Location of glomerular immune deposits, not codeposition of immunoglobulin G, influences definitive renal outcomes in immunoglobulin A nephropathy

ABSTRACT Background It has been suggested that the prognosis of immunoglobulin (IgA) nephropathy (IgAN) is adversely affected if there is codeposition of IgG in the glomeruli or if immune deposits are present in the glomerular capillary walls. We sought to understand how these variables affect clinical outcome. Methods A total of 80 IgAN biopsies were retrospectively divided into groups: (i) IgA without IgG deposition versus IgA + IgG and (ii) immune deposits restricted to the mesangium versus mesangium and peripheral capillary walls (PCWs). The association of these groups with the composite primary outcome of renal replacement therapy, renal transplant, death or doubling of serum creatinine (SCr) concentration was determined. The change in estimated glomerular filtration rate (eGFR) was also assessed. Covariates examined were age, sex, race, SCr and proteinuria level at biopsy and at follow-up, duration of follow-up, treatment, Oxford score and presence of crescents. Results IgG codeposition showed a trend toward endocapillary hypercellularity (P = 0.082); there were no other baseline differences between the IgA (n = 55) and IgA + IgG (n = 25) groups. At a median follow-up time of 29 months, the combined primary outcome was reached in 24 patients, 16 with IgA and 8 with IgA + IgG (P = 0.82). Patients with immune deposits in the PCWs (n = 21) presented with higher baseline proteinuria than those with deposits limited to the mesangium (n = 59; P = 0.025), were more likely to have crescents/segmental glomerular necrosis on biopsy (P = 0.047) and were more likely to reach the combined primary outcome (P = 0.026). Biopsies with crescents/segmental glomerular necrosis were associated with endocapillary hypercellularity (P < 0.001). Conclusions In this multicenter IgAN cohort, IgG co-deposition and the location of glomerular immune deposits in the PCWs were both associated with greater histologic activity on renal biopsy, but only the location of glomerular immune deposits in the PCWs was associated with a significantly increased risk for end-stage renal disease, transplant, death and/or doubling of SCr.

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Depression is associated with progression of diabetic nephropathy in type 1 diabetes

10.2337/figshare.13073387 ◽

2020 ◽

Author(s):

Aila J. Ahola ◽

Valma Harjutsalo ◽

Carol Forsblom ◽

François Pouwer ◽

Per-Henrik Groop ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Renal Disease ◽

End Stage Renal Disease ◽

Symptoms Of Depression ◽

Increased Risk ◽

Stage Renal Disease ◽

End Stage

OBJECTIVE To investigate the relationship between depression and diabetic nephropathy progression in type 1 diabetes. RESEARCH DESIGN AND METHODS Data from 3730 participants without end-stage renal disease at baseline, participating in the Finnish Diabetic Nephropathy Study, were included. Depression was assessed in three ways. Depression diagnoses were obtained from the Finnish Care Register for Health Care. Antidepressant agent purchase data were obtained from the Drug Prescription Register. Symptoms of depression were assessed using the Beck Depression Inventory (BDI). Based on their urinary albumin excretion rate (AER) participants were classified into those with normal AER, microalbuminuria, and macroalbuminuria. Progression from normal AER to either microalbuminuria, macroalbuminuria, or end-stage renal disease; or from microalbuminuria to macroalbuminuria or ESRD; or from macroalbuminuria to ESRD, during the follow-up period was investigated. RESULTS Over a mean follow-up period of 9.6 years, renal status deteriorated in 18.4% of the participants. Diagnosed depression and antidepressant purchases before baseline were associated with 53% and 32% increased risk of diabetic nephropathy progression, respectively. Diagnosed depression assessed during follow-up remained associated with increased risk of disease progression (32%). BDI-derived symptoms of depression showed no association with the progression, but the total number of antidepressant purchases modestly reduced the risk [0.989 (0.982–0.997), P=0.008]. Dividing the sample based on median age, the observations followed those seen in the whole group. However, symptoms of depression additionally predicted progression in those ≤36.5 years. CONCLUSIONS Diagnosed depression and antidepressant purchases are associated with the progression of diabetic nephropathy in type 1 diabetes. Whether successful treatment of depression reduces the risk needs to be determined.

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P0228THE NEFIGARD TRIAL: THE EFFECT OF NEFECON® (BUDESONIDE) IN PATIENTS WITH PRIMARY IGA NEPHROPATHY AT RISK OF DEVELOPING END-STAGE RENAL DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0228 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Jonathan Barratt ◽

Andrew Stone ◽

Jens Kristensen

Keyword(s):

Placebo Group ◽

Renal Disease ◽

Iga Nephropathy ◽

End Stage Renal Disease ◽

Primary Outcome ◽

Stage Renal Disease ◽

End Stage ◽

Full Approval

Abstract Background and Aims Since the first description of IgA nephropathy (IgAN) over 50 years ago, it has been recognised that the mucosal immune system plays a crucial role in the pathogenesis of this common global cause of kidney failure. Recently, particular attention has focussed on the importance of the gut-associated lymphoid tissue (GALT) as the potential source of the poorly O-galactosylated IgA1 that triggers the formation of nephritogenic immune complexes in IgAN. Pathway analysis based on a large meta-analysis of genome wide association studies identified the intestinal immune network for IgA production as the most enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway in IgAN. Furthermore, separate studies have shown that the IgA in glomerular IgA deposits is indistinguishable from mucosal IgA. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. After 9 months’ treatment, urine protein–creatinine ratio (UPCR) was reduced by 29.3% in the NEFECON® 16 mg group compared with the placebo group. Estimated glomerular filtration rate (eGFR) dropped 4.7 ml/min/1.73 m2 in the placebo group with no deterioration seen in the NEFECON® 16 mg group. Incidence of patients reporting adverse events was similar in all groups. These data led to the design of the NefIgArd study which aims to assess the efficacy, safety, and tolerability of NEFECON® 16 mg in patients with IgAN at risk of end-stage renal disease. Method The NefIgArd study is a randomised, double-blind, placebo-controlled Phase 3 trial, with two parts – PART A a 15–35-day screening period, 9-month treatment and 3-month follow-up period; and PART B a 12-month no-treatment follow-up period (Figure). The study is recruiting across 146 nephrology clinics in 19 countries. Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria >1 g/24 h and eGFR between 35 and 90 ml/min per 1.73 m2 (CKD-EPI) despite optimised renin–angiotensin system blockade. Patients are randomised on a 1:1 ratio to NEFECON® 16 mg/day or placebo. Consistent with the Kidney Health Initiative White Paper “Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy” published in early 2019, the primary outcome of Part A is to assess the effect of NEFECON® 16 mg on 24 h UPCR at 9 months compared with placebo. The Part B primary outcome is based on data presented at the NKF/FDA/EMA workshop in March 2018 that supported eGFR slope as an endpoint for full approval and will assess the effect of NEFECON® 16 mg on a 2-year eGFR-based endpoint compared with placebo. In comparison with other studies that are recruiting, we believe that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of non-protocol treatments and loss of patients from the study that could dilute the true treatment effect of NEFECON®. Results As of 1 January 2020, 207 patients have been randomised, and Part A is expected to complete in Q4 2020, with Part B completing in 2022. To ensure the NefIgArd study results are fully translatable to the global IgAN population, NefIgArd will also open in China in 2020. Conclusion The NefIgArd study builds on the experience of the NEFIGAN trial, the largest commercially sponsored study ever completed in IgAN. The design of the NefIgArd study has used state-of-the-art data to evaluate kidney outcomes, using proteinuria as a reasonably likely surrogate of the effect of NEFECON® on long-term kidney outcomes and confirming long-term renoprotection using an NKF/FDA/EMA-suggested eGFR-based endpoint as a basis for full approval.

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Depression is associated with progression of diabetic nephropathy in type 1 diabetes

10.2337/figshare.13073387.v1 ◽

2020 ◽

Author(s):

Aila J. Ahola ◽

Valma Harjutsalo ◽

Carol Forsblom ◽

François Pouwer ◽

Per-Henrik Groop ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Renal Disease ◽

End Stage Renal Disease ◽

Symptoms Of Depression ◽

Increased Risk ◽

Stage Renal Disease ◽

End Stage

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Prevalence of renal insufficiency (RI) in cancer (Ca) patients (pts) with bone metastases (BM).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e12508 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e12508-e12508

Author(s):

Kristina S Chen ◽

Rohini Khorana Hernandez ◽

Jane M Quigley ◽

Melissa A. Pirolli ◽

David Quach ◽

...

Keyword(s):

Renal Function ◽

Therapeutic Outcomes ◽

Increased Risk ◽

Gault Formula ◽

Skeletal Related Events ◽

Stage Renal Disease ◽

End Stage ◽

Require Dose ◽

Electronic Medical Record Database

e12508 Background: Upon diagnosis of BM, cancer pts are at increased risk of serious debilitating bone complications. Of the U.S. approved bone-modifying agents (BMAs) [bisphosphonates (BPs), RANKL inhibitor] for the prevention of skeletal-related events (SREs) in these pts, BPs are nephrotoxic and may require dose adjustment or discontinuation. As low persistence to BMAs is associated with higher rates of SREs (Hatoum et al 2008), understanding the extent of RI in a real-world setting is warranted. K/DOQI guidelines recommend monitoring renal function using estimated glomerular filtration rate (eGFR) along with serum creatinine (SCr). Methods: Oncology Services Comprehensive Electronic Records (OSCER), a large electronic medical record database from U.S oncology clinics, was used. Cancer pts (age ≥ 18) with BM diagnosis in 2008 – 2012 were identified excluding acute renal failure, end-stage renal disease, and multiple myeloma. RI prevalence was examined using SCr and eGFR calculated with aMDRD and Cockroft-Gault formula. RI was defined as elevated SCr > 1.2 mg/dl or eGFR < 60 and < 90 ml/min/1.73m2. The analysis was also performed in the subgroup receiving BMAs. Results: The cohort included 15,623 pts (mean age 67.1±12.0, weight 76.5±18.5 kg; female; 56%). Using highest SCr during follow-up, 36% had elevated SCr, 87% eGFR < 90, and 47% eGFR < 60. Among pts with BM diagnosis in 2011 (n=3,839) and normal SCr (taken 1 month before or 3 months after diagnosis; n=3,192), almost 60% of the pts had mildly decreased renal function (eGFR < 90), and 8% had moderately decreased renal function (eGFR < 60) (table). Rates of RI based on eGFR estimated by both formulas were consistent. Conclusions: Nearly half of the cancer pts with BM had RI (eGFR < 60) during the course of their disease. As the risk of renal impairment is high in this population, assessment of renal function using eGFR and careful treatment consideration is imperative to achieve optimal therapeutic outcomes. [Table: see text]

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Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study

Cardiovascular Diabetology ◽

10.1186/s12933-021-01317-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Huajie Zou ◽

Yongping Xu ◽

Xiaoyu Meng ◽

Danpei Li ◽

Xi Chen ◽

...

Keyword(s):

Kidney Function ◽

Proportional Hazards ◽

Linear Trend ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

Increased Risk ◽

Stage Renal Disease ◽

End Stage ◽

Kidney Function Decline

Abstract Background ANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study. Methods We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting. Results There were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up (718.42 ± 378.17 vs. 522.04 ± 283.07 pg/mL, p < 0.001). Compared with the first quartile, multivariable-adjusted hazard ratio (95% confidence intervals [CIs]) for kidney function decline was 2.59 (95% CI, 1.41–4.77) for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD (relative risk: 1.33; 95% CI, 1.01–1.74). The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline (p for nonlinear trend = 0.66, p for linear trend < 0.001). Conclusions Participants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.

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Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

Current Vascular Pharmacology ◽

10.2174/1570161118666200317151553 ◽

2020 ◽

Vol 19 (1) ◽

pp. 41-54 ◽

Cited By ~ 1

Author(s):

Stefanos Roumeliotis ◽

Athanasios Roumeliotis ◽

Xenia Gorny ◽

Peter R. Mertens

Keyword(s):

Oxidative Stress ◽

Renal Disease ◽

End Stage Renal Disease ◽

Close Association ◽

Omega 3 ◽

Endstage Renal Disease ◽

Increased Risk ◽

Underlying Mechanisms ◽

Stage Renal Disease ◽

End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

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Endovascular mechanical thrombectomy and stenting in a case of central vein thrombosis

BMJ Case Reports ◽

10.1136/bcr-2020-236508 ◽

2021 ◽

Vol 14 (2) ◽

pp. e236508

Author(s):

Rajesh Vijayvergiya ◽

Navjyot Kaur ◽

Saroj K Sahoo ◽

Ashish Sharma

Keyword(s):

Mechanical Thrombectomy ◽

Transluminal Angioplasty ◽

Brachiocephalic Vein ◽

Central Vein ◽

Vein Thrombosis ◽

Catheter Directed Thrombolysis ◽

Stage Renal Disease ◽

End Stage ◽

Vein Stenosis

Central vein stenosis and thrombosis are frequent in patients on haemodialysis for end-stage renal disease. Its management includes anticoagulation, systemic or catheter-directed thrombolysis, mechanical thrombectomy and percutaneous transluminal angioplasty (PTA). Use of mechanical thrombectomy in central vein thrombosis has been scarcely reported. We hereby report a case of right brachiocephalic vein thrombosis with underlying stenosis, which was successfully treated by mechanical thrombectomy followed by PTA and stenting. The patient had a favourable 10 months of follow-up.

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Uremic Toxins and Their Relation with Oxidative Stress Induced in Patients with CKD

International Journal of Molecular Sciences ◽

10.3390/ijms22126196 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6196

Author(s):

Anna Pieniazek ◽

Joanna Bernasinska-Slomczewska ◽

Lukasz Gwozdzinski

Keyword(s):

Oxidative Stress ◽

Uremic Toxins ◽

Water Medium ◽

Induce Insulin Resistance ◽

Risk Of Mortality ◽

Increased Risk ◽

Stage Renal Disease ◽

End Stage

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

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Characteristics of patients with coexisting DNAJB9-associated fibrillary glomerulonephritis and IgA nephropathy

Clinical Kidney Journal ◽

10.1093/ckj/sfaa205 ◽

2020 ◽

Author(s):

Samar M Said ◽

Alejandro Best Rocha ◽

Anthony M Valeri ◽

Mohamad Sandid ◽

Anhisekh Sinha Ray ◽

...

Keyword(s):

Iga Nephropathy ◽

Immunoglobulin A ◽

Renal Survival ◽

Hepatitis C Infection ◽

Clinicopathologic Characteristics ◽

Fibrillary Glomerulonephritis ◽

Kaplan Meier ◽

Dense Deposits ◽

End Stage

Abstract Background Coexistence of fibrillary glomerulonephritis (FGN) and immunoglobulin A (IgA) nephropathy (IgAN) in the same kidney biopsy (FGN–IgAN) is rare, and the clinicopathologic characteristics and outcome of this dual glomerulopathy are unknown. Methods In this study, 20 patients with FGN–IgAN were studied and their characteristics were compared with 40 FGN and 40 IgAN control patients. Results Concurrent IgAN was present in 1.8% of 847 consecutive FGN cases and was the second most common concurrent glomerulopathy after diabetic nephropathy. FGN–IgAN patients were overwhelmingly White (94%) and contrary to FGN patients were predominantly (60%) males. Compared with IgAN patients, FGN–IgAN patients were older, had higher proteinuria, a higher incidence of renal insufficiency, and a lower incidence of microhematuria and gross hematuria at diagnosis. Six (30%) patients had malignancy, autoimmune disease or hepatitis C infection, but none had a secondary cause of IgAN or clinical features of Henoch–Schonlein purpura. Histologically, all cases exhibited smudgy glomerular staining for immunoglobulin G and DnaJ homolog subfamily B member 9 (DNAJB9) with corresponding fibrillary deposits and granular mesangial staining for IgA with corresponding mesangial granular electron-dense deposits. On follow-up (median 27 months), 10 of 18 (56%) FGN–IgAN patients progressed to end-stage kidney disease (ESKD), including 5 who subsequently died. Serum creatinine at diagnosis was a poor predictor of renal survival. The proportion of patients reaching ESKD or died was higher in FGN–IgAN than in IgAN. The median Kaplan–Meier ESKD-free survival time was 44 months for FGN–IgAN, which was shorter than IgAN (unable to compute, P = 0.013) and FGN (107 months, P = 0.048). Conclusions FGN–IgAN is very rare, with clinical presentation and demographics closer to FGN than IgAN. Prognosis is guarded with a median renal survival of 3.6 years. The diagnosis of this dual glomerulopathy requires careful evaluation of immunofluorescence findings, and electron microscopy or DNAJB9 immunohistochemistry.

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Timing of orchidopexy and its relationship to postoperative testicular atrophy: results from the ORCHESTRA study

BJS Open ◽

10.1093/bjsopen/zraa052 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

◽

C Skerritt ◽

C Bradshaw ◽

N Hall ◽

L McCarthy ◽

...

Keyword(s):

Primary Outcome ◽

Testicular Atrophy ◽

Wound Infections ◽

Atrophy Rate ◽

Younger Age ◽

Increased Risk ◽

Hospital Stays ◽

Reoperation Rates ◽

International Audit

Abstract Background In 2011 a consensus statement from the British Association of Paediatric Urologists recommended lowering the age at orchidopexy to under 1 year. There are concerns that a younger age at operation may increase postoperative testicular atrophy. The ORCHESTRA study aimed to establish the current age at orchidopexy in a multicentre, international audit and to see whether testicular atrophy was affected by age at operation. Methods The study was undertaken over a 3-month period in 28 centres in boys undergoing orchidopexy for unilateral, palpable undescended testes. Data collection was done using a standardized, predetermined protocol. The primary outcome was postoperative testicular atrophy. Secondary outcomes were wound infections, reoperations, and unplanned hospital stays related to anaesthetic events. Results A total of 417 patients were included, of whom only 48 (11.5 per cent) underwent orchidopexy before 1 year of age. There was no difference in anaesthetic complications in boys aged less than 1 year versus older patients: 0 of 48 (0 per cent) versus 6 of 369 (1.6 per cent) (P = 0.999). Complete follow-up was available for 331 patients (79.4 per cent). There was no difference in atrophy rate between those aged less than 1 year and older boys: 1 of 37 (3 per cent) versus 9 of 294 (3.1 per cent) (P = 0.999). Reoperation rates were 0 of 37 (0 per cent) and 7 of 294 (2.4 per cent) respectively (P = 1.000). There were more wound infections in boys under 1 year of age: 4 of 37 (11 per cent) versus 7 of 294 (2.4 per cent) (P = 0.025). Conclusion Only 11.5 per cent of boys underwent surgery before the age of 1 year. There was no increased risk of postoperative testicular atrophy with early surgery, although there was a higher rate of wound infection. Further study is required to demonstrate that early orchidopexy is not inferior to orchidopexy undertaken in boys aged over 1 year.

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