Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

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.

Current State and Future of Research in Nephrology.

The focus of this article is to review the available funding opportunities for the nephrology workforce at all career levels and review the current challenges involved in the career of a physician-scientist. While the scarcity of nephrology fellows for training programs is a continuing challenge, increased funding for the National Institutes of Health is encouraging particularly for early career investigators. In addition to National Institutes of Health funding, other funding sources are also discussed as they provide much needed bridge funding during key transition periods for young careers. Recent initiatives such as the Advancing American Kidney Health, KidneyX, and National Institute of Diabetes and Digestive and Kidney Diseases' Kidney Precision Medicine Project offer new research opportunities for bringing much needed innovation to improve lives of people with kidney diseases. The time is now for us to seize the opportunity and ensure that a strong workforce will be able to take advantage of these potential game changers for nephrology.

Therapy-induced chemoexosomes: Sinister small extracellular vesicles that support tumor survival and progression.

Chemotherapy involves the use of multiple cytotoxic or cytostatic drugs acting by various mechanisms to kill or arrest the growth of cancer cells. Chemotherapy remains the most utilized approach for controlling cancer. Emerging evidence indicates that cancer cells activate various pro-survival mechanisms to cope with chemotherapeutic stress. These mechanisms persist during treatment and often help orchestrate tumor regrowth and patient relapse. Exosomes due to their nature of carrying and transferring multiple biologically active components have emerged as key players in cancer pathogenesis. Recent data demonstrates that chemotherapeutic stress enhances the secretion and alters the cargo carried by exosomes. These altered exosomes, which we refer to as chemoexosomes, are capable of transferring cargo to target tumor cells that can enhance their chemoresistance, increase their metastatic behavior and in certain cases even aid in endowing tumor cells with cancer stem cell-like properties. This mini-review summarizes the recent developments in our understanding of the impact chemoexosomes have on tumor survival and progression.

Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression.

Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.

BACKGROUND: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. METHODS: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. RESULTS: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. CONCLUSIONS: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.

Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury.

Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal immunoglobulin free light chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1ß, as well as the profibrotic agent TGF-ß by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.

Unique sex- and age-dependent effects in protective pathways in acute kidney injury.

Sex and age influence susceptibility to acute kidney injury (AKI), with young females exhibiting lowest incidence. In these studies, we investigated mechanisms which may underlie the sex/age-based dissimilarities. Cisplatin (Cp)-induced AKI resulted in morphological evidence of injury in all groups. A minimal rise in plasma creatinine (PCr) was seen in Young Females, whereas in Aged Females, PCr rose precipitously. Relative to Young Males, Aged Males showed significantly, but temporally, comparably elevated PCr. Notably, Aged Females showed significantly greater mortality, whereas Young Females exhibited none. Tissue KIM-1 and plasma NGAL were significantly lower in Young Females than all others. IGFBP7 levels were modestly increased in both Young groups. IGFBP7 levels in Aged Females were significantly elevated at baseline relative to Aged Males, and increased linearly through day 3, when these levels were comparable in both Aged groups. Plasma cytokine levels similarly showed a pattern of protective effects preferentially in Young Females. Expression of the drug transporter MATE2 did not explain the sex/age distinctions. Heme oxygenase-1 (HO-1) levels (~28-kDa species) showed elevation at day 1 in all groups with highest levels seen in Young Males. Exclusively in Young Females, these levels returned to baseline on day 3, suggestive of a more efficient recovery. In aggregate, we demonstrate, for the first time, a distinctive pattern of response to AKI in Young Females relative to males which appears to be significantly altered in aging. These distinctions may offer novel targets to exploit therapeutically in both females and males in the treatment of AKI.

Outcomes of arteriovenous fistulas and grafts with or without intervention before successful use.

OBJECTIVE: Arteriovenous fistulas (AVFs) are considered superior to arteriovenous grafts (AVGs) because of longer secondary patency after successful cannulation for dialysis. We evaluated whether access interventions before successful cannulation affect the relative longevity of AVFs and AVGs after successful use. METHODS: This retrospective study of a prospective database identified patients who initiated dialysis with a catheter and subsequently had a permanent access (289 AVFs and 310 AVGs) placed between January 1, 2006, and December 31, 2011, and were successfully cannulated for dialysis at a large medical center. Patients were monitored until June 30, 2014, and we evaluated the clinical outcomes (secondary patency and frequency of interventions) of the vascular accesses. RESULTS: An intervention before successful cannulation was required more frequently with AVFs than with AVGs (50.5% vs 17.7%; odds ratio, 4.74; 95% confidence interval [CI], 3.26-6.86; P < .0001). Compared with AVFs that matured without interventions, those that required intervention had shorter secondary patency after successful cannulation (hazard ratio, 1.84; 95% CI, 1.30-2.60; P < .0001) and required more interventions per year after successful use (rate ratio [RR], 1.81; 95% CI, 1.49-2.20; P < .0001). Similarly, AVGs that required intervention before successful cannulation had shorter secondary patency than those without prior intervention (odds ratio, 1.98; 95% CI, 1.52-4.02; P < .0001) and required more interventions per year after successful use (RR, 1.49; 95% CI, 1.27-1.74; P < .0001). AVFs requiring intervention before maturation had inferior secondary patency compared with AVGs that were cannulated without prior intervention (hazard ratio, 1.45; 95% CI, 1.08-2.01; P = .01), but required fewer annual interventions after successful use (RR, 0.57; 95% CI, 0.49-0.66; P < .0001). CONCLUSIONS: The patency advantage of AVFs over AVGs is no longer evident in patients requiring an AVF intervention before successful cannulation, but the AVFs require fewer interventions after successful use.

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes.

Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PE-containing exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.

Heme Oxygenase-1 Regulates Myeloid Cell Trafficking in AKI.

Renal ischemia-reperfusion injury is mediated by a complex cascade of events, including the immune response, that occur secondary to injury to renal epithelial cells. We tested the hypothesis that heme oxygenase-1 (HO-1) expression, which is protective in ischemia-reperfusion injury, regulates trafficking of myeloid-derived immune cells in the kidney. Age-matched male wild-type (HO-1(+/+)), HO-1-knockout (HO-1(-/-)), and humanized HO-1-overexpressing (HBAC) mice underwent bilateral renal ischemia for 10 minutes. Ischemia-reperfusion injury resulted in significantly worse renal structure and function and increased mortality in HO-1(-/-) mice. In addition, there were more macrophages (CD45(+) CD11b(hi)F4/80(lo)) and neutrophils (CD45(+) CD11b(hi) MHCII(-) Gr-1(hi)) in HO-1(-/-) kidneys than in sham and HO-1(+/+) control kidneys subjected to ischemia-reperfusion. However, ischemic injury resulted in a significant decrease in the intrarenal resident dendritic cell (DC; CD45(+)MHCII(+)CD11b(lo)F4/80(hi)) population in HO-1(-/-) kidneys compared with controls. Syngeneic transplant experiments utilizing green fluorescent protein-positive HO-1(+/+) or HO-1(-/-) donor kidneys and green fluorescent protein-negative HO-1(+/+) recipients confirmed increased migration of the resident DC population from HO-1(-/-) donor kidneys, compared to HO-1(+/+) donor kidneys, to the peripheral lymphoid organs. This effect on renal DC migration was corroborated in myeloid-specific HO-1(-/-) mice subjected to bilateral ischemia. These mice also displayed impaired renal recovery and increased fibrosis at day 7 after injury. These results highlight an important role for HO-1 in orchestrating the trafficking of myeloid cells in AKI, which may represent a key pathway for therapeutic intervention.

Distinct populations of label-retaining cells in the adult kidney are defined temporally and exhibit divergent regional distributions.

DNA label-retention, or retention of a thymidine analog, is a characteristic of slow cycling cells and has been used to identify stem cells in several organ systems. Recent findings have demonstrated inconsistent localization of label-retaining cells (LRCs) in the kidney. Differences in the dose and timing of administration of deoxyuridine, the length of the chase period, and the species of animal used have made understanding the distinctions between these findings difficult. In the present studies, we utilized a dual loading scheme in the same animal to demonstrate that the cells labeled at different ages identified independent populations of LRC that distributed globally in an anti-parallel manner in the kidney. Loading with a DNA label in neonates identified LRC more often in the papilla, while administering the DNA label in adult mice identified LRC prominently in the cortex and the outer medulla. Furthermore, the tissue compartment distribution (epithelial-endothelial-interstitial) as well as the specific distribution within the nephron epithelia differed for these populations. These findings highlighted the complexity of the dynamics of cell proliferation in the kidney throughout the postnatal and adult period and call attention to the confusion associated with the term "label-retaining cells" for different timings of the loading and chase periods. This study indicated that the results of previous studies should be viewed as nonoverlapping and that further studies are needed to ascertain the role of each of these populations in the steady-state maintenance and injury recovery of the kidney.

Restless legs syndrome in an Indian urban population.

BACKGROUND: The prevalence of restless legs syndrome (RLS) in India is unknown. OBJECTIVES: The primary objective was to assess the occurrence of RLS in residents of Bangalore. The secondary objective was to correlate demographic and socioeconomic factors with RLS occurrence and severity. METHODS: This was a cross-sectional, questionnaire-based survey conducted during August 2005 among adult residents of Bangalore, who participated in a face-to-face interview. Diagnosis of RLS was based on fulfillment of all National Institutes of Health/International Restless Legs Syndrome Study Group (NIH/IRLSSG) essential criteria. Severity of RLS was assessed using the IRLSSG scale. RESULTS: RLS occurred in 27 (2.1%) of 1266 respondents. Predominant symptoms included "pulling," "tingling" and "pain". RLS was associated with delayed sleep onset and RLS severity correlated with the duration of delay in sleep onset. RLS was associated with per-capita income less than the equivalent of US$1/day, education less than high school level, chronic daily alcohol consumption and chronic blood loss. CONCLUSION: This is the first Indian population study on RLS which reveals prevalence of the disorder in a South Indian urban population at 2.1%. Larger studies are warranted to better characterize RLS in India.