Jacquelyn L. Bainbridge, PharmD, FCCP

• Professor, Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado

http://www.ucdenver.edu/academics/colleges/pharmacy/Departments/ClinicalPharmacy/DOCPFaculty/A-G/Pages/BainbridgeJacciPharmD.aspx

We report here an analysis of the effects of calcimimetics administration on renal fibrosis models 5 medications for hypertension purchase cytotec 100 mcg mastercard. Others believe the disease is caused by water contaminated with heavy minerals or agrochemicals medications known to cause pancreatitis generic cytotec 100mcg with mastercard. Hence medications migraine headaches cytotec 200 mcg fast delivery, even if concentrations of toxins are in "acceptable range" symptoms vomiting diarrhea purchase 200 mcg cytotec mastercard, the cumulative intake may reach toxic levels medicine for pink eye buy 100 mcg cytotec otc. If this hypothesis is correct treatment statistics buy cytotec 200mcg with visa, purified water should reduce the incidence of the disease. If toxins and agrochemical are responsible, the remedy is providing highly purified water to those at risk. Background: Human kidney contains around 1 million nephrons, more than 2 dozen different cell types. We have employed a kidney micro-organoid in suspension culture this method eventually accelerates kidney organoids to the industrial scale and differentiates from traditional low throughput transwell organoids. These observations clearly demonstrate the use of micro-kidney organoids to study renal diseases in-vitro for drug discovery applications with human translatable functional biomarkers. Conclusions: Impact statement: Kidney micro-organoids provide a platform for high throughput modeling of human kidney diseases related fibrosis, inflammation and genetic disease like polycystic kidney disease with human translatable biomarkers in drug discovery. All rats were anesthetized to collect fecal samples from large intestine directly and blood at the end of 10 weeks feeding. Bioinformatics tools, including sequence alignment, abundance, and taxonomic diversity, were used in microbiome data analyses. Correlation analysis between differential genera and changed biochemical indicators were measured. The abundance of g-Lactobacillus, g-Phascolarctobacterium and g-Ruminococcus showed no difference. Conclusions: Chronic intermittent hypoxia can interact with uromodulin to affect serum phosphorous in umod-/- rats. This process provides a molecular explanation for several previously unexplained clinical phenomena in the context of gout and renal failure. Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China, Shanghai, China. Methods: Overall, 202 patients with kidney disease underwent renal biopsy, scoring of kidney fibrosis and determination of the area of kidney fibrosis. Background: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether the biopsy measurement of tubular damage atrophy and interstitial fibrosis was associated with lower tubular secretory clearance in persons undergoing kidney biopsy. Methods: the Boston Kidney Biopsy Cohort is a prospective cohort study of persons undergoing native kidney biopsies for clinical indications. We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. Results: Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were African American. After adjusting for age, sex and race, these associations remained essentially unchanged. Phosphorus, or phosphate in its oxidized circulating form, is normally removed from the body by healthy kidneys. Methods: For in vitro experiments, human lung fibroblasts were treated with 0 to 5 mM sodium phosphate. In vivo, we placed C57Bl/6 mice on a high phosphate (3%) diet to elevate serum phosphate levels in absence of kidney injury and administered bleomycin via oropharyngeal aspiration to generate an acute pulmonary inflammatory response. Our results indicate that the existence of a pulmo-renal crosstalk is exaggerating pulmonary injury. Additionally, due to the non-linear regulation of the elements, the identification of causal variants as well as their target genes is even more challenging. Results: We identified genome-wide functional elements and thousands of interactions between the distal elements and target genes. The results revealed that risk variants for renal tumor and chronic kidney disease were enriched in kidney tubule cells. Conclusions: Our results produce valuable multi-omic resource and establish a bioinformatic pipeline in dissecting functions of kidney diseases-associated variants based on cell type-specific epigenetic landscape. Background: Oxidant stress plays a key role in the development and progression of uremic cardiomyopathy. Partial nephrectomy was performed in C57Bl6 mice in order to produce experimental uremic cardiomyopathy. Specific expression of NaKtide in adipocytes was achieved using a lentivirus construct driven by an adiponectin promoter. The overall analysis showed a widespread normalization of gene expression by pNaKtide/adipose specific NaKtide treatments that were altered in uremic cardiomyopathy. Conclusions: the study provides a detailed genome-wide molecular information about adipocyte function in relation to uremic cardiomyopathy pathogenesis. Background: the aldosterone antagonist spironolactone has antifibrotic effects but its clinical use is limited due hyperkalemia, especially in patients with kidney disease. The novel nonsteroidal and selective mineralocorticoid antagonist finerenone has recently been developed with pronounced antifibrotic activity at doses which have only limited effect on the potassium homeostasis. The exact molecular transcriptional targets of spironolactone and finerenone, however, remain unknown. Outcome parameters included blood pressure, serum and urine electrolytes, albuminuria, renal and cardiac histology. Results: Finerenone and spironolactone resulted the same degree of blood pressure reduction. Serum potassium was elevated in the spironolactone group at weeks 6, but it was unchanged compared to controls in the finerenone group. Single-nuclei open chromatin and gene expression profiling uncovered genomic alterations in different cell types in finerenone-treated kidneys. Single cell epigenome analysis highlighted transcriptional targets of aldosterone, spironolactone and finerenone. Background: Previous studies have shown that even isolated mild tubular injury leads to more severe glomerular damage in response to subsequent injury. Further experimental validation of the effects of the identified molecules on glomerular injury are warranted. It is a large molecule the administration of which leads to increased enzyme activity in plasma, but not in the urine or kidney tissue. These changes in enzymatic activities were accompanied by a significant increase in kidney Ang-(1-7) (90 vs. Rhode Island Hospital, Brown University Rnode Island Hospital, Brown University, Providence, China. Protein expression or activation was determined by immunofluorescent microscopy and immunoblot analysis. These encompassed genes with a variety of functions such as immunomodulation (Erdr1, Gp2), cytoskeletal/extracellular matrix fibers (Lama1, Cttnbp2) and signal transduction (Camk2b, Ptprn2). One down-regulated gene was a direct neighbor to the Umod locus (Gp2) on chromosome 7. Background: My previous studies have found that Intestinal macrophages in the uremic rats are polarized towards a proinflammatory phenotype and assist bacterial translocation resulting in microinflammation. However, it is still unclear what kind of mechanism activates intestinal macrophages in uremia. Methods: Male Sprague-Dawley rats were randomly divided into two groups: sham, uremia. Immunochemistry was used to analyze the expression of macrophage-inducible C-type lectin (Mincle). Conclusions: the solution to this scientific problem will not only clarify the molecular mechanism of intestinal bacteria in controlling the activation of intestinal macrophages, but also to clarify the micro-inflammation state of uremia. We saw significant metabolic activity for a wide range of metabolites: Uptake and excretion rates rapidly changed during the first 24h of culture, after which they declined. However, limited information exists on the molecular mechanisms regulating these cells. Blood pressure, urinary albumin/creatinine ratio, serum creatinine (Scr) and renal histopathology were measured. Collagen crosslinking and fibrosis progression were assessed histologically and biochemically. Background: Macrophage accumulation and activation play an essential role for kidney fibrosis, the underlying mechanisms remain to be explored. Methods: Analyzing the kidneys of patients and animal models with kidney fibrosis. These mice developed less renal fibrosis as indicated by less macrophage accumulation, tubular atrophy or extracellular matrix deposition. The histone demethylase, Jmjd3, is a transcriptional co-activator that promotes endothelial regeneration. Tongji University, Shanghai, China Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China, Shanghai, China. Background: Cisplatin is a commonly used chemotherapeutic agent with doselimiting nephrotoxicity. Other models of renal fibrosis have demonstrated that macrophages can play a pro-fibrogenic role by differentiating into myofibroblasts, the main effector of fibrotic development. Results: Flow cytometric analysis revealed significantly increased numbers of renal infiltration of Ly6C hi inflammatory monocytes and F4/80 lo infiltrating macrophages after four doses of cisplatin. These populations remained elevated above vehicle treated controls after a 6-month age out. These early events orchestrate an immune response that continues up to 6-months after cisplatin treatment. Rats (10-11 weeks old female, n=13-17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, blood pressure, proteinuria, kidney histology and gene expression. Results: Placebo-treated rats demonstrated a 50% mortality rate over the course of 7 weeks (figure). Drug treatment resulted in variable degrees of survival benefit, most prominent and statistically significant in the low dose combination group (figure). Low dose combination revealed an early, sustained and efficacious proteinuria reduction (-86%, p<0. Treatment with finerenone and the combination significantly decreased systolic blood pressure while empagliflozin alone and in combination acted strongly glucosoric. Combination of these two modes of action at low dosages revealed efficacious reduction in proteinuria and mortality indicating a strong potential for combined clinical use in respective cardiorenal patient populations. These findings underscore the major component of microvascular injury in the development of ischemic kidney disease. Wright,4 Christian Kemmer,4 Cyrille Maugeais,4 Jean-Philippe Carralot,4 Stephan Roever,4 Judith T. Pressly,1,2 Christopher Pedigo,1,2 Laura Barisoni,5 Armando Mendez,6 Jacopo Sgrignani,7 Andrea Cavalli,7,8 Sandra M. Background: Pathological accumulation of cholesterol in podocytes is associated with the progression of kidney disease. In vivo efficacy studies of Cpds A & G were conducted in mouse models of proteinuric kidney disease (Adriamycin-induced nephropathy and Alport Syndrome). This may represent a promising new therapeutic strategy for the treatment of kidney diseases and disorders of cellular cholesterol homeostasis. Here we investigated the therapeutic potential of Runcaciguat in rat models of hypertension associated chronic kidney disease. In the 8-week-treated Renin-transgenic rats, Runcaciguat significantly and dose-dependently improved mortality from 58% (placebo) to 56%, 39% and 28% (@ 1, 3, 10 mg/kg). At all tested doses, Runcaciguat significantly reduced kidney and heart hypertrophy and increased creatinine clearance. Our data strongly suggest that Runcaciguat represents a promising treatment option for hypertensive kidney disease patients. Cellular and molecular mechanisms responsible for these benefits are incompletely understood. Here we investigated potential effects and mechanisms in a relevant preclinical mouse kidney fibrosis model. Results: Myofibroblast accumulation was dose-dependently reduced in finerenonetreated mice (-22% @ 3 mg/kg, p=0. Conclusions: Finerenone has direct anti-fibrotic properties resulting in reduced myofibroblast and collagen deposition in a mouse model of progressive kidney fibrosis. Background: Metformin, first-line drug for type-2 diabetes, exerts benign pleiotropic actions beyond its prescribed use and emerging data show protective effects against the development/progression of renal impairment. Canagliflozin treatment did not alter the increase in serum creatinine as indicated by serum creatinine levels at week 8 (5. In contrast, metformin treatment almost completely prevented the increase from week 4 or 5 on, as indicated by the serum creatinine levels after 8 (2. Here we characterized the kidneyprotective properties of a recently identified, potent and selective V1a receptor antagonist. James, Pasquale Cantarella, Mark Charbonneau, Ron Shmueli, Jr Gao, Vincent Isabella, Mylene Perreault. Increased oxalate levels can lead to the formation of kidney stones and, ultimately, to kidney failure. These observations highlight the need for a treatment that targets both conditions. Mononuclear cell infiltration was also massively increased, in particular in the perivascular areas. In the liver, inflammation and fibrosis were also attenuated, specifically in the periportal zone that has been shown to be correlated with the severity of the disease.

Pfeffer M medicine to increase appetite cytotec 200mcg line, Burdmann E medicine 503 cytotec 200mcg online, Chen C treatment 7 cytotec 100 mcg amex, et al: A trial of darbepoetinalfa in type 2 diabetes and chronic kidney disease treatment x time interaction cheap 200 mcg cytotec otc, N Engl J Med 361:2019-2032 treatment uti infection cytotec 200 mcg amex, 2009 medicine yeast infection discount cytotec 100mcg free shipping. It is important to note that the distribution of pore sizes for high-flux membranes is such that it does not allow for the passage of albumin. The two major components of the hemodialysis procedure that will be discussed are the dialyzer and the dialysate. These hollow fibers are made of thin, semipermeable membranes and are encased in a plastic tubing device that allows blood to be pumped from the patient into the inside of these hollow fibers while an aqueous solution, the dialysate, is pumped outside these hollow fibers, typically in the opposite direction of the blood flow, to maximize the diffusion gradients across the membranes. The manufacturing process of these membranes is such that, regardless of whether it is a low-flux or a high-flux membrane, the pore sizes are not uniform, and there is a distribution of pore sizes that allows the diffusion or removal Diffusion describes the movement of solutes from a milieu with high concentrations across a semipermeable membrane into a milieu where it is in lower concentration. The rate and amount of solute that diffuses across the membrane in either direction depends on the difference in concentration between the blood and dialysate compartments, the molecular size of the solute, the characteristics of the membrane including its surface area, thickness, and porosity, and the conditions of flow. These membrane characteristics are generally labeled "mass transfer characteristic" or "coefficient of diffusion," and are specific for the membrane used and the solute under consideration. Using urea as the prototype solute, hemodialysis allows the movement of urea from the blood compartment, where it is in high concentration, to the dialysate compartment across the hollow fiber membranes. Thus, as blood is pumped and traverses through the dialyzer inside hollow fibers, urea concentration of the blood is reduced; concurrently, the urea concentration of the dialysate increases as it traverses outside the hollow fibers in the opposite direction. If the blood and dialysate were to flow in the same direction, then the urea concentration gradient between the blood and dialysate compartments would be considerably reduced at the exit site of the dialyzer, whereas a countercurrent flow ensures maximum difference in concentration and therefore higher flux of solute from the blood compartment; accordingly, most dialysis procedures use countercurrent flow of blood and dialysate. The principles of diffusion apply not only to urea and other solutes that have a higher concentration in the blood than dialysate, but also to the diffusion of substances that have a higher concentration in the dialysate than blood. An example of the latter is the diffusion of bicarbonate from the dialysate into the blood compartment. A useful way to express the diffusion of a substance across the dialysis membrane is termed "clearance," analogous to the clearance of solutes in the native kidney. The curves are constructed based partially on data and partially on theoretical projection. The actual values may vary depending on the surface area of the membrane and operating conditions. The curve for native glomeruli represents the summation of all the glomeruli in two normal kidneys. Clearance of solutes by diffusion (via either conventional or high-efficiency/high-flux dialysis) deteriorates rapidly with increase in molecular mass of the solute. In contrast, clearance by convection (hemofiltration or glomeruli) remains constant over a wide range of molecular mass. In Greenberg A, editor: Primer on kidney diseases, ed 4, Philadelphia, 2005, National Kidney Foundation/Saunders, ch 90. A, Low-flux membranes have small pores that are highly permeable to small solutes such as water and urea (60 Da) but restrict the transport of middle molecules such as 2-microglobulin (2M). Because of their small pores, they also tend to have low ultrafiltration coefficients, although the ultrafiltration coefficient can be increased by increasing the surface area of the membrane. A low-flux membrane can be either high efficiency or low efficiency for urea transport, depending on its surface area and, to a lesser extent, its thickness. B, High-flux membranes have large pores that facilitate the transport of middle molecules such as 2M in addition to small molecules. A high-flux membrane can be either high efficiency or low efficiency, depending on its surface area and, to a lesser extent, its thickness. In Greenberg A, editor: Primer on kidney diseases, ed 3, Philadelphia, 2001, National Kidney Foundation/Saunders, ch 47. In general, the relative contribution of convective transport to the overall clearance for small molecules, such as urea, is minor, but it is more substantial for larger molecules. Convection the simple equation for solute clearance does not take into account convective clearance of solutes. Convection refers to the mass transport of solutes along with the fluid it is dissolved in (plasma water) and is driven by the higher hydrostatic pressures in the blood compartment generated by the blood pump. The amount of solute removed by convection is not dependent on the concentration of the solute, but rather on the difference in hydrostatic pressure between the blood and dialysate compartment and the characteristic of the membrane, termed the "sieving coefficient. Because any solute removed from the blood compartment appears in the dialysate, another expression of solute clearance (K) that includes both convective and diffusive removal is based on the measurement of the concentration of that solute at the outlet of the dialysate; this is true for all solutes that are not already present in dialysate. The mass transfer coefficient is usually represented as KoA where A is the effective surface area of the specific dialyzer. B Glomerular capillary Basement membrane Bowman space Fluid reabsorption Renal tubule C Figure 58. Because of diffusive loss across the semipermeable hemodialysis membrane (dotted line), the plasma concentration in the blood outlet is much lower. The thin arrow across the dialysis membrane represents a small amount of fluid loss (which is not necessary for solute removal). A high dialysate flow rate is used to maintain the concentration gradient across the dialysis membrane for solute removal. Plasma concentrations of solutes in the blood compartment remain unchanged as blood travels the length of the fiber and are similar to their concentrations in the ultrafiltrate. The hemofiltration membrane (broken line) has relatively large pores, which allow the necessary removal of a large volume of fluid (heavy arrow). Replacement fluid is infused into the blood outlet to lower the plasma concentration of solutes and compensate for the fluid loss. Analogous to hemofiltration, plasma concentration of solutes remains unchanged throughout the length of the glomerular capillary and is similar to that in Bowman space. Fluid removal across the glomerular basement membrane (broken curve) is large (heavy arrow). Reabsorption of fluid from the renal tubules lowers the plasma concentration of the solutes. In Greenberg A, editor: Primer on kidney diseases, ed 4, Philadelphia, 2005, National Kidney Foundation, Saunders, ch 90. However, in the absence of fluid reabsorption mediated by the renal tubules in the native kidney, the hemofiltration technique relies on infusion of large amounts of fluids to replace the large convective fluid losses, generally middialyzer or at the outlet of the dialyzer. Because of the requirement of large volumes of sterile solutions to replace the ultrafiltrate, hemofiltration is not widely used for the treatment of chronic dialysis patients in the United States, and is commercially available only through one manufacturer in the United States. In this chapter, we will limit the detailed discussion to the hemodialysis procedure. Net Clearance solute (both diffusive and convective) and does not depend on the extent of partitioning of the solute between plasma water and red blood cells or on calculation of the sieving coefficient of the membrane, it is the more easily used and accurate measurement of solute clearance. Hemofiltration A technique that allows for the removal of solutes as well as plasma water primarily or solely by convection. In this technique, there is no dialysate flow, and the ultrafiltrate has the same composition as plasma water. This plateau is reached at different clearance values depending on the size of the solute and the specific membrane characteristics (porosity, thickness, surface charge, the chemical composition of the membrane, and so forth). The summative membrane characteristics are called the mass transfer coefficient (Ko). The mass transfer coefficient is specific for the membrane used and the solute being considered; for dialyzers, this is usually represented as KoA, where A is the effective surface area of the specific dialyzer. Manufacturers generally provide the KoA of the different solutes for the specific dialyzer, and the clearance of specific solutes at different blood and dialysate can be calculated from such values. However, it is important to keep in mind that these KoA values are determined by manufacturers in aqueous solutions, and will result in a higher calculated value for these solute clearances than is observed clinically. Another important caveat in the relationship between higher clearance and higher blood flow rate is the fact that, in the clinical setting, blood flow rate measured by the blood pump may not accurately represent the actual blood flow rate flowing through the hollow fibers of the dialyzer. A practical implication of these observations is that, although the clearance of most solutes theoretically increases with higher blood and dialysate flow rates, in practice the maximum prescribed blood flow rate should not exceed a rate at which the negative pre-pump pressure. Finally, although these limitations to blood flow rate do not apply to dialysate flow, there are also practical limits to increasing the dialysate flow rate; not only is the expense of preparing water for dialysate preparation increased, but, because of the limitation of the mass transfer coefficient for specific solutes and specific dialysis membranes, the optimal combination of dialysate flow is approximately 1. Thus, if the maximum blood flow rate (above which the negative arterial pressure prepump exceeds -250 mm Hg) is 350 mL/min, then the optimal dialysate flow is around 600 to 700 mL/min. Assessing the Dialysis Dose where Cpost is the urea concentration at the completion of dialysis, and Cpre is the urea concentration before the start of dialysis. The other variable that determines the net impact of solute removal from the patient by hemodialysis is the volume of distribution of the solute. Thus, the dose of dialysis is usually defined as Kt/V, where V is the volume of distribution of that particular solute. Urea has been the index molecule used to define the dose of dialysis, because it is easily measured, it is small and therefore diffuses readily across a dialysis membrane, and, importantly, its volume of distribution (total body water) can be calculated from the weight of the patient. Thus, the dose of dialysis traditionally Although solute clearance by diffusion is dependent on the size of the solute molecule, other considerations, such as the electrical charge of the molecule and its effective size, also impact the net transfer of uremic solutes across the membrane. Although phosphate has a low molecular weight and, based on its molecular size, would be expected to be easily cleared by high-flux dialysis membranes, in reality phosphate is cleared rather poorly during dialysis because of its high negative charge and the large number of water molecules that circulate with the phosphate moiety; additionally, because of the large intracellular reservoirs of phosphate and slow transfer from the intracellular to the plasma compartment, net phosphate clearance by dialysis is poor. This results in a time-dependent slow clearance during conventional dialysis, with moderate clearance and declining removal during the first 2 hours of standard hemodialysis, and negligible removal afterward. However, as discussed later, the removal of phosphates is higher during longer dialysis treatments, such as occurs with nocturnal dialysis (approximately 8 hours), because the longer dialysis time allows the timedependent transfer of phosphate from intracellular to the plasma compartment; accordingly, patients treated with nocturnal dialysis often require fewer or no phosphate binders. Extracellular Volume Control (Ultrafiltration) Another important function of hemodialysis is the removal of excess fluid that accumulates in the absence of effective kidney function. Modern dialysis equipment adjusts these hydrostatic pressure gradients by varying the negative ("suction") pressure in the dialysate compartment rather than increasing the pressure in the blood compartment; this avoids the potential for increased lysis of red blood cells. However, as this rapid transfer of plasma water occurs at the inlet of the dialyzer, the concentration of protein (oncotic pressure) rapidly rises in the blood compartment; because these proteins are also negatively charged, there is a corresponding development of a "concentration polarization," whereby there is a rapid increase in negatively charged plasma protein concentration at the membrane surface (inside the blood compartment). This has the effect of disproportionately increasing the oncotic pressure at the interface between the blood compartment and the surface of the membrane. The high oncotic pressure at the surface of these high-flux membranes inhibits further ultrafiltration to the extent that, toward the blood outlet of high-flux dialysis membranes, "reverse filtration" may occur, with dialysate solutions moving across the membrane into the blood compartment. Although there are numerous abnormalities in the concentration of various metabolites that result from kidney failure, acid-base (bicarbonate) balance and potassium concentration are examples of the use of various dialysate solutions to correct such abnormalities. One of the functions of dialysis is to compensate for this metabolic acidosis by replenishing blood bicarbonate. Most often, this is accomplished using formulations of dialysate solutions with bicarbonate concentrations, generally between 30 and 32 mEq/L. However, this product cannot simply be added as a component of dialysate, because the presence of other electrolytes needed in the dialysate (specifically calcium and magnesium) would result in their precipitation as carbonates, thereby reducing the concentration of all three components. Current dialysate delivery technology requires the preparation of two separate dialysate streams, one called "acid concentrate," which combines all the ingredients of dialysate except sodium bicarbonate, and a second stream that contains sodium bicarbonate and sodium chloride. One important detail in the choice of dialysate bicarbonate levels is the presence of acetate in the formulation of the "acid concentrate" mentioned earlier. Depending on the manufacturer and whether the concentrate is liquid or powder, most "acid concentrates" contain 4 to 8 mEq/L of acetate (acetic acid) to maintain an acidic milieu and to prevent precipitation of calcium and magnesium salts. It is important that the prescription for the dialysate bicarbonate take into consideration the concentration of the acetate, because the acetate is rapidly metabolized (Krebs cycle) to bicarbonate on a 1:1 ratio. Thus, when the dialysate prescription is for a "bicarbonate level of 35 mEq/L," the effective total buffer in the dialysate may be as high as 42 mEq/L, depending on the amount of acetate; this may result in marked postdialysis alkalemia. There are ongoing studies about the optimal concentration of total buffer, but most observation data suggest that a total buffer of around 35 to 37 mEq/L is optimal; ideally, such a concentration should be adjusted for each patient, depending on their dietary intake, protein catabolic rate, and the resulting predialysis and postdialysis bicarbonate level. In the absence of kidney function, potassium (and other electrolytes such as magnesium) accumulates in the blood; accordingly, an important function of dialysis is to reduce the potassium concentration between dialysis episodes to a level that prevents significant predialysis hyperkalemia while avoiding significant hypokalemia after dialysis. Because potassium removal depends on the difference in potassium concentration between the blood and the dialysate, in concept the simplest way in which potassium removal can be maximized is to use a dialysate potassium concentration of 0 mEq/L. In the opinion of the author, the optimal dialysate potassium for almost all patients is 2 or 3 mEq/L, and, for patients with a high predialysis potassium level, the best (safest) option is still to use a dialysate potassium of 2 or 3 mEq/L while extending the dialysis duration to remove more potassium but at a slower rate, which reduces the risk of arrhythmias. If the patient is competent to make decisions, and the patient and physician are in agreement, there is little that should stand in the way of carrying out their choice, be it for or against the initiation of dialysis. Such a discussion provides the nephrology team with an opportunity to advise the patient about In the United States, more than 40% of patients who initiate dialysis do so without previous active follow-up by nephrologists, even though most patients have had some interaction with the healthcare system before kidney failure. Even for patients who are followed by nephrologists, there may be reluctance by the patient and even by the nephrologist to discuss fully the therapeutic options for treating kidney failure. Unless such discussion occurs, the patient will typically end up on hemodialysis-ill-prepared, resentful, and depressed. A number of publications have highlighted the advantages of using the 30-20-10 "rule of thumb" for an orderly process of patient referral to a nephrologist and initiation of kidney replacement therapy. It is essential to allay the anxiety and fear common in patients nearing kidney failure. Whenever possible, family members should be included in the decision-making process, and all members of the nephrology team, including the nephrologist, nurses, social workers, transplant coordinators, and dieticians, should participate in this process. If possible, patients and interested family members should visit the dialysis unit well before requiring dialysis, as this simple exercise may help alleviate many of their fears and misconceptions. Because most patients also anticipate much pain during dialysis, it should be stressed that almost no pain is involved. The need for compliance with diet, fluid intake, medications, and dialysis schedules should be stressed, and the patient should be empowered to participate in his or her own care, helping to ensure compliance and improve satisfaction. For patients presenting with an acute need to start dialysis, one option to consider is to frame dialysis initiation specifically as a trial, stressing that the decision to initiate is temporary and should not be binding. However, if a synthetic graft is all that is possible because of poor native vasculature, backup access is not recommended, because the risk-to-benefit ratio of synthetic grafts is unacceptably high in this situation. Although access should be planned first in the nondominant arm, sites should be preserved in the other arm as well. The use of the nondominant arm is preferred, particularly for self-dialysis, as it makes self-cannulation more likely. Radial arteries and cephalic veins should be preserved except in life-threatening situations.

In an unobstructed kidney xerostomia medications that cause generic 200mcg cytotec mastercard, when glomerular filtration is disrupted tubular functions collapse symptoms appendicitis discount cytotec 100mcg amex. In prolonged obstruction of the kidney medicine qid generic cytotec 200mcg without prescription, both glomerular and tubular functions are compromised medicine x ed generic cytotec 100 mcg free shipping. Glomerular capillary blood flow and luminal pressure remain below baseline until the obstruction is relieved symptoms after flu shot purchase 200 mcg cytotec mastercard. It is during this last phase that the majority of permanent damage is done to the kidney crohns medications 6mp buy discount cytotec 100mcg line. The return to baseline function is dependent on the overall duration and severity of the initial obstruction. In the first hours after obstruction, differences between the two occur in the blood flow to the glomeruli and the ureteral pressure profiles. Between 12 and 24 hours after the initial obstruction, there is a switch from afferent arteriolar vasodilation to vasoconstriction. Triphasic relationship of left ureteral luminal pressure and left renal blood flow after occlusion of the left ureter. These events alter the amount of filtrate, the composition of the filtrate, tubular transport proteins, and tubular blood flow. The actual triggers for the loss of receptor and enzyme activity are still poorly understood. Possible signals include decreased filtrate substrates, natriuretic substances, and direct tubular hydrostatic pressure. This results in a reduction in K+ movement into the lumen, and ultimately hyperkalemia. Loss of Na+ reabsorption from the distal tubule results in impaired urinary acidification in the obstructed kidney. This decrease in cation reabsorption reduces the opposite passive excretion of H+ into the collecting duct lumen down the electrochemical gradient, and a "voltagedependent acidosis" occurs. Urinary acidification occurs in the early phases of obstruction suggesting an intact proton pump. This prevents Na+ transport from the tubular lumen into the medullary interstitium, which is critical to the countercurrent multiplier that creates the medullary gradient. Without the ability to reabsorb Na+ in the ascending limb and dilute the filtrate as it enters the distal convoluted tubule, the solutes required to maintain the gradient are excreted. Urea recycling is another process used by the nephron to increase the gradient for urinary concentration. Urea within the filtrate passively exits the collecting duct at its inner medullary segment and enters the interstitium. A maximum medullary interstitial osmotic gradient is created with the recycling of urea. This urea transporter defect reduces the maximal concentrating effect of the gradient by disrupting urea recycling and allowing urea to be excreted. The activated pathways producing fibrosis do not differ significantly from fibrosis noted with other disease processes. At the cellular level, there is an increase in the number of fibroblast and myofibroblasts. Epithelial tubular cells and endothelial cells transform into mesenchymal cells, losing their epithelial or endothelial phenotype. There are no good data that support medical intervention to block these pathways in the hope of reducing kidney scarring. Aggressive rehydration to "chase" the volume of fluid excreted, rather than kidney pathology, results in "iatrogenic" diuresis after relief of obstruction. Initial treatment is the same as in physiologic postobstructive diuresis, with resuscitation with water and electrolytes and frequent measurement of serum and electrolytes. In severe cases, laboratory testing every 4 to 6 hours may be required until a stable balance has been created with diet, fluid, and electrolyte therapy. During obstruction, apoptosis is increased through external and internal cellular signals. Intrinsic activation occurs from oxidative stress, which causes intracellular release of a number of substances from damaged organelle. Mitrochondrial release of cytochrome-c is a known trigger in many organ systems for apoptosis, and this occurs within the kidney. The external and internal pathways converge on a single pathway to continue apoptosis through effector caspases, which cleave the nucleus to create apoptotic bodies. There are 12 different caspases, with 3, 8, and 12 identified within the obstructed kidney tissue. Rarely, urethral stones, generally from prior stricture disease or surgical reconstruction, occlude the urethra or meatus. Stones in the calyces from infundibular stenosis produce pain and infection but do not produce obstructive uropathy. The location of the infundibulum deep within the renal parenchyma makes open surgical management difficult. Endoscopic laser ablation of the calyx may be considered with obliteration of the calyx and resulting loss of function of that portion of the kidney to prevent future obstruction, infection, and pain. Once within the renal pelvis, a small calcification can form a nidus to create a larger obstructing stone. The retroperitoneal location of the kidney, away from other vital structures and bowel gas, allows for shock waves to penetrate the kidney and fragment the stone. Larger stones require prolonged and repetitive shock-wave treatment, which may damage the surrounding parenchyma. Ureteroscopy is a very effective technique (greater than 85% success) in selected cases. It treats the stone and allows for direct visualization of the ureter and renal pelvis. This ensures there is no structural pathology that may have predisposed the patient to produce the original stone. The rate of diuresis is based on the severity of volume overload, urea accumulation, and electrolyte disturbances that occurred during obstruction. Before release of the obstruction, there is a downregulation of the Na+ transporters, and the inability to reabsorb Na+ diminishes the osmotic gradient necessary for urinary concentration. In the distal tubule, downregulation and reduced aquaporin activity promote aquaresis. In the postsurgical patient who is unable to drink, approximately 75% of the urine volume is replaced with 0. Ureteroscopy becomes the treatment of choice for the majority of mid- and lowerureteral stones. Retrograde access is again the preferred choice, but antegrade access through the renal pelvis and down the ureter can be performed. Balloon dilation with a simultaneous full-thickness wall incision of the stricture is a good option. Postprocedure, temporary stenting facilitates drainage and minimizes extravasation of acidic urine, which can impair healing and result in restenosis. Extensive stricture disease of the ureter or urethra from tuberculosis, infection, or malignancy may require open surgical resection of the diseased portion with reanastomosis. It is a friable, frondular tumor with a solid stalk found primarily in older patients with a history of tobacco use. Treatment of obstruction is dependent on tumor location; those that fill the renal pelvis can be treated initially with a ureteral stent. Initial treatment includes an attempt with local cystoscopic excision or unroofing the orifice. When unresectable by cystoscopy, a temporizing stent or nephrostomy tube can be placed until surgical reconstruction with ureteral reimplantation and possible cystectomy can be completed. Retroperitoneal adenopathy along the aorta or vena cava adjacent to the ureter can also produce obstruction. Large pelvic masses may obliterate the normal anatomy of the bladder and ureteral orifices. The relatively slow and gradual prostatic enlargement can come from benign or malignant causes. The chronic increase in voiding pressure produces a hydrostatic stress to the smooth muscles of the bladder, resulting in bladder muscle hypertrophy. A subsequent increase in fibroblast and smooth muscle results in bladder wall trabeculations and eventual bladder wall deterioration. The loss of muscle tone culminates in bladder dysfunction with the ultimate cause of the uropathy being urinary retention. It is this bladder deterioration that produces the functional obstruction and uropathy. Chronic elevated bladder resting pressures above 40 cm H2O can also produce obstructive uropathy from disrupted ureteral peristalsis. This increases the size of the urethral lumen and allows voiding pressures to decrease. Spinal cord trauma and myelomeningocele are the most common causes of neurogenic bladder in the adult and pediatric population, respectively. The voiding reflex in the normal adult relaxes the urinary sphincter during bladder contraction. The bladder fills to a maximum safe volume, but the patient does not recognize the continued urine production. Incontinent diversions, such as ileal conduits or cutaneous ureterostomies, are other options. Many patients prefer a continent reconstruction with intermittent catheterization through the urethra or cutaneous stoma, such as a Mitrofanoff or Indiana Pouch. Upper urinary tract deterioration with hydroureteronephrosis is generally seen before the irreversible uropathy. High resting pressures and dysfunctional voiding result in bladder trabeculations and cellules, with the development of secondary grade 5 reflux. Patients presenting with pain, infection, or reduced kidney function should be surgically repaired. Asymptomatic abnormalities identified incidentally do not always require treatment. In the adult, there are several anatomic defects that can obstruct the urinary system. Chronic intermittent flank pain previously believed to be of gastrointestinal origin is another common presentation. Treatment of stones and infection will improve the symptoms, but recurrent stone formation or infection is common. Open surgery or laparoscopic pyeloplasty is an excellent option for reconstruction, approaching a 95% to 97% success rate. Determination of a functional problem may require a furosemide nuclear scan to examine if kidney dysfunction is caused by obstruction. In a cooperative adult, it is possible to recreate pain during the high urinary flow of the furosemide phase of the study. In the rare equivocal patient with intermittent pain, an indwelling double-J stent can be placed to bypass a possible obstruction to observe if the pain is relieved. The distal ureteral narrowing is to the right with proximal healthy, but dilated, vascularized ureter to the left. Hydronephrosis occurs in 40% to 100% of pregnant women depending on the amount of dilation considered abnormal. Postpartum dilation may be seen for up to 6 weeks and is not considered pathologic. Two mechanisms contribute to the hydroureteronephrosis of pregnancy: ureteral compression and hormonal relaxation. By the twentieth week, the gravid uterus achieves adequate size to reach the pelvic rim and extrinsically compress the ureter producing a partial mechanical obstruction. The right kidney is more likely to be dilated because of the position of the uterus. A total of 10% to 15% of women will have hydronephrosis during the first trimester. Hormones present during pregnancy, including estrogen and progesterone that relax the smooth muscle of the ureters, also contribute to hydroureteronephrosis. Identification of hydronephrosis frequently occurs during routine prenatal ultrasound. Follow-up for even moderate hydroureteronephrosis is not needed unless the individual becomes symptomatic. Treatment of true obstruction from severe extrinsic compression or nephrolithiasis can be performed cystoscopically with ureteral stent placement. Early stent encrustation does occur and will require frequent stent exchange to prevent stent obstruction. Prenatal obstruction from a congenital defect can produce dramatic damage to the urinary tract and kidney function. Fortunately, in the majority of children with prenatal hydronephrosis, postnatal development of the urinary tract in the first year results in self-correction of the defect, and a normal unaffected urinary system develops. The goal of managing prenatal congenital defects is to identify the 10% to 30% that will develop progressive disease if left untreated. Dramatic hydronephrosis with parenchymal thinning can be monitored if kidney function is comparable to the unaffected contralateral kidney. Laparoscopic pyeloplasty is an excellent technique, except in children less than 1 year old where a slightly higher failure rate is seen. Active infection requires close management with early surgical intervention for any systemic progression of illness.

The uptake and catabolism of these proteins are very efficient medications multiple sclerosis cheap cytotec 100mcg visa, with the kidney readily handling approximately 500 mg of free light chains that are produced daily by the normal lymphoid system medicine 54 543 discount cytotec 200mcg fast delivery. However treatment quadratus lumborum cheap cytotec 200 mcg online, in the setting of a monoclonal gammopathy medications during breastfeeding order cytotec 100 mcg otc, production of monoclonal light chains increases symptoms menopause purchase cytotec 200 mcg with mastercard, and binding of light chains to the megalin-cubilin complex can become saturated symptoms 3 days before period buy cytotec 100mcg with mastercard, allowing light chains to be delivered to the distal nephron and to appear in the urine as Bence Jones proteins. Light chains can be isotyped as kappa or lambda based on sequence variations in the constant region of the protein. Thus, although possessing similar structures and biochemical properties, no two light chains are identical; however, there are enough sequence similarities among light chains to permit categorizing them into subgroups. Free light chains, particularly the isotype, often homodimerize before secretion into the circulation. The multiple kidney lesions from monoclonal light-chain deposition affect virtually every compartment of the kidney (see Box 26. A classic kidney presentation of multiple myeloma is Fanconi syndrome, which is produced almost exclusively by members of the I subfamily. The qualitative urine dipstick test for protein also has a low sensitivity for detection of light chains. Although some Bence Jones proteins react with the chemical impregnated onto the strip, other light chains cannot be detected; the net charge of the protein may be an important determinant of this interaction. Because of the relative insensitivity of routine serum protein electrophoresis and urinary protein electrophoresis for free light chains, these tests are not recommended as screening tools in the diagnostic evaluation of the underlying etiology of renal disease. Highly sensitive and reliable immunoassays are available to detect the presence of monoclonal light chains in the urine and serum and are adequate tests for screening when both urine and serum are examined. When a clone of plasma cells exists, significant amounts of monoclonal light chains appear in the circulation and the urine. In healthy adults, the urinary concentration of polyclonal light-chain proteins is about 2. Causes of monoclonal light-chain proteinuria, a hallmark of plasma cell dyscrasias, are listed (Box 26. Immunofixation electrophoresis is sensitive and detects monoclonal light chains and immunoglobulins even in very low concentrations, but it is a qualitative assay that may be limited by interobserver variation. A nephelometric assay that quantifies serum free and light chains is also useful to nephrologists, because most of the kidney lesions in paraproteinemias are caused by light-chain overproduction and much less commonly heavy chains or intact immunoglobulins. Because an excess of light chains, compared to heavy chains, is synthesized and released into the circulation, this sensitive assay detects small amounts of serum polyclonal free light chains in healthy individuals. This assay can also distinguish polyclonal from monoclonal light chains and further quantifies the free light-chain level in the serum. In the evaluation of kidney disease, particularly if amyloidosis is suspected, perhaps the ideal screening tests for an associated plasma cell dyscrasia include immunofixation electrophoresis of serum and urine and quantification of serum free and light chains. They are named according to the precursor protein that polymerizes to produce amyloid. The identification of the type of amyloid protein is an essential first step in the management of these patients. Cardiac infiltration frequently produces congestive heart failure and is a common presenting manifestation of primary amyloidosis. Infiltration of the lungs and gastrointestinal tract is also common, but often produces few clinical manifestations. Dysesthesias, orthostatic hypotension, diarrhea, and bladder dysfunction from peripheral and autonomic neuropathies can occur. Amyloid deposition can also produce an arthropathy that resembles rheumatoid arthritis, a bleeding diathesis, and a variety of skin manifestations that include purpura. In the early stage, amyloid deposits are usually found in the mesangium and are not associated with an increase in mesangial cellularity. Deposits may also be seen along the subepithelial space of capillary loops and may penetrate the glomerular basement membrane in more advanced stages. Immunohistochemistry demonstrates that the deposits consist of light chains, although the sensitivity of this test is not high. Amyloid has characteristic tinctorial properties and stains with Congo red, which produces an apple-green birefringence when the tissue section is examined under polarized light and with thioflavins T and S. On electron microscopy, the deposits are characteristic, randomly oriented, nonbranching fibrils 7 to 10 nm in diameter. In some cases of early amyloidosis, glomeruli may appear normal on light microscopy; however, careful examination can identify scattered monotypic light chains on immunofluorescence microscopy. In uncertain cases, the amyloid can be extracted from tissue and examined using tandem mass spectrometry to determine the chemical composition of the Figure 26. Note: From +, uncommon but can occur during the course of the disease, through ++++, extremely common during the course of the disease. As the disease advances, mesangial deposits progressively enlarge to form nodules of amyloid protein that compress the filtering surfaces of the glomeruli and cause renal failure. Proteinuria ranges from asymptomatic nonnephrotic proteinuria to nephrotic syndrome. Reduced kidney function is present in 58% to 70% of patients at the time of diagnosis. Scintigraphy using 123I-labeled serum amyloid P component, which binds to amyloid, can assess the degree of organ involvement from amyloid infiltration, but this test is not currently widely available. Internalization and processing of light chains by mesangial cells produce amyloid in vitro. Presumably, intracellular oxidation or partial proteolysis of light chains allows formation of amyloid, which is then extruded into the extracellular space. With continued production of amyloid, the mesangium expands, compressing the filtering surface of the glomeruli and producing progressive renal failure. There is evidence that amyloidogenic light chains also have intrinsic biological activity that modulates cell function independently of amyloid formation. Almost half achieved a complete hematologic response, which portended improved long-term survival. Isolated deposition of monoclonal heavy chains, termed heavy-chain deposition disease, is extremely rare. These nodules, which are composed of light chains and extracellular matrix proteins, begin in the mesangium. Immunofluorescence microscopy demonstrates the presence of monotypic light chains in the glomeruli. Under electron microscopy, deposits of light-chain proteins are present in a subendothelial position along the glomerular capillary wall, along the outer aspect of tubular basement membranes, and in the mesangium. The response to monoclonal light-chain deposition includes expansion of the mesangium by extracellular matrix proteins to form nodules and eventually glomerular sclerosis. Although deposition of light chain is the prominent feature of these glomerular lesions, both heavy chains and light chains can be identified in the deposits. In these specimens, the punctate electron-dense deposits appear larger and more extensive than deposits that contain only light chains, but it is unclear whether the clinical course of these patients differs from the course of isolated light-chain deposition without heavy-chain components, and the management is similar. However, patients appear to benefit from the same therapeutic approach as that administered for multiple myeloma. The serum creatinine concentration at presentation is an important predictor of subsequent outcome, so intervention should be early in the course of the disease. Melphalan/prednisone therapy improves kidney prognosis, but the long-term toxicity of melphalan makes this approach less attractive. The novel chemotherapeutic agents that include thalidomide- and bortezomib-based regimens also appear to have efficacy in this setting. This glycoprotein is a constituent of normal human glomerular basement membrane and elastic fibrils. The presence of albuminuria and other findings of nephrotic syndrome are important clues to the presence of glomerular injury and not cast nephropathy. The amount of excreted light chain is usually less than that found in cast nephropathy and can be difficult to detect in some patients. Because kidney manifestations generally predominate and are often the sole presenting features, it is not uncommon for nephrologists to diagnose the plasma cell dyscrasia. Other organ dysfunction, especially liver and heart, can develop and is related to deposition of light chains in those organs. Unlike amyloid, these fibrils are thicker (18 to 22 nm) and Congo red and thioflavin T stains are negative. Most patients with fibrillary glomerulonephritis do not have a plasma cell dyscrasia; however, occasionally a plasma cell dyscrasia is present, so screening is advisable. Patients typically manifest nephrotic syndrome and varying degrees of renal failure; progression to end-stage renal failure is the rule. Immunotactoid, or microtubular, glomerulopathy is even more uncommon than fibrillary glomerulonephritis and is usually associated with a plasma cell dyscrasia or other lymphoproliferative disorder. The deposits in this lesion contain thick (greater than 30 nm), organized, microtubular structures that are located in the mesangium and along capillary walls. Cryoglobulinemia, which is discussed in Chapter 28, should be considered in the differential diagnosis and should be ruled out clinically. Treatment of the underlying plasma cell dyscrasia is indicated for this rare disorder. Characteristically, multiple intraluminal proteinaceous casts are identified mainly in the distal portion of the nephrons. The casts are usually acellular, homogeneous, and eosinophilic with multiple fracture lines. Immunofluorescence and immunoelectron microscopy confirm that the casts contain light chains and Tamm-Horsfall glycoprotein. Persistence of the casts produces giant cell inflammation and tubular atrophy that typify myeloma kidney. Note the randomly arranged relatively straight fibrils with an approximate diameter of 7 to 10 nm (arrows). A useful distinction from fibrillary glomerulonephritis (B) is that amyloid fibrils will stain with Congo red or thioflavin T. B, Electron micrograph of a glomerulus from a patient with fibrillary glomerulonephritis. Careful examination demonstrates that the fibrils are larger (approximately 20 nm in diameter). The overall ultrastructural appearance resembles amyloid except that the fibrils are approximately twice as thick. Charles Jennette, Department of Pathology, University of North Carolina at Chapel Hill. The findings include tubules filled with cast material (arrows) and presence of multinucleated giant cells. However, many patients present to nephrologists primarily with symptoms of renal failure or undefined proteinuria; further evaluation then confirms a malignant process. Cast nephropathy should therefore be considered when proteinuria (often more than 3 g/day), particularly without concomitant hypoalbuminemia or albuminuria, is found in a patient who is in the fourth decade of life or older. Diagnosis of myeloma may be confirmed by finding monoclonal immunoglobulins or light chains in the serum and urine and by bone marrow examination, although typical intraluminal cast formation on kidney biopsy is virtually pathognomonic. Nearly all patients with cast nephropathy have detectable monoclonal light chains in the urine or blood. Myeloma casts contain Tamm-Horsfall glycoprotein and occur initially in the distal nephron, which provides an optimum environment for precipitation with free light chains. Casts occur primarily because light chains coaggregate with Tamm-Horsfall glycoprotein. Tamm-Horsfall glycoprotein, which is synthesized exclusively by cells of the thick ascending limb of the loop of Henle, comprises the major fraction of total urinary protein in healthy individuals and is the predominant constituent of urinary casts. Cast-forming Bence Jones proteins bind to the same site on the peptide backbone of Tamm-Horsfall glycoprotein; binding results in coaggregation of these proteins and subsequent occlusion of the tubule lumen by the precipitated protein complexes. Coaggregation of Tamm-Horsfall glycoprotein with light chains also depends on the ionic environment and the physicochemical properties of the light chain, and not all patients with myeloma develop cast nephropathy, even when the urinary excretion of light chains is high. Increasing concentrations of sodium chloride or calcium, but not magnesium, facilitate coaggregation. The loop diuretic, furosemide, augments coaggregation and accelerates intraluminal obstruction in vivo in the rat. Finally, the lower tubule fluid flow rates of the distal nephron allow more time for light chains to interact with Tamm-Horsfall glycoprotein and subsequently to obstruct the tubular lumen. Conditions that further reduce flow rates, such as volume depletion, can accelerate tubule obstruction or convert nontoxic light chains into cast-forming proteins. Volume depletion and hypercalcemia are recognized factors that promote acute kidney injury from cast nephropathy. Prompt and effective chemotherapy should start on diagnosis of multiple myeloma, which is present in virtually all patients with cast nephropathy. An advantage with a more aggressive approach is the potential for rapid reductions in the levels of circulating monoclonal light chain. Other therapeutic approaches have been attempted, but they currently lack randomized controlled trials to support their use. For example, patients with advanced kidney failure and refractory myeloma have been treated successfully with bortezomib- and thalidomide-based therapies. Nonmyeloablative allogeneic stem-cell transplantation, so-called mini-allograft therapy, may also provide beneficial results in myeloma without the attendant complications such as severe graft-versus-host disease. Studies suggest that interstitial fibrosis can develop rapidly in cast nephropathy, promoting persistent and ultimately irreversible kidney failure. Because clinical evidence suggests that prompt reduction in circulating free light chains accelerates renal recovery in cast nephropathy, the delay in reduction of free light-chain levels associated with chemotherapy has provoked exploration of extracorporeal removal of circulating free light chains, with mixed results. For example, kidney biopsy to document cast nephropathy was not a prerequisite for entry into the study. In addition, the study may have been underpowered to detect differences between the groups. Although these early and important studies support this technique for rapid reduction in serum lightchain concentrations, randomized trials, which are ongoing, should inform medical practice.

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