Assessment of Glomerular Filtration Rate in Patients with Cancer: A Statement from the American Society of Onco-Nephrology.

Accurate assessment of glomerular filtration rate (GFR) is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of cancer patients have baseline chronic kidney disease (CKD), and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface-area (BSA)-adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD-EPI equations, with 2,508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (8 studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the ASON Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

Safely correct hyponatremia with continuous renal replacement therapy: A flexible, all-purpose method based on the mixing paradigm.

Treating chronic hyponatremia by continuous renal replacement therapy (CRRT) is challenging because the gradient between a replacement fluid's [sodium] and a patient's serum sodium can be steep, risking too rapid of a correction rate with possible consequences. Besides CRRT, other gains and losses of sodium- and potassium-containing solutions, like intravenous fluid and urine output, affect the correction of serum sodium over time, known as osmotherapy. The way these fluids interact and contribute to the sodium/potassium/water balance can be parsed as a mixing problem. As Na/K/H2 O are added, mixed in the body, and drained via CRRT, the net balance of solutes must be related to the change in serum sodium, expressible as a differential equation. Its solution has many variables, one of which is the sodium correction rate, but all variables can be evaluated by a root-finding technique. The mixing paradigm is proved to replicate the established equations of osmotherapy, as in the special case of a steady volume. The flexibility to solve for any variable broadens our treatment options. If the pre-filter replacement fluid cannot be diluted, then we can compensate by calculating the CRRT blood flow rate needed. Or we can deduce the infusion rate of dextrose 5% water, post-filter, to appropriately slow the rise in serum sodium. In conclusion, the mixing model is a generalizable and practical tool to analyze patient scenarios of greater complexity than before, to help doctors customize a CRRT prescription to safely and effectively reach the serum sodium target.

Hemoconcentration of Creatinine Minimally Contributes to Changes in Creatinine during the Treatment of Decompensated Heart Failure.

Background: Worsening serum creatinine is common during treatment of acute decompensated heart failure (ADHF). A possible contributor to creatinine increase is diuresis-induced changes in volume of distribution (VD) of creatinine as total body water (TBW) contracts around a fixed mass of creatinine. Our objective was to better understand the filtration and nonfiltration factors driving change in creatinine during ADHF. Methods: Participants in the ROSE-AHF trial with baseline to 72-hour serum creatinine; net fluid output; and urinary KIM-1, NGAL, and NAG were included (n=270). Changes in VD were calculated by accounting for measured input and outputs from weight-based calculated TBW. Changes in observed creatinine (Crobserved) were compared with predicted changes in creatinine after accounting for alterations in VD and non-steady state conditions using a kinetic GFR equation (Cr72HR Kinetic). Results: When considering only change in VD, the median diuresis to elicit a ≥0.3 mg/dl rise in creatinine was -7526 ml (IQR, -5932 to -9149). After accounting for stable creatinine filtration during diuresis, a change in VD alone was insufficient to elicit a ≥0.3 mg/dl rise in creatinine. Larger estimated decreases in VD were paradoxically associated with improvement in Crobserved (r=-0.18, P=0.003). Overall, -3% of the change in eCr72HR Kinetic was attributable to the change in VD. A ≥0.3 mg/dl rise in eCr72HR Kinetic was not associated with worsening of KIM-1, NGAL, NAG, or postdischarge survival (P>0.05 for all). Conclusions: During ADHF therapy, increases in serum creatinine are driven predominantly by changes in filtration, with minimal contribution from change in VD.

[Creatinine] can change in an unexpected direction due to the volume change rate that interacts with kinetic GFR: Potentially positive paradox.

[Creatinine] was proved to change in the opposite direction of the kinetic GFR (GFRK ), but does the [creatinine] also change in the opposite direction of the volume rate? If volume is administered and the [creatinine] actually goes up, then the two changes move in the same direction and their ratio is positive, paradoxically. The equation that describes [creatinine] as a function of time was differentiated with respect to the volume rate. This partial first derivative has a global maximum that can be positive under definable conditions. Knowing what makes the maximum positive informs when the derivative will be positive over some continuous domain of volume rate inputs. The first derivative versus volume rate curve has a maximum and a minimum point depending on the GFRK . If GFRK is below a calculable value, then the curve's minimum vanishes, letting it descend to -∞ and not allowing the derivative to ever be positive. If GFRK lies between a lower and a higher calculable value, then the curve's maximum vanishes, letting the derivative diverge to +∞ , though the clinical scenario is unrealistic. If GFRK is above the higher calculable value, then the curve's absolute maximum can become positive by decreasing the creatinine generation rate or increasing the initial [creatinine]. The derivative is potentially positive under these clinically realizable circumstances. The combination of parameters above can align in septic patients (low creatinine generation rate) with kidney failure (high initial [creatinine]) who are put on continuous dialysis (high GFRK ). If a first derivative is positive, removing more volume can improve the [creatinine] and, dismayingly, giving more volume can worsen the [creatinine]. This paradox is explained by a covert interplay between the ambient [creatinine] and GFRK that excretes creatinine faster than its volume of distribution declines.

Ratio Profile: Physiologic Approach to Estimating Appropriate Intravenous Fluid Rate to Manage Hyponatremia in the Syndrome of Inappropriate Antidiuresis.

A hyponatremic patient with the syndrome of inappropriate antidiuresis (SIAD) gets normal saline (NS), and the plasma sodium decreases, paradoxically. To explain, desalination is often invoked: if urine is more concentrated than NS, the fluid's salts are excreted while some water is reabsorbed, exacerbating hyponatremia. But comparing concentrations can be deceiving. They should be converted to quantities because mass balance is key to unlocking the paradox. The [sodium] equation can legitimately be used to track all of the sodium, potassium, and water entering and leaving the body. Each input or output "module" can be counterbalanced by a chosen iv fluid so that the plasma sodium stays stable. This equipoise is expressed in terms of the iv fluid's infusion rate, an easy calculation called the ratio profile. Knowing the infusion rate that maintains steady state, we can prescribe the iv fluid at a faster rate in order to raise the plasma sodium. Rates less than the ratio profile may risk a paradox, which essentially is caused by an iv fluid underdosing. Selecting an iv fluid that is more concentrated than urine is not enough to prevent paradoxes; even 3% saline can be underdosed. Drinking water adds to the ratio profile and is underestimated in its ability to provoke a paradox. In conclusion, the quantitative approach demystifies the paradoxical worsening of hyponatremia in SIAD and offers a prescriptive guide to keep the paradox from happening. The ratio profile method is objective and quickly deployable on rounds, where it may change patient management for the better.

In creatinine kinetics, the glomerular filtration rate always moves the serum creatinine in the opposite direction.

INTRODUCTION: When the serum [creatinine] is changing, creatinine kinetics can still gauge the kidney function, and knowing the kinetic glomerular filtration rate (GFR) helps doctors take care of patients with renal failure. We wondered how the serum [creatinine] would respond if the kinetic GFR were tweaked. In every scenario, if the kinetic GFR decreased, the [creatinine] would increase, and vice versa. This opposing relationship was hypothesized to be universal. METHODS: Serum [creatinine] and kinetic GFR, along with other parameters, are described by a differential equation. We differentiated [creatinine] with respect to kinetic GFR to test if the two variables would change oppositely of each other, throughout the gamut of all allowable clinical values. To remove the discontinuities in the derivative, limits were solved. RESULTS: The derivative and its limits were comprehensively analyzed and proved to have a sign that is always negative, meaning that [creatinine] and kinetic GFR must indeed move in opposite directions. The derivative is bigger in absolute value at the higher end of the [creatinine] scale, where a small drop in the kinetic GFR can cause the [creatinine] to shoot upward, making acute kidney injury similar to chronic kidney disease in that regard. CONCLUSIONS: All else being equal, a change in the kinetic GFR obligates the [creatinine] to change in the opposite direction. This does not negate the fact that an increasing [creatinine] can be compatible with a rising kinetic GFR, due to differences in how the time variable is treated.

Improving on the Adrogué-Madias Formula.

The Adrogué-Madias (A-M) formula is correct as written, but technically, it only works when adding 1 L of an intravenous (IV) fluid. For all other volumes, the A-M algorithm gives an approximate answer, one that diverges further from the truth as the IV volume is increased. If 1 L of an IV fluid is calculated to change the serum sodium by some amount, then it was long assumed that giving a fraction of the liter would change the serum sodium by a proportional amount. We challenged that assumption and now prove that the A-M change in [sodium] ([Na]) is not scalable in a linear way. Rather, the Δ[Na] needs to be scaled in a way that accounts for the actual volume of IV fluid being given. This is accomplished by our improved version of the A-M formula in a mathematically rigorous way. Our equation accepts any IV fluid volume, eliminates the illogical infinities, and most importantly, incorporates the scaling step so that it cannot be forgotten. However, the nonlinear scaling makes it harder to obtain a desired Δ[Na]. Therefore, we reversed the equation so that clinicians can enter the desired Δ[Na], keeping the rate of sodium correction safe, and then get an answer in terms of the volume of IV fluid to infuse. The improved equation can also unify the A-M formula with the corollary A-M loss equation wherein 1 L of urine is lost. The method is to treat loss as a negative volume. Because the new equation is just as straightforward as the original formula, we believe that the improved form of A-M is ready for immediate use, alongside frequent [Na] monitoring.

Perspectives From an Onconephrology Interest Group: Conference Report.

INTRODUCTION AND OBJECTIVE: Onconephrology is a new and evolving field that deals with kidney complications in patients with cancer as well as the management of cancer in patients with preexisting kidney disease. With increasing numbers of patients with cancer with kidney-related complications, the field has garnered increased attention. Thus, an annual Greater Toronto Area Onconephrology Interest Group symposium was held in May 2019. The objective of the meeting was to demonstrate the junctures between oncology and nephrology by highlighting recent data regarding (1) kidney impairment in solid organ malignancies, (2) management and treatment of kidney cancer, (3) kidney impairment in hematologic malignancies, (4) malignancy and kidney transplantation, and (5) hyponatremia in patients with cancer. METHODS AND SOURCES OF INFORMATION: Through a structured presentation, the group explored key topics discussed at a Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Onconephrology. Expert opinions, clinical trial findings, and publication summaries were used to illustrate patient and treatment-related considerations in onconephrology. KEY FINDINGS: Kidney complications in patients with cancer are a central theme in onconephrology. An estimated 12% to 25% of patients with solid organ malignancies have chronic kidney disease (CKD), although in certain cancers, the prevalence of CKD is higher. Kidney impairment is also a common complication of some hematologic malignancies. The incidence of renal failure in patients with multiple myeloma is estimated at 18% to 56% and light chain cast nephropathy is seen in approximately 30% of these patients. In addition, there appears to be a bidirectional relationship between kidney cancer and CKD, with some data sets suggesting the risk increases as kidney function declines. Cancer is also of concern in patients with preexisting kidney disease. Kidney transplant recipients have a greater risk of cancer and a higher risk of cancer-related mortality. Kidney complications have also been associated with novel cancer therapies, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. An estimated 2% to 4% of patients initiating an immune checkpoint inhibitor may develop nephrotoxicity, whereas up to 40% of patients on CAR T-cell therapy experience cytokine release syndrome (CRS). Tumor lysis syndrome and electrolyte abnormalities, such as hyponatremia, have also been reported with CAR T-cell therapy. While the incidence and prevalence of hyponatremia vary depending on the cancer type and serum sodium cutoff point, hyponatremia may be seen in up to 46% of patients hospitalized in cancer centers. CONCLUSIONS: Onconephrology is a developing field and the themes arising from this meeting indicate a need for greater collaboration between oncologists and nephrologists. Educational symposia and onconephrology fellowship programs may allow for improved cancer care for patients with kidney disease.

CONTEXTE ET OBJECTIFS: L'onconéphrologie est une discipline nouvelle et évolutive qui traite les complications néphrologiques chez les patients atteints d'un cancer et assure également la prise en charge des patients soignés en oncologie et présentant une néphropathie préexistante. En mai 2019, le symposium du Greater Toronto Area Onconephrology Interest Group a eu pour objectif de démontrer les points de jonction entre l'oncologie et la néphrologie en mettant en évidence les données récentes concernant : 1) l'insuffisance rénale en présence de tumeurs malignes touchant les organes solides; 2) la prise en charge et le traitement des cancers rénaux; 3) l'insuffisance rénale en présence de tumeurs malignes hématologiques; 4) la malignité et la transplantation rénale; et 5) l'hyponatrémie chez les patients atteints d'un cancer. SOURCES ET MÉTHODOLOGIE: Par le biais d'une présentation structurée, le groupe s'est penché sur les thèmes clés discutés lors d'une conférence du KDIGO portant sur les controverses entourant l'onconéphrologie. Des avis d'experts, des résultats d'essais cliniques et des résumés de publications ont été utilisés pour illustrer les considérations relatives aux patients et aux traitements en onconéphrologie. PRINCIPAUX RÉSULTATS: Les complications rénales chez les patients atteints d'un cancer sont un thème central en onconéphrologie. On estime qu'environ 12 à 25 % des patients présentant une tumeur maligne touchant les organes solides sont atteints d'insuffisance rénale chronique (IRC), bien que la prévalence soit plus élevée pour certains cancers. L'insuffisance rénale s'avère également une complication fréquente de certaines tumeurs malignes hématologiques. L'incidence d'IRC chez les patients atteints d'un myélome multiple est estimée entre 18 et 56 %, et une néphropathie à chaînes légères est observée chez environ 30 % de ces patients. En outre, on soupçonne l'existence d'une relation bidirectionnelle entre le cancer du rein et l'IRC; certains ensembles de données suggérant que le risque de cancer augmenterait avec le déclin de la fonction rénale. Le cancer est également préoccupant chez les patients ayant une néphropathie préexistante. Enfin, les receveurs d'une greffe rénale présentent un risque accru de cancer et de mortalité liée au cancer. Les complications rénales ont également été associées aux nouveaux traitements contre le cancer, comme les inhibiteurs du point de contrôle immunitaire et les thérapies par cellules CAR T. Environ 2 à 4 % des patients amorçant un traitement par les inhibiteurs de point de contrôle immunitaire pourraient développer une néphrotoxicité, alors que jusqu'à 40 % des patients traités par cellules CAR T présentent un syndrome de relargage de cytokines. Le syndrome de lyse tumorale et des anomalies électrolytiques, comme l'hyponatrémie, ont également été observés chez les patients traités par cellules CAR T. Bien que l'incidence et la prévalence de l'hyponatrémie varient en fonction du type de cancer et du seuil de natrémie, jusqu'à 46 % des patients hospitalisés dans les centres de cancérologie présentent cette anomalie. CONCLUSION: L'onconéphrologie est une discipline en évolution et les thèmes issus de ce colloque soulignent le besoin d'accroître la collaboration entre les oncologues et les néphrologues. Les symposiums à caractère éducatif et les programmes de bourses d'études et de recherche en onconéphrologie pourraient améliorer les soins oncologiques prodigués aux patients atteints de néphropathies.

The value of kinetic glomerular filtration rate estimation on medication dosing in acute kidney injury.

BACKGROUND: In acute kidney injury (AKI), medication dosing based on Cockcroft-Gault creatinine clearance (CrCl) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rates (eGFR) are not valid when serum creatinine (SCr) is not in steady state. The aim of this study was to determine the impact of a kinetic estimating equation that incorporates fluctuations in SCrs on drug dosing in critically ill patients. METHODS: We used data from participants enrolled in the NIH Acute Respiratory Distress Syndrome Network Fluid and Catheters Treatment Trial to simulate drug dosing category changes with the application of the kinetic estimating equation developed by Chen. We evaluated whether kinetic estimation of renal function would change medication dosing categories (≥60, 30-59, 15-29, and <15mL/min) compared with the use of CrCl or CKD-EPI eGFR. RESULTS: The use of kinetic CrCl and CKD-EPI eGFR resulted in a large enough change in estimated renal function to require medication dosing recategorization in 19.3% [95 CI 16.8%-21.9%] and 23.4% [95% CI 20.7%-26.1%] of participants, respectively. As expected, recategorization occurred more frequently in those with AKI. When we examined individual days for those with AKI, dosing discordance was observed in 8.5% of total days using the CG CrCl and 10.2% of total days using the CKD-EPI equation compared with the kinetic counterparts. CONCLUSION: In a critically ill population, use of kinetic estimates of renal function impacted medication dosing in a substantial proportion of AKI participants. Use of kinetic estimates in clinical practice should lower the incidence of medication toxicity as well as avoid subtherapeutic dosing during renal recovery.

Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience.

RATIONALE & OBJECTIVE: The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. STUDY DESIGN, SETTING, & PARTICIPANTS: We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. RESULTS: We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6-56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. CONCLUSIONS: Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Estimating Creatinine Clearance in the Nonsteady State: The Determination and Role of the True Average Creatinine Concentration.

Creatinine clearance is a tenet of nephrology practice. However, with just a single creatinine concentration included in the denominator of the creatinine clearance equation, the resulting value seems to apply only in the steady state. Does the basic clearance formula work in the nonsteady state, and can it recapitulate the kinetic glomerular filtration rate (GFR) equation? In the kinetic state, a nonlinear creatinine trajectory is reducible into a "true average" value that can be found using calculus, proceeding from a differential equation based on the mass balance principle. Using the fundamental theorem of calculus, we prove definitively that the true average is the correct creatinine to divide by, even as the mathematical model accommodates clinical complexities such as volume change and other factors that affect creatinine kinetics. The true average of a creatinine versus time function between 2 measured creatinine values is found by a definite integral. To use the true average to compute kinetic GFR, 2 techniques are demonstrated, a graphical one and a numerical one. We apply this concept to a clinical case of an individual with acute kidney injury requiring dialysis; despite the effects of hemodialysis on serum creatinine concentration, kinetic GFR was able to track the underlying kidney function and provided critical information regarding kidney function recovery. Finally, a prior concept of the maximum increase in creatinine per day is made more clinically objective. Thus, the clearance paradigm applies to the nonsteady state as well when the true average creatinine is used, providing a fundamentally valid strategy to deduce kinetic GFRs from serum creatinine trends occurring in real-life acute kidney injury and kidney recovery.

Kinetic glomerular filtration rate equation can accommodate a changing body volume: Derivation and usage of the formula.

Ascertaining a patient's kidney function is more difficult to do when the serum creatinine is changing than when it is stable. To accomplish the task, various kinetic clearance equations have been developed. To date, however, none of them have allowed for ongoing changes to the creatinine's volume of distribution. These diluting or concentrating effects on the [creatinine] can greatly impact the accuracy of kidney function assessment. Described herein is a model of creatinine kinetics that also accommodates volume changes. The differential equation is solved for the kinetic glomerular filtration rate (GFR), which is helpful information to the physician. Some of the equation's discontinuities, such as from dividing by a volume rate of zero, can be resolved by using limits. Being "volume-capable," the new kinetic equation reveals how a changing volume influences the maximum rate of rise in [creatinine], a parameter that heretofore was chosen empirically. To show the advantages of incorporating volume, the new and old kinetic equations are applied to a clinical case of overzealous fluid resuscitation. Appropriately, when the volume gain's dilution of [creatinine] is taken into account, the creatinine clearance is calculated to be substantially lower. In conclusion, the kinetic GFR equation has been upgraded to handle volume changes simultaneously with [creatinine] changes.

Kinetic Glomerular Filtration Rate in Routine Clinical Practice-Applications and Possibilities.

When the [creatinine] is changing, the kidney function can still be tracked with a quantitative technique called kinetic glomerular filtration rate (GFR). The equation yields useful information on the severity of acute kidney injury, the clinical course of kidney and dialysis clearances, and the timing of kidney recovery. It has been validated in at least 3 independent studies, where it performed sufficiently well in intensive care unit and kidney transplant settings, and in head-to-head comparisons with biomarkers. Because it is based on a mathematical model, the kinetic GFR faces limitations depending on the accuracy of its assumptions. As the assumptions more accurately reflect the complexities of biology, some of these limitations can be overcome in a more sophisticated model. Kinetic GFR is an easy-to-use, low-cost tool that should be more widely incorporated into medical practice.

Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes.

In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome.

Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy.

BACKGROUND/AIMS: Tumor necrosis factor (TNF)-α is believed to play a role in diabetic kidney disease. This study explores the specific effects of TNF-α with regard to nephropathy-relevant parameters in the podocyte. METHODS: Cultured mouse podocytes were treated with recombinant TNF-α and assayed for production of monocyte chemoattractant protein-1 (MCP-1) by enzyme-linked immunosorbent assay (ELISA). TNF-α signaling of MCP-1 was elucidated by antibodies against TNF receptor (TNFR) 1 or TNFR2 or inhibitors of nuclear factor-kappaB (NF-κB), phosphatidylinositol 3-kinase (PI3K) or Akt. In vivo studies were done on male db/m and type 2 diabetic db/db mice. Levels of TNF-α and MCP-1 were measured by RT-qPCR and ELISA in the urine, kidney and plasma of the two cohorts and correlated with albuminuria. RESULTS: Podocytes treated with TNF-α showed a robust increase (∼900%) in the secretion of MCP-1, induced in a dose- and time-dependent manner. Signaling of MCP-1 expression occurred through TNFR2, which was inducible by TNF-α ligand, but did not depend on TNFR1. TNF-α then proceeded via the NF-κB and the PI3K/Akt systems, based on the effectiveness of the inhibitors of those pathways. For in vivo relevance to diabetic kidney disease, TNF-α and MCP-1 levels were found to be elevated in the urine of db/db mice but not in the plasma. CONCLUSION: TNF-α potently stimulates podocytes to produce MCP-1, utilizing the TNFR2 receptor and the NF-κB and PI3K/Akt pathways. Both TNF-α and MCP-1 levels were increased in the urine of diabetic db/db mice, correlating with the severity of diabetic albuminuria.

Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice.

BACKGROUND: CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model. METHODS: Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney. RESULTS: Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment. CONCLUSION: Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.

Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely.

It is often desirable to estimate the GFR (eGFR) at the bedside to assess AKI or renal recovery. Current eGFR equations estimate kidney function when the plasma creatinine is stable, but do not work if the plasma creatinine is changing rapidly. To analyze kidney function in the acute setting, a simple formula is proposed that requires only a modest number of inputs that are readily obtainable from clinical laboratory data. The so-called kinetic eGFR (KeGFR) formula is derived from the initial creatinine content, volume of distribution, creatinine production rate, and the quantitative difference between consecutive plasma creatinines over a given time. For that period, the deciphered creatinine excretion then yields the creatinine clearance rate. The additional formula variables needed are any steady-state plasma creatinine, the corresponding eGFR by an empirical formula, and the maximum increase in creatinine per day if anuric. The kinetic formula complements clinical intuition but also adds a quantitative and visual dimension to the assessment of kidney function, demonstrated by its analysis of GFRs underlying the plasma creatinine fluctuations in several scenarios of AKI or renal recovery. Deduced from first principles regarding the physiology of creatinine balance, the KeGFR formula enhances the fundamental clearance equation with the power and versatility to estimate the kidney function when the plasma creatinine is varying acutely.

Visualizing the mouse podocyte with multiphoton microscopy.

The podocyte is a highly specialized kidney glomerular epithelial cell that plays an essential role in glomerular filtration and is believed to be the target of numerous glomerular diseases leading to proteinuria. Despite the leaps in our understanding of podocyte biology, new methodologies are needed to facilitate research into the cell. Multiphoton microscopy (MPM) was used to image the nephrin knockout/green fluorescent protein (GFP) knock-in heterozygote (Nphs1(tm1Rkl)/J) mouse. The nephrin promoter restricts GFP expression to the podocytes that fluoresce green under excitation. From the exterior of an intact kidney, MPM can peer into the renal parenchyma and visualize the podocytes that outline the globular shape of the glomeruli. Details as fine as the podocyte's secondary processes can be resolved. In contrast, podocytes exhibit no fluorescence in the wildtype mouse and are invisible to MPM. Phenotypically, there are no significant differences between wildtype and Nphs1(tm1Rkl)/J mice in body weight, urinary albumin excretion, creatinine clearance, or glomerular depth. Interestingly, the glomeruli are closer to the kidney capsule in female mice, making the gender the preferred choice for MPM. For the first time, green fluorescent podocytes in a mouse model free of confounding phenotypes can be visualized unequivocally and in the "positive" by MPM, facilitating intravital studies of the podocyte.

A glimpse of various pathogenetic mechanisms of diabetic nephropathy.

Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor ß and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.

Abnormalities in signaling pathways in diabetic nephropathy.

Diabetic nephropathy (DN) is characterized by a plethora of signaling abnormalities that together ultimately result in the clinical and pathologic hallmarks of DN, namely progressive albuminuria followed by a gradual decline in glomerular filtration rate leading to kidney failure, and accompanied by podocyte loss, progressive glomerular sclerosis and, ultimately, progressive tubulointerstitial fibrosis. Over the past few years, the general understanding of the abnormalities in signaling pathways that lead to DN has expanded considerably. In this review, some of the important pathways that appear to be involved in driving this process are discussed, with special emphasis on newer findings and insights. Newer concepts regarding signaling changes in bradykinin, mTOR, JAK/STAT, MCP-1, VEGF, endothelial nitric oxide synthase, activated protein C and other pathways are discussed.