of elderly patients, the most common cause was IMN (75.4%), followed by MCD (5.3%) and FSGS (5.3%). In the AKI of elderly patients after renal biopsy, the most common pathological type was IMN (26.2%), followed by AAV (24.3%). Conclusion NS was the most common clinical syndrome of elderly patients after renal biopsy in Guangxi. IMN was the most common pathological type in the elderly NS and primary glomerular diseases; AAV was the most common cause of secondary glomerular diseases; and IMN and AAV were the main causes of AKI. Key words: Elderly; Renal pathology; Nephrotic syndrome; Idiopathic membranous nephropathy; Acute kidney injury; ANCA-associated vasculitis

Background and Aims Membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are the most frequent types of primary glomerulonephrites in the adulthood. Glomerulonephritides may progress into end-stage renal disease despite appropriate treatment. Both the manifestations of the glomerulonephritides and medications for treatment might yield cardiovascular events such as venous thromboembolism, coronary artery disease and stroke. The purpose of this study is to compare three different types of primary glomerulonephritides in terms of all-cause mortality, kidney-related and cardiovascular outcomes. Method All patients who underwent kidney biopsy between 01.01.2000 and 01.06.2022 in Hacettepe University Hospital were screened and cases with primary glomerulonephritis and follow-up data were enrolled. Data regarding baseline demographics, laboratory and kidney pathology reports and outcomes were obtained. The primary end-point was defined as all-cause mortality. Kidney related and cardiovascular outcomes were determined as secondary end-points. Results population was 39 (18-81) years. Membranous nephropathy was present in 36.5% (n = 172), focal segmental glomerulosclerosis was present in 25.9% (n = 122) and IgA nephropathy was present in 37.6% (n = 177) of the cases. Age (p < 0.001), frequency of diabetes (p = 0.004) and smoking history (p = 0.020) were significantly higher in patients with membranous nephropathy than both FSGS and IgA nephropathy. Serum albumin levels were lower (p < 0.001), while total cholesterol (p < 0.001), LDL cholesterol (p < 0.001) and proteinuria levels (p < 0.001) were higher both in patients with membranous nephropathy than the other two groups and in patients with FSGS than IgA nephropathy. Median duration of follow-up was 120.2 (1.7-273.3) months (Table 1). All-cause mortality rate was significantly higher in patients with membranous nephropathy than the other two groups (p = 0.005); however the type of glomerulonephritides was not found to be related to all-cause mortality (HR: 1.07; 95% CI: 0.65-1.77; p = 0.770). Age (HR: 1.079; 95% CI: 1.05-1.10; p < 0.001), serum creatinine (HR: 1.35; 95% CI: 1.10-1.66; p = 0.003) and serum albumin (HR: 0.60; 95% CI: 0.38-0.95; p = 0.030) levels were found to be associated with all-cause mortality in patients with primary glomerulonephritides. The rates of ischemic stroke, atrial fibrillation and steroid induced diabetes were similar between all of the glomerulonephritides subgroups. Acute coronary syndrome (p = 0.015), coronary revascularization (p = 0.021) and venous thromboembolic events were more frequent in patients with membranous nephropathy than IgA nephropathy. There was no difference in terms of cardiovascular outcomes between the patients with FSGS and IgA nephropathy (Table 1). Although the remission rate was significantly higher in patients with membranous nephropathy than the other two groups (p < 0.001); there was not a distinct difference in relapse rates. Progression to end-stage renal disease was prominently lower in patients with membranous nephropathy than the other groups (p = 0.003) and loss of glomerular filtration rate per year was significantly higher in cases with FSGS compared to other groups (p = 0.021). Conclusion All-cause mortality risk was higher in patients with membranous nephropathy because of higher age at diagnosis and accompanying higher burden of comorbidities including diabetes and dyslipidemia. FSGS had a worse prognosis in terms of kidney related outcomes compared to other glomerulonephritides due to higher loss of glomerular filtration rate per year and increased rates of progression to end-stage renal disease. Intensive cardiovascular risk reduction strategies should be applied especially in patients with membranous nephropathy due to increased mortality rates.

Objective To observe the expressions and distribution of transient receptor potential cation channel 6 (TRPC6) and integrin-linked kinase (ILK) in the glomeruli of renal biopsy tissue of patients with proteinuric kidney diseases, and to investigate the effect of TRPC6 over-expression on ILK in vitro. Methods The archival histological specimens of patients admitted to Tangdu hospital from 2012 to 2013, with 24-hour urinary protein over 1 g, were collected. The expressions and distribution of TRPC6 and ILK in the glomeruli of renal biopsy tissue were observed by immunohistochemistry. MPC5 podocytes were cultured in vitro and they were stimulated with 10-7 mol/L ADR for 12, 24 and 36 h. The pcDNA3.1(+)-TRPC6 plasmid and pcDNA3.1(+) were transfected into MPC5 podocytes by liposome 2000 reagent to establish the TRPC6 overexpression group and the negative control group respectively. Western blotting was used to detect the expressions of TRPC6 and ILK protein. Results There were 14 cases of membranous nephropathy, 13 cases of focal segmental glomerulosclerosis (FSGS), 15 cases of membranoproliferative glomerulonephritis, 12 cases of mesangial proliferative glomerulonephritis, 10 cases of hyperplastic sclerosis nephritis, 15 cases of IgA nephropathy, 13 cases of purpura nephritis, 15 cases of lupus nephritis, 13 cases of hypertensive renal injury, 14 cases of diabetic nephropathy and 9 cases of normal renal tissue included. In glomerulus, TRPC6 was expressed mainly in podocytes, and the expressions of TRPC6 in these renal tissues were higher than that in normal renal tissues (all P 0.05). The expressions of TRPC6 and ILK were positively correlated in renal tissues of FSGS and diabetic nephropathy (r=0.906, P<0.001; r=0.783, P=0.001 respectively). The expressions of TRPC6 and ILK protein in 24 and 36 h stimulating with ADR were significantly higher than that in the control group (all P<0.05). The expression of ILK in the TRPC6 overexpression group was significantly higher than that in the normal control group (P<0.05). Conclusions The expressions of TRPC6 and ILK increase in the glomeruli of patients with kidney diseases with proteinuria being the main manifestation, especially in FSGS and diabetic nephropathy. The up-regulation of TRPC6 can increase the expression of ILK protein, which may be involved in podocyte injury. Key words: Renal insufficiency, chronic; Podocytes; TRPC cation channels; Protein-serine-threonine kinases

The prevalence of glomerular diseases differs according to geographic area, race, age and indications for a renal biopsy. This study was conducted to evaluate the distribution and changing patterns of renal diseases during the past 20 years in a large patient population in Korea. Patients aged 16 years or older who underwent a renal biopsy at Severance Hospital in the Yonsei University Health System from 1987 to 2006 were enrolled. All medical records were reviewed retrospectively. In total, 1818 patients (M:F = 1.02:1) were reviewed. Glomerulonephritis (GN) comprised 85.9% of the total biopsied cases. The most common primary GN was IgA nephropathy (IgAN) (28.3%), which was followed by minimal change disease (MCD) (15.5%), membranous nephropathy (MN) (12.3%), focal segmental glomerulosclerosis (FSGS) (5.6%) and membranoproliferative GN (MPGN) (4.0%). The most common secondary GN was lupus nephritis (8.7%). The most common idiopathic nephrotic syndrome was MCD (38.5%), which was followed by MN and IgAN. Among 128 (7.4%) patients who were HBsAg-positive, MN (30.5%) and MPGN (21.1%) were the most common GN. When the incidence rates between 1987-91 and 2002-06 were compared, IgAN increased from 25.6 to 34.5%, while MCD (from 23.2 to 7.0%) and MPGN (from 6.7 to 1.7%) decreased significantly (P < 0.01). IgAN was the most common primary GN, and MCD was the most common cause of nephrotic syndrome. In the 5-year quartile comparison, the relative frequency of IgAN increased, while the relative frequency of MCD and MPGN decreased significantly during the past 20 years.

BackgroundAlthough glomerular diseases are the third most frequent cause of end‐stage kidney disease worldwide, little is known about their long‐term outcomes.MethodsIn patients with chronic kidney disease (CKD) stage 3–5 enrolled in the Swedish Renal Registry, we compared risks of hospitalization, kidney replacement therapy (KRT), major cardiovascular events (MACE), and death of the four most frequent primary glomerular diseases (IgA nephropathy [IgAN], focal segmental glomerulosclerosis [FSGS], minimal change disease [MCD], and membranous nephropathy [MN]), and patients with CKD due to the most common non‐communicable diseases (control‐CKD).ResultsWe identified 2396 patients with glomerular disease (97% biopsy‐proven, 69% men, 57 years, eGFR 29 mL/min/1.73 m2, uACR 88 mg/mmol, 1524 with IgAN, 398 FSGS, 94 MCD, and 380 MN) and 37,697 controls (64% men, 74 years, eGFR 25 mL/min/1.73 m2, uACR 23 mg/mmol), mainly with diabetic nephropathy and nephroangiosclerosis. The median follow‐up was 6.3 (3.3; 9.9) years. Compared with control‐CKD, patients with primary glomerular diseases generally had a lower risk of hospitalization, MACE (adjusted hazard ratios [HRs] ranging from 0.44 to 0.88 depending on the etiology) and death (HRs ranging 0.45–0.76). Patients with IgAN and FSGS had a faster eGFR decline and a higher rate of KRT (HRs 1.26 [95%CI: 1.15–1.37] and 1.34 [1.15–1.57], respectively). Conversely, patients with MN and MCD had a lower KRT rate and slower eGFR decline.ConclusionDespite having a lower relative risk of hospitalization, cardiovascular events and mortality, patients with IgAN and FSGS are at higher risk of CKD progression than the most common etiologies of CKD, emphasizing the need for more stringent treatment strategies in these patients.

BackgroundThe largest data on the epidemiology of primary glomerular diseases (PGDs) are obtained from the databases of countries or centers. Here, we present the extended results of the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group.MethodsData of patients who underwent renal biopsy and received the diagnosis of PGD were recorded in the database prepared for the study. A total of 4399 patients from 47 centers were evaluated between May 2009 and May 2019. The data obtained at the time of kidney biopsy were analyzed. After the exclusion of patients without light microscopy and immunofluorescence microscopy findings, a total of 3875 patients were included in the study.ResultsThe mean age was 41.5 ± 14.9 years. 1690 patients were female (43.6%) and 2185 (56.3%) were male. Nephrotic syndrome was the most common biopsy indication (51.7%). This was followed by asymptomatic urinary abnormalities (18.3%) and nephritic syndrome (17.8%). The most common PGD was IgA nephropathy (25.7%) followed by membranous nephropathy (25.6%) and focal segmental glomerulosclerosis (21.9%). The mean total number of glomeruli per biopsy was 17 ± 10. The mean baseline systolic blood pressure was 130 ± 20 mmHg and diastolic blood pressure was 81 ± 12 mmHg. The median proteinuria, serum creatinine, estimated GFR, and mean albumin values were 3300 (IQR: 1467–6307) mg/day, 1.0 (IQR: 0.7–1.6) mg/dL, 82.9 (IQR: 47.0–113.0) mL/min and 3.2 ± 0.9 g/dL, respectively.ConclusionsThe distribution of PGDs in Turkey has become similar to that in other European countries. IgA nephropathy diagnosed via renal biopsy has become more prevalent compared to membranous nephropathy.

A 26-year-old woman contacted our office asking for an urgent call back. She had a history of steroid-dependent and frequently relapsing minimal change disease, and calls like this usually meant her home dipsticks had turned positive. Instead, she reported that she had just tested positive for the 2019 novel coronavirus (SARS-CoV-2 or COVID-19). She had a low-grade fever, myalgias, and a reduced sense of smell, but fortunately no cough or shortness of breath. She was worried about her dipsticks, however, which were still negative. What was usually a reassuring do-it-yourself test now frightened her. "Does that mean the rituximab is still in my system?" she asked, referring to the infusion she had done about 4 months earlier. As COVID-19 infections spread across the world, nephrologists and their patients face difficult decisions regarding management of glomerular diseases. Our Center for Glomerular Diseases has fielded countless questions in the last few weeks, not just from patients but from other nephrologists about the most appropriate way to handle immunosuppression in the current climate. Should lupus nephritis patients reduce their mycophenolate mofetil doses or stop the drug altogether? Should membranous nephropathy patients with rising titers of antibodies to the phospholipase A2 receptor (PLA2R) proceed with their scheduled rituximab infusions? Should severe ANCA-associated GN patients in the midst of an intravenous course of cyclophosphamide switch over to oral cyclophosphamide to avoid trips into the infusion center? Of course, there are no perfect, or even evidence-based, answers to these and other inquiries. Here, we offer some insight as to how our center in New York City, currently the world's hottest spot for COVID-19 infections, has adapted the management of our glomerular disease patients to reduce complications of potential COVID-19 disease (Table 1). We also speculate on how our practice will be altered in the future, even at a time when, hopefully, COVID-19 infections are a thing of the past. Table 1. - Concise guidelines for management of glomerular disease patients during the COVID-19 pandemic (opinion-based) Component Recommendations Immunosuppression Discontinue antimetabolites for patients with confirmed or suspected infection Consider discontinuation of antimetabolites for patients in sustained remission >12 mo Favor short-acting, reversible agents over long-acting infusions Avoid therapy initiation for marginal criteria or nonstandard indications Avoid therapy initiation for minimally symptomatic patients with stable eGFR Convert intravenous infusions to oral formulation when possible (e.g., cyclophosphamide) and utilize home infusion services in lieu of hospital- or clinic-based infusion suites For patients in clinical trials with potential patient benefit, continue study drug by sending medication to their home if an oral or subcutaneous agent, or dosing in a COVID-19–compliant infusion center if an intravenous agent Diagnosis and monitoring Reserve biopsies for critical decision-making needs Consider empirical treatment, without biopsy, for conditions with high pretest probability diagnoses (e.g., RPGN with positive ANCA serologies) Limit blood draws to safety laboratories performed at commercial (i.e., non–hospital-based) laboratories Utilize home urine dipsticks for proteinuria monitoring Utilize commercially shipped collection kits for 24-h urine collections that can be done at home and shipped back Postpone protocol biopsies Supportive care Continue ACE inhibitors or ARBs in the absence of clear contraindications at this point Continue prophylactic antibiotics (e.g., TMP-SMX) Encourage social distancing Encourage use of masks while outside of the house Complete recommended vaccinations for influenza and pneumococcus (PCV13 and PPSV23) to prevent secondary or coinfection Office management Change all appointments to telemedicine video visits Allow office staff to manage phones and patient messages from home Develop a standard script of recommendations for patients calling with questions about possible COVID-19 exposure based on CDC guidelines Use telemedicine video visits rather than telephone calls for patients concerned about COVID-19 infectious symptoms to best triage respiratory status ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; TMP-SMX, trimethoprim-sulfamethoxazole; PCV, pneumococcal conjugate vaccine; PPSV, pneumococcal polysaccharide vaccine; RPGN, rapidly progressive glomerulonephritis; CDC, Centers for Disease Control and Prevention. While considering the impact of immunosuppression on COVID-19 outcomes, nephrologists must simultaneously account for the potential impact on kidney outcomes from withholding immunosuppression. Therefore, we are still advising that patients who are at high risk of progression to ESKD without immediate therapy begin standard of care immunosuppression regimens. These patients are principally those with rapidly progressive glomerulonephritides due to lupus, ANCA, and anti–glomerular basement membrane-associated disease. In addition, patients with severe forms of nephrotic syndrome that are already manifesting reductions in kidney function, or complications related to proteinuria and hypoalbuminemia (e.g., deep venous thrombosis and anasarca), fit this criterion. In contrast, we have advised many of our patients who otherwise would be treated with immunosuppression to postpone treatment until their local transmission rates of COVID-19 are low enough that social distancing measures are no longer recommended. These include the following: (1) membranous nephropathy patients with nephrotic syndrome and/or rising anti-PLA2R antibody titers, but without complications and with preserved eGFR, (2) minimal change disease or FSGS patients with preserved eGFR, and (3) IgA nephropathy patients with endocapillary hypercellularity and/or low crescentic burden on kidney biopsy with preserved eGFR. In addition, for diseases without a validated standard of care regimen, such as immune complex or complement-mediated forms of membranoproliferative GN, we are not advocating immunosuppressive therapy at this time regardless of clinical parameters. Glomerular disease patients who started immunosuppressive therapy prior to the COVID-19 pandemic require a risk-benefit assessment regarding continuation of immunosuppression, which should account for the potential impact of modifying or stopping treatment, as well as patient access to therapies. Patients in the midst of an intravenous induction regimen (e.g., EuroLupus dosing of intravenous cyclophosphamide for lupus nephritis) can be changed to an equivalent oral induction regimen if one exists (e.g., use of oral cyclophosphamide or high-dose mycophenolate mofetil for lupus nephritis) to potentiate stay-at-home adherence and avoid exposure to health care settings. Likewise, many patients who would receive pulse methylprednisolone intravenous treatments can be treated with high-dose oral prednisone or oral methylprednisolone. We have leveraged home infusion services to maintain necessary infusions while minimizing (without eliminating) social contact. Alterations to maintenance immunosuppression regimens should be individualized according to disease status and drug class. For example, stable patients on chronic immunosuppression should lower their doses to the safest level that will maintain remission; for many of our patients, this translates to a 50% drop in cumulative dose. If disease remission already extends >12 months, we consider immediate cessation of antimetabolites like mycophenolate mofetil or azathioprine, and we are not dosing maintenance rituximab infusions. Patients in sustained remission on maintenance steroids can, if on a low and alternate-day dose, discontinue these agents; otherwise, we begin a taper with dose adjustments every 2 weeks. We do not adjust the dose of calcineurin inhibitors in line with recommendations from our kidney transplant colleagues, who have recently reported that COVID-19–infected allograft recipients maintained on calcineurin inhibitors alone, with the antimetabolite held, have similar hospital-based outcomes compared with non–immune suppressed COVID-19–infected patients (1). As many glomerular disease patients are young without significant comorbidities, suspected or confirmed cases of COVID-19 infection can often be managed at home without the need for hospitalization. For such patients, we recommend discontinuation of antimetabolites as part of their management and ask for continued communication on their clinical course with our office. Patients with glomerular diseases who require hospitalization for COVID-19 respiratory illnesses should, in addition to holding their antimetabolites, be started on stress doses of corticosteroids if on a long-term steroid regimen. If hydroxychloroquine and azithromycin are started on patients with nephrotic-range proteinuria, close monitoring of calcium levels is required, and it is mandatory to confirm that a baseline electrocardiogram has a normal QTc interval. Our Center for Glomerular Diseases averages about 3000 annual office visits for glomerular disease care. Since mid-March 2020, we have moved the entirety of our clinic to telemedicine encounters using video visits. Telemedicine video visits with our physicians and support staff have been helpful to answer patients' questions, allay their concerns, and maintain contact with them during home sequestration. Patients can monitor their BPs, daily weights, and symptoms of glomerular disease and relate these in real time to our staff. For example, peripheral edema can be easily visualized with cell phone and tablet cameras. Laboratory surveillance is a critical component of managing glomerular disease patients. We have limited this surveillance to primarily focus on safety laboratories that can be drawn at a commercial laboratory (i.e., not a hospital-based laboratory) that is enforcing social distancing among its clients. As an alternative, for some patients we have been able to use laboratory services that provide home testing visits. We have always relied on the use of urine dipsticks for home monitoring of disease status and include a review of dipstick results in our telemedicine visits. Importantly, if a patient contacts our office with symptoms suggestive of COVID-19 infection, such as cough, fever, and/or myalgias, a video visit potentiates better assessment of dyspnea and respiratory effort than a phone call for triaging whether the patient should be seen at an emergency room for oxygen therapy and potential hospital admission. New enrollment into clinical trials has been paused during the COVID-19 crisis, but glomerular disease patients enrolled in therapeutic clinical trials that offer the prospect of direct benefit to participants should continue on the study drug. Many single-arm but also randomized clinical trials, particularly in phases 2 and 3, allow participants access to novel or unapproved therapies and thus have the prospect of benefit. The Food and Drug Administration has provided guidance (2) on conducting clinical trials during the pandemic, which includes sending study drugs to participants if oral or subcutaneous agents, or dosing study drugs in an outpatient infusion center with appropriate protocols for safe infusion therapy if an intravenous agent. The American College of Rheumatology has provided recommendations (3) for facilities providing infusion therapy during the COVID-19 crisis (Table 2). Visits that do not require study drug administration can be converted to telemedicine encounters. Study laboratories that are required for safety monitoring can be performed at commercial laboratories, at which time outcome-associated laboratories that are standard (e.g., creatinine and proteinuria) can also be collected. Some clinical trials have provided subjects with mailing kits for biosamples procured at local laboratories, so that these specimens can still be processed at a central study laboratory. Table 2. - Infusion suite strategies to reduce risk of COVID-19 infection (adapted from American College of Rheumatology guidance document) Strategy Postpone all nonessential infusions Adjust schedule so that waiting rooms and infusion suites allow for social distancing with chairs at least 2 m apart Provide face masks for all patients and staff to wear within the facility Frequently clean and decontaminate all equipment and surfaces in patient areas with appropriate contact time for disinfectant Verbally inform patients and post signs about appropriate social distancing and hygiene procedures Recommend remote check-in (e.g., over the phone from outside the facility) to minimize waiting time Screen staff with temperature checks at beginning and end of shift Screen patients by phone prior to their visit about infectious symptoms and exposure to individuals with known COVID-19 infection Kidney biopsies fit the definition of "elective procedures," which have been cancelled in many institutions at this time. We still are performing kidney biopsies in settings where we expect that findings are crucial for the immediate management of patients (e.g., rapidly progressive GN). Patients with apparent primary nephrotic syndrome and preserved eGFR should not undergo biopsies at this time; they can be managed empirically with calcineurin inhibitors with a biopsy to follow at a safer date. The use of anti-PLA2R antibody testing to diagnose primary membranous nephropathy can be helpful in this situation (4). Protocol biopsies to assess the efficacy of immunosuppression and activity versus chronicity of disease, as well as research biopsies for clinical trials or observational studies, should be cancelled. As we reduce our glomerular disease patients' exposure to immunosuppression, we often need to adjust our conservative therapies, particularly renin-angiotensin-aldosterone system blocking agents and diuretics. Despite recent controversies regarding the possible impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 transmission, we adhere to the recommendations made by experts across various disciplines (cardiology, nephrology, and hypertension) not to discontinue these drugs (5–67). Therefore, we keep our patients on these agents and, if proteinuria is heavy in patients being weaned off immunosuppression, consider either increasing the dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blockers or, alternatively, keeping the dose unchanged but adding a mineralocorticoid receptor blocker (e.g., eplerenone). For patients already on chronic hydroxychloroquine therapy, we are continuing the drug but not altering the dose; in the event of a drug shortage, we will need to consider dose reductions for these patients. We are not starting any patients on this drug prophylactically and are seeing cases of COVID-19 infection in lupus patients on maintenance hydroxychloroquine. We anticipate that our management of glomerular disease patients will be altered by our current COVID-19–influenced practices even when the current pandemic has resolved. We have seen significantly lower rates of rapidly progressive GN in our hospitalized patients and disease relapses in our clinic patients since widespread adoption of social distancing. We have heard similar reports from our colleagues in other disciplines (e.g., fewer myocardial infarctions seen by cardiologists). This seemingly quiescent disease state supports the hypothesis that environmental exposures, including but not limited to infections, may be a major trigger of glomerular disease onset and relapse. While we do not foresee advocating formal social distancing for immunosuppressed patients outside of a pandemic window, we will repeatedly reinforce patient education on measures to reduce infectious exposures such as strict avoidance of sick contacts, frequent handwashing, avoiding touching of the face, and, whenever possible, staying at least 2 m away from other individuals. We also foresee wide adoption of telemedicine encounters to reduce time in healthcare settings for many of our glomerular disease patients, especially in follow-up visits when these patients are often on their highest doses of immunosuppressants. Most importantly, given forecasts of a possible second wave of COVID-19 infections after the current pandemic has abated, as well as broader speculation that we are now firmly entrenched in an era of viral pandemics, we will need to consider the degree to which we are immunosuppressing all of our glomerular disease patients regardless of current infection rates. Fortunately, the field of glomerular diseases has been moving in this direction well before the emergence of COVID-19. For example, the Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis study showed noninferior outcomes in Anti-Neutrophil Cytoplasm Antibody-associated GN with a reduced dose of corticosteroids compared with a standard dose of corticosteroids (8), the Supportive versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global trials argued against use of high dose corticosteroids for IgA nephropathy (9,10), and the Membranous Nephropathy Trial of Rituximab study found better long-term outcomes with just one or two dosing intervals of rituximab compared with year-long therapy with cyclosporine (11). But we likely will need to go even further than these trials and begin to question, for each glomerular disease, how much immunosuppression is needed to induce a remission and whether long-term maintenance therapy is required to sustain this remission. In other words, the debates on risks versus benefits of immunosuppression that we are forced to have now in the face of widespread COVID-19 infections should continue past this year, when our world, and our patients, will be very different because of what we are experiencing now. Disclosures Dr. Ahmad, Dr. Ahn, Dr. Appel, Dr. Bomback, Dr. Canetta, and Dr. Radhakrishnan have nothing to disclose. Funding Dr. Bomback and Dr. Canetta are supported, in part, by National Institutes of Health grant UM1DK100876.

C4d is a byproduct of the activation of the classic and lectin complement pathways. Being routinely used as a marker for antibody-mediated rejection, the significance of C4d in native kidney disease is currently being widely studied. We evaluated glomerular and extraglomerular C4d staining in 82 biopsies of proliferative and nonproliferative glomerulonephritis diagnosed in our institution. The staining pattern of C4d was tabulated in various glomerular diseases. All biopsies of membranous nephropathy including membranous lupus nephritis (Class V) and immune complex-mediated membranoproliferative glomerulonephritis (MPGN) consistently showed C4d deposits along glomerular basement membrane mirroring the location of immunoglobulin and complement in these conditions. Conversely, other glomerular diseases like IgA nephropathy, postinfectious glomerulonephritis, focal segmental glomerulosclerosis, minimal change disease, and diabetic nephropathy showed variable mesangial and capillary wall C4d deposits. To summarize, the consistent pattern of C4d staining in membranous nephropathy (primary and secondary)and immune complex-mediated MPGN can be used as a valuable adjunct tool in establishing the diagnosis, especially when immunofluorescence findings are limited by inadequate sampling.C4d reactivity in other glomerular diseases are variable and may not aid as a diagnostic tool in renal biopsy evaluation.

Background and Aims The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) remains unknown to date. Some circulating permeability factors are discussed. This work assessed molecule candidates for permeability in serum samples of patients with nephrotic syndrome (NS). Method Forty-one patients with chronic glomerulonephritis (CGN) were included in our study. Seventeen patients had FSGS, 7 patients had MCD, 5 patients had membranoproliferative glomerulonephritis (MPGN), 6 patients had IgA nephropathy, and 6 patients had membranous nephropathy (MN). The laboratory data were compared with the clinical and histological features of nephritis. Serum levels of uPAR and CLCF-1 were measured by ELISA. Results The serum levels of plasminogen activator urokinase receptor (uPAR) were higher in FSGS patients before treatment than in patients with other morphological forms (MCD, IgA nephropathy, MN and MPGN). The levels of uPAR in serum did not correlate with daily proteinuria, serum creatinine/eGFR, arterial hypertension, the number of sclerosed glomeruli or tubulointerstitial fibrosis. No correlations were found between the levels of cardiotrophin-like cytokine factor 1 (CLCF-1) in serum and creatinine levels/glomerular filtration rate, the percentage of sclerosed glomeruli or the severity of tubulointerstitial fibrosis. There were no significant differences between the histological variants of nephritis. However, we found correlations between CLCF-1 levels and proteinuria (Rs = 0. 397, p = 0.015) and triglycerides levels (Rs = 0. 475, p = 0.003). Conclusion The data indicate an increase in the serum uPAR levels of FSGS before treatment. CLCF-1 levels in serum do not depend on histological forms of CGN, kidney function or immunosuppressive treatment, but they correlate with proteinuria and serum lipids in patients with NS.

Objective To detect serum level of anti-M-type phospholipase A2 receptor (PLA2R) antibody in elderly patients with idiopathic membranous nephropathy (IMN) and to explore its clinical significance in IMN disease. Methods A total of 134 patients with renal biopsy-proved glomerular diseases were enrolled in this study, including 42 elderly cases with IMN, 45 non-elderly cases with IMN, 19 elderly cases with minimal change nephropathy (MCN), 12 elderly cases with IgA nephropathy (IgAN), 8 elderly cases with hepatitis B-associated membranous nephropathy (HBV-MN) and 8 elderly cases with focal segmental glomerulosclerosis (FSGS). Western blotting was used to detect serum anti-PLA2R antibody and the correlation of anti-PLA2R antibody with laboratory parameters in elderly IMN patients was analyzed. Results The elderly and non-elderly patients with IMN showed that the positive rate of anti-PLA2R antibody was 71.4% and 73.3%, respectively (P>0.05). The positive rate of anti-PLA2R antibody in elderly IgA nephropathy, HBV-MN and MCN patients was 16.7%, 12.5% and 5.3% respectively. Anti-PLA2R antibody was not detected in serum from elderly FSGS patients. The positive rates of serum anti-PLA2R antibody were significantly higher in both elderly and non-elderly IMN patients than in elderly patients with secondary MN and other types of glomerlonephritis (P<0.01). Furthermore, anti-PLA2R autoantibody level was positively correlated with 24-hour urine protein level and negatively correlated with the concentration of serum albumin in elderly patients with IMN (P<0.01). Conclusions Anti-PLA2R antibody is a sensitive serological marker of IMN. Detection for anti-PLA2R antibody might be helpful for the diagnosis of both elderly and non-elderly IMN and for the monitor of IMN disease severity. Key words: Glomerulonephritis, membranous; Phospholipase A2; Antibodies, antiphospholipid

Recent studies have suggested that small leucine-rich proteoglycans (SLRP) of the extracellular matrix play a major role in modulating the activity of growth factors and in regulating the deposition of collagens. In this study, the expression of the SLRPs biglycan and decorin in the glomeruli of patients with primary glomerular disease (minimal change disease, IgA nephropathy, and membranous nephropathy) and urine immunoreactive levels examined. Renal biopsy specimens were obtained from patients with minimal change disease, IgA nephropathy and membranous nephropathy. Immunohistochemical staining was performed on fresh-frozen samples using anti-biglycan and anti-decorin antibodies. Examination of urine proteoglycan excretion from a total of 26 patients and 8 normal volunteers was performed by indirect ELISA. In normal kidney samples, biglycan and decorin expression was found predominantly in the intrarenal arteries and tubulointerstitium, with only minimal expression in the glomeruli. Glomerular expression of these proteoglycans in glomerular disease was unchanged in all of the 4 patients examined with minimal change disease. In the case of IgA nephropathy or membranous nephropathy, some of the patients showed minimally increased immunostaining of either biglycan or decorin, but there were no signs of simultaneous upregulation of both proteoglycans. To further examine the changes in proteoglycan expression, ELISA was performed on urine samples. Urine biglycan levels were below detection levels, but high values of urine decorin immunoreactivity were found in the patients with glomerular disease. A significant negative correlation was found between urine decorin and creatinine clearance. These results suggest that distinct changes in the expression of the SLRPs biglycan and decorin may be seen in patients with primary glomerular disease. Moreover, the negative relationship between urine decorin levels and renal function supports the hypothesis that decorin may be involved in the pathophysiology of renal dysfunction in humans.