Common iliac artery stenosis presenting as renal allograft dysfunction in two diabetic recipients.

BACKGROUND: Suprarenal common iliac artery stenosis is an uncommon but reversible cause of allograft dysfunction in renal transplant recipients. METHOD: We describe two diabetic renal transplant recipients with worsening hypertension, edema, and azotemia. Magnetic resonance angiography (MRA) demonstrated tight stenoses in the common iliac artery proximal to the allograft anastomosis site with patent renal transplant artery in both cases. These findings were later confirmed with carbon dioxide angiography. RESULTS: No acute rejection was noted on renal biopsy in either case. Placement of percutaneous iliac artery Wallstents resulted in decrease of serum creatinine from 6.5 to 2.0 mg/dl and 1.7 to 1.0 mg/dl within 2 and 4 weeks, respectively. CONCLUSION: Common iliac artery stenosis should be suspected in renal transplant recipients presenting with worsening hypertension, edema and azotemia. MRA for screening followed by carbon dioxide angiography and placement of intravascular stents for focal vascular obstructive lesions reverses allograft dysfunction.

Post-transplant diabetes: incidence, relationship to choice of immunosuppressive drugs, and treatment protocol.

Post-transplant diabetes mellitus (PTDM) is one of the feared complications of immunosuppressive therapy. Despite advances, including the introduction of the steroid-sparing calcineurin inhibitors, cyclosporine and tacrolimus, the incidence rate remains greater than 10% to 30%, especially in minority populations. PTDM increases the subsequent risk of both graft loss and patient death, and predisposes patients to all complications of diabetes, including retinopathy and neuropathy. Patients should be monitored closely, especially during the first 3 months post-transplant, and treated aggressively, should glucose intolerance be detected. Minimization of immunosuppression dose, diet, oral hypoglycemic agents, and insulin have all been used in the treatment of PTDM, however, the insulin-sensitizing agents have not been studied. It is hoped that newer immunosuppressive regimens and, ultimately, the ability to achieve tolerance will eventually solve the problem of PTDM.

Cloning of the human platelet F11 receptor: a cell adhesion molecule member of the immunoglobulin superfamily involved in platelet aggregation.

This study demonstrates that the human platelet F11 receptor (F11R) functions as an adhesion molecule, and this finding is confirmed by the structure of the protein as revealed by molecular cloning. The F11R is a 32-/35-kd protein duplex that serves as the binding site through which a stimulatory monoclonal antibody causes platelet aggregation and granule secretion. A physiological role for the F11R protein was demonstrated by its phosphorylation after the stimulation of platelets by thrombin and collagen. A pathophysiological role for the F11R was revealed by demonstrating the presence of F11R-antibodies in patients with thrombocytopenia. Adhesion of platelets through the F11R resulted in events characteristic of the action of cell adhesion molecules (CAMs). To determine the structure of this protein, we cloned the F11R cDNA from human platelets. The predicted amino acid sequence demonstrated that it is an integral membrane protein and an immunoglobulin superfamily member containing 2 extracellular C2-type domains. The structure of the F11R as a member of a CAM family of proteins and its activity in mediating adhesion confirm each another. We conclude that the F11R is a platelet-membrane protein involved in 2 distinct processes initiated on the platelet surface. The first is antibody-induced platelet aggregation and secretion that are dependent on both the FcgammaRII and the GPIIb/IIIa integrin and that may be involved in pathophysiological processes associated with certain thrombocytopenias. The second is an F11R-mediated platelet adhesion that is not dependent on either the FcgammaRII or the fibrinogen receptor and that appears to play a role in physiological processes associated with platelet adhesion and aggregation. (Blood. 2000;95:2600-2609)

Outcome of twin pregnancy in a renal transplant recipient treated with tacrolimus.

Our report describes the outcome of a twin pregnancy in a woman who was maintained on tacrolimus after a living related renal transplant. Both babies born at 32 weeks of gestation developed severe respiratory distress requiring ventilator assistance and went on to develop congestive heart failure. Echocardiograms on both babies showed dilated heart chambers. Twin A succumbed to complications, but twin B, who was treated more aggressively with vasopressors, recovered. Autopsy findings on twin A revealed a thrombotic cardiomyopathy with degeneration of cardiac muscle. We believe that the unusual outcome in this set of twins may have been a result of cardiomyopathy secondary to tacrolimus used by the mother during her pregnancy.

Enhancement of human platelet aggregation and secretion induced by rapamycin.

BACKGROUND: Rapamycin is a new immunosuppressive drug of the macrolide type. Despite binding to one of the FK-binding proteins as the initial step in intracellular action, further effects differ from those of the other fungally derived macrolides, cyclosporine and tacrolimus. We have previously demonstrated an enhancement of agonist-mediated platelet activation by cyclosporine and tacrolimus which was associated with increased phosphorylation of two intracellular platelet proteins, p20 and p40. Because rapamycin utilizes the same class of binding proteins as tacrolimus, but its action is not associated with the inhibition of calcineurin, we postulated that if the stimulatory effect of cyclosporine or tacrolimus was due to calcineurin inhibition, rapamycin should not affect platelets in a similar fashion. METHODS: Normal, washed human platelets were treated with various concentrations of rapamycin (from ng to microg/ml), and pre-incubated at 37 degrees C with rapamycin for various periods (1-30 min). Several platelet functional parameters were measured in samples treated with rapamycin and these parameters were compared with control platelet samples treated with the vehicle for the same period. Platelet aggregations following exposure to ADP or to the thrombin equivalent, TRAP-6, were measured as changes in optical transmission in a Chronolog lumi-aggregometer. Each experiment was repeated at three or more times and the mean results were used for statistical comparison. RESULTS: Rapamycin-treated platelets demonstrated an increase in their dose- and time-dependent sensitivity to ADP, resulting in a significantly enhanced primary wave of ADP-induced platelet aggregation followed by a secondary wave of aggregation, indicative of granule secretion. Furthermore, rapamycin-treated platelets showed significantly enhanced sensitivity to TRAP-6 as demonstrated by an increase in the initial velocity of aggregation, an increase in their maximal extent of aggregation and an enhancement of granular ATP secretion. Concentrations of rapamycin in the ng range, as well as short pre-incubation times (within min), were sufficient to cause significant enhancement of agonist-induced platelet aggregation and secretion (P < 0.001) as compared with their vehicle controls. CONCLUSIONS: Rapamycin significantly potentiates agonist-induced platelet aggregation in a time- and dose-dependent manner. As these findings are similar to those observed with the other fungal macrolides, we hypothesize that inhibition of calcineurin may not be necessary for the increase in intracellular protein phosphorylation observed following exposure of platelets to cyclosporine or tacrolimus. Whether the rapamycin-induced enhancement of sensitivity to agonists and platelet hyperaggregability explains the thrombocytopenia observed in patients when high doses of rapamycin are administered in the clinical setting, and whether these effects are synergistic with cyclosporine, are questions which remain to be investigated.

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?

BACKGROUND: Despite use of lower doses of corticosteroid hormones after renal allotransplantation in the era of cyclosporine and tacrolimus, posttransplant diabetes mellitus remains a common clinical problem. METHODS: We prospectively investigated the effect of posttransplant diabetes on long-term (mean follow-up, 9.3+/-1.5 years) graft and patient survival in the 11.8% of our renal transplant population (n = 40) who developed diabetes after kidney transplantation, and we compared outcome in 38 randomly chosen nondiabetic control patients who had received transplants concurrently. RESULTS: Twelve-year graft survival in diabetic patients was 48%, compared with 70% in control patients (P = 0.04), and Cox's regression analysis revealed diabetes to be a significant predictor of graft loss (P = 0.04, relative risk = 3.72) independent of age, sex, and race. Renal function at 5 years as assessed by serum creatinine level was inferior in diabetic patients compared to control patients (2.9+/-2.6 vs. 2.0+/-0.07 mg/dl, P = 0.05). Two diabetic patient who experienced graft loss had a clinical course and histological features consistent with diabetic nephropathy; other diabetes-related morbidity in patients with posttransplant diabetes included ketoacidosis, hyperosmolar coma or precoma, and sensorimotor peripheral neuropathy. Patient survival at 12 years was similar in diabetic and control patients (71% vs. 74%). CONCLUSIONS: Posttransplant diabetes mellitus is associated with impaired long-term renal allograft survival and function, complications similar to those in non-transplant-associated diabetes may occur in posttransplant diabetes, and, hence, as in non-transplant-associated diabetes, tight glycemic control may also be warranted in patients with posttransplant diabetes.

Severe hyperparathyroidism associated with prolonged hungry bone syndrome in a renal transplant recipient.

Although widely believed to resolve within 6 to 12 months of successful renal transplantation, hyperparathyroidism may persist or develop after renal transplantation and eventually require parathyroidectomy. Avid calcium retention by demineralized bones (hungry bone syndrome) is well-recognized after parathyroidectomy and usually resolves after a few weeks. This report documents the case of a renal transplant recipient with persistent hyperparathyroidism who developed a pathological fracture of the pelvis and required parathyroidectomy 1 year after transplant and then manifested severe and prolonged hungry bone syndrome lasting for more than 20 months postoperatively. The clinical features and treatment of hyperparathyroidism in renal transplant recipients are discussed, as are diagnosis, pathogenesis, and management of hungry bone syndrome. Recognition of renal transplant recipients at greater risk for severe hungry bone syndrome should permit earlier and more aggressive management of this sometimes protracted complication of parathyroid surgery.

Anemia following renal transplantation: erythropoietin response and iron deficiency.

To define the etiology of anemia post-renal transplantation, we assessed hematologic parameters and EPO levels in 38 anemic and 16 non-anemic control renal transplant recipients (RTRs) with varying degrees of allograft function at periods > 3 months post-transplantation. Significant differences between the two groups were found for serum creatinine (Cr) 291.7 +/- 26.5 vs. 203.3 +/- 26.5 mumol/l, p < 0.01; iron 9.3 +/- 0.92 vs. 13.6 +/- 1.7 mumol/l, p < 0.05; and ferritin 345.5 +/- 90.8 vs. 91.1 +/- 18.5 micrograms/l, p < 0.01. Serum EPO levels were inappropriately low in anemic patients with no significant correlation between EPO and Cr or hematocrit (Hct) levels. Serum iron was the only predictive factor for anemia on regression analysis (p < 0.05). Ferritin levels did not correlate with serum iron or Hct, and may be falsely elevated in iron deficient RTRs. Iron deficiency, poor renal function and inappropriately low EPO levels are major contributors to the 12% of our outpatient renal transplant population who are anemic.

Unemployment in inner-city renal transplant recipients: predictive and sociodemographic factors.

Studies of dialysis patients report unemployment rates of 60% to 75%; however, it is generally believed that following transplantation, improvement in well-being and removal of time constraints imposed by the dialytic regimen afford improvement in employment status. We studied 58 stable renal transplant recipient attending an outpatient transplant clinic by questionnaire, administered anonymously. Only 25 (43%) of the patients were currently employed. Employed and unemployed patients did not differ when compared for age, gender, race, cause of renal disease, type of transplant or prior dialysis, time on dialysis or time since transplantation, years of education, or prestige score or classification ("blue collar" v "white collar") of prior job. In the employed group, 24 (96%) patients had worked before developing kidney disease compared with 23 (70%) patients in the unemployed group (P < 0.05). While on dialysis, 19 (79%) of the employed patients continued working compared with 10 (30%) of the unemployed patients (P < 0.005). Major reasons for discontinuing work after starting dialysis for both groups were subjective illness (feeling too sick, 51%), followed by interference of the dialysis regimen with time necessary for work (32%). Only 15% of the previously employed patients did not work after transplantation because of feeling too sick. By multiple logistic regression, the strongest predictors of employment posttransplant were being more than 1 year posttransplant (odds ratio, 2.35; 95% confidence interval, 1.01 to 5.5) and having been employed before transplantation (odds ratio, 3.79; 95% confidence interval, 1.60 to 9.02). Over half of the unemployed patients (20 [61%]) expressed interest in job training. Eighty percent to 90% of patients in both groups were insured by Medicare, with the second greatest number insured by Medicaid. Of the 15 unemployed patients insured by Medicaid, 67% reported that their decision not to work was related to fear of losing Medicaid benefits because they could not afford medications without it. Despite no difference in actual type of insurance carried, 17 (51%) of the unemployed patients believed their health insurance coverage was inadequate compared with four (12%) of the employed patients (P = 0.005, chi-squared test). Unemployment remains a significant problem for our population of inner-city renal transplant recipients. Attention to job retention or retraining during the early renal disease and dialysis therapy period may promote better rehabilitation following transplantation. However, for this population, with limited employment opportunities, removal of disincentives to work, including loss of Insurance and Inability to pay for medications, will be necessary before we can provide optimal rehabilitation for renal transplant recipients from all social strata.

The effect of kidney size on cadaveric renal allograft outcome.

Chronic rejection is the commonest cause of long-term renal allograft loss. Though immunologic factors are thought dominant in its pathogenesis, nonimmunologic factors, in particular, hyperfiltration damage related to reduced renal mass, have also been proposed as factors in the causation of chronic allograft rejection. We assessed the influence of renal size on graft survival and function in all cyclosporine-treated cadaver donor adult renal allograft recipients engrafted at a single center between June 1989 and July 1994, whose grafts functioned for > or = to 3 months (n=169). Patients were divided into 4 groups based on the ratio of kidney volume to recipient body surface area (volume/BSA) (ml/m2), and outcome in groups compared by methods including Cox's proportional hazards and Kaplan-Meier analysis. No significant differences between groups existed for serum creatinine levels, presence of significant proteinuria, or 1- and 5-year graft survival. There was no correlation between volume/BSA and either serum creatinine or degree of proteinuria at 3, 6, 12, 36, and 60 months posttransplant. Volume/BSA was similar in patients with good or poor renal function (58 +/-21 vs. 56 +/- 28 ml/m2), with or without significant proteinuria (57 +/- 24 vs. 60 +/- 25 ml/m2) or in patients who lost their grafts to chronic rejection compared with those with stable allograft function (64 +/- 34 vs. 59 +/- 24 ml/m2). Volume/BSA was not a predictor of graft survival on multivariate regression. We conclude that donor kidney size has no apparent effect on cadaveric renal allograft outcome in the short and intermediate-term, suggesting that close matching of donor kidney size to recipient size is not presently indicated.

Hyperlipidemia and glucose intolerance in the post-renal transplant patient.

This review examines the relationship between renal transplantation and two important metabolic consequences: hyperlipidemia and glucose intolerance. Before cyclosporine, hypertriglyceridemia and hypercholesterolemia were common abnormalities that worsened in the cyclosporine era. In addition to obesity, steroid use, and reduced renal function, cyclosporine plays an independent role in elevating cholesterol levels, with particular reference to the modulation of the low-density lipoprotein receptor. Management includes maintaining low levels of steroid, manipulation of cyclosporine appropriately, diets low in fat and cholesterol, and an exercise program. Pharmacologic management in general revolves around the HMG-COA reductase drugs, which can be used safely if liver function tests and muscle enzymes are monitored. The unmasking of clinically important glucose intolerance occurs in 5 to 10% of patients in the cyclosporine era, not different from the earlier experience. Steroids and cyclosporine independently can worsen glucose tolerance to unmask a genetic predisposition to Type II diabetes in some and to even create glucose intolerance in otherwise normal individuals. Management is based on dietary and immunosuppressive drug dosing manipulations and the judicious use of oral hypoglycemic agents. Half of these recipients may ultimately need insulin. In summary, hyperlipidemia and glucose intolerance remain important metabolic consequences of renal transplantation that affect long-term patient survival unless recognized and treated.

Clinical studies with the NOVA ISE for IMg2+.

The Nova ISE for IMg2+ was utilized to examine IMg2+ in plasma and serum of patients with a variety of pathophysiologic and disease syndromes (e.g., long-term renal transplants [LTRT], during and before cardiac surgery, migraine headaches, head trauma, pregnancy, chronic fatigue syndrome [CFS], non-insulin dependent diabetes mellitus [NIDDM], asthma and after excessive dietary intake of Mg). The results indicate that LTRT treated with cyclosporin A, migraine, head trauma, pregnancy, NIDDM, diseased pregnant, and asthmatic patients all on the average, exhibit significant depression in IMg2+ but not total Mg (TMg). Patients with CFS failed to exhibit changes in serum IMg2+ or TMg levels. Increased dietary load of Mg, for only 6 days, resulted in significant elevations of serum IMg2+ but not TMg. Correlations between the clinical course of several of these syndromes and the fall in IMg2+ were found. The Ca2+/Mg2+ ratio appears to be an important guide for signs of peripheral vasoconstriction and or spasm and possibly enhanced atherogenesis. Overall, the data point to important uses for ISE's for IMg2+ in the diagnosis and treatment of disease states.

Ionized and total magnesium levels in cyclosporin-treated renal transplant recipients: relationship with cholesterol and cyclosporin levels.

1. Ionized magnesium, measured using a newly developed ion-selective electrode, total magnesium, and ionized and total calcium were evaluated in 39 stable, long-term, cyclosporin-treated renal transplant recipients and compared with those of age-matched, non-transplanted control subjects. Total cholesterol, cyclosporin trough level, serum creatinine, time after-transplant and the ratio of ionized calcium to ionized magnesium were also measured in renal transplant recipients and the relationships between these variables and ionized and total magnesium were evaluated. 2. Renal transplant recipients exhibited marked deficits in ionized magnesium, with a mean value of 0.54 +/- 0.01 mmol/l as compared with 0.61 +/- 0.006 mmol/l for normal control subjects (P < or = 0.05), with a more moderate deficit in total magnesium. Values for ionized and total calcium did not differ. By stepwise linear multiple regression analysis, ionized magnesium was significantly related to cyclosporin trough level and total cholesterol but not to serum creatinine, time after transplant or the dose of cyclosporin. Ionized magnesium correlated inversely with cyclosporin trough level and directly with total cholesterol. The ratio of ionized calcium to ionized magnesium was elevated in renal transplant recipients when compared with control subjects and correlated positively with the cyclosporin trough level. 3. Deficits in ionized magnesium are common during the late post-transplant period in cyclosporin-treated renal transplant recipients. Ionized magnesium may be a more sensitive clinical parameter than total magnesium in this population, in whom total magnesium may be only mildly decreased in the setting of a severe deficit in ionized magnesium. 4. Ionized magnesium correlates with the cyclosporin level.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of early hyperlipidemia on graft and patient survival in cyclosporine-treated renal transplant patients.

Hyperlipidemia commonly occurs following renal transplantation. As hyperlipidemia has been postulated to contribute to renal dysfunction in animal models, the effect of early hyperlipidemia was studied in a cohort of 43 cyclosporine-treated renal transplant recipients over a 4-year follow-up period. Hypercholesterolemia occurred in 25 patients, with 18 patients remaining normolipidemic during the initial 3 months following transplantation. Prospective follow-up over a 4-year period was available for 16 of the 18 normolipidemic patients and 25 patients who developed hyperlipidemia, as well as 11 other hyperlipidemic patients who were not included in the initial analysis. Graft function was maintained in 11 (69%) of the patients with early normolipidemia and there has been one patient death (7%). Of the hypercholesterolemic group, two patients were lost to follow-up and 23 of the remaining 34 (68%) had persistent graft function. There have been two patient deaths (6%). No deaths from cardiovascular deaths have occurred in either group, all deaths resulting from infection/sepsis. Mean cholesterol values at 4-year follow-up were 202.0 +/- 11.2 mg/dL for the patients with early normolipidemia 282.9 +/- 14.3 mg/dL for the patients with early hyperlipidemia (p < 0.00001). The most recent cholesterol value was not associated with pretransplant cholesterol value, creatinine, or cyclosporine dose, but was associated with cholesterol value at 3 months both by regression analysis (P < 0.0001) and by Pearson R (r = 0.71, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)