Association of Proton Pump Inhibitor Use and Immune Checkpoint Inhibitor Mediated Acute Kidney Injury: A Meta-Analysis and a Review of Related Outcomes.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they pose the risk of immune-related adverse events, including ICI-mediated acute kidney injury (ICI-AKI). Recent studies have implicated proton pump inhibitors (PPIs) as potential contributors to ICI-AKI development. This meta-analysis examines the association between PPI use and ICI-AKI, exploring a potential modifiable risk factor in ICI therapy, while also reviewing the possible outcomes of ICI-AKI. METHODS: We conducted a comprehensive systematic review and meta-analysis of observational studies, assessing the risk of ICI-AKI in cancer patients concurrently using PPIs and potential outcomes. Odds ratios (ORs) were pooled using random-effects models. Subgroup analyses and sensitivity analyses were performed to evaluate heterogeneity and potential biases. RESULTS: A total of 14 studies involving 12,694 patients were included. In total, we analyzed 639 patients with all-cause AKI and 779 patients with ICI-AKI. The pooled OR for the overall incidence of AKI from all-cause was 1.57 (95% Confidence Interval (CI), 1.02 to 2.40) among patients on PPIs. Specifically, the risk of ICI-AKI associated with PPI use was significantly higher, with a pooled OR of 1.84 (95% CI 1.16 to 2.90). This indicates approximately 84% higher likelihood of developing ICI-AKI with concurrent use of PPIs. Additionally, among patients with ICI-AKI, 67% had complete or partial recovery of renal function, 32% progressed to chronic kidney disease (CKD) and about 36% died during a follow-up period of at least 3 months. CONCLUSION: This meta-analysis highlights the importance of cautious PPI prescription in cancer patients undergoing ICI therapy. Clinicians are advised to evaluate the risks and benefits of PPI use and consider alternative therapies when feasible.

Rechallenge With High-Dose Methotrexate After Treatment With Glucarpidase in Adult Patients With Lymphoma.

PURPOSE: Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS: This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS: Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION: In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Management of hypertension in patients with cancer: challenges and considerations.

The survival rates of many cancers have significantly improved due to recent advancements in cancer screening and therapeutics. Although better cancer outcomes are encouraging, additional health challenges have surfaced, the utmost of which is the burden imposed by various cardiovascular and renal toxicities of anticancer therapies. To improve the overall outcome of patients with cancer, it is essential to understand and manage these treatment-related adverse effects. The cardiovascular side effects of antineoplastic therapies are well-known and include left ventricular dysfunction, heart failure, myocardial ischaemia, QT prolongation, arrhythmia and hypertension. Among these, hypertension is the most common complication, prevalent in about 40% of all cancer patients, yet frequently overlooked and undertreated. This review explores the intricate connection between cancer and hypertension and provides distinct approaches to diagnosing, monitoring and managing hypertension in patients with cancer. We also outline the challenges and considerations that are relevant to the care of patients receiving anticancer drugs with prohypertensive potential.

Immune checkpoint inhibitors and their interaction with proton pump inhibitors-related interstitial nephritis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and outcomes, leading to an expanding use in millions of patients worldwide. However, they can cause a spectrum of immune-related adverse events (irAEs). Essentially, any organs can be affected by irAEs, which have emerged as therapy-limiting side effects. In the kidneys, ICI-associated acute interstitial nephritis (ICI-AIN) leads to acute kidney injury (AKI) in 2%-5% of patients on ICI therapy. AKI associated with ICI therapy pathologically presents with AIN in nearly 90% of the cases, but the pathophysiology of ICI-AIN remains to be defined. The generation of autoreactive T cells in patients receiving AIN-inducible drugs, such as proton pump inhibitors (PPIs), is one of the leading theories, supported by a higher incidence of ICI-AIN in patients on these AIN-inducible drugs. In this review, we will discuss our understanding of the incidence, potential pathophysiological mechanisms, clinical presentations, risk factors, diagnosis, and management of PPI-related AIN and its interaction with ICI therapy.

Renal ischemia alters the transcriptomic and epigenetic profile of inflammatory genes in swine scattered tubular-like cells.

BACKGROUND: Scattered tubular-like cells (STCs) are differentiated renal tubular cells that during recovery from ischemic injury dedifferentiate to repair other injured renal cells. Renal artery stenosis (RAS), often associated with chronic inflammatory injury, compromises the integrity and function of STCs, but the underlying mechanisms remain unknown. We hypothesized that RAS alters the transcriptomic and epigenetic profile of inflammatory genes in swine STCs. METHODS: STCs were harvested from pig kidneys after 10 weeks of RAS or sham (n=6 each). STC mRNA profiles of inflammatory genes were analyzed using high-throughput mRNA-sequencing (seq) and their DNA methylation (5mC) and hydroxymethylation (5hmC) profiles by DNA immunoprecipitation and next-generation sequencing (MeDIP-seq) (n=3 each), followed by an integrated (mRNA-seq/MeDIP-seq) analysis. STC protein expression of candidate differentially expressed (DE) genes and common proinflammatory proteins were subsequently assessed in vitro before and after epigenetic (Bobcat339) modulation. RESULTS: mRNA-seq identified 57 inflammatory genes up-regulated in RAS-STCs versus Normal-STCs (>1.4 or <0.7-fold, P<0.05), of which 14% exhibited lower 5mC and 5% higher 5hmC levels in RAS-STCs versus Normal-STCs, respectively. Inflammatory gene and protein expression was higher in RAS-STCs compared with Normal-STCs but normalized after epigenetic modulation. CONCLUSIONS: These observations highlight a novel modulatory mechanism of this renal endogenous repair system and support development of epigenetic or anti-inflammatory therapies to preserve the reparative capacity of STCs in individuals with RAS.

Immune Checkpoint Inhibitor-Associated Sarcoidosis Reaction in the Kidney: Case Report.

Sarcoid-like granulomas can be a manifestation of immune-related adverse events associated with immune checkpoint inhibitor (ICI) treatment. To our knowledge, kidney biopsy-proven sarcoid-like granulomas have not been described in the context of a sarcoid-like reaction associated with ICI treatment. We describe a man in his early 60s with renal cell carcinoma who was undergoing treatment with the ICIs nivolumab and ipilimumab, and was hospitalized for treatment of acute kidney injury stage 3, hypercalcemia, and hyponatremia 10 weeks after starting ICI treatment. Results from his workup showed parathyroid hormone-independent hypercalcemia (ionized calcium, 3.3 mEq/L) with an elevated 1,25-dihydroxyvitamin D level. A kidney biopsy specimen showed sarcoid-like noncaseating granulomas. The patient began a corticosteroid regimen with a 500 mg bolus dose of methylprednisolone and continued treatment with prednisone, 80 mg once daily for the first week and then a taper for 8 weeks. His kidney function gradually improved as hypercalcemia resolved. After 2 weeks of treatment, his creatinine values returned to baseline. This case shows that ICI treatment can be associated with kidney sarcoidosis. Because ICIs are increasingly used to treat cancer, physicians should be aware of this possible inflammatory complication so that they can use appropriate diagnostic and therapeutic approaches.

Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors.

Introduction: Immune checkpoint inhibitors (ICIs) induce impressive antitumor responses but may lead to acute kidney injury (AKI) associated with ICI therapy (AKI-ICI). Biomarkers distinguishing AKI-ICI from AKI because of other causes (AKI-other) are currently lacking. Because ICIs block immunoregulatory pathways, we hypothesized that biomarkers related to immune cell dysregulation, including tumor necrosis factor alpha (TNF-α) and other markers of B and T cell activation in the systemic circulation and kidney tissue, may aid with the diagnosis of AKI-ICI. Methods: This is a prospective study consisting of 24 participants who presented with AKI during ICI therapy, adjudicated to either have AKI-ICI (n = 14) or AKI-other (n = 10). We compared markers of kidney inflammation and injury (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) as well as plasma and urine levels of T cell-associated cytokines (TNF-α, interferon-γ, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-9, and IL-10) between groups. We also compared T-cell responses in the systemic circulation and in kidney tissue across groups, using mass cytometry systems. Results: We observed increase in several specific immune cells, including CD4 memory, T helper cells, and dendritic cells in the kidney tissue, as well as in the urine cytokines IL-2, IL-10, and TNF-α, in patients who developed AKI-ICI compared to patients with AKI-other (P < 0.05 for all). The discriminatory ability of TNF-α on AKI cause was strong (area under the curve = 0.814, 95% confidence interval: 0.623-1.00. The CD4+ T cells with memory phenotype formed the dominant subset. Conclusion: These results suggest that specific T-cell responses and their respective cytokines may be indicative of AKI associated with ICI therapy and may help to differentiate AKI-ICI from AKI-other. Urine TNF-α is a promising biomarker for AKI-ICI, which is most often caused by acute interstitial nephritis (AIN), and TNF-α pathway may serve as a potential target for therapeutic intervention.

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension-Mechanisms and Mitigation.

Cardiovascular disease and cancer are 2 of the leading causes of death worldwide. Although improvements in outcomes have been noted for both disease entities, the success of cancer therapies has come at the cost of at times very impactful adverse events such as cardiovascular events. Hypertension has been noted as both, a side effect as well as a risk factor for the cardiotoxicity of cancer therapies. Some of these dynamics are in keeping with the role of hypertension as a cardiovascular risk factor not only for heart failure, but also for the development of coronary and cerebrovascular disease, and kidney disease and its association with a higher morbidity and mortality overall. Other aspects such as the molecular mechanisms underlying the amplification of acute and long-term cardiotoxicity risk of anthracyclines and increase in blood pressure with various cancer therapeutics remain to be elucidated. In this review, we cover the latest clinical data regarding the risk of hypertension across a spectrum of novel anticancer therapies as well as the underlying known or postulated pathophysiological mechanisms. Furthermore, we review the acute and long-term implications for the amplification of the development of cardiotoxicity with drugs not commonly associated with hypertension such as anthracyclines. An outline of management strategies, including pharmacological and lifestyle interventions as well as models of care aimed to facilitate early detection and more timely management of hypertension in patients with cancer and survivors concludes this review, which overall aims to improve both cardiovascular and cancer-specific outcomes.

Onconephrology 2022: An Update.

Onconephrology is an upcoming and expanding subspecialty that deals with the intersections between hematology/oncology and nephrology. With the paradigm shift in the understanding of cancer immunobiology and mechanisms of oncotherapeutic drug toxicities, it is important for a nephrologist to have a sound understanding of this field. Over the last 5 years, there have been immense developments in our understanding of kidney-related adverse events from various targeted, immuno- and cellular-based therapies. Pathogenic mechanisms of electrolyte imbalance, hypertension (oncohypertension), and AKI from multiple forms of cancer therapies have been explored. Significant research has also been conducted in the field of transplant onconephrology. In this review, we have tried to assimilate the most recent updates in the last 2 years in this ever-growing and fascinating field.

Cancer Therapy-Related Hypertension: A Scientific Statement From the American Heart Association.

Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis.

BACKGROUND: Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis. METHODS: A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls. RESULTS: sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9-3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7-1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls. CONCLUSION: Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.

Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

The 'other' big complication: how chronic kidney disease impacts on cancer risks and outcomes.

Cancer is the second leading cause of death in people with chronic kidney disease (CKD) after cardiovascular disease. The incidence of CKD in patients with cancer is higher than in the non-cancer population. Across various populations, CKD is associated with an elevated risk of cancer incidence and cancer death compared with people without CKD, although the risks are cancer site-specific. Higher risk of cancer is detectable in mild CKD [estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m2], although this risk is more obvious if sensitive markers of kidney disease are used, such as cystatin C. Independent of eGFR, albuminuria is associated with increased risk of site-specific cancer incidence and death. Here, we explore the potential mechanisms for the increased risk of cancer observed in CKD, including patient factors (shared risks such as cardiometabolic disease, obesity, smoking, diet, lifestyle and environment), disease (genetic, inflammatory and infective) and treatment factors. In particular, we discuss the ways in which renal adverse events associated with conventional chemotherapies and newer systemic anti-cancer therapies (including targeted and immunotherapies) may contribute to worse cancer outcomes in people with CKD. Finally, we review the potential benefits of acknowledging increased risk of cancer in risk prediction tools used for the management of CKD.

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.

Incidence and Risk Factors for Acute Kidney Injury After Chimeric Antigen Receptor T-Cell Therapy.

OBJECTIVE: To evaluate the association of baseline and postinfusion patient characteristics with acute kidney injury (AKI) in the month after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: We retrospectively reviewed records of 83 patients with non-Hodgkin lymphoma undergoing CAR-T therapy (axicabtagene ciloleucel) between June 2016 and November 2020. Patients were followed up to 1 month after treatment. Post-CAR-T AKI was defined as a more than 1.5-fold increase in serum creatinine concentration from baseline (on the day of CAR-T infusion) at any time up to 1 month after CAR-T therapy. RESULTS: Of 83 patients, 14 (17%) developed AKI during follow-up. At 1 month after CAR-T infusion, 10 of 14 (71%) AKI events had resolved. Lower baseline estimated glomerular filtration rate, use of intravenous contrast material, tumor lysis prophylaxis, higher peak uric acid and creatine kinase levels during follow-up, and change in lactate dehydrogenase from baseline to peak level within 1 month after initiation of CAR-T therapy were significantly associated with AKI incidence during follow-up. Incidence of AKI was also higher in patients who received higher doses of corticosteroids and tocilizumab. CONCLUSION: Acute kidney injury occurred in approximately 1 in 6 patients who received axicabtagene ciloleucel for non-Hodgkin lymphoma. Patients with high tumor burden receiving higher total doses of corticosteroids or tocilizumab should be closely monitored for development of AKI. Lower baseline kidney function at CAR-T initiation, exposure to contrast material, and progressive increase in levels of tumor lysis markers (uric acid, lactate dehydrogenase, creatine kinase) after CAR-T infusion may predict risk of AKI during the 1 month after infusion.

Monoclonal Gammopathy-Related Kidney Diseases.

Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.

Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells.

BACKGROUND: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. METHODS: CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (n = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. RESULTS: Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, p ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. CONCLUSIONS: Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease.