Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Inflammation from sterile dialysis solutions and the longevity of the peritoneal barrier.

There now exists a significant amount of evidence from both animal and human studies that commercially-available dialysis solutions result in the changes of the peritoneal barrier. Mesothelial cells undergo an epithelial-to-mesenchymal transition after less than one year of dialysis. After more than 6 years of peritoneal dialysis, there is extensive fibrosis and vasculopathy in the submesothelial compact zone. Clinical studies demonstrate that the structural changes apparently correlate with alterations in transport function and progressive ultrafiltration failure. The possible mechanisms of inflammation include macrophage peroxide production, acidic dialysis solutions, glucose and its degradation products, the presence of a foreign body, and the integrated signaling of the chemokine-cytokine cascade of the peritoneal cellular immune response in conjunction with biofilm on the peritoneal catheter. Basic and translational research efforts are discussed to portray our current knowledge in this area and to outline the remaining questions.

Distributed model of peritoneal fluid absorption.

The process of water reabsorption from the peritoneal cavity into the surrounding tissue substantially decreases the net ultrafiltration in patients on peritoneal dialysis. The goal of this study was to propose a mathematical model based on data from clinical studies and animal experiments to describe the changes in absorption rate, interstitial hydrostatic pressure, and tissue hydration caused by increased intraperitoneal pressure after the initiation of peritoneal dialysis. The model describes water transport through a deformable, porous tissue after infusion of isotonic solution into the peritoneal cavity. Blood capillary and lymphatic vessels are assumed to be uniformly distributed within the tissue. Starling's law is applied for a description of fluid transport through the capillary wall, and the transport within the interstitium is modeled by Darcy's law. Transport parameters such as interstitial fluid volume ratio, tissue hydraulic conductance, and lymphatic absorption in the tissue are dependent on local interstitial pressure. Numerical simulations show the strong dependence of fluid absorption and tissue hydration on the values of intraperitoneal pressure. Our results predict that in the steady state only approximately 20-40% of the fluid that flows into the tissue from the peritoneal cavity is absorbed by the lymphatics situated in the tissue, whereas the larger (60-80%) part of the fluid is absorbed by the blood capillaries.

Transport of protein in the abdominal wall during intraperitoneal therapy. I. Theoretical approach.

Intraperitoneal therapies such as peritoneal dialysis or regional chemotherapy use large volumes of solution within the peritoneal cavity. These volumes increase intraperitoneal hydrostatic pressure (P(ip)), which causes flow of the solution into tissues that surround the cavity. The goal of this paper is to integrate new experimental findings in a rigorous mathematical model to predict protein transport from the cavity into tissue. The model describes non-steady-state diffusion and convection of protein through a deformable porous medium with simultaneous exchange with the microcirculation and local tissue binding. Model parameters are dependent on local tissue pressure, which varies with P(ip). Solute interactions with the tissue in terms of local distribution volume (solute void space), local binding, and retardation relative to solvent flow are demonstrated to be major determinants of tissue concentration profiles and protein penetration from the peritoneal cavity. The model predicts the rate of fluid loss from the cavity to the abdominal wall in dialysis patients to be 94 ml/h, within the observed range of 60-100 ml/h. The model is fitted to published transport data of IgG, and the retardation coefficient f is estimated to be 0.3, which markedly reduces the rate of protein penetration and is far lower than previously published estimates. With the value of f = 0.3, model calculations predict that P(ip) of 4.4 mmHg and dialysis duration of 24 h result in several millimeters of protein penetration into the tissue.

The role of extracellular matrix in transperitoneal transport of water and solutes.

OBJECTIVE: To define the extracellular matrix (ECM), to discuss the physical properties of its components and their impact on transport, and to review data in humans and in animals on the importance of hyaluronan to peritoneal dialysis. METHODS: Literature survey. RESULTS: The ECM fills the interstitium between parenchymal cells and blood vessels in the subperitoneal interstitium. It is responsible for the interstitial resistance to solute and water transfer through the peritoneal barrier. Major components are collagen and hyaluronan, which are synthesized locally in the peritoneal tissue. Synthesis and deposition of these components increase with inflammation, and concentrations of the components influence the mechanical properties of the tissue and the interstitial Starling forces as well as transport. Removal of hyaluronan appears to increase the rates of water and large-solute transport. Addition of hyaluronan to dialysate appears to enhance fluid recovery and to reduce protein loss. CONCLUSION: Many of the physicochemical properties of ECM components are well described, but a large knowledge gap remains concerning the in vivo consequences of specific alterations in the interstitial components. More research is needed.

In vivo peritoneal chamber: linking structure and transport function.

OBJECTIVE: The present study aimed to develop an animal model of chronic peritoneal exposure that directly links transport with the tissue involved. METHODS: Daily, rats were intraperitoneally infused through subcutaneous ports with 20 mL of these solutions: isotonic Krebs (K), K + 2.5% mannitol (M), K + 2.5% N-acetylglucosamine (NAG). Controls included catheter-only (CC) and age-control rats (AC). After 2 months, each rat was anesthetized and a plastic chamber was affixed to the abdominal wall serosa to isolate a portion of the peritoneum for transport studies. In the first 90 minutes, a hypertonic solution (approximately 500 mosm/kg) containing 14C-mannitol was placed in chamber. The volume and 14C concentration were measured to determine the rate of osmotic flux (flow/Area(chamber)) into the chamber and the flux of mannitol from the chamber to the tissue. At 90 minutes, fluorescein isothiocyanate conjugate (FITC)-albumin was given intravenously. The rate of appearance of that substance in the chamber was measured over a period of 180 minutes and divided by Area(chamber) to determine the average flux. After the rat was humanely killed, the tissue under the chamber was collected for analysis of its hyaluronan concentration ([HA]). RESULTS: All data are given as mean +/- standard error: [table: see text]. CONCLUSIONS: In the present pilot study, no significant correlations were observed, but the number of animals in each group was small (n = 3-4). Nevertheless, the results demonstrate the ability of the chamber technique to determine transperitoneal transport of water, small solutes, and protein, and to link those values directly to the structure of the tissue lying below the chamber. Thus, chronic treatment can be directly correlated with peritoneal structure and transport function.

Effect of intraperitoneal pressures on tissue water of the abdominal muscle.

A major factor that affects solute and water transport through tissue is the state of tissue hydration. The amount of interstitial water directly affects the transport coefficients for both diffusion and convection. To investigate the effect of simultaneous exposure of tissue to hydrostatic and osmotic pressures on the state of tissue hydration and the pattern of distribution of tissue water, we dialyzed rats with isotonic (290 mosmol/kg) or hypertonic (510 mosmol/kg) solution at intraperitoneal pressures (P(ip)) between 0 and 6 mmHg, and we infused isotopic markers intravenously and determined their equilibrium distribution volumes (V(D)) in the anterior abdominal muscle (AAM) by quantitative autoradiography. Total tissue water volume (theta(TW)) was determined from dry-to-wet weight ratios. theta(urea), the V(D) of [(14)C]urea, equals the sum of the extracellular water volume (theta(EC), V(D) of [(14)C]mannitol) and intracellular water volume (theta(IC) = theta(urea) - theta(EC)). If theta(if) = interstitial water volume and theta(IV) = vascular water volume (V(D) of (131)I-labeled IgG), then theta(EC) = theta(if) + theta(IV). AAM hydrostatic pressure profiles were measured by a micropipette/servo-null system and demonstrated that elevation of P(ip) above 3 mmHg significantly (P < 0.05) increases mean tissue pressure (P(T)) to the same level regardless of intraperitoneal osmolality. The increase in P(T) resulted in a nonlinear tissue expansion primarily in the interstitium regardless of osmolality. From 0 to 6 mmHg, theta(if) (in ml/g dry tissue) increased from 0.59 +/- 0.02 to 1.7 +/- 0.05 and to 1.5 +/- 0.05 after isotonic and hypertonic dialysis, respectively, whereas theta(IC) increased from 2.8 +/- 0.08 to 3.0 +/- 0.1 after isotonic dialysis and decreased to 2.6 +/- 0.1 after hypertonic dialysis. After dialysis at 6 mmHg with isotonic or hypertonic solutions, theta(IV) increased from 0.034 +/- 0.001 to 0. 049 +/- 0.001 and 0.042 +/- 0.002, respectively. theta(urea) during hypertonic dialysis at P(ip) between 0 and 6 mmHg increased in a nonlinear fashion (F = 26.3, P < 0.001), whereas theta(IC) invariably decreased (F = 11.1, P < 0.001) and theta(if) doubled from its control value at low P(ip). In conclusion, elevation of intraperitoneal hydrostatic pressure causes tissue expansion, primarily in interstitium, irrespective of osmolality of the bathing solution. Tissue hydrostatic pressure is therefore the primary determinant of tissue properties with respect to hydration, which in turn affects diffusive and convective transport.

Changes in the peritoneal interstitium and their effect on peritoneal transport.

Transperitoneal transport is a complicated process that includes diffusion and convection across the walls of blood microvessels into tissue interstitium, transport through the interstitium, and final passage across the peritoneum to the dialysis solution in the cavity. The purpose of this paper is to briefly review the normal physiology of this process and then to summarize the events that occur in response to inflammation within the cavity. These events begin with stimulation of macrophages, which in turn secrete cytokines. The cytokines stimulate mesothelial cells and fibroblasts in the tissue to synthesize and secrete other mediators. Those mediators initiate the complex events through which leukocytes migrate from blood vessel lumens through the interstitium and into the cavity. Much of the available data is from model in vitro systems, and therefore in vivo events must be deduced or hypothesized.

Blood flow does not limit peritoneal transport.

OBJECTIVE: We investigated the assumption that blood flow to the microvessels underlying the peritoneum does not limit solute or water exchange between the blood and the dialysis fluid. DESIGN: Small plastic chambers were affixed to the serosal side of the liver, cecum, stomach, and abdominal wall of anesthetized rats. Solutions that contained labeled solutes or that were made hypertonic were placed into the chambers, which restricted the area of transfer across the tissue to the base of the chamber and which permitted calculation of mass or water transfer rates on the basis of area. The local blood flow was monitored continuously with a laser Doppler flowmeter during three periods of observation: control, after 50%-70% reduction of the blood flow, and postmortem. RESULTS: Urea transfer across all serosa, except for the liver, showed no difference in mean mass transfer coefficient (cm/min) between control (0.0038-0.0046) and after 70% flow reduction (0.0037-0.0040), but demonstrated a significant decrease with blood flow equal to zero (0.0020). These tissues demonstrated small but insignificant decreases in osmotic water flow into the chamber (0.7-0.9 microL/min/cm2 under control conditions versus 0.4-0.7 microL/min/cm2 with reduced blood flow). The liver demonstrated limitations in water and solute transport with a 70% decrease in blood flow. CONCLUSION: Because the liver makes up a small part of the peritoneal area, we conclude that large drops in blood flow do not limit overall solute or water transfer across the peritoneum during dialysis, and therefore acute peritoneal dialysis may be an appropriate modality for ICU patients in shock and renal failure.

Hydrostatic and osmotic pressures modulate partitioning of tissue water in abdominal muscle during dialysis.

OBJECTIVES: To investigate the effect of simultaneous exposure of anterior abdominal muscle (AAM) to changes in intraperitoneal hydrostatic pressure (Pip) and to osmolality of peritoneal fluid on total tissue water (TTW) and on the pattern of distribution of TTW in the AAM. DESIGN: A pilot study of single 60-min dwells in anesthetized Sprague-Dawley (SD) rats, dialyzed with either isotonic (290 mOsm/kg) or hypertonic (510 mOsm/kg) dialysis solutions at nominal Pip of 0 mmHg or 6 mmHg. MEASUREMENTS: TTW (from dry-weight-to-wet-weight ratios) can be divided into the extracellular volume [theta(ec), from quantitative autoradiography (QAR) with 14C-mannitol] and intracellular volume (theta(ic) = TTW - theta(ec)). Theta(ec) = theta(if) + theta(iv), where theta(if) = interstitial volume and theta(iv) = vascular volume [from QAR with 131I-immunoglobulin G (IgG)]. All measured parameters are standardized to tissue dry weight and expressed as mean +/- standard error. RESULTS: Regardless of the osmolality of the dialysis solution, elevation of Pip to 6 mmHg results in tissue expansion, primarily in theta(if), which is doubled to 1.71+/-0.11 mL/g dry weight and 1.60+/-0.17 mL/g dry weight with isotonic and hypertonic dialysis, respectively, as compared to controls (0.64+/-0.04 mL/g dry weight). The local theta(iv) was not affected by Pip or osmolality of the bathing solution. The overall theta(iv) is 0.046+/-0.006 mL/g dry weight. A two-way analysis of variance (ANOVA) to access the effect of osmolality and Pip on theta(ic) demonstrated no significant change in theta(ic) (F = 1.2, p > 0.1) as calculated for controls (3.13+/-0.19 mL/g dry weight), after isotonic dialysis (3.13+/-0.20 mL/g dry weight), or after hypertonic dialysis (2.77+/-0.30 mL/g dry weight). CONCLUSION: Elevation of Pip to 6 mmHg significantly increased TTW and expanded the tissue. Tissue expansion is primarily in interstitium (theta(if)), which is doubled from control value regardless of dialysis fluid osmolality.

Tissue sources and blood flow limitations of osmotic water transport across the peritoneum.

Despite the daily use of hypertonic solutions to remove fluid from patients throughout the world who are undergoing peritoneal dialysis, the tissue sources of this water flow are unknown. To study this phenomenon in specific tissues, small plastic chambers were affixed to parietal and visceral surfaces of the peritoneum and were filled with either an isotonic or hypertonic solution. The volume changes over 60 to 90 min were determined and divided by the chamber area to yield the volume flux. The hypertonic solution produced a positive flux into the chamber of 0.6 to 1.1 microl/min per cm2 in all tissues tested. In contrast, the isotonic solution resulted in a net loss or an insignificant change in the chamber volume. Additional experiments tested the influence of blood flow on the hypertonic water flux during periods of control, reduced (50 to 80%), or postmortem (no) blood flow, as determined by laser Doppler flowmetry. With the exception of the liver, small but insignificant changes in the flux into the chamber were observed during the period of reduced flow; all water fluxes were markedly depressed during the postmortem period. It is concluded that both parietal and visceral tissues are sources of osmotically induced water flow into the cavity. Except for the liver, marked blood flow reductions have small but insignificant effects on osmotic water transport.

In vivo effects of hydrostatic pressure on interstitium of abdominal wall muscle.

Fluid loss from the peritoneal cavity to surrounding tissue varies directly with intraperitoneal hydrostatic pressure (Pip). According to Darcy's law [Q = -KA(dPif/dx)], fluid flux (Q) across a cross-sectional area (A) of tissue will increase with an increase in either hydraulic conductivity (K) or the interstitial fluid hydrostatic pressure gradient (dPif/dx, where x is distance). Previously, we demonstrated that in the anterior abdominal muscle (AAM) of rats, dPif/dx increases by only 40%, whereas K rises fivefold between Pip of 1.5 and 8 mmHg. Because K is a function of interstitial volume (thetaif), we hypothesized that perturbations of Pip would change Pif and expand the interstitium, increasing thetaif. To test this hypothesis, we used dual-label quantitative autoradiography (QAR) to measure extracellular fluid volume (thetaec) and intravascular volume (thetaiv) in the AAM of rats within the Pip range from -2.8 to +8 mmHg. thetaif was obtained by subtraction (thetaec - thetaiv). dPif/dx was measured with a micropipette and a servo-null system. Local thetaiv did not vary with Pip and averaged 0.010 +/- 0.002 ml/g, and thetaif averaged 0. 19 +/- 0.01 ml/g at Pif 0.001) in the SC. We conclude that the mechanisms responsible for the increase in K with Pip include expansion of the interstitium, dilution of interstitial macromolecules, and washout from the AAM to SC of interstitial macromolecules responsible for resistance to fluid flow.

Clinical importance of intraperitoneal pressure in peritoneal dialysis and measures to counteract its effect on net ultrafiltration.

Experiments in animals and in humans have shown that fluid loss from the peritoneal cavity to the body increases with large increments in the intraperitoneal hydrostatic pressure (IPP). We have demonstrated previously that much of this fluid loss occurs to the abdominal wall and is driven by the hydrostatic pressure gradient (i.p. pressure-skin pressure) that develops across the wall whenever therapeutic or pathologic volumes of fluid reside in the cavity. We hypothesized that eliminating the pressure difference across the wall by applying an equal and opposite pressure [abdominal counterpressure (ACP)] would decrease fluid movement into the wall and decrease fluid movement from the cavity. In addition, we hypothesized that net ultrafiltration or net fluid recovery would increase with ACP. To address these hypotheses, we dialyzed rats for 3 hours in the supine position at constant levels of IPP (4, 6, and 8 cmH2O) with isotonic or hypertonic dialysis solutions containing a protein marker of fluid movement. We measured total fluid loss, fluid marker concentration in the abdominal wall, and lymph flow. In separate animals, we repeated the experiments with ACP. Total fluid loss as determined by protein clearance and fluid marker deposition in the abdominal wall was decreased in all experiments. Lymph flow was unchanged by ACP. While ACP increased the net fluid recovery in isotonic dialysis, no change was observed in the hypertonic case. Analogous experiments were carried out in six dialysis patients with or without ACP during a 4-hour dialysis with 1.5% dextrose solution performed in the supine position at i.p. hydrostatic pressure of 4-6 cmH2O. No significant difference was noted in the measured net ultrafiltration between control and ACP studies. We conclude that the careful application of ACP does decrease fluid loss (particularly to the abdominal wall) during isotonic or hypertonic dialysis in the rat. However, ACP results in improved fluid recovery only with isotonic dialysis in rats and has no effect on the recovery of fluid during peritoneal dialysis in humans.

Tissue-level transport mechanisms of intraperitoneally-administered monoclonal antibodies.

Monoclonal antibodies (MAbs), produced for specific tumor antigens, can be linked with radioisotopes or metabolic toxins and administered intraperitoneally (i.p.) to treat metastatic cancer located on the peritoneum. Despite their specific binding properties, these proteins distribute to the serosal surface of all tissues surrounding the cavity in the same manner as other serum proteins. Recent data have raised a problem of access of the solution containing the MAb to significant portions of the peritoneal surface. If the MAb does arrive at the surface of the tumor, it penetrates via diffusion and convection. The rapidity and depth of penetration of the MAb are very dependent on the binding characteristics of the MAb to the tumor cells. Current data indicate that tumors often have a large interstitial space relative to normal muscle, and this can accelerate both diffusion and convection. However, a highly permeable tumor vasculature in the absence of lymphatic drainage has also been shown to produce interstitial pressure gradients from the center toward the periphery of the tumor, setting up a potential outward flow which may be a significant barrier to the movement of MAbs into the nodule. While theoretical mechanisms of diffusion, convection, and binding are well established, there is still a great need for in vivo data.

Blood flow limitations of solute transport across the visceral peritoneum.

In a previous study, no limitations to urea transfer across the parietal peritoneum were demonstrated with decreases in local blood flow of 70%. It was hypothesized that the visceral peritoneum would have similar characteristics. To address this problem at the tissue level, diffusion chambers were affixed to the serosal side of the stomach, cecum, or liver of anesthetized rats (n = 6 each tissue), and solutions containing 14C urea were placed in the chamber. During each experiment, the local chamber blood flow was measured with laser Doppler flowmetry, and, simultaneously, the disappearance of the tracer versus time was determined under three conditions: control, after 60 to 70% blood flow reduction, and postmortem (flow = 0). The results showed no difference in the urea mass transfer coefficient (MTC; mean +/- SEM; cm/min x 10[3]) between control and blood flow reduction for the stomach (4.0 +/- 0.4 versus 3.6 +/- 0.3) or for the cecum (4.6 +/- 0.3 versus 4.0 +/- 0.3). However, the MTC was significantly decreased by local blood flow reduction in the liver (5.4 +/- 0.2 versus 2.6 +/- 0.2). Postmortem data demonstrated significant reductions in the MTC with blood flow equal to zero. It is concluded that a 60 to 70% blood flow reduction from control values does not limit solute transperitoneal transfer in the hollow viscera but causes significant changes in the mass transfer across the liver surface. Because the liver makes up only a small portion of the effective exchange area, overall transperitoneal solute transfer should not be greatly affected by significant decreases in blood flow.

Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure.

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk)1/2. The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.

A method to test blood flow limitation of peritoneal-blood solute transport.

Current transperitoneal transport models assume that effective blood flow to the microcirculation does not limit solute exchange with dialysate in the cavity. Despite evidence that gas transfer across the peritoneum (assumed to equal the effective blood flow) occurs at rates that exceed maximum urea transfer rates by a factor of two to three, the assumption has been strongly challenged. To address this problem at the tissue level, a technique to determine the effect of local blood flow on small-solute transport was developed in this study. Diffusion chambers were affixed to the serosal side of the anterior abdominal wall of rats, and solutions containing radiolabeled urea or mannitol were placed in the chambers. During each experiment, the local blood flow beneath the chamber was monitored with laser Doppler flowmetry and the disappearance of the tracer versus time was simultaneously measured under three conditions of blood flow: control, 30% of control, and zero blood flow. The results demonstrated no significant differences for either solute between control and the condition in which blood flow was reduced by 70%. However, there was a significant reduction in the rate of mass transfer with no blood flow. It was concluded that blood flow at > or = 30% of control values does not limit solute transfer across the abdominal wall peritoneum during dialysis.

Computerized kinetic modeling: a new tool in the quest for adequacy in peritoneal dialysis.

Until recently, kinetic modeling of peritoneal dialysis (PD) was performed by engineers, scientists, or nephrologists at major teaching institutions. Now there are several "user-friendly" computer programs which permit the practicing nephrologist and dialysis staff to monitor adequacy of the individual PD patient and to optimize the dialysis prescription. In this brief article, the capabilities, methods, and data requirements of three programs are reviewed, and specific recommendations for the selection of a particular program are discussed.