Onconephrology: mitigation of renal injury in chemotherapy administration.

PURPOSE OF REVIEW: Onconephrology was first coined as a name for the intersection of cancer medicine and nephrology in the early 2010s. It was recognized then that beyond and understanding of kidney physiology, a new generation of nephrologists skilled in both molecular biology and precision medicine were needed to deal with the challenges of emerging cancer therapies. Stem cell transplants, biologic agents, adjuvants blocking basic cellular signaling pathways, immunotherapy were found to promote novel anticancer outcomes, but also to pose new risks to the kidneys. The field rapidly overlapped with emerging expertise in vascular glomerular disease, glomerular disease, and the same biologic agents now applied to auto immune systemic and kidney diseases. RECENT FINDINGS: Many categories of chemotherapeutic agents have been discovered to have adverse renal side effects. In this review, we address classic chemotherapeutic nephrotoxicity and oncologic clinical situations leading to acute kidney injury. We also review the frontiers of nephrotoxicity reported with cell cycle inhibitors, diverse classes of tyrosine kinase inhibitors, immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, anticancer vaccines, and thrombotic microangiopathies triggered by malignancy and chemotherapy. The aim will be to focus on published strategies to mitigate nephrotoxicity. SUMMARY: As onconephrology expands into its own field, it gives birth to new subdisciplines. An understanding that patient populations want the benefits of chemotherapy without the renal (and other) systemic toxicities is emerging. A need to develop a new class of molecular and genetic experts in onconephrology to mitigate nephrotoxicity from chemotherapy is apparent and urgent.

Associations of interdialytic weight gain in the long intervals with mortality and residual kidney function decline.

INTRODUCTION: Interdialytic weight gain (IDWG) is crucial in the association between long interdialytic intervals and mortality in hemodialysis patients. The impact of IDWG on changes in residual kidney function (RKF) has not been evaluated thoroughly. This study examined the associations of IDWG in the long intervals (IDWGL) with mortality and rapid RKF decline. METHODS: This retrospective cohort study included patients who initiated hemodialysis in the United States dialysis centers from 2007 to 2011. IDWGL was defined as IDWG in the two-day break between dialysis sessions. This study examined the associations of seven categories of IDWGL (0% to <1%, 1% to <2%, 2% to <3% [reference], 3% to <4%, 4% to <5%, 5% to <6%, and ≥6%) with mortality using Cox regression models and rapid decline of renal urea clearance (KRU) using logistic regression models. The continuous relationships between IDWGL and study outcomes were investigated using restricted cubic spline analyses. FINDINGS: Mortality and rapid RKF decline were assessed in 35,225 and 6425 patients, respectively. Higher IDWGL categories were linked to increased risk of adverse outcomes. The multivariate adjusted hazard ratios (95% confidence intervals) of all-cause mortality for 3% to <4%, 4% to <5%, 5% to <6%, and ≥6% IDWGL were 1.09 (1.02-1.16), 1.14 (1.06-1.22), 1.16 (1.06-1.28), and 1.25 (1.13-1.37), respectively. The multivariate adjusted odds ratios (95% confidence intervals) of rapid decline of KRU for 3% to <4%, 4% to <5%, 5% to <6%, and ≥6% IDWGL were 1.03 (0.90-1.19), 1.29 (1.08-1.55), 1.17 (0.92-1.49), and 1.48 (1.13-1.95), respectively. When IDWGL exceeded 2%, the hazard ratios of mortality and the odds ratios of rapid KRU decline continuously increased. DISCUSSION: Higher IDWGL was incrementally associated with higher mortality risk and rapid KRU decline. IDWGL level over 2% was linked to higher risk of adverse outcomes. Therefore, IDWGL may be utilized as a risk parameter for mortality and RKF decline.

Prognostic Nutritional Index as a Predictor of Mortality in 101,616 Patients Undergoing Hemodialysis.

High mortality in dialysis patients is linked to malnutrition and inflammation. Prognostic nutritional index (PNI), calculated from serum albumin level and total lymphocyte count, has been developed as a prognostic marker for cancer patients. We investigated the clinical utility of PNI in predicting mortality in patients undergoing hemodialysis. Thus, 101,616 patients who initiated hemodialysis in United States dialysis centers between 2007 and 2011 were included in this retrospective cohort study. Using the Cox regression model, we assessed the relationship between PNI and mortality. Further, the predictive value of PNI for one-year mortality was compared with that of its constituent using area under the receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement. Higher PNI quartiles were incrementally associated with lower mortality; in patients with PNI values of 39.5−<43.1, 43.1−<46.6, and ≥46.6 (reference: PNI < 39.5), case-mix adjusted hazard ratios (95% confidence intervals) were 0.66 (0.64, 0.68), 0.49 (0.48, 0.51), and 0.36 (0.34, 0.37), respectively. PNI predicted mortality better than serum albumin level or total lymphocyte count alone. In the subgroup analysis, PNI performed well in predicting mortality in patients aged < 65 years. Our results indicate that PNI is a simple and practical prognostic marker in patients undergoing hemodialysis.

New and old approaches to nutritional management of acute and chronic glomerulonephritis.

PURPOSE OF REVIEW: It has been well published that a low protein diet (0.6-0.8 g/kg/day) is optimal for nutritional management of chronic kidney disease and with care be used without inducing protein malnutrition. RECENT FINDINGS: Though care with this approach must be demonstrated in patients with end-stage renal disease and with prominent protein energy wasting, another category of renal patient exists for whom dietary recommendations need more exploration. The Kidney Disease Improving Global Outcomes consortium, actually identifies renal disease as those patients with reduced filtration and those with excessive proteinuria excretion. Proteinuria, indeed, has proven to be a serious marker predisposing renal patients to atherosclerotic heart disease, venous thromboembolism, cerebrovascular accidents, and overall mortality. We discuss what is known about nutritional strategies to curb proteinuria and control inflammation in the setting of glomerulonephritis. SUMMARY: While this area of management of a set of conditions maybe nascent, it has the potential to provide incredible breakthroughs in nutritional management of auto immune diseases of the kidney specifically and the body writ large.

Changing landscape of living kidney donation and the role of telemedicine.

PURPOSE OF REVIEW: There has been a decline in living kidney donation over the last two decades. Donors from low-income families or racial/ethnic minorities face greater disproportionate geographic, financial, and logistical barriers to completing lengthy and complex evaluations. This has contributed to the decreased proportion of these subgroups. The authors view telemedicine as a potential solution to this problem. RECENT FINDINGS: Since the initial decline of donors in 2005, biologically related donors have experienced a lack of growth across race/ethnicity. Conversely, unrelated donors have emerged as the majority of donors in recent years across race/ethnicity, except for unrelated black donors. Disparities in access to living kidney donation persist. Telemedicine using live-video visits can overcome barriers to access transplant centers and facilitate care coordination. In a U.S. survey, nephrologists, surgeons, coordinators, social workers, and psychologists/psychologists across transplant centers are favorably disposed to use telemedicine for donor evaluation/follow-up beyond the coronavirus disease 2019 pandemic. However, with the waning of relaxed telemedicine regulations under the Public Health Emergency, providers perceive payor policy and out-of-state licensing as major factors hindering telemedicine growth prospects. SUMMARY: Permanent federal and state policies that support telemedicine services for living kidney donation can enhance access to transplant centers and help overcome barriers to donor evaluation.

Thrombotic Microangiopathy Syndromes-Common Ground and Distinct Frontiers.

Thrombotic microangiopathies (TMAs) have in common a terminal phenotype of microangiopathic hemolytic anemia with end-organ dysfunction. Thrombotic thrombocytopenic purpura results from von Willebrand factor multimerization, Shiga toxin-mediated hemolytic uremic syndrome causes toxin-induced endothelial dysfunction, while atypical hemolytic uremic syndrome results from complement system dysregulation. Drug-induced TMA, rheumatological disease-induced TMA, and renal-limited TMA exist in an intermediate space that represents secondary complement activation and may overlap with atypical hemolytic uremic syndrome clinically. The existence of TMA without microangiopathic hemolytic features, renal-limited TMA, represents an undiscovered syndrome that responds incompletely and inconsistently to complement blockade. Hematopoietic stem cell transplant-TMA represents another more resistant form of TMA with different therapeutic needs and clinical course. It has become apparent that TMA syndromes are an emerging field in nephrology, rheumatology, and hematology. Much work remains in genetics, molecular biology, and therapeutics to unravel the puzzle of the relationships and distinctions apparent between the different subclasses of TMA syndromes.

Association of serum potassium with decline in residual kidney function in incident hemodialysis patients.

BACKGROUND: Hyperkalemia is associated with kidney function decline in patients with non-dialysis dependent chronic kidney disease, but this relationship is unclear for residual kidney function (RKF) among hemodialysis (HD) patients. METHODS: We conducted a retrospective cohort study of 6655 patients, who started HD January 2007 and December 2011 and who had data on renal urea clearance (KRU). Serum potassium levels were stratified into four groups (i.e. ≤4.0, >4.0 to ≤4.5, >4.5 to ≤5.0 and >5.0 mEq/L) and 1-year KRU slope for each group was estimated by a linear mixed-effects model. RESULTS: Higher serum potassium was associated with a greater decline in KRU, and the greatest decrease in KRU (-0.20, 95% confidence interval -0.50 to -0.06) was observed for baseline potassium >5.0 mEq/L in the fully adjusted model. Mediation analysis showed that KRU slope mediated 1.78% of the association between serum potassium and mortality. CONCLUSIONS: Hyperkalemia is associated with a decline in RKF amongst incident HD patients. These findings may have important clinical implications in the management of hyperkalemia in advanced CKD if confirmed in additional clinical trials.

Acute interstitial nephritis observed with three different triggering agents.

A 70-year-old female patient developed acute interstitial nephritis (AIN) after treatment with non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPI), and Bromhexine. Renal biopsy confirmed the diagnosis, and the patient was treated with oral prednisone. Careful attention to timing of acute kidney injury (AKI) is crucial to diagnosing AIN.

Intravitreal vascular endothelial growth factors hypertension, proteinuria, and renal injury: a concise review.

PURPOSE OF REVIEW: Nearly 20 years ago, vascular endothelial growth factor (VEGF)inhibitors (VEGFi) were adapted from systemic use from antiangiogenesis roles to intravitreal uses. Initially bevacizumab a murine immunoglobulin was injected 'off label' as a treatment for diabetic macular edema and age-related macular degeneration. Throughout the following decade aflibercept and finally ranibizumab were adapted and obtained Food and Drug Administration approval for intravitreal use. Initially systemic absorption was thought to be quite low after intravitreal injections and was quoted as being 200-fold lower than levels postulated to induce significant VEGF inhibition. Pharmacodynamic studies obtained in 2014 and again in 2017 revealed significant systemic absorption and detectable VEGF inhibition, this has since been confirmed in multiple subsequent studies. RECENT FINDINGS: A few case reports of renal dysfunction and glomerular disease related to VEGFi were initially identified. Mixed findings on effects on blood pressure were noted in studies. More recently, 32 cases of de-novo glomerular disease and/or proteinuria exacerbation were identified. New studies have corroborated increased blood pressure, proteinuria exacerbation in patients with pre-existing nephrotic syndrome, and systemic VEGF depletion. Further, the most common lesion of systemic VEGFi nephrotoxicity, thrombotic microangiopathy, has recently been reported by our group. SUMMARY: We will review the pharmacokinetic, translational, and epidemiological data that year upon year establish the finite-yet real risk of intravitreal VEGFi.

Reconciling Systolic Blood Pressure Intervention Trial with Eighth Joint National Commission: a nuanced view of optimal hypertension control in the chronic kidney disease population.

PURPOSE OF REVIEW: Universally lowering blood pressure (BP) may adversely affect some populations especially in the older population. Recent landmark trials revealed cardiovascular benefits of tight controlling systolic BP (SBP) more than several recent BP targets. Implementing the evidence from the studies and guidelines in some populations is reviewed. RECENT FINDINGS: Eighth Joint National Commission (JNC-8) on hypertension issued conservative guidelines that provided an evolutionary change to BPcontrol in the elderly. However, intensive BP control with SBP < 120 mmHg in Systolic Blood Pressure Intervention Trial (SPRINT) focuses on the improvement of cardiovascular and cerebrovascular outcomes. Although increasingly guidelines are trending toward the SPRINT results, it is noteworthy that not all populations show a favorable outcome with intensive BP control given hypotensive risks to memory, kidney function, orthostasis, and morbidity risks. SUMMARY: Some populations may benefit from implementing the more intensive SBP target, whereas others such as elderly hypertensive patients may benefit from a more liberal SBP target. In the spirit of 'Primum non Nocere', we call for and suggest that a marriage of both SPRINT and JNC-8 recommendations be undertaken to champion the most cardiovascular protections for the greatest number of patients possible whereas preventing complications in vulnerable populations such as the elderly. Among the chronic kidney disease (CKD) population, SBP < 120 mmHg may not necessarily lead to favorable CKD outcomes.

Review of intravitreal VEGF inhibitor toxicity and report of collapsing FSGS with TMA in a patient with age-related macular degeneration.

Intravitreal vascular endothelial growth factor (VEGF) receptor blockade is used for a variety of retinal pathologies. These include age-related macular degeneration (AMD), diabetic macular edema (DME) and central retinal vein obstruction. Reports of absorption of intravitreal agents into systemic circulation have increased in number and confirmation of depletion of VEGF has been confirmed. Increasingly there are studies and case reports showing worsening hypertension, proteinuria, renal dysfunction and glomerular disease. The pathognomonic findings of systemic VEGF blockade, thrombotic microangiopathies (TMAs), are also being increasingly reported. One lesion that occurs in conjunction with TMAs that has been described is collapsing focal segmental glomerulosclerosis (cFSGS). cFSGS has been postulated to occur due to TMA-induced chronic glomerular hypoxia. In this updated review we discuss the mechanistic, pharmacological, epidemiological and clinical evidence of intravitreal VEGF toxicity. We review cases of biopsy-proven toxicity presented by our group and other investigators. We also present the third reported case of cFSGS in the setting of intravitreal VEGF blockade with a chronic TMA component that was crucially found on biopsy. This patient is a 74-year-old nondiabetic male receiving aflibercept for AMD. Of the two prior cases of cFSGS in the setting of VEGF blockade, one had AMD and the other had DME. This case solidifies the finding of cFSGS and its association with chronic TMA as a lesion that may be frequently encountered in patients receiving intravitreal VEGF inhibitors.

Ibuprofen-associated minimal change disease and acute interstitial nephritis with possibly linked membranous glomerulonephritis.

Non-steroidal anti-inflammatory drugs are not only potent analgesics and antipyretics but also nephrotoxins, and may cause electrolyte disarray. In addition to the commonly expected effects, including hyperkalemia, hyponatremia, acute renal injury, renal cortical necrosis, and volume retention, glomerular disease with or without nephrotic syndrome or nephritis can occur as well including after years of seemingly safe administration. Minimal change disease, secondary membranous glomerulonephritis, and acute interstitial nephritis are all reported glomerular lesions seen with non-steroidal anti-inflammatory use. We report a patient who used non-steroidal anti-inflammatory drugs for years without diabetes, chronic kidney disease, or proteinuria; he then developed severe nephrotic range proteinuria with 7 g of daily urinary protein excretion. Renal biopsy showed minimal change nephropathy, a likely secondary membranous glomerulonephritis, and acute interstitial nephritis present simultaneously in one biopsy. Cessation of non-steroidal anti-inflammatory drug use along with steroid treatment resulted in a moderate improvement in renal function, though residual impairment remained. Urine heavy metal screen returned with elevated levels of urine copper, but with normal ceruloplasmin level. Workup suggested that the elevated copper levels were due to cirrhosis from non-alcoholic fatty liver disease. The membranous glomerulonephritis is possibly linked to non-steroidal anti-inflammatory drug exposure, and possibly to heavy metal exposure, and is clinically and pathologically much less likely to be a primary membranous glomerulonephritis with negative serological markers.

Sodium zirconium cyclosilicate for the management of chronic hyperkalemia in kidney disease, a novel agent.

INTRODUCTION: Hyperkalemia is a common finding in patients with advanced kidney disease for multiple reasons. Renin-Angiotensin-Aldosterone-System Inhibitors (RAASi) that are indicated for slowing down progression of kidney disease are often associated with hyperkalemia which becomes a limiting factor in their use and titration to the maximum dose. Having a safe, effective, tolerable, and affordable potassium binder can help optimize RAAS inhibition in the setting of kidney disease. AREAS COVERED: Although sodium polystyrene sulfonate has been a mainstay of acute management of hyperkalemia for decades, evidence regarding its efficacy is limited, and its chronic use is not routinely recommended for concerns regarding toxicity. The concern of gastrointestinal (GI) adverse effects with sodium polystyrene sulfonate has spurred the development of alternatives. Sodium zirconium cyclosilicate (SZC) is a promising agent that selectively binds potassium in the gut and eliminates it, while being safe for chronic use based on 1 year of data. Even though we do not have head-to-head studies among the three currently available binders, SZC stands out in rapidity of onset and efficacy. EXPERT OPINION: In this review, we summarize the general management of hyperkalemia, including new agents. We review the pre-clinical and clinical data relating to sodium zirconium cyclosilicate.

Complement-Mediated Thrombotic Microangiopathy Associated with Lupus Nephritis Treated with Eculizumab: A Case Report.

Thrombotic microangiopathies (TMAs) involve multiple organ systems due to the presence of microangiopathic hemolysis. One such condition, atypical hemolytic uremic syndrome (aHUS), is a complement-mediated process that is part of a spectrum of disorders that have underlying complement dysfunction of the alternative pathway due to overactivity or decreased self-nonself discrimination by innate immunity. Complement-amplifying conditions such as pregnancy may unmask a diagnosis of aHUS. We present an important case of a pregnant 23-year-old Hispanic female who presented in mid-gestation (21 weeks) with an initial diagnosis of systemic lupus erythematosus (SLE) complicated by aHUS. She met clinical criteria for aHUS on presentation and was found to have a pathogenic CFHR1-3 homozygous deletion. She has been treated with intravenous and oral steroids, cyclophosphamide, subsequently also with plasma exchange, and finally with eculizumab with partial improvement in renal function. This case adds to the emerging literature showing that SLE and aHUS (or complement-mediated TMA) can be successfully treated with C5 blockade.

Calcium Transport in the Kidney and Disease Processes.

Calcium is a key ion involved in cardiac and skeletal muscle contractility, nerve function, and skeletal structure. Global calcium balance is affected by parathyroid hormone and vitamin D, and calcium is shuttled between the extracellular space and the bone matrix compartment dynamically. The kidney plays an important role in whole-body calcium balance. Abnormalities in the kidney transport proteins alter the renal excretion of calcium. Various hormonal and regulatory pathways have evolved that regulate the renal handling of calcium to maintain the serum calcium within defined limits despite dynamic changes in dietary calcium intake. Dysregulation of renal calcium transport can occur pharmacologically, hormonally, and via genetic mutations in key proteins in various nephron segments resulting in several disease processes. This review focuses on the regulation transport of calcium in the nephron. Genetic diseases affecting the renal handling of calcium that can potentially lead to changes in the serum calcium concentration are reviewed.

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin.

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

Building a hemodiafiltration system from readily available components for continuous renal replacement therapy under disasters and pandemics: preparing for an acute kidney injury surge during COVID-19.

PURPOSE OF REVIEW: The novel corona virus (SARS-CoV2) has been demonstrated to cause acute kidney injury due to direct cellular toxicity as well as due to a variety of autoimmune glomerular diseases. The concept of a surge of infected patients resulting in an overwhelming number of critical patients has been a central concern in healthcare planning during the COVID-19 era. RECENT FINDINGS: One crucial question remains as to how to manage patients with end stage renal disease and acute kidney injury in case of a massive surge of critically ill infected patients. Some publications address practical and ingenious solutions for just such a surge of need for renal replacement therapy. We present a plan for using a blood pump, readily available dialysis filter, and a prefilter and postfilter replacement fluid set up. This is in conjunction with multiple intravenous pumps to develop a simple hemofiltration apparatus. SUMMARY: The current set up may be a readily available option for use in critical situations where the need for renal replacement therapy outstrips the capacity of traditional hemodialysis services in a hospital or region.

Renal-Cerebral Pathophysiology: The Interplay Between Chronic Kidney Disease and Cerebrovascular Disease.

OBJECTIVES: Cerebrovascular disease has increasingly been linked to overall vascular health. Pathologic conditions like diabetes, hypertension, and kidney disease have been shown to affect brain health and cerebrovascular and nervous systems. Acute kidney injury (AKI) and chronic Kidney Disease (CKD) represent a variety of vascular insults that can adversely affect cerebral health. Hypertension, fluctuations in blood pressure, and diabetic vasculopathy are known risk factors for cerebrovascular disease associated with CKD. Other emerging areas of interest include endothelial dysfunction, vascular calcification due to calcium and phosphorus metabolism dysregulation, and uremic neuropathy present the next frontier of investigation in CKD and cerebrovascular health. METHODS: It has become apparent that the interrelation of AKI and CKD with vascular health, chemical homeostasis, and hormonal regulation upset many aspects of cerebral health and functioning. Stroke is an obvious connection, with CKD patients demonstrating a higher proclivity for cerebrovascular accidents. Cerebral bleeding risk, uremic neuropathies, sodium dysregulation with impacts on nervous system, vascular calcification, and endothelial dysfunction are the next salient areas of research that are likely to reveal key breakthroughs in renal-cerebral pathophysiology. RESULTS: In this review nephrological definition are discussed in a neuro-centric manner, and the areas of key overlap between CKD and cerebrovascular pathology are discussed. The multifaceted effects of renal function on the health of the brain are also examined. CONCLUSION: This review article aims to create the background for ongoing and future neurological-nephrological collaboration on understanding the special challenges in caring for patients with cerebrovascular disease who also have CKD.