Trial Outcomes in Glomerular Diseases

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are associated with the occurrence of immune-related adverse events. Despite their low incidence, renal complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, identify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored immunosuppressive drugs when renal response is not achieved.

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Understanding glomerular diseases through proteomics

Expert Review of Proteomics ◽

10.1080/14789450.2021.1908893 ◽

2021 ◽

pp. 1-21

Author(s):

E. Mavrogeorgis ◽

H. Mischak ◽

J. Beige ◽

A. Latosinska ◽

J. Siwy

Keyword(s):

Glomerular Diseases

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PRO: Carbapenems should be used for ALL infections caused by ceftriaxone-resistant Enterobacterales

JAC-Antimicrobial Resistance ◽

10.1093/jacamr/dlab013 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

David L Paterson ◽

Burcu Isler ◽

Patrick N A Harris

Keyword(s):

Antibiotic Resistance ◽

Observational Studies ◽

Randomized Trials ◽

Antibiotic Resistance Genes ◽

Definitive Treatment ◽

In Vitro Activity ◽

Genes Encoding ◽

Amoxicillin Clavulanate ◽

Trial Outcomes

Abstract Ceftriaxone resistance in the Enterobacterales is typically the result of production of ESBLs or AmpC β-lactamases. The genes encoding these enzymes are often co-located with other antibiotic resistance genes leading to resistance to aminoglycosides, quinolones and trimethoprim/sulfamethoxazole. Carbapenems are stable to ESBLs and AmpC giving them reliable in vitro activity against producers of these β-lactamases. In contrast, piperacillin/tazobactam and amoxicillin/clavulanate are compromised by co-production of OXA-1, which is not inhibited by tazobactam or clavulanate. These in vitro findings provide an explanation for the MERINO trial outcomes, where 3.7% (7/191) randomized to meropenem died compared with 12.3% (23/187) randomized to piperacillin/tazobactam as definitive treatment of bloodstream infection due to ceftriaxone-resistant organisms. No randomized trials have yet put cefepime and carbapenems head to head, but some observational studies have shown worse outcomes with cefepime. We argue that carbapenems are the antibiotics of choice for ceftriaxone-resistant Enterobacterales.

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P0234LOW URINARY CITRATE LEVELS ARE NOT SPECIFIC OF AUTOSOMAL POLYCYSTIC KIDNEY DISEASE (ADPKD) AND ARE PRESENT WHEN RENAL FUNCTION IS IMPAIRED IN ALL NEPHROPATIES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0234 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Francisco-Jose Borrego-Utiel ◽

Enoc Merino Garcia ◽

Isidoro Herrera ◽

Clara Moriana Dominguez ◽

Victoria Camacho Reina ◽

...

Keyword(s):

Renal Function ◽

Uric Acid ◽

Kidney Disease ◽

Renal Impairment ◽

Polycystic Kidney Disease ◽

Normal Renal Function ◽

Serum Bicarbonate ◽

Polycystic Kidney ◽

Glomerular Diseases ◽

Urinary Citrate

Abstract Background and Aims In polycystic kidney disease (PKD) it is frequently found a reduction in urinary citrate that is related with degree of renal impairment but it is unknown if this alteration is specific or if it is also present in other nephropathies. Recently it has been suggested that urinary citrate could be a marker of covert metabolic acidosis and reflects acid retention in chronic kidney disease (CKD). Our aim was to compare urinary citrate in PKD with other renal diseases and to show its relation with serum bicarbonate and excretion of uric acid and calcium. Method We determined citrate, calcium and uric acid in 24-hour urine in patients with PKD and with other nephropathies with varied degree of renal impairment followed in a outpatient clinic of nephrology. Results We included 291 patients, 119 with glomerular diseases, 116 with PKD, 21 with other nephropathies, and 35 patients with normal renal function. Urinary citrate was higher in women (Females 309±251 mg/gCr vs. males 181±145 mg/gCr, p<0.001) and in patients with normal renal function (normal 380±210 mg/gCr; PKD 203±166 mg/gCr; glomerular 279±282 mg/gCr; p<0,001). PKD patients showed similar values of urinary citrate to patients with glomerular diseases and with other nephropathies. We observed a progressive reduction in urinary citrate parallel to degree of renal impairment, in a comparable way among patients with PKD and glomerular diseases. We did not observe a relationship between urinary citrate and serum bicarbonate levels. Calcium and uric acid elimination in ADPKD patients was similar to other nephropathies and lower to patients with normal renal function. However, serum uric acid was significantly higher in glomerular patients than other nephropathies after adjust with glomerular filtration rate and sex. Conclusion Hypocitraturia is not specific of PKD but it is also present in all nephropathies. Urinary citrate are related to degree of renal impairment and it is not related with serum bicarbonate. We think that it could be interesting to study urinary citrate as a marker of renal function and its role as prognostic factor of renal deterioration.

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Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress

AJP Renal Physiology ◽

10.1152/ajprenal.00162.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. F1308-F1317 ◽

Cited By ~ 28

Author(s):

Leopoldo Raij ◽

Runxia Tian ◽

Jenny S. Wong ◽

John C. He ◽

Kirk N. Campbell

Keyword(s):

Oxidative Stress ◽

Glomerular Filtration ◽

Biologically Active ◽

Current Evidence ◽

Glomerular Sclerosis ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Filtration Barrier ◽

Focal Segmental Glomerular Sclerosis

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap −/− model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2−) that promotes endothelin-1 synthesis. Plg via O2− also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a “second hit” in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.

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