Predictors of liver donation without kidney recovery in a cohort of expanded criteria donors: identifying opportunities to improve expanded criteria donor kidney utilization.

To maximize deceased donation, it is necessary to facilitate organ recovery from expanded criteria donors (ECDs). Utilization of donors meeting the kidney definition for ECDs increases access to kidney transplantation and reduces waiting times; however, ECDs often do not proceed to kidney recovery. Based on a prospective study of three Organ Procurement Organizations in the United States, we describe the characteristics of donors meeting the Organ Procurement and Transplant Network (OPTN) ECD kidney definition (donor age 60+ or donor age 50-60 years with two of the following: final serum creatinine > 1.5 mg/dL, history of hypertension, or death from cerebral vascular accident) who donated a liver without kidney recovery. ECDs with organs recovered between February 2003 and September 2005 by New England Organ Bank, Gift of Life Michigan, and LifeChoice Donor Services were studied (n = 324). All donors were declared dead by neurological criteria. Data on a wide range of donor characteristics were collected, including donor demographics, medical history, cause of death, donor status during hospitalization, serological status, and donor kidney quality. Logistic regression models were used to identify donor characteristics predictive of liver-alone donation. Seventy-four of the 324 donors fulfilling the ECD definition for kidneys donated a liver alone (23%). History of diabetes, final serum creatinine > 1.5 mg/dL, age 70+, and presence of proteinuria were associated with liver-alone donation in univariate models. On multivariate analysis, only final serum creatinine > 1.5 mg/dL and age 70+ were independently predictive of liver donation alone. Older age and elevated serum creatinine may be perceived as stronger contraindications to kidney donation than the remaining elements of the ECD definition. It is likely that at least a proportion of these liver-alone donors represent missed opportunities for kidney transplantation.

Association of marital status with access to renal transplantation.

In this report we evaluated the association of marital status with access to renal transplantation. We analyzed data from the USRDS. In patients with ESRD aged ≥ 27 (mean age of first marriage in the US), we analyzed the association of marital status with two outcomes: (1) likelihood of being placed on the waiting list for renal transplantation or first transplant, (2) likelihood of receiving kidney transplant in patients already listed. We analyzed marital status as a categorical variable: (1) not married (including never been married and widowed); (2) divorced or separated; and (3) currently married. Subgroups based on age, race, sex, donor type and diabetic status were also analyzed. After adjustments for the included independent variables and compared to individuals never married or widowed, those who were divorced/separated (HR 1.55, p < 0.001) and currently married (HR 1.54, p < 0.001) had a higher likelihood of being placed on the transplant waiting list. Once listed, married individuals had higher chances of getting transplanted as well (HR 1.28, p = 0.033). This trend was consistent in most of the subgroups studied. We demonstrated that being married is associated with better access to renal transplantation compared to those who were never married/widowed.

Islet cell transplantation tolerance.

Curative islet transplantation for type 1 diabetes currently requires lifelong systemic immunosuppression. Induction of islet transplantation tolerance would be far preferable. We have previously demonstrated that blockade of costimulation by the administration of a donor-specific transfusion in combination with anti-CD154 monoclonal antibody leads to permanent islet and prolonged skin allograft survival in mice. The protocol requires the presence of CD4+ T cells, interferon-gamma, and CTLA4, and involves the deletion of CD8+ alloreactive T cells. Translation of this strategy into clinical practice will, however, require attention to at least two issues. First, we have observed that the presence of viral infection during tolerance interferes with tolerance induction. Second, we have observed that our tolerance induction protocol is ineffective in autoimmune nonobese diabetic mice. We hypothesize that resistance to tolerance induction in nonobese diabetic mice is due to the presence of memory autoreactive cells. To overcome the deleterious effects of viral infection and of primed memory responses, it may be necessary to modify current tolerance induction strategies based on costimulatory blockade. These modifications may require patient isolation, the generation of hematopoietic chimerism, or treatments that target the specific T-cell populations, cytokines, and/or costimulatory factors responsible for resistance. Such modifications may make it possible to extend tolerance induction to the "real world" situation of individuals with type 1 diabetes who are likely to harbor both memory allo-and autoreactive immune cells.

The renal effects of nonsteroidal anti-inflammatory drugs: summary and recommendations.

The renal effects of nonsteroidal anti-inflammatory drugs are reviewed with special emphasis on the clinical, pathophysiologic, and risk factors for acute renal failure. Renal papillary necrosis and chronic renal insufficiency can occur with the prolonged use of these drugs, although the prevalence of this manifestation of nonsteroidal anti-inflammatory drug nephrotoxicity is unknown. Current recommendations based on a critical literature survey are provided, along with a list of suggested areas in which more research is needed.

Triple therapy in cadaveric renal transplantation: role of induction cyclosporine and targeted levels to avoid rejection.

The updated data on 61 consecutive cadaveric transplants performed at our institution from 1987 to 1990 (followup 31 to 82 months, median 54 months) were analyzed with emphasis on cyclosporine monitoring and long-term results. All patients received triple therapy with cyclosporine induction, azathioprine and prednisone regardless of graft function, and they were preferentially placed on the calcium blocker nifedipine. We monitored 12-hour cyclosporine trough levels in whole blood using high performance liquid chromatography and the dose was adjusted to maintain levels at 150 ng./ml. or greater for the first 3 months. In 17 of 61 patients (28%) 22 rejection episodes occurred and 20 nephrotoxicity episodes occurred in 17 of 61 patients (28%). There was no significant difference in the mean cyclosporine levels among 32 rejection, nonrejection, nephrotoxic and nonnephrotoxic cases at any interval. Rejection occurred by 1 month in 13 (76%) and by 3 months in 15 (88%) of 17 patients. Comparisons were made in the first month to define the desirable cyclosporine levels by calculating the mean cyclosporine only within 10 to 14 days of rejection or nephrotoxicity events. The mean cyclosporine level before rejection was significantly lower than that for nephrotoxicity (188 +/- 113 versus 304 +/- 62 ng./ml., p < 0.01). The median cyclosporine level for first month rejection was also significantly lower than that for nonrejection (156 versus 218 ng./ml., p < 0.05) and it was significantly greater for nephrotoxicity versus nonnephrotoxicity (272 versus 218 ng./ml., p < 0.05). Of 13 rejections in the first month 10 (77%) were associated with mean levels of less than 210 ng./ml. Actuarial graft survival at 1, 3 and 5 years was 93.4%, 87.8% and 78.5%, respectively. The 3-year graft survival was significantly worse for patients who experienced acute rejection episodes versus those who did not (68.8% versus 96.7%, p < 0.05) but it was not different for nephrotoxic versus nonnephrotoxic groups (85.6% versus 79.6%). Long-term function was not influenced by the occurrence of acute nephrotoxicity events. These findings confirm the efficacy of triple therapy with induction cyclosporine in cadaveric transplantation, yielding improved short-term and intermediate graft survival without any adverse effects on long-term graft function. Specific cyclosporine level monitoring is invaluable, particularly initially, with high target levels of 200 ng./ml. or greater. The use of calcium blockers may have allowed higher cyclosporine dosing in the first 3 months, mitigating against cyclosporine associated chronic nephrotoxicity.

Simultaneous quadruple immunosuppression with cyclosporine induction therapy in high risk renal transplant recipients.

High risk renal transplant recipients experience excess graft loss despite overall improvements in the results of cadaveric renal transplantation. We evaluated a novel immunosuppression regimen consisting of simultaneous administration of OKT3, cyclosporine, azathioprine and prednisone. Of the 12 high risk patients studied 5 received 2 transplants, 1 received 3 transplants and 8 had peak panel reactive antibodies of greater than 60%. The protocol consisted of cyclosporine (7 mg./kg. orally or 3 mg./kg. intravenously per day) starting from the day of transplant regardless of graft function; 5 mg. OKT3 per day for 10 to 14 days starting intraoperatively; 5 mg./kg. azathioprine per day for 2 days, then 1.5 mg./kg. per day and adjusted according to white blood cell counts, and prednisone taper at 2 to 0.4 mg./kg. per day on day 10. The dose of cyclosporine was increased to 14 mg./kg. per day orally when serum creatinine was less than 3 mg./dl. The cyclosporine whole blood levels (measured by high performance liquid chromatography) were maintained between 250 and 400 ng./ml. in the first 3 months. Followup evaluations ranged from 3 to 28 months (median 8.5). Seven patients (58.3%) had acute tubular necrosis and required dialysis support for 2 to 5 weeks. Six patients (including 5 with acute tubular necrosis) experienced 1 episode of acute rejection in the first 3 months (2 of these were due to accelerated vascular rejection). Two rejections responded to pulse steroid treatment, while 4 (including 2 with vascular rejection) were treated with antilymphoblast globulin rescue therapy for 10 to 14 days. Symptomatic cytomegalovirus pneumonia occurred in 3 patients (25%). There were no deaths or graft losses. No case of malignancy was observed to date. The serum creatinine is less than 2 mg./dl. in 9 patients, and 2.5 to 2.9 mg./dl. in the remaining 3. We conclude that simultaneous quadruple immunosuppressive regimen that includes induction cyclosporine and OKT3 is a highly effective therapy for high risk patients, yielding excellent short-term and intermediate success rates. Long-term results of this regimen, including neoplastic potentiation, cannot be addressed because of the limited followup of these patients.

Defective glomerular beta-adrenergic signal transmission in spontaneously diabetic rats.

Previous studies in experimental diabetes have demonstrated cardiovascular abnormalities of the beta-adrenergic system and reduced adrenergically stimulated renal renin secretion. To examine the defect in the beta-adrenergic signal, glomerular cyclic adenosine monophosphate (cAMP) levels were measured in response to isoproterenol and other humoral agonists (coincubated with the phosphodiesterase inhibitor isomethylxanthine) in nondiabetic and diabetic BB/Wor rats. Basal (unstimulated) levels of glomerular cAMP did not differ between control and diabetic BB/Wor rats, nor did cAMP accumulation differ on incubation with the humoral agonists PGE2 and histamine. However, on incubation with varied concentrations of the nonselective beta-adrenergic agonist isoproterenol, control glomeruli demonstrated a twofold increase in cAMP while a negligible response was observed in diabetic glomeruli. Peak levels of cAMP were higher in control (192 +/- 24 pmol/mg protein) than in diabetic (141 +/- 8 pmol/mg protein) glomeruli (p < 0.01). No differences were observed on incubation with the adenylate cyclase stimulator forskolin. Measurement of glomerular beta-adrenoreceptors by coincubation with iodine 125-labeled cyanopindolol demonstrated no differences in either receptor number (Bmax) or affinity (KD). These data indicate that a specific defect in beta-adrenergic signalling exists in glomerular tissue from spontaneously diabetic rats. Because no decrease in forskolin-stimulated adenylate cyclase was observed, defective coupling of the receptor to its effector, perhaps through the guanine nucleotide stimulatory protein, may account for these observations.

Post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management.

To define better the prevalence and pathophysiology of lymphoceles following renal transplantation, we prospectively evaluated 118 consecutive renal transplants performed in 115 patients (96 cadaveric, 22 living-related, 7 secondary and 111 primary). Ultrasonography was performed post-operatively and during rehospitalizations or whenever complications occurred. Perirenal fluid collections were identified in 43 patients (36%). Lymphoceles with a diameter of 5 cm. or greater were identified in 26 of 118 cases (22%). Eight patients (6.8%) had symptomatic lymphoceles requiring therapy. The interval for development of symptomatic lymphoceles was 1 week to 3.7 years (median 10 months). Risk factors for the development of lymphoceles were examined by univariate and multivariate analysis, and included patient age, sex, source of transplants (cadaver versus living-related donor), retransplantation, tissue match (HLA-B/DR), type of preservation, arterial anastomosis, occurrence of acute tubular necrosis-delayed graft function, occurrence of rejection, and use of high dose corticosteroids. Univariate analysis showed a significant risk for the development of lymphoceles in transplants with acute tubular necrosis-delayed graft function (odds ratio 4.5, p = 0.004), rejection (odds ratio 25.1 p < 0.001) and high dose steroids (odds ratio 16.4, p < 0.001). When applying multivariate analyses using stepwise logistic regression, only rejection was associated with a significant risk for lymphoceles (symptomatic lymphoceles--odds ratio 25.08, p = 0.0003, all lymphoceles--odds ratio 75.24, p < 0.0001). When adjusting for rejection, no other risk factor came close to being significant (least p = 0.4). Therapy included laparoscopic peritoneal marsupialization and drainage in 1 patient, incisional peritoneal drainage in 4 and percutaneous external drainage in 3 (infected). All symptomatic lymphoceles were successfully treated without sequelae to grafts or patients. We conclude that allograft rejection is the most significant factor contributing to the development of lymphoceles. Therapy of symptomatic lymphoceles should be individualized according to the presence or absence of infection.

Nonoperative management of post-transplantation bladder leak: serendipitous salutary effect of temporary cyclosporine nephrotoxicity and oligoanuria.

Post-transplantation bladder leak, a potentially serious complication, is traditionally managed by reexploration and closure, and may require percutaneous placement of a nephrostomy tube. We report intractable bladder leakage that persisted following reclosure in a patient who also had cyclosporine nephrotoxicity. The attendant oligoanuria obviated the need for nephrostomy drainage and allowed healing of the bladder leak. The patient subsequently recovered from cyclosporine injury and regained renal function.

Blood pressure, pulse, and neurohumoral responses to nitroprusside-induced hypotension in normotensive aging men.

In order to assess the effects of age on blood pressure, pulse, and neurohumoral responses to hypotensive stress, we infused nitroprusside into healthy young and old men until mean arterial blood pressure was reduced 20% from basal. Elderly subjects were much more sensitive to nitroprusside. Pulse increases in response to this hypotensive stress were markedly reduced in the elderly, but renin, vasopressin, and norepinephrine responses were not different between young and old. We conclude that cardioacceleration, one of the primary defenses against hypotension, is impaired with age. However, neurohumoral responses to hypotension are intact in the elderly.

Evidence that circulating 6keto prostaglandin E1 causes the platelet defect of Bartter's syndrome.

Bartter's syndrome is associated with activation of prostaglandin metabolism. In the present study we provide several lines of evidence that a circulating metabolite of prostacyclin, 6ketoPGE1 is responsible for a defect in platelet function present in patients with Bartter's syndrome. In platelet aggregometry studies, plasma from patients contained platelet inhibitory activity which was fully neutralized by coincubation with antibody directed against 6ketoPGE1. Fractionation of lipophilic extracts of plasma by high pressure liquid chromatography yielded a platelet inhibitory fraction which comigrated with authentic 6ketoPGE1 and was neutralized by anti 6ketoPGE1 antibody. Lastly, direct measure of the plasma concentration of 6ketoPGE1 by specific radioimmunoassay indicates a 2-fold increase in patients with Bartter's syndrome (133 +/- 9.1 vs 60.7 +/- 12.3 picograms/ml; p less than 025). These studies provide firm evidence that the platelet dysfunction present in patients with Bartter's syndrome is attributable to an increase in the plasma concentration of 6ketoPGE1. In addition, these data provide further evidence in support of the centrality of activation of prostaglandin metabolism in the pathophysiology of Bartter's syndrome.

The renal concentrating defect associated with potassium depletion is independent of prostaglandin E2.

Prostaglandin E2 (PGE2) impairs the hydrosmotic effect of vasopressin in toad bladder and mammalian kidney. Because some studies in animals have suggested that potassium depletion enhances renal PGE2 production, the present study examined whether the renal concentrating defect of potassium depletion in humans is mediated by PGE2. Five normal volunteers were studied before and after moderate potassium depletion achieved by 10 days of dietary potassium restriction and administration of a polystyrene sulfonate potassium exchange resin (Kayexalate). Maximal urinary osmolality (Umax) decreased from 1,094 +/- 58 (mean +/- SEM) to 820 +/- 26 mmol/kg (mOsm/kg) (P less than 0.01) following potassium depletion, but urinary PGE2 excretion did not change (496 +/- 145 and 435 +/- 186 ng/d, respectively). Indomethacin suppressed PGE2 excretion significantly, but failed to increase Umax in either the normal or the potassium-depleted state (1,094 +/- 34 and 825 +/- 56 mmol/kg, respectively). It is concluded that the renal concentrating defect produced by moderate potassium restriction in humans is not mediated by PGE2.

Role of prostaglandins and calcium in the effects of Entamoeba histolytica on colonic electrolyte transport.

We have previously shown that Entamoeba histolytica lysates contain the neurohormones serotonin, neurotensin, immunoreactive substance P, and probably acetylcholine, and that amebic lysates inhibit sodium and chloride absorption and stimulate chloride secretion in the rat descending colon as measured by the Ussing chamber-voltage clamp technique. We now demonstrate that these transport effects have both calcium-dependent and calcium-independent components. In addition, arachidonic acid metabolites of the cyclooxygenase pathway are probably involved in the Entamoeba histolytica-induced changes in colonic transport that are not dependent on Ca++ entry. Prostaglandin E2 (10(-5) M), indomethacin (10(-6) M), piroxicam (5 x 10(-5) M), and mepacrine (10(-4) M) partially inhibited the amebic lysate effect on active transport in the rat descending colon. In addition, verapamil (10(-4) M) partially inhibited the effect of amebic lysates. The effect of verapamil was additive with that of indomethacin, totally blocking the effect of amebic lysate on short-circuit current. However, amebic lysates do not contain prostaglandin E2 as measured by sensitive radioimmunoassay. Amebic lysates stimulated prostaglandin E2 release from rat colonic mucosal strips. Amebic lysate significantly increased colonic cyclic adenosine monophosphate content. Piroxicam inhibited the lysate-induced increase in colonic cyclic adenosine monophosphate content. These results indicate that although amebic lysate does not contain prostaglandin E2, it caused arachidonic acid metabolites to be produced by the cyclooxygenase pathway, and these are probably involved in the Entamoeba histolytica-induced changes in colonic transport. Neurohormones in Entamoeba histolytica may act directly on colonic tissue to stimulate intestinal secretion, probably via a Ca+(+)-dependent mechanism that is blockable by verapamil, or indirectly via stimulation of prostaglandin E2 generation and release from the rat colon via a cyclic adenosine monophosphate-dependent mechanism. These effects appear separate. The cyclic adenosine monophosphate-dependent secretion is the predominant mechanism in this model of colonic amebic diarrhea.

Direct hemodynamic effect of insulin in the isolated perfused kidney.

The hemodynamic effect of insulin was examined in isolated perfused kidneys. Experiments were designed to study the effect of the hormone on basal hemodynamics and in the presence of angiotensin II (ANG II). Physiological insulin concentrations caused both renal vasodilation and increased glomerular filtration rate (GFR) during basal perfusion periods and attenuated the vasoconstrictor action of ANG II while limiting the ANG II-induced reduction of GFR. Insulin also increased fractional sodium reabsorption and diminished the natriuretic effect of ANG II. The addition of insulin to perfusions in which ANG II was infused from the start caused renal vasodilation, although supraphysiological concentrations were required. Kidneys perfused with hyperoncotic albumin to prevent filtration similarly demonstrated a vasodilatory effect of insulin that did not require glomerular filtration. Inhibition of prostaglandin (PG) synthesis with indomethacin prevented the vasodilatory effects of insulin. These data support the hypothesis that insulin causes renal vasodilation by a PG-dependent process.

Control of hypertension and reversal of renal failure in undifferentiated connective tissue disease by enalapril.

Activation of the renin angiotensin system is important in the development of accelerated hypertension and progression to acute renal failure in scleroderma and undifferentiated connective tissue disease. Inhibition of angiotensin-converting enzyme activity may effectively control blood pressure and ameliorate renal insufficiency. To our knowledge, we describe the first reversal of dialysis-dependent renal insufficiency by enalapril maleate and recovery and maintenance of near-normal renal function in a patient suffering from undifferentiated connective tissue disease with sclerodermatous features. The pathophysiologic mechanisms and long-term treatment implications with angiotensin-converting enzyme inhibitors in this setting are discussed.