The Kinetics of Cystatin C: A Marker for Dialysis Adequacy

When 90% or more of native kidney function is lost, renal replacement therapy must be initiated to sustain life. Renal transplantation is the preferred method, but availability is limited. The ideal dialysis prescription remains elusive. Small molecular weight molecules (such as urea and creatinine) have been used as markers of both kidney (native and transplant) and dialysis toxin clearance (function), but there are pitfalls in using these markers to assess total ‘renal’ dose (kidney plus dialysis). Body weight, gender and other factors also affect the concentrations of these small molecules, but not cystatin C. Furthermore, cystatin C has been shown to be a better marker for estimating kidney function than creatinine, and is associated with cardiovascular morbidity and mortality. Studies have shown that it is removed by dialysis. Therefore, we investigated the use of cystatin C, a naturally occurring endogenous protein, as a marker for estimating dialysis adequacy and renal clearance. This investigation was comprised of four studies to understand the kinetics of cystatin C in patients with advanced kidney disease with or without dialysis. We found that the amount of cystatin C reduction was influenced positively by hemodialysis blood flow rate and treatment time, and negatively by ultrafiltration rate. We further demonstrated that renal hyperfiltration significantly influenced the error of creatinine-based glomerular filtrate rate equation, but not for the cystatin C equation. Therefore, cystatin C appears to be a useful marker for the assessment of kidney function in patients with advanced kidney disease but not yet on dialysis. This was taken further in our third study where we developed an equation, which gave a better estimate of residual renal function than previously published equations in patients on dialysis but who have some remaining kidney function. Finally, we confirmed our hypothesis that cystatin C is cleared during dialysis by both diffusion and convection. It is distributed mainly in the extracellular space but equilibrates slowly between the extravascular and intravascular spaces. Furthermore, we have shown that cystatin C while cleared by dialysis is stable between dialysis treatments rather than being influenced by a single dialysis treatment. It is a marker for both dialysis and renal clearances and, thus, gives a stable index of total renal clearance. The long term goal will be to define the cystatin C threshold level that influences patient morbidity and mortality and to allow better dialysis prescriptions for patients with varying (and changing) residual renal function

Hemodialysis in children: general practical guidelines

Over the past 20 years children have benefited from major improvements in both technology and clinical management of dialysis. Morbidity during dialysis sessions has decreased with seizures being exceptional and hypotensive episodes rare. Pain and discomfort have been reduced with the use of chronic internal jugular venous catheters and anesthetic creams for fistula puncture. Non-invasive technologies to assess patient target dry weight and access flow can significantly reduce patient morbidity and health care costs. The development of urea kinetic modeling enables calculation of the dialysis dose delivery, Kt/V, and an indirect assessment of the intake. Nutritional assessment and support are of major importance for the growing child. Even if the validity of these “urea only” data is questioned, their analysis provides information useful for follow-up. Newer machines provide more precise control of ultrafiltration by volumetric assessment and continuous blood volume monitoring during dialysis sessions. Buffered bicarbonate solutions are now standard and more biocompatible synthetic membranes and specific small size material dialyzers and tubing have been developed for young infants. More recently, the concept of “ultrapure” dialysate, i.e. free from microbiological contamination and endotoxins, has developed. This will enable the use of hemodiafiltration, especially with the on-line option, which has many theoretical advantages and should be considered in the case of maximum/optimum dialysis need. Although the optimum dialysis dose requirement for children remains uncertain, reports of longer duration and/or daily dialysis show they are more effective for phosphate control than conventional hemodialysis and should be considered at least for some high-risk patients with cardiovascular impairment. In children hemodialysis has to be individualized and viewed as an “integrated therapy” considering their long-term exposure to chronic renal failure treatment. Dialysis is seen only as a temporary measure for children compared with renal transplantation because this enables the best chance of rehabilitation in terms of educational and psychosocial functioning. In long term chronic dialysis, however, the highest standards should be applied to these children to preserve their future “cardiovascular life” which might include more dialysis time and on-line hemodiafiltration with synthetic high flux membranes if we are able to improve on the rather restricted concept of small-solute urea dialysis clearance

IMPROVING HEMODIALYSIS TREATMENT: MODELING, EXPERIMENTAL DESIGN, AND CLINICAL STUDIES

Ph.DDOCTOR OF PHILOSOPH

Mathematical modelling of microcirculation in a poroelastic model of the liver, and its application to the study of ascites

The liver performs many vital functions in the body and has a natural ability to regenerate itself, except in the case of repeated or severe damage often caused by liver diseases. Damage due to liver disease occurs in the form of scarring of healthy liver tissue, a process known as fibrosis. Chronic fibrosis can lead to liver cirrhosis, a condition that is irreversible and often requires liver transplantation. Cirrhosis manifests itself in the form of increased tissue stiffness and decreased tissue permeability, which then leads to a marked decrease in blood perfusion and functioning of the liver tissue. As a homeostatic response, hepatic portal blood pressure also increases, which then leads to an increased outflow of excess interstitial fluid across the surface of the liver and into the surrounding peritoneal cavity. The abnormal accumulation of fluid in the peritoneal cavity is known as ascites and is characterised by large abdominal girth, abdominal pain and discomfort. The aim of this thesis was to model the microcirculation of blood and interstitial fluid in the liver, so as to investigate the changes in vasculature that lead to impaired blood perfusion and the formation of ascites. To that end, we have developed a dual-porosity, dual-permeability deformable model of the liver tissue using the Biot theory of poroelasticity. We then used the model as part of a compartmental model of the peritoneal cavity and investigated the effect of liver disease (fibrosis/cirrhosis) on the accumulation of fluid in the peritoneal cavity. By varying the degree of liver tissue stiffness, we simulated and compared different stages of liver fibrosis, as well as predicted the severity of the resulting ascites. This makes our model an improvement on the current literature, with the aim of future use in informing and improving disease treatment strategies.Open Acces

Intraperitoneal chemotherapy for peritoneal metastases : an expert opinion

Introduction: The rationale for intraperitoneal (IP) drug delivery for patients with peritoneal metastases (PM) is based on the pharmacokinetic advantage resulting from the peritoneal-plasma barrier, and on the potential to adequately treat small, poorly vascularized PM. Despite a history of more than three decades, many aspects of IP drug delivery remain poorly studied. Areas covered: We outline the anatomy and physiology of the peritoneal cavity, including the pharmacokinetics of IP drug delivery. We discuss transport mechanisms governing tissue penetration of IP chemotherapy, and how these are affected by the biomechanical properties of the tumor stroma. We provide an overview of the current clinical evidence on IP chemotherapy in ovarian, colorectal, and gastric cancer. We discuss the current limitations of IP drug delivery and propose several potential areas of progress. Expert opinion: The potential of IP drug delivery is hampered by off-label use of drugs developed for systemic therapy. The efficacy of IP chemotherapy for PM depends on cancer type, disease extent, and mode of drug delivery. Results from ongoing randomized trials will allow to better delineate the potential of IP chemotherapy. Promising approaches include IP aerosol therapy, prolonged delivery platforms such as gels or biomaterials, and the use of nanomedicine

Progress in Hemodialysis

Hemodialysis (HD) represents the first successful long-term substitutive therapy with an artificial organ for severe failure of a vital organ. Because HD was started many decades ago, a book on HD may not appear to be up-to-date. Indeed, HD covers many basic and clinical aspects and this book reflects the rapid expansion of new and controversial aspects either in the biotechnological or in the clinical field. This book revises new technologies and therapeutic options to improve dialysis treatment of uremic patients. This book consists of three parts: modeling, methods and technique, prognosis and complications

Bioimpedance as a predictor of survival in renal failure and associated comorbidities.

Background: Renal failure requiring dialysis is associated with a high mortality. One of the contributing causes is overhydration. Overhydration can be assessed by bioimpedance analysis (BIA)– the non-invasive electrical measure of small current through the tissues that estimates the proportion of fluid that is intracellular water (ICW, typically muscle which is healthy) and extracellular (ECW, which in excess causes tissue oedema and is potentially dangerous). Several studies indicate that a extracellular water to total body water (TBW) ratio is associated with increased risk of death in dialysis patients but it is not clear if this is independent of other risk factors for death, namely comorbidity. Aims and objectives: To establish the prognostic value of BIA in the prediction of survival on dialysis in the context of other known predictors of survival or hospitalisation. With further analysis of the applicability of the same scenario to heart failure patients. Methodology: To conduct a systematic review using a standardised approach including a prespecified research question, search terms and criteria for study inclusion. With independent selection for inclusion in the study and quality appraisal by multiple authors with different backgrounds and experience. Results: 2701 studies identified by literature search, plus an additional 4 through reference checking. 38 papers included in final analysis, 4 of which were regarding heart failure cohorts. Analysis of the research shows that BIA is an independent predictor of mortality. Conclusion: BIA shown to be an independent predictor of mortality in dialysis patients, further research needed to extrapolate to heart failure (HF) populations