The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy.

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.

Renal transplantation, past, present and future.

In the absence of immunosuppression, renal transplantation was sporadically and unsuccessfully performed during the first half of this century. Over the past 40 years, immunosuppressive drug regimens have evolved greatly and transformed solid-organ transplantation into a routine clinical procedure with a 1-year graft survival between 80% and 90%. The original immunosuppressive scheme was based on the administration of glucocorticoids and azathioprine. However, many patients developed acute rejection which required very high dose of prednisone. As a consequence, a high mortality rate due to opportunistic infections was frequently observed, since this immunosuppressive regimen nonselectively inhibited elements of host resistance such as monocytes, granulocytes, and macrophages. In the early Eighties, the introduction of monoclonal antibodies directed against the CD3 molecule and of cyclosporine, a lymphokine synthesis inhibitor, allowed a more effective control of acute allograft rejection and a more specific target with maintenance immunosuppression. Furtherly, with the knowledge of molecular immunology the better understanding of the cellular and molecular mechanisms that underlie the immunological response to transplanted organs, led to the discovery of new immunosuppressive agents, such as tacrolimus, rapamycin, interleukin-2 monoclonal antibodies, and mycophenolate mofetil. All these drugs showed a more selective mechanism for T- and B-cell alloimmune responses. The results of recent clinical trials based on the combination of these drugs with steroids and cyclosporine reduced the incidence of acute rejection episodes to less than 10% and permitted a steroid-sparing policy in kidney transplantation. Today, the main problem is related to the side-effects of vigorous and prolonged immunosuppression, mainly infections and malignancies. If it were possible to obtain permanent immunological tolerance, immunosuppressive therapy could be minimized. In this respect, the new generation of drugs, FTY 20, antisense oligonucleotides and agents capable of blocking the costimulatory pathway of allorecognition, might have the potential of favoring tolerance in the host against alloantigens.

Lessons from 494 permanent accesses in 348 haemodialysis patients older than 65 years of age: 29 years of experience.

Currently, patients older than 65 years of age constitute more than 42% of all new enrolments for dialytic treatment in the USA and Italy. Most of these patients are treated by in-centre haemodialysis (HD), with problems connected to vascular access. Personal experience of 494 new vascular accesses in 348 'difficult' HD-patients older than 65 years over 29 years showed the best results from 221 elbow fistulas in comparison with 32 forearm fistulas (78% vs 57.2% at 3 years; P < 0.05). Among various vascular substitutes, the homologous saphenous vein (HSV) graft, alone or mixed (MX) gave the best secondary patency in comparison with other organic-semiorganic (OSO) or synthetic graft (SYN) angioaccesses with values of 59.4% for HSV, 66.3% for MX, 21.9% for OSO, and 38.6% for SYN grafts, respectively at 3 years.

Pediatric renal transplantation from the early 1970's through the cyclosporine years at Policlinico University Hospital of Milan.

In our 27 years' experience, 268 kidney transplantations have been carried out in 243 patients, who were under age 18 at the time of operation. Most (84.7%) received a cadaver donor graft. Immunosuppressive treatment with Cyclosporine (CsA) of the most recent 190 recipients resulted in a one-year graft survival rate gain from 51.0-86.5% compared with conventional azathioprine and prednisone therapy previously administered. The impact of the donor age was perhaps the main factor determining the outcome of pediatric transplantation, with a one-year graft survival rate ranging from 71.0-94.2% for grafts from donors aged 2-24 months or 11-18 years, respectively. Exvivo reconstruction and variations of the standard technique assure better success in the case of small kidneys (9 cases) or grafts with multiple/damaged arteries (58 cases).

Randomized study with cyclosporine in kidney transplantation: 10-year follow-up.

This study presents the 10-yr follow-up results of a multicenter controlled trial on 108 recipients of cadaveric renal transplantation, randomized to receive cyclosporine (N = 55) or azathioprine (N = 53), both in combination with steroids. The 10-yr patient survival rate was 89% in the cyclosporine group and 83% in the azathioprine group (P = not significant [NS]); the 10-yr graft survival was 56% and 35%, respectively (log-rank test, P = 0.009). The half-life of grafts functioning after 1 yr was 15.4 +/- 3.9 versus 10.6 +/- 3.6, P = NS). The rate of early rejection in the cyclosporine group was significantly lower than that in the azathioprine group (0.30 versus 1.4, P < 0.01). Although the mean creatinine clearance rate was always higher in the azathioprine group, the decline in graft function from the first to the tenth yr was not significantly different between the two groups (-13.0 +/- 16.4 versus -12.3 +/- 19 mL/min, P = NS). In cadaveric renal transplantation, cyclosporine allows better graft survival than azathioprine, not only in the short term but also in the long term, with similar attrition of graft function for up to 10 yr.

Twenty-five years of transplant experience at Policlinico University Hospital of Milan.

1. CsA treatment played a major role in the improvement of renal transplantation in the third era of our experience for every class of recipient. Many of the most recent patients involved higher risks than in previous eras. 2. The type of donor (LD or CD) did not make a significant difference in patient or graft survival rates up to 4 years. However, the survival rate of LD kidney transplants was better in later follow-ups than that of CD transplants. Pediatric and older kidneys can be used safely, although a lower survival rate is achieved by these grafts. 3. The sex and the side (right or left) of the donor kidney does not affect the outcome of transplantation. 4. In both multiorgan and single-kidney donor origin, there was no difference in graft survival. As all MOD kidneys were flushed with UW Solution and all SKD kidneys were flushed with EC Solution, we can assume that there is no difference in graft outcome, whichever of these solutions is employed. 5. The limited availability of CD grafts has been overcome by using marginal kidneys and adopting extracorporeal microvascular techniques. The results compared well with those of normal allografts. 6. The transplant outcome is penalized by expected higher mortality in older patients. And in pediatric patients there is a higher rate of graft failure due to rejection. 7. Retransplanted grafts under CsA have a better success rate than those using conventional therapy. 8. Extrarenal pathology and the actual risk ratio for CsA-treated recipients still need to be defined by future follow-ups. 9. Our results in renal transplantation, particularly from CDs, could be defined as good in comparison to those of other large transplant centers. 10. The main problem remains that the supply of CD kidneys has decreased in recent years, whereas the demand is increasing, perhaps due to the opening of other transplant centers, an inadequate policy for organ procurement, and ineffective legislation, the last being essential to promote kidney transplantation.

Advantages of cyclosporine as sole immunosuppressive agent in children with transplanted kidneys.

A prospective study of intentional stopping of steroids 6 months after transplantation was done with 29 pediatric renal transplant recipients with a mean age of 10.4 +/- 3.4 years. Immunosuppression consisted of cyclosporine and methylprednisolone. We stopped giving MP to 24 children: to twenty after six months, four after 11-20 months. "Crude graft survival" was 97% during a mean follow-up of 36.7 +/- 15 months. The rejection rate was 48% during the first 6 months and 29% in the period after stopping MP. At present, 20/24 children (83%) have remained on CsA alone (18 patients) or CsA and azathioprine (2 patients) during a mean follow-up of 30 +/- 17 months. CsA nephrotoxicity occurred in 20.6% of patients, gum hypertrophy in 45%, hypertrichosis in 24%, and neurological symptoms in two patients (6.8%). Linear growth significantly improved after stopping MP: mean catch-up growth for prepuberal children 1.38 height standard deviation score (HSDS) and for pubertal children 1.6 HSDS. Bone age did not increase more rapidly than chronologic age. Weight/height index (W/HI) also improved. There was also a significant reduction in the use of antihypertensive drugs. Calculated glomerular filtration rate was decreased, though not significantly, after stopping MP. Thus, when graft survival is good, stopping corticosteroids corrects the major handicap of children with irreversible uremia--the poor linear growth--and improves the W/HI and control of arterial pressure. Longer follow-up periods are necessary to exclude significant worsening of renal function and an increased incidence of chronic rejection after stopping the steroid.

Pregnancy in kidney recipients under cyclosporine.

About 1 of every 50 women of child-bearing age who have a functioning kidney transplant become pregnant. Successful pregnancies following kidney allotransplantation with conventional immunosuppressive treatment are well described, and there is no evidence of abnormalities in the infants born. The use of cyclosporine (CSA) means new problems for the pregnant women and the fetus: the risk of congenital abnormalities, fetal growth retardation, hepato- and nephrotoxicity. We report the experience of 16 pregnancies in 16 of our kidney transplant patients, of which 7 were treated with CSA.

A randomized prospective trial comparing cyclosporine monotherapy with triple-drug therapy in renal transplantation.

In a prospective trial 151 recipients of renal transplants were randomly assigned to treatment with CsA alone (74 patients) and to low dose of AZA, prednisolone, and CsA (77 patients). At two years, graft survival was 84% for the monotherapy and 90% for the triple therapy. This difference was not statistically significant. The number of rejection episodes was similar in the two groups, but the severity of rejection was significantly worse among the patients on monotherapy. More kidneys were lost because of rejection (6 versus 3), and a higher number of methylprednisolone pulses was used for treating rejection (5.2 +/- 2.3 versus 4.3 +/- 2.9; P = 0.0077). CsA nephrotoxicity episodes were more frequent among patients on monotherapy (23 versus 7; P less than 0.02). Infectious episodes were equally distributed between the two groups. Creatinine clearance was poorer in the monotherapy-treated patients at the third month (42 +/- 16 ml/min versus 48 +/- 15 ml/min; P = 0.02), but no differences were observed between the two groups since the sixth month after transplantation. Many patients on monotherapy required changes in maintenance therapy. In fact, one patient was switched to conventional immunosuppression because of Cremophor-induced anaphylaxis. Another patient who developed Kaposi's sarcoma 4 months after surgery was switched to steroids alone. Excluding 5 patients who lost their grafts a few days after transplantation, only 30 of 74 patients (40%) could be kept without steroids. We conclude that both the therapeutic protocols can give good results in renal allotransplantation; however, monotherapy could create some problems in keeping the balance between drug toxicity and significant immunosuppression. On the contrary, triple therapy is easier to handle, especially in the early posttransplant period when the differential diagnosis between acute rejection and CsA-related nephrotoxicity can be difficult even for a skilled clinician.

Maintained cellular function of adrenal medullary cells in parkinsonian dysautonomia.

Adrenal gland involvement in Parkinson's disease was reported by different authors. Further studies became relevant after adrenal was proposed as dopaminergic donor for neurotransplantation. Chromaffin cells were grown in culture and the effects of nerve growth factor (NGF) tested: no differences were observed between parkinsonian and control cells. The expression of the beta-NGF mRNA in the parkinsonian adrenal was analyzed: a specific cDNA was synthesized and a 168 bp portion amplified using PCR. The products were identified and the identity of the fragment was confirmed by sequencing. Quantitative PCR demonstrated a beta-NGF mRNA concentration exceeding 5 fg/micrograms of total adrenal RNA. These findings demonstrate the retained functional capacity of the parkinsonian adrenal to respond to NGF and express the beta-NGF mRNA.