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Natriuretic response to head-out immersion in humans with recent kidney transplants.

1. Recently implanted kidneys may have decreased flexibility to adjust sodium excretion to volume challenges, since modulation by renal sympathetic nerve activity is absent. To examine this hypothesis, we studied the natriuretic response to head-out water immersion in eight patients with well-functioning renal allografts of 37 days (range 24-56 days), at a time when renal re-innervation has probably not occurred. 2. By the third hour of head-out water immersion, sodium excretion had increased equally in the patients (from 120 +/- 21 to 204 +/- 37 mumol/min) and in eight healthy control subjects (from 105 +/- 9 to 191 +/- 19 mumol/min). 3. Glomerular filtration rate was 60 +/- 6 ml/min in the patients and 113 +/- 6 ml/min in the control subjects, and did not change upon head-out water immersion. Estimated renal plasma flow increased upon head-out water immersion in the control group but not in the patients. Blood pressure decreased similarly in both groups. The renal vascular resistance, calculated from these data, decreased in response to head-out water immersion in the control subjects but not in the renal transplant patients. 4. Head-out water immersion suppressed plasma renin activity only in the normal group, whereas the plasma aldosterone level was suppressed in both groups. The natriuretic response in patients was associated with about 3-fold elevated plasma levels of atrial natriuretic peptide. 5. Since renal re-innervation at 37 days after transplantation is very unlikely, these data suggest that inact renal innervation is not mandatory for a normal natriuretic response to head-out water immersion in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Risk factors and mortality associated with calciphylaxis in end-stage renal disease.

BACKGROUND: We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. METHODS: Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. RESULTS: Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR = 0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001). CONCLUSIONS: Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.

Alkaline Phosphatase↗

Peripheral nerve revascularization: a current literature review.

The revascularization of peripheral nerve grafts is reviewed in detail. The endoneurial vasculature is examined and noted to be anatomically dissimilar to a conventional capillary bed although, physiologically, it must subserve similar metabolic functions. Autografts, allografts, and xenografts are considered, as is the effect of graft caliber. The clinical implications for vascularized nerve grafting are discussed.

Animals↗

Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease.

OBJECTIVE: Recombinant human growth hormone (rhGH) has been used to improve the growth retardation associated with chronic renal insufficiency (CRI) and end-stage renal disease. We determined the incidence of one of four targeted adverse events (AEs): malignancy, slipped capital femoral epiphysis (SCFE), avascular necrosis (AN), and intracranial hypertension (ICH). STUDY DESIGN: During a 6.5-year period, we prospectively assessed patients enrolled in the CRI, dialysis, and transplant registries of the North American Renal Transplant Cooperative Study. The availability of an untreated control population facilitated determining whether or not there was the association between the AE and rhGH treatment. RESULTS: Of the targeted AE, the only significant relation with rhGH treatment was the presence of ICH in patients with CRI; however, in all 3 instances, ICH occurred 2, 50, and 1131 days after discontinuation of rhGH. Considering that the mechanism of ICH in rhGH-treated patients is thought to be increased CSF production, rhGH probably had no role in the development of ICH in at least 2 of the 3 patients with CRI. A number of nontargeted AE were identified that have been associated with rhGH treatment in patients without renal disease. The incidence of glucose intolerance, pancreatitis, progressive deterioration of renal function, acute allograft rejection, and fluid retention were not more frequent in those receiving rhGH treatment compared with the control population. CONCLUSIONS: This report validates the importance of a control population in ascribing AE to any therapeutic intervention. Previously identified AE associated with rhGH treatment are infrequent in patients with CRI and end-stage renal disease.

Adolescent↗

Islet cell transplantation in treatment of diabetes.

Transplantation of isolated islets in volunteer patients with functioning renal allografts reduced their insulin requirements for up to 18 months. These trials were based on experiments with rats with induced diabetes in which plasma glucose levels and glucosuria were decreased, and retinal and renal complications prevented or reversed. The approach may make possible correction of the carbohydrate metabolism defect.

Adult↗

Anaesthesia for patients with transplanted hearts and lungs undergoing non-cardiac surgery.

Heart and lung transplantation is now accepted as a means of treating some end-stage cardiopulmonary diseases. These patients may present with a wide variety of non-cardiopulmonary conditions requiring anaesthesia and surgery, possibly at a place distant from their original transplant centre. In general, for much elective, acute or even emergency surgery, if the allograft is functioning satisfactorily, these patients should present few problems during anaesthesia, provided the anaesthetist has some understanding of the pathophysiology of the transplanted organ and recognizes the differences (potential and specific to cardiopulmonary transplantation) between such patients and any other subject.

Adult↗

Assessment of ultrasound guided percutaneous ethanol injection and parathyroidectomy in patients with tertiary hyperparathyroidism.

BACKGROUND: Tertiary hyperparathyroidism continues to cause significant morbidity in patients with chronic renal failure. This is frequently resistant to medical management and may ultimately require a surgical parathyroidectomy. Recent studies have reported upon the technique of percutaneous ethanol ablation for both primary and tertiary hyperparathyroidism. In this study we report on a 5 year experience using ethanol injection and compare the results with surgical parathyroidectomy. METHODS: A prospective study in 39 patients with tertiary hyperparathyroidism, 25 were dialysis dependent and 14 had a functioning renal allograft. Twenty-two patients underwent percutaneous fine needle ethanol injection (PFNEI) and 17 underwent surgical parathyroidectomy. RESULTS: A > 30% reduction in intact parathyroid hormone (iPTH) was achieved in 11 of 22 patients undergoing PFNEI after a mean of 1.8 +/- 1.4 injections per gland. In four patients, symptomatic hyperparathyroidism recurred and they required further PFNEI or surgical parathyroidectomy at 17, 28, 46, and 48 months later. There was no significant reduction in iPTH in 11 patients following PFNEI after a mean of 2.5 +/- 1.3 injections per gland. They all required a subsequent surgical parathyroidectomy for symptomatic hyperparathyroidism. Four patients developed a laryngeal nerve palsy following PFNEI, two of which were permanent. Seventeen patients underwent successful surgical parathyroidectomy as a primary procedure. CONCLUSION: Whilst PFNEI is successful in primary hyperparathyroidism, when typically only one adenoma is present, the effectiveness of PFNEI is unpredictable and the long term results are poor compared with those of surgical parathyroidectomy in tertiary hyperparathyroidism. The procedure is not without complications and makes subsequent surgery more difficult. Therefore it can only be recommended for patients with a known single parathyroid gland such as patients in whom hyperparathyroidism has recurred following a previous surgical subtotal parathyroidectomy and who are unsuitable for further surgery.

Administration, Cutaneous↗

Growth of vascularized composite mandibular allografts in young rabbits.

Forty-one hemimandible allografts were transplanted in young rabbits immunosuppressed with cyclosporine. The majority of the grafts demonstrated normal wound healing, and growth of hair, bone, and teeth. The mandibular body and the premolars showed significant growth in length. The allografted mandibles functioned sufficiently that the rabbits took oral nourishment soon after surgery. Long-term survival was limited by a toxic "wasting syndrome" specific for rabbits under treatment with cyclosporine.

Animals↗

Management of severe pancreatitis in renal transplant recipients.

OBJECTIVE: The authors determine if any aspects of the treatment of renal transplant patients with pancreatitis were of particular benefit with regard to graft and patient survival. BACKGROUND: The incidence of pancreatitis in renal transplant patients is low (1%-2%), but the mortality of the disease approaches 100%. Although several descriptive reports have been published, there is no consensus-regarding management. METHODS: The authors conduct a retrospective chart review. RESULTS: Twenty-one patients were identified with posttransplant pancreatitis (1.3% incidence). The cause of pancreatitis was presumed to be maintenance immunosuppression in all cases. Patients were classified by dynamic computed tomography (CT) scans having 1) mild/edematous disease (4 patients), 2) localized abscess or pseudocyst (6 patients), or 3) severe disease (11 patients). Patients with mild/edematous pancreatitis did well with medical management. The six patients with localized abscess or pseudocyst were successfully treated with standard operative intervention. Of the 11 patients with severe disease, 6 had several days of intensive medical management before operation, and all died. The other five patients underwent early operative intervention based principally on CT scan findings, and all survived. The latter group had multiple operations and four of five had functioning renal allografts at discharge. CONCLUSION: The severity of pancreatitis in the posttranplant patients may be difficult to assess by clinical criteria. Dynamic CT scanning is, therefore, essential in defining the extent of disease. Early, and perhaps repeated, operations may be lifesaving in those patients having CT scan findings of severe pancreatitis.

Adult↗

Noninvasive measurement of blood flow and extraction fraction.

We describe the theory of a technique for the noninvasive measurement of organ blood flow which is based on the principle of fractionation of cardiac output and is applicable with any recirculating gamma emitting tracer. The technique effectively determines the count rate that would be recorded over the organ if the tracer behaved like radiolabelled microspheres and was completely trapped in the organ's vascular bed on first pass. After correction for organ depth, the estimated first pass activity plateau, expressed as a fraction of the injected dose, is equal to the organ's fraction of the cardiac output (CO). By extending the theory, organ extraction fraction of extractable tracers or mean transit time of nonextractable tracers can be measured. Renal blood flow (RBF) to the normal left kidney in 18 subjects without evidence of renal disease was estimated by the technique to be 10.4% CO (S.D. 1.2), for the right kidney 9.0% CO(S.D. 1.1), and for both, 19.4% CO (S.D. 1.5). In a separate series of eight patients, RBF values were highly reproducible when obtained on successive days (standard deviation of change: 0.67% CO for the left kidney, 0.63% CO for the right and 0.78% CO for both). The extraction fraction of DTPA (filtration fraction) was 8.5% (1.7) in the left kidney and 9.7% (2.1) in the right kidney. This parameter was less reproducible than RBF, with standard deviations of the changes equal to 1.17% for the left kidney and 1.31% for the right. Stable, well-functioning, renal allografts in children had a mean blood flow of 20.6% CO (S.D. 3.7). Transplant blood flow in eight patients with rejection was less than 5.2% CO. In patients without splenomegaly, splenic blood flow, splenic extraction fraction of sulphur colloid and splenic red cell mean transit time were 4.3% CO (S.D. 0.9), 41% (S.D. 13.8), and 36.9 s (S.D. 4.6), respectively.

Blood Circulation↗

Cell-mediated cytotoxicity toward the donor in patients with well-functioning kidney grafts. Possible mechanism of specifically reduced cytotoxic response.

Patients with well-functioning kidney allografts from one-HLA-haplotype--mismatched related donors have strongly reduced donor-specific cell-mediated cytotoxicity 2-10 years after having received their grafts. This could also be demonstrated in secondary in vitro cell-mediated lympholysis (CML). Even though secondary donor-specific CML did not exceed 10% at an effector-to-target cell ratio of 50:1, specific lysis of donor target cells increased significantly with increasing effector cell concentrations. The weak cytotoxicity toward the donor could be enhanced neither through pool-cell stimulation nor by adding exogenous Interleukin 2 (IL-2) during the induction phase. Furthermore, growth factors were produced in the cultures during the induction of cytotoxic cells in concentrations comparable to those of the sibling control. Thus no evidence could be obtained that lack of IL-2 was causing the decreased cytotoxicity in these patients. Our studies indicate that in vivo depletion of cytotoxic cells with high lytic efficiency is probably the reason for the strongly reduced donor-specific cytotoxicity.

Cytotoxicity, Immunologic↗

New approaches to donor crossmatching and successful transplantation of highly sensitized patients.

A class I HLA molecule may bear not only a private or unique determinant, but a shared, yet discrete, public epitope. These public determinants occur with a much higher frequency in the random donor population than the associated private determinants--and thus, are encountered more often in random donor blood transfusions and in renal transplantation. Sera from highly sensitized dialysis patients have been reported to contain a restricted number of antibodies to public determinants rather than a diverse array of antibodies directed against the private HLA-AB epitopes. As detailed in this report, comprehensive serum analysis of the public antibodies in highly sensitized transplant candidates has optimized identification of potential crossmatch-compatible donors and has avoided needless crossmatches. During the past two years, the incidence of renal transplantation from cadaveric donors to highly sensitized recipients has doubled at this institution. At 10-25 months following transplantation, 70% of these allografts are functioning. Private HLA class I antigen incompatibility was not a barometer for exclusion in the final donor crossmatch of these highly sensitized recipients. Furthermore, positive donor T cell crossmatches with sera obtained more than six months prior to transplantation may not represent an impediment to successful transplantation. We conclude that the approach of detailed antibody analysis can result in an improved outlook for successful transplantation of more dialysis patients who are highly sensitized to the class I HLA alloantigens.

Antibodies↗

The clinical and pathological course of hepatitis B liver disease in renal transplant recipients.

A prospective study of the clinical and pathological sequelae of hepatitis B disease in 22 immunosuppressed renal transplant patients is reported. All patients had allografts that functioned for more than 1 year, and all were hepatitis B surface antigen (HBsAg)-positive following transplantation. None of the 18 patients who had serial HBsAg tests converted to HBsAg negative. Serial liver biopsies were performed in 19 patients and one liver biopsy was available in the remaining three patients. Follow-up ranged from 12 to 93 months. Seven patients ultimately developed cirrhosis, 6 developed chronic active hepatitis, 5 developed chronic persistent hepatitis, and in 4 the presence of HB virus in hepatocytes was the sole morphologic alteration. The initial liver biopsy was not an accurate predictor of ultimate severity of liver disease because 5 of the 12 patients with virus only or chronic persistent hepatitis subsequently developed chronic active hepatitis or cirrhosis. Clinical liver dysfunction occurred in 8 patients, all of whom had chronic active hepatitis or cirrhosis. Three patients died with hepatic failure and 2 with hepatoma. The risk of death from liver disease in HBsAg-positive renal transplant patients was 5% per patient-year. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Biochemical evidence of persistent liver dysfunction recurred in 1 patient only; 4 patients converted to the HBsAg-negative state; and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of chronic active hepatitis, leading to cirrhosis and death from hepatoma and hepatic failure.

Adolescent↗

The impact of renal transplantation on the course of hepatitis B liver disease.

To establish the impact of transplantation on the course of chronic hepatitis B liver disease we performed a prospective study of the clinical and pathological sequelae of hepatitis B disease in all 22 patients who had renal allografts that functioned for more than 1 year and who were hepatitis B surface antigen (HBsAg)-positive following transplantation. No patient converted to HBsAg-negative. During a mean follow-up of 83 months serial liver biopsies were performed in 20 patients and 1 liver biopsy was available in the remaining 2 patients. Eleven patients died of liver disease, 5 of whom died of hepatic failure, 3 with hepatoma, 2 of gastrointestinal hemorrhage, and 1 of ascites with pleuroperitoneal fistula. Aggressive liver disease was observed in the vast majority of patients: 12 ultimately developed cirrhosis, (mean follow-up 81 months), 6 chronic active hepatitis (mean follow-up 93 months), 3 chronic persistent hepatitis (mean follow-up 89 months), and in 1 patient the presence of HB virus in hepatocytes was the sole morphologic alteration (follow-up 42 months). There was a marked tendency to progression in that 82% of patients with virus only, reactive hepatitis, or chronic persistent hepatitis on initial biopsy subsequently developed chronic active hepatitis or cirrhosis. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Four patients converted to the negative state. Biochemical evidence of persistent liver dysfunction occurred in only 1 patient and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of cirrhosis, leading to death from hepatoma and hepatic failure. This course is worse than that in dialysis patients. Renal transplantation of HBsAg-positive patients with end-stage renal failure may be inadvisable.

Aspartate Aminotransferases↗

Natural killer cell subsets in long-term renal allograft recipients. A phenotypic and functional study.

Natural Killer cell subsets were studied in 39 long-term renal allotransplant recipients receiving conventional immunosuppression and 26 normal controls. Two-color flow cytometry analysis was used to determine coexpression of 2 surface antigens known to allow a phenotypic and functional discrimination of NK cells--Leu-7 a marker of large granular lymphocytes, and Leu-11c directed against the FcgammaR. In 11 patients and controls, these NK cell subsets were compared with actual NK activity assessed by killing of K562 target cells. Our data clearly show that, in long-term kidney recipients, the absolute number of NK cells (Leu-11c+) is significantly decreased compared with that of the control group. Furthermore, the most cytotoxic NK cell subset (Leu-7-/Leu-11c+ phenotype) is markedly diminished in the transplant population, whereas the less cytotoxic subset (Leu-7+/Leu-11c+) is unchanged. Finally, actual NK cell activity closely correlates with both relative and absolute numbers of these 2 NK cell subsets. These data provide convincing evidence that NK activity is impaired in long-term kidney recipients because of a diminished number of NK effector cells.

Adult↗

Evidence of donor-specific cellular suppressor activity in donor-specific cell-mediated lympholysis unresponsiveness in renal transplant patients.

Twenty patients with well-functioning kidney grafts from one-haplotype-mismatched related donors, were studied 1-10 years after transplantation (A). Another group of six patients were studied at various times after transplantation (B). The presence of donor-specific transplantation tolerance, using mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) tests was investigated, as well as the possible existence of cells with suppressive activity. All recipients were transfused prior to transplantation and treated with conventional immunosuppression. The patients in group A showed MLC reactivity against donor and third-party cells, indicating a allogeneic response capacity. The CML activity against the donor was low, however, and remained low also following removal of adherent cells. The CML activity toward third-party cells was within the normal range of unmatched individuals. In group B, two of six recipients and high postoperative CML activity against the donor. Both recipients showed clinical signs of rejection. In the remaining four recipients, the antidonor CML reactivity one week after transplantation was lower than the preoperative level. The decrease was even more pronounced at 12 months, although the reactivity against third-party cells was unaltered. The CML reactivity from unrelated fourth-party individuals toward donors was suppressed when cells from recipients with long-term functioning kidneys were added to the cell cultures. The results suggest the presence of a donor-specific cellular suppressor mechanism underlying the donor-specific CML unresponsiveness in recipients with long-term-functioning kidney allografts.

Adolescent↗

Segmental small intestinal allografts in the dog. I. Morphological and functional indices of rejection.

Fourteen dogs received an orthotopically vascularized allograft of a 100-cm length of terminal ileum as a Thiry-Vella segment. Absorption, motility, myoelectrical activity and morphology of the allograft were studied to determine the most reliable indices of rejection. The earliest histological evidence of rejection occurred at a mean of 6.2 +/- 0.9 days and was coincident with significant deterioration in the absorption of water, alanine, lauric acid, sodium, and glucose. Intestinal motility did not decrease until 7-8 days after transplantation, and intestinal myoelectrical activity was unchanged for a further 2-3 days, by which time graft necrosis was imminent. Reduced intestinal motility occurs only after rejection is established, and is therefore of little use as an index of rejection, while recording intestinal myoelectrical activity is valueless and serves only to confirm graft death. Decreased intestinal absorption of water, sodium, glucose, alanine, and lauric acid are present as early as the first changes in mucosal histology and are useful indices of rejection of intestinal allografts.

Animals↗

Treatment of growth failure in children after renal transplantation.

Growth failure continues to be a problem in the management of children with renal failure. Children have improved growth after successful renal transplantation, but seldom have "catch-up" growth, or normal adult height. In this study we report the findings of an open label pilot study to determine the safety and efficacy of the use of recombinant human growth hormone (rhGH) in children with growth failure after successful renal transplantation. Eleven children completing at least 1 year of treatment had a mean age of 11.5 years (+/- 3.3) and mean bone age of 8.4 years (+/- 2.4), and were significantly growth-retarded (mean standard deviation score of -3.18 [+1.1]). After receiving rhGH (0.05 mg/kg) subcutaneously each day the height velocity increased from 5.2 cm/year to 8.4 cm/year (P = 0.003), and the standard deviation score improved from -3.18 to -2.23 (P = 0.004). Treatment was associated with advancement in Tanner stage from 1 to 2.8 (P = 0.004), increased bone age from 8.4 years to 10.9 years (P = 0.0002), and although it was not at the point of statistical significance, moderate decrease in creatinine clearance from 75 ml/1.73m2/min to 60 ml/1.73m2/min (P = 0.1). The advancement in Tanner stage and bone age was not out of proportion to the advancement in height age. These data suggest that children with functioning renal allografts have improved growth with supraphysiologic doses of rhGH.

Adolescent↗