Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era.

BACKGROUND: The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. METHODS: Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in pre- and post-KAS periods. RESULTS: The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20-29 y and 13% vs 18% in age group 30-39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50-59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). CONCLUSIONS: The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.

Coloduodenovesical Fistula After Simultaneous Pancreas-Kidney Transplant: Case Report and Review of the Literature.

BACKGROUND: Complicated diverticulitis after transplantation occurs in as many as 3.5% of cases and carries a 25% mortality rate. Diagnosis of complicated diverticulitis in this population can be challenging because of abnormal presentations caused by immunosuppression. Only 4 cases of fistulization after kidney transplantation are described in the literature; none occurred after simultaneous pancreas-kidney transplant. METHODS: We present a first case of a coloduodenovesical fistula in a patient 9 years after simultaneous pancreas-kidney transplant. The patient presented with intermittent episodes of elevated creatinine and recurrent urinary tract infection. The presence of fistula was strongly suspected in cystoscopy, but, despite extensive investigation, a fistula tract could not be identified. RESULTS: The patient ultimately underwent surgical exploration for positive cystoscopy examination, continuation of urinary complaints, and presence of multiple colonic diverticula in computed tomography scan. At surgical exploration, a fistula track was identified between the sigmoid colon and duodenal stump of the pancreas allograft. Subsequently, sigmoidectomy, bladder repair, and enteric conversion of the pancreas transplant were performed. CONCLUSIONS: Complications of diverticulitis should be considered in organ transplant recipients presenting with recurrent urinary infection and elevated creatinine, and surgical exploration might be indicated even if unable to well-define the fistula tract.

Food insecurity and budgeting among Liberians in the US: how are they related to socio-demographic and pre-resettlement characteristics.

Objectives of this study: (1) Examine food insecurity (FI) prevalence and its relationship with sociodemographic and pre-resettlement characteristics; (2) Investigate differences in amount of money spent on food/month by food security status and socio-demographic characteristics. A pilot study with semi-structured in-home interviews was conducted with Liberian caregivers (n = 33). FI was indicated in 61% of households. FI was higher among women >40, had ≤ high school education and those making ≤$1,000/month. Women arriving in US >15 years of age were more likely to be food insecure. Participants spent an average $109/month on groceries/member. Food insecure women, and those without a car spent more money on food (P < .10). Liberian women in this sample experience high levels of FI upon resettlement. Besides poor economic conditions, pre-resettlement characteristics were associated with food security status. These findings call for future research to understand how preresettlement conditions affect food choices, budgeting and thereby food security status.

Drug interactions with psychostimulants.

The psychostimulants methylphenidate, dextroamphetamine, and pemoline are among the most common medications used in child and adolescent psychiatry. Often, these agents are used in combination with other medications. This review summarizes reported drug interactions and assesses both causality and clinical significance. A computerized search was undertaken using MEDLINE (1966 to 1998) to obtain all pertinent reports of adverse events associated with the coadministration of psychostimulants and other drugs. A total of 38 reports involving 25 different drugs from various classes were systematically evaluated along with research studies conducted to specifically assess drug interactions. Methylphenidate appeared to be involved primarily in pharmacokinetic interactions suggestive of cytochrome P450 inhibition while dextroamphetamine and pemoline were more often involved in apparent pharmacodynamic interactions. The published data support the safe use of psychostimulants with most classes of medications with few absolute contraindications.

Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia.

We have recently demonstrated that substitution of imidazoline moieties for the amidine groups of pentamidine produces a molecule that is effective against rat Pneumocystis carinii pneumonia and that is apparently less toxic than pentamidine. For this reason, 10 novel imidazoline substituted compounds were evaluated for their effect against rat P. carinii pneumonia. While several of the new compounds were observed to have advantages over pentamidine in the treatment of disease in the rat model, only one compound stood out as a potential new clinical agent. Treatment for 2 weeks with intravenous (i.v.) doses of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DIMP) at 1 mg/kg per day produced an anti-P. carinii pneumonia effect equivalent to i.v. doses of pentamidine at 10 mg/kg per day. Although pentamidine and one of the test drugs, 1,3-di(4-imidazolinophenoxy)propane, showed no activity against P. carinii pneumonia when administered per os, DIMP exhibited potent anti-P. carinii pneumonia activity when given by daily gavage doses of 40 and 25 mg/kg. DIMP retained significant activity when given every other day by a gavage dose of 25 mg/kg. No toxicity was observed with the drug at any of the dose levels or by either of the routes of administration. However, the low solubility of the drug prevented testing at higher i.v. doses. Our conclusion is that DIMP has the potential of providing a safer and more effective alternative to pentamidine for the treatment of P. carinii pneumonia.

Body composition changes in rats with experimental cancer cachexia: improvement with exogenous insulin.

Exogenous insulin treatment has been shown to improve food intake and host weight of cachectic tumor-bearing (TB) rats, but the composition of the host weight gain has not been quantitated. Sixty-six Fischer 344 rats were randomized to seven groups: early nontumor-bearing (NTB) (n = 10) who underwent compositional analysis (CA) on the day the methylcholanthrene sarcoma was implanted in TB rats; pretreatment-NTB (n = 10) and pretreatment-TB (n = 10) who underwent CA 25 days later when rats began treatment with saline or insulin; and finally saline-treated NTB (n = 9), saline-treated TB (n = 9), insulin-treated NTB (n = 9), and insulin-treated TB (n = 9), who underwent CA following 5 days of treatment with daily saline or neutral protamine hagedorn insulin 2 units/100 g. Body weight and food intake were measured daily. For compositional analysis, the tumor was separated from the host in TB rats and the entire rat in NTB animals was homogenized, lyophilized and analyzed for fat, water, protein, potassium, chloride, and sodium. The tumor was processed in a similar fashion. In response to insulin, NTB rats ate significantly more food, and had an increase in body weight gain. Compositional analysis of insulin-treated NTB rats indicated a slight, but insignificant, increase in body fat and a similar insignificant decrease in body protein. TB rats ate significantly less than NTB rats during the 5-day experimental period, and insulin treatment significantly increased food intake to levels similar to NTB animals. Compositional analysis indicated that the tumor-bearing state resulted in a significant decrease in total host water, protein, fat, potassium, sodium, and chloride. Insulin administration resulted in preservation of host nitrogen, fat, potassium, sodium, and chloride in cachectic tumor-bearing rats. Insulin treatment did not affect tumor dry weight or composition. The results suggest that exogenous insulin, can preserve normal host composition of TB rats during cachectic decline.

Preoperative insulin reverses cachexia and decreases mortality in tumor-bearing rats.

As a model of surgical stress in the cancer-bearing animal, we resected large flank sarcomas from cachectic rats under ether anesthesia and closed wounds primarily. The metabolic cost of tumor resection was measured using a long-term continuous indirect calorimeter. In the immediate postresection period energy balance decreased and host energy expenditure increased significantly (P less than 0.005). In animals with similar tumor weights, mortality following resection was determined by the degree of cachectic depletion. We then considered whether improvement of preoperative host nutritional status with insulin treatment might improve a subsequent surgical outcome. Insulin, when administered exogenously to cachectic tumor-bearing rats, has been shown to stimulate food intake and preserve host weight and does not stimulate tumor growth. When individual rats bearing a cachexia-producing flank sarcoma demonstrated a decline in food intake to less than 75% of predicted (approximately 25 days after tumor implantation), they were randomized to receive either daily injections of NPH insulin (2 units/100 g/day) for 5 days or no treatment for 5 days. Animals then underwent tumor resection and 14-day survival was measured. All resections were performed in an unbiased manner without the surgeon's knowledge of each rat's treatment status. In an experiment using 59 rats, insulin-treated rats had a threefold higher 5-day preoperative food intake and did not lose weight in the preoperative period, while untreated rats lost 17 g (P less than 0.001). Mortality in the insulin-treated group was 10% versus 28% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Energy expenditure and motor activity in rats receiving total parenteral nutrition.

Rats with intravascular catheters connected to infusion systems are frequently used in the investigation of nutritional and metabolic problems. Although the animal is often referred to as "unrestrained," there is no information on the effect of the catheter assembly or total parenteral nutrition (TPN) on total (TEE), activity (AEE), and resting (REE) energy expenditure (TEE = REE + AEE). Male Fischer 344 rats were studied in an analytical respiration calorimeter. Normal unoperated rats, aseptically catheterized orally fed rats from postoperative day 1 to 7, and TPN rats were studied. Orally fed catheterized rats had weight loss, negative nitrogen balance, negative energy balance, elevated REE, and normal AEE during the first 4 postoperative days. Their weight gain, positive nitrogen balance, AEE, and REE were almost identical to those of normal rats over postoperative days 5 through 7. REE and AEE in TPN rats were similar to values in normal rats. These data indicate that catheter operation and TPN cause no abnormality in AEE and REE if adequate time is allowed for recovery from catheter operation and strict attention is given to asepsis.

Cancer cachexia.

Cancer cachexia is a complex syndrome that includes host tissue wasting, anorexia, asthenia, and abnormal host intermediary metabolism. It is present in approximately 50% of cancer patients during treatment and nearly 100% of treated cancer patients at death. Cachexia has a detrimental impact on cancer therapy. The central problem of cancer cachexia is that energy balance is not maintained, and the host has a relative hypophagia which results in host tissue wasting. The tumor by its nature and obligate growth can continue to consume glucose, amino acids, and lipids at the expense of the host. This produces abnormal host intermediary metabolism including elevated glucose production and recycling, decreased muscle protein synthesis, and increased muscle and fat breakdown. The exact mechanisms of cancer cachexia have been only partially elucidated. The identification of signal molecules like cachectin which mediate these changes may be on the horizon. Nutritional support can reverse some of the derangements seen with cachexia, and there is evidence that functional lean body mass or body cell mass can be restored in some (but not all) patients. However, nutritional support has not yet improved response to chemotherapy or radiation therapy, nor has it improved host tolerance of chemotherapy. It has improved operative mortality and morbidity in cachectic cancer patients undergoing major surgical procedures. Optimum host nutritional support appears to be dependent on high insulin concentrations in both humans and rats. Insulin and exercise may be methods to preserve host lean tissue and feed the host rather than the tumor. Future studies depend on better definition of tumor-bearing host metabolism, altering the relationship between neoplasm and host to preferentially feed the host, and making the neoplasm more susceptible to effective treatment.

Parabiotic transfer of cancer anorexia/cachexia in male rats.

To demonstrate that the anorexia and depletion of cachexia reverses on tumor removal, F344 rats underwent sarcoma resection when their food intake fell to 0 g/day. In survivors of surgery, reversal in food intake was apparent within 3 days postoperatively, followed after 2 days by gain in host weight. To detect whether the transmission of anorexia/cachexia in these tumor-bearing (TB) rats was via the circulation, four groups were studied: single non-tumor bearing (NTB); single TB; parabiotic NTB; and parabiotic TB. The measured blood exchange rate between parabiotic halves was 1.2-1.5%/min. No cachectic effect was detected in either half of the NTB parabionts. There was no evidence of sarcoma metastases in the tumor-free half of the parabiotic TB pair. All the rats associated with the presence of tumor showed cachectic effects but the degree and timing of effect varied among the three conditions, single TB, parabiotic TB half, and parabiotic tumor-free half. In all variables examined (fall in food intake, time of first fall in food intake, host weight loss, elevation of blood urea nitrogen) the severities were always in the same sequence: single TB greater than parabiotic TB half greater than parabiotic tumor-free half greater than NTB. In addition, the TB parabiotic pair had a significantly longer survival time and grew a significantly larger tumor than did the single TB animal. The parabiotic tumor had a slower initial growth rate and a slower deceleration rate than the singlet tumor. These results provide evidence for the humoral mediation of cancer-associated cachexia.

Insulin reversal of cancer cachexia in rats.

The anabolic effects of exogenous neutral protamine hagedorn insulin on tumor-bearing (TB) and non-tumor-bearing (NTB) rats were examined. Exogenous insulin (2 units/100 g/day) produced similar hypoglycemia in TB and NTB rats. Food intake and body weight gain were significantly increased by insulin in NTB rats. In TB rats in an early stage of cachexia, insulin increased food intake and host weight (total body weight minus tumor weight). In TB rats with severe cachexia, insulin increased food intake and stabilized host weight when untreated TB controls were not eating and were losing weight. When daily insulin administration was started at an early stage of tumor growth and continued until death, there was again significant enhancement of host weight and food intake. Heart and adrenal weights were significantly reduced in insulin-treated TB animals. Tumor growth was not stimulated by insulin treatment. Survival time was slightly reduced in TB rats treated with long-term insulin. Survival time in TB rats randomized to insulin during late cachectic decline was not different from untreated TB controls. Insulin did not have any measurable effect on energy expenditure or the motor activity compartment of energy expenditure in either TB or NTB rats. Insulin treatment can reverse experimental cancer cachexia. It is a nutritional therapy which preferentially feeds the host over the tumor. As yet, its beneficial effects have not prolonged survival of tumor-bearing animals.

Endurance exercise modifies cachexia of tumor growth in rats.

Food intakes, body composition, skeletal muscle mass, muscle protein synthesis, and myofibrillar protein degradation were studied in normal, food-restricted (FR), and Walker 256 tumor-bearing (TB) male Sprague-Dawley rats which were exercised (E) or maintained in a sedentary state. Exercise was enforced 3 times per wk for 100 min X session-1 at 20 m X min-1 on a 13% incline for 7 wk. Tumors were transplanted 3 wk after beginning the exercise program and were allowed to grow for 29 d. Food restriction was initiated during the last 2 wk of tumor growth. Food intakes and body lipid stores were reduced in all E groups, whereas body nitrogen was reduced only in the TBS animals. All E animals had significantly higher gastrocnemius muscle/body weight ratios than their sedentary counterparts, with the greatest ratio noted for the TBE animals. Muscle protein synthesis, measured by incorporation of [3H]tyrosine into gastrocnemius muscle, was significantly depressed in both FR and TB animals. Muscle protein breakdown, estimated by urinary 3-methylhistidine excretion, was significantly elevated in TB animals and slightly increased in FR animals. The results suggest that tumor presence significantly alters protein turnover to a greater extent than elicited by food restriction alone. Additionally, although exercise may have initially protected the animal by retarding tumor growth and muscle mass depletion, in the end, the energy costs of exercise accelerated the catabolic state.

Contribution of inert mass to experimental cancer cachexia in rats.

An inert artificial tumor (AFT) was inflated in male F344 rats to simulate, experimentally, the growth in mass of large transplantable tumors that produce cachexia. The AFT depressed host weight gain and skeletal muscle mass up to 30% and food intake up to 20% of the depression induced by tumors of comparable size. When the growth rate of the AFT was low, there was no depression of food intake. Work-induced hypertrophy of skeletal muscles, as assessed by a gastrocnemius tenotomy model, was approximately equal to that of normal, tumor-bearing, and AFT-bearing animals. The AFT elevated host total energy expenditure by 12.5% and compartment-of-energy expenditure attributable to motor activity by 10.5%. The elevation of energy expenditure accounted for most of the depression of weight gain of AFT-bearing animals below that of intact animals. The large mass of most transplantable tumors leads to an overestimate of the malignant tissue-depletive effects of tumor and an under-estimate of the asthenic effects.

Synergistic stimulation of food intake by simultaneous insulin and cold.

Insulin administered to rats during simultaneous exposure to cold increases food intake by more than the sum of the separate feeding responses and prevents the normal cold-induced loss of body weight. On withdrawal of insulin with cold maintained, all the body weight maintained by insulin is immediately lost and body weight thereafter is identical to that of rats exposed to cold only. Accumulated food intake for the joint treatment and after withdrawal of insulin with cold maintained is greater than for cold exposure only. There is no increase in metabolic cost due to insulin. Energy density of weight gain during insulin treatment is high and of weight loss on withdrawal of insulin with cold maintained is very low. These responses do not conform with commonly proposed models of feeding control.

Contributions of reduced hunger and premature satiety to cancerous hypophagia in rats.

Tumor-induced reduction in food intake in 2 rat-tumor organisms was distributed approximately equally between reduction in average size (premature satiety) and reduction in frequency (impaired perception of hunger) of effective meals. In both organisms, the frequency of futile meals (activity at food dish without any food ingestion) increased in the tumor-bearing state, and total meal frequency (effective plus futile meals) was unchanged from the tumor-free state. It is proposed that the presence of tumor reduces some meals to zero size and that satiety can occur in the cephalic phase of digestion before any food has been ingested. By this interpretation, cancer hypophagia would be entirely attributable to premature satiety.

Tumor and host carcass changes during total parenteral nutrition in an anorectic rat-tumor system.

The independent effects of total parenteral nutrition (TPN) on tumor growth and host carcass are important in designing effective nutritional support. In this study, a TPN regimen was used to keep substrate intake at normal levels during a 10-day period of tumor-induced anorexia and cachexia in rats transplanted with a sarcoma. Tumor mass was increased in TPN-supported animals compared to orally-fed controls. Tumor composition (water, fat, nitrogen) was similar in all tumors. Host carcass mass in tumor-bearing (TB) animals was increased by TPN as compared to orally-fed TB controls, but not to the same extent as in orally-fed or TPN-supported nontumor-bearing controls. Host carcass composition determinations demonstrated significantly increased fat content but no significant change in protein or water content in TB-TPN animals compared to orally-fed TB animals. This study demonstrates increased tumor growth and increased host carcass fat stores secondary to TPN.

In vivo estimation of size of experimental tumors.

The precision and accuracy of various estimates of experimental tumor size from lineal dimensions were examined on capsules implanted subcutaneously and inflated to precisely known weights in Fischer 344 rats. The method of tying the final product of three dimensions to the measured excised weight gave a value with no significant systematic bias and the lowest error of estimate (root mean square of deviation = 4.35 g).

Growth and body composition during long-term total parenteral nutrition in the rat.

Detailed metabolic data indicating the adequacy of long-term total parenteral nutrition in the rat are not available. In this study an aseptic catheterization technique and a presumed adequate intravenous diet were used to support the nutrition of growing male Fischer 344 rats for a 21-day period. These animals were compared with sham-operated rats after 21 days of ad libitum access to one of two adequate oral diets. Total parenteral nutrition rats demonstrated weight gains that were similar to those in the rats consuming the oral diets. Body composition and nitrogen storage studies indicated fat and protein accumulation in total parenteral nutrition rats that were similar to those in the orally fed animals, but with a tendency toward increased fat and decreased nitrogen retention. These data indicate that apparently normal growth and development can be achieved with total parenteral nutrition in rats by meticulous attention to detail.