De novo focal glomerular sclerosis in an identical twin renal transplant recipient.

A patient with end-stage renal failure caused by bilateral kidney stones received a kidney transplant from his identical twin. No immunosuppressive therapy was given. After a few days he developed a urinary fistula from a polar artery section, which spontaneously healed. Renal function remained subnormal, blood pressure and urinalysis were normal. After one year proteinuria appeared, and after about four years it entered a nephrotic range. Renal biopsy showed focal glomerular sclerosis (FGS). In the following years progressive renal insufficiency and arterial hypertension developed, and the patient had to be submitted to regular dialysis about 9 years after transplantation. As far as we know this is the first case of late renal failure in an isograft related to the development of de novo FGS. It is suggested that de novo FGS in this isotransplant was related to the partial loss of renal mass caused by polar necrosis, which caused glomerular hyperfiltration. Another possible contributing factor may be kidney denervation, which removes an important mechanism for adjustment of renal arterial flow.

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.

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.

The Milan clinical trial with cyclosporine in cadaveric renal transplantation. A three-year follow-up.

Between February and November 1983, 108 recipients of cadaveric renal transplants entered a randomized multicenter trial and were treated either with cyclosporine (CsA) and prednisone (n = 55) or with conventional treatment based on azathioprine (Aza) and glucocorticoids (n = 53). The graft survival probability at 3 years was 76% for CsA patients and 48% for Aza patients (P less than 0.001). The cumulative number of acute rejections was significantly lower in the CsA group (32 vs. 104, P less than 0.001). Incidence of early posttransplant anuria was similar in both groups and did not affect renal function after three years. Nephrotoxicity in CsA patients, when present, was handled by reducing the dose of CsA, but in 12/55 patients a change to conventional therapy was thought to be necessary. However, in this group of 12, one patient lost the allograft because of irreversible rejection and one patient died 14 months later because of an infection. Mean creatinine clearance after three years was significantly lower in the CsA patients (54.7 +/- 2.6 ml/min) than in Aza patients, (67.2 +/- 4.9 ml/min, P less than 0.05). Considering only patients with grafts functioning after three years and still on the original randomized therapy, the mean creatinine clearance was similarly and significantly decreased from 1 to 3 years in both groups. There were no significant differences in occurrence of severe infections. Side effects such as hypertension, hypertrichosis, tremor and gum hyperplasia were more frequent in CsA patients.

A randomized trial comparing triple-drug and double-drug therapy in renal transplantation.

A controlled trial was carried out in 86 cadaveric and 14 living haploidentical renal transplant recipients to compare the effects of low doses of cyclosporine (CsA), azathioprine (Aza) and steroids with those of higher doses of CsA plus steroids. Patients were followed for 12-26 months after transplantation. The actuarial 2-year patient and graft survival rate was 100% for living-donor transplants. In cadaver renal transplants the 2-year patient survival rate was 100% for patients assigned to the triple regimen and 93% for those allocated to the double regimen. The actuarial 2-year cadaver graft survival rates were 86% and 90.6%, respectively. There were significantly more patients who had severe infections (P less than 0.05), particularly interstitial pneumonia (P less than 0.005), in the double-therapy group. On the other hand, there were more patients who rejected and more patients with severe rejections; more pulses of steroids were also required for patients on the triple regimen, although these differences were not significant. The mean trough blood levels of cyclosporine at the various times were about half as high in patients on triple therapy. There were no differences between the two groups in creatinine clearance at any time. A control renal biopsy, taken from patients with stable renal function after 6-12 months, showed only mild abnormalities. The lesions were semiquantitatively assessed. There was a higher score for interstitial infiltrate in patients on triple therapy (P less than 0.05). On the other hand, the incidence and the mean score of interstitial fibrosis were greater in patients on double therapy, although these differences were not significant. Thus, although similar results were obtained with both regimens, at the doses we used double therapy seems to have more powerful immunosuppressive effects and may prevent rejection, either acute or chronic, better. However, it might expose the patient to a greater risk of infection and of cyclosporine-related nephrotoxicity than triple therapy.

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.

Use of homologous vein grafts for chronic hemodialysis.

The Authors propose using of homologous saphenous vein grafts, coming from a normal saphenectomy by stripping in patients affected by primary varicose veins. The graft is preserved in a particular solution at 4 degrees C in a normal refrigerator and transplanted in uremic patients, which have no more vessels suitable for creating a conventional arteriovenous fistula.

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.