New guidelines and therapeutic updates for the management of lupus nephritis.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) can be a devastating condition, striking young patients often in their prime reproductive years. Lupus nephritis is a common and serious complication occurring in roughly 50% of SLE cases, indicating a high likelihood of disease progression, morbidity, and mortality. As the early trials of steroid therapy, and later cyclophosphamide (CYC), therapeutic changes had been stagnant. Then came the introduction of mycophenolate mofetil (MMF) in the 2000s. After the Aspreva Lupus Management Study, there had been a dearth of trials showing positive therapy results. Since 2020, new studies have emerged for lupus nephritis involving the use of anti-BLYS agents, novel calcineurin inhibitors, CD20 blockade, and antiinterferon agents. Nephrology and rheumatology society guidelines in the United States and across the world are still catching up. RECENT FINDINGS: Although therapeutic guidelines are being developed, updates that have come through have focused on improved diagnostic and monitoring guidelines. One theme is the recommendation of increasingly tight proteinuria control and firmer guidelines for the rapid induction of remission. The reality of multitarget therapy and the expectation of rapid induction for a more complete remission are being widely recognized. SUMMARY: The need for more complete and more rapid induction and control of lupus nephritis is undisputed according to the evidence and guidelines, and the medications to achieve this are growing at a rate not seen over the prior two decades. What remains is a stepwise approach to recognize how to best optimize therapy. Based on available evidence, an algorithm for induction and maintenance treatment of lupus nephritis used by the University of California Irvine Lupus Nephritis clinic, is recommended.

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.

Thrombotic microangiopathy - the importance of a multidisciplinary approach.

PURPOSE OF REVIEW: The purpose of this review is to highlight the importance of a multidisciplinary thrombotic microangiopathies (TMA) Team. This goal will be accomplished through review of the complement system, discuss various causes of thrombotic microangiopathies (TMA), and aspects of their diagnosis and management. In so doing, readers will gain an appreciation for the complexity of this family of disorders and realize the benefit of a dedicated multidisciplinary TMA Team. RECENT FINDINGS: TMA causes derive from multiple specialty areas, are difficult to timely recognize, pose complex challenges, and require multidisciplinary management. Hematopoietic stem cell transplant-associated TMA (TA-TMA) and TA-TMA related multiorgan dysfunction syndrome (TA-TMA MODS) are areas of burgeoning research; use of complement testing and eculizumab precision-dosing has been found to better suppress complement activity in TA-TMA than standard eculizumab dosing. Newer tests are available to risk-stratify obstetric patients at risk for severe pre-eclampsia, whose features resemble those of TA-TMA MODS. Numerous disorders may produce TMA-like findings, and a systematic approach aids in their identification. TMA Teams elevate institutional awareness of increasingly recognized TMAs, will help expedite diagnostic and therapeutic interventions, and create pathways to future TMA-related research and facilitate access to clinical trials. SUMMARY: Establishment of a TMA-Team is valuable in developing the necessary institutional expertise needed to promptly recognize and appropriately manage patients with TMA.

Tolvaptan-induced isolated elevation of bilirubin in a patient with Gilbert syndrome.

Tolvaptan is the current standard of treatment for autosomal dominant polycystic kidney disease. It operates by acting on V2 receptors and blocks vasopressin interactions, causing a reduction in the rate of renal cyst growth and preserving kidney function. The current known risks of tolvaptan involve a serious liver injury characterized by an elevation in total bilirubin and alanine transaminase and aspartate transaminase levels. In this report, we document a unique liver injury characterized by an elevated bilirubin with normal alanine transaminase and aspartate transaminase levels in a patient who is homozygous for the UGT1A1 consistent with Gilbert syndrome.

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.

A randomized study to compare oral potassium binders in the treatment of acute hyperkalemia.

BACKGROUND: The KBindER (K+ Binders in Emergency Room and hospitalized patients) clinical trial is the first head-to-head evaluation of oral potassium binders (cation-exchange resins) for acute hyperkalemia therapy. METHODS: Emergency room and hospitalized patients with a blood potassium level ≥ 5.5 mEq/L are randomized to one of four study groups: potassium binder drug (sodium polystyrene sulfonate, patiromer, or sodium zirconium cyclosilicate) or nonspecific laxative (polyethylene glycol). Exclusion criteria include recent bowel surgery, ileus, diabetic ketoacidosis, or anticipated dialysis treatment within 4 h of treatment drug. Primary endpoints include change in potassium level at 2 and 4 h after treatment drug. Length of hospital stay, next-morning potassium level, gastrointestinal side effects and palatability will also be analyzed. We are aiming for a final cohort of 80 patients with complete data endpoints (20 per group) for comparative statistics including multivariate adjustment for kidney function, diabetes mellitus, congestive heart failure, metabolic acidosis, renin-angiotensin-aldosterone system inhibitor prescription, and treatment with other agents to lower potassium (insulin, albuterol, loop diuretics). DISCUSSION: The findings from our study will inform decision-making guidelines on the role of oral potassium binders in the treatment of acute hyperkalemia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04585542 . Registered 14 October 2020.

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.

Onconephrology and Thrombotic Microangiopathy: Looking Beyond the Horizon.

Thrombotic microangiopathies (TMAs) represent a complex interaction of endothelial and podocyte biology, nephron physiology, complement genetics, and oncologic therapies with host immunology. The complexity of various factors, such as molecular causes, genetic expressions, and immune system mimicking, along with incomplete penetrance, make it difficult to find a straightforward solution. As a result, there may be variations in diagnosis, study, and treatment approaches, and achieving a consensus can be challenging. Here, we review the molecular biology, pharmacology, immunology, molecular genetics, and pathology of the various TMA syndromes in the setting of cancer. Controversies in etiology, nomenclature, and points requiring further clinical, translational, and bench research are discussed. Complement-mediated TMAs, chemotherapy drug-mediated TMAs, TMAs in monoclonal gammopathy, and other TMAs central to onconephrology practice are reviewed in detail. In addition, established and emerging therapies within the US Food and Drug Administration pipeline subsequently are discussed. Finally, a comprehensive review of critical areas of onconephrology clinical practice is presented as practical value to the clinical practitioner and seeds of investigation to be sown among the community of atypical hemolytic uremic syndrome researchers.

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.