Acute kidney injury in patients treated with immune checkpoint inhibitors

Antígeno CTLA-4; InmunoterapiaAntigen CTLA-4; ImmunoteràpiaCTLA-4 antigen; ImmunotherapyBackground Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

An Unusual Cause of Paraparesis in a Patient on Chronic Steroid Therapy

Background/Objective: Spinal epidural lipomatosis is the excessive deposition of unencapsulated fat in the epidural space. This is a rare disorder often associated with high levels of endogenous steroids or the administration of exogenous steroids. Case Description: A 32-year-old man with congenital kyphosis treated with prednisolone daily for 5 months for interstitial lung disease developed compressive myelopathy. Findings: Magnetic resonance imaging showed congenital kyphosis along with epidural lipomatosis compressing the cord. Cessation of steroid therapy was associated with improvement in the symptoms. Conclusions: Spinal epidural lipomatosis is a rare side effect of chronic steroid therapy that may occur with relatively short-term, low-dose regimens. In patients with congenital vertebral anomalies, spinal fat deposition may worsen the neurological status in an already compromised cord. Discontinuation of steroid therapy is beneficial; some patients may require surgical intervention for decompression

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

APOL1 variants in African populations mediate resistance to trypanosomal infection but increase risk for kidney diseases through unknown mechanisms. APOL1 is expressed in glomerular podocytes and does not vary with underlying kidney disease diagnoses or APOL1 genotypes, suggesting that the kidney disease–associated variants dysregulate its function rather than its localization or abundance. Structural homology searches identified vesicle-associated membrane protein 8 (VAMP8) as an APOL1 protein interactor. VAMP8 colocalizes with APOL1 in the podocyte, and the APOL1:VAMP8 interaction was confirmed biochemically and with surface plasmon resonance. APOL1 variants attenuate this interaction. Computational modeling of APOL1’s 3-dimensional structure, followed by molecular dynamics simulations, revealed increased motion of the C-terminal domain of reference APOL1 compared with either variant, suggesting that the variants stabilize a closed or autoinhibited state that diminishes protein interactions with VAMP8. Changes in ellipticity with increasing urea concentrations, as assessed by circular dichroism spectroscopy, showed higher conformational stability of the C-terminal helix of the variants compared with the reference protein. These results suggest that reference APOL1 interacts with VAMP8-coated vesicles, a process attenuated by variant-induced reduction in local dynamics of the C-terminal. Disordered vesicular trafficking in the podocyte may cause injury and progressive chronic kidney diseases in susceptible African Americans subjects. Kidney Disease-associated variants in the Apoliprotein L1 lead to a closed or autoinhibited conformation of the carboxy terminal domain, attenuating its interaction with VAMP8

Akustische Gang-und Laufanalyse für Sport- und Medizinanwendungen

Beeinträchtigungen des menschlichen Gehens können je nach Ausprägung für den Patienten eine erhebliche Beeinträchtigung im täglichen Leben darstellen. Sie können verschiedene Ursachen wie z.B. eine Sportverletzung, Krankheiten wie Diabetes, Sauerstoffunterversorgungen des Gehirns, z.B. nach einem Schlaganfall oder nach einem Badeunfall, oder andere Erkrankungen des Nervensystems haben. Das veränderte Gehen kann im Rahmen von Rehabilitationsmaßnahmen auf dem Laufband mit eingelassener Drucksensormatrix unter visueller Darstellung und Auswertung der plantaren Druckverteilung dargestellt werden. Dies macht jedoch ein persönliches Erscheinen des Patienten beim Arzt oder in der Klinik erforderlich und ist zeitlich beschränkt, da diese diagnostischen Laufbänder nur in wenigen Einrichtungen zu Verfügung stehen. Seit einiger Zeit werden vor allem für Sportler mobile Anwendungen für visuelle Darstellungen des Gangbildes z.B. auf dem Smartphone oder nachträglich auf dem Rechner angeboten (z.B. Systeme von Moticon(c) , Novel(c) oder Sensoria(c)), jedoch sind diese noch recht teuer und zum Teil anfällig gegenüber mechanischen, dauerhaften und sich wiederholenden Belastungen, was oft an der empfindlichen Kabelanbindung der Einlage liegt. Zudem sind sie in ihren Messfrequenzen (bis max. 100 Hz) oder in ihren Auflösungen (max. 8 Sensoren bei 100 Hz) stark eingeschränkt und damit für Laufanalysen mit höheren Schrittfrequenzen nicht geeignet. Im Gegensatz zur visuellen Darstellung erlaubt die Einbeziehung des menschlichen Gehörs auf Grund dessen Empfindlichkeit bei unbewusster Signalwahrnehmung ein schnelleres und intuitiveres Erlernen neuer Bewegungsabfolgen. Dies wurde bereits in Studien zur Optimierung des Bewegungsablaufs bei der deutschen Ruder-Nationalmannschaft, erfolgreich eingesetzt. Dieses akustische Bio-Feedback ist zudem für Patienten von Vorteil, da der enge Zusammenhang zwischen Akustik und Motorik unbewusste Adaptionen des Bewegungsablaufs erleichtert

Plasma apolipoprotein L1 levels do not correlate with CKD

Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to 3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans

APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease

APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes from Tg-G0 and Tg-G2 mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia