Single-center experience with renal transplantation in patients with Wegener's granulomatosis

Between 1980 and 1995, 13 patients with end-stage renal disease due to Wegener's granulomatosis received 14 renal transplants (10 cadaveric, 4 living related). The mean follow-up in the 13 successfully transplanted patients was 50 months (4–107 months). One patient had primary nonfunction and received another graft 4 months later. Three episodes of acute rejection occurred in two patients, and one of these patients lost her graft due to severe vascular rejection 4 months after transplantation. Two patients died with well-functioning grafts (one of metastatic cancer and one of sepsis). One patient presented with perisinusitis and had a mild recurrence of Wegener's disease. None of the patients developed recurrent disease in the transplanted organ. At the last follow-up, the mean creatinine ( ± SD) in the 12 patients with functioning grafts was 1.6 ± 0.6 mg/dl. We conclude that renal transplantation is an excellent treatment for renal failure due to Wegener's granulomatosis. Recurrence of the disease is uncommon in patients under immunosuppression, but careful monitoring is extremely important. Received: 1 July 1996 Received after revision: 6 September 1996 Accepted: 23 September 1996     

Renal hemodynamic effect of tacrolimus in renal transplanted children

Like cyclosporine (CsA), tacrolimus acts through the inhibition of renal phosphatase calcineurin. CsA induces reversible vasoconstriction, causing a transient reduction of renal plasma flow in patients with renal transplantation. The aim of this study was to determine the effect of tacrolimus on renal plasma flow in renal transplanted children. Eight children were studied with a median age of 10.6 years, a mean glomerular filtration rate (inulin clearance) of 55 ml/min per 1.73 m² (range 29–95), and a mean follow-up after transplantation of 5.6 months. Effective renal plasma flow (ERPF) was studied in each patient for 12 h after tacrolimus administration. Clearan- ces were obtained every 2 h for 12 h after drug administration. Tacrolimus pharmacokinetics was also studied. Average ERPF at the start of the test was 289 ml/min per 1.73 m² (range 177–404, SD±106). Variation in each of the 2-h periods was not significant, although a mild reduction of plasma flow was observed in three of the eight children. No correlation was found between tacrolimus AUC, peak, or trough levels and renal blood flow variations. Despite the relatively small number of patients studied, these data suggest that, in vivo, a therapeutic oral dose of tacrolimus is not necessarily followed by a significant reduction of ERPF in renal transplanted children. Received: 15 November 2000 / Revised: 3 April 2001 / Accepted: 16 May 2001     

Delayed acute renal failure in post-transplant period in young children from unexplained etiology

This report describes six young children (5 male) who developed delayed acute renal failure (DARF) in the early post-kidney-transplant (Tx) period in the absence of acute rejection (AR) or other diagnosable conditions. These young children, aged 16.5 ± 3.1 (12–21) months [mean ± SD, (range)] and weighing 8.5 ± 1.7 (7.1 – 11.4) kg received a primary renal Tx (5 living-related donor, 1 cadaver) between 1984 and 1992. Immunosuppression included prednisone, azathioprine, and Minnesota antilymphocyte globulin (MALG, n = 5); one patient received cyclosporine and no MALG. Initially, all patients had good urine output (UO). They became systemically ill and abruptly developed diminished UO on post-operative day (POD) 6.5 ± 1 (4 – 8). DARF was accompanied by fever (39.1 – 40.4°C, n = 6), thrombocytopenia (platelets <100,000/mm³, n = 6), leukocytosis, or leukopenia (white cell count >20,000/mm³, n = 4 or <1,000/mm³, n = 1). Four patients had diarrhea. Three had ascites and one was surgically explored for suspected urinary leak. None showed significant urinary obstruction by renal ultrasound. Renograms showed intact blood flow. Renal biopsy showed tubular ectasia (n = 6), vascular congestion (n = 5), focal glomerular endothelial swelling (n = 4), and capillary thrombi (n = 3). None showed AR. Five patients required dialysis for 11 ± 4 (7 – 15) days. All patients survived. One patient, treated for suspected AR with the monoclonal antibody OKT3, developed shock and lost her graft on POD 12 due to vascular thrombosis. Renal functional recovery in the remaining five patients took 14 ± 5 (6 – 20) days and their serum creatinine at discharge was 0.7 ± 0.5 (0.3 – 1.6) mg/dl. We report DARF from undetermined etiology occurring in the first 2 weeks of renal Tx in young children. Treatment is supportive care including dialysis. Recognition of this complication will help avoid risky investigations or unnecessary treatment for rejection. Received August 21, 1996; received in revised form February 14, 1997; accepted March 4, 1997     

Treatment of focal glomerulosclerosis with pulse steroids and oral cyclophosphamide

Patients with steroid-resistant nephrotic syndrome often have an unsatisfactory long-term outcome and are at risk of developing chronic renal failure. We prospectively treated 65 children with idiopathic steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with intravenous pulses of corticosteroids and oral cyclophosphamide. Dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg) was administered intravenously, initially 6 pulses on alternate days, followed by 4 fortnightly and 8 monthly pulses. Oral cyclophosphamide therapy was given for 12 weeks and tapering doses of prednisolone were administered for 52 weeks. The mean age at treatment was 85.7± 44.9 months. Five patients developed serious infections during administration of initial alternate-day pulses and were excluded. Of 59 patients who completed initial alternate-day therapy, 17 had complete and 8 partial remission; 34 (57.6%) patients did not respond to treatment. The median urine protein to creatinine ratio decreased from 10.0 to 0.75 (P<0.005) and serum albumin increased from 1.9 g/dl to 2.4 g/dl (P<0.01). The median duration of follow-up after stopping pulse therapy was 25.6 months. Thirty-four patients were followed for more than 3 years (median 4.5 years). Of these, 22 (64.7%) patients had a favorable outcome; persistent complete remission was seen in 15 patients and steroid-responsive relapses in 7. Seven patients had non- nephrotic-range proteinuria, 2 had nephrotic-range proteinuria, and 3 (8.8%) were in chronic renal failure. There was no significant difference in the short- and long-term outcome of patients with initial (n=28) and late resistance (n=31). The outcome in patients receiving intravenous dexamethasone (n=48) or methylprednisolone (n=11) was also similar. The chief side effects included worsening of height standard deviation score (47.4%), transient hypertension (42.5%), and serious infections (18.5%). We conclude that prolonged treatment with intravenous corticosteroids and oral cyclophosphamide is beneficial in patients with steroid-resistant FSGS. Expensive protocols can be successfully modified and used, depending upon the availability of health resources. Received: 14 November 2000 / Revised: 14 June 2001 / Accepted: 14 June 2001     

A case of post-transplant hyperparathyroidism treated with ethanol injection

A 15-year-old boy with chronic renal failure secondary to Alport’s syndrome underwent living-related renal transplantation from his 48-year-old father. His primary immunosuppressive regimen was composed of tacrolimus, mizolibine, and methylprednisolone. The postoperative course was satisfactory with one episode of mild acute rejection, treated successfully with methylprednisolone pulse therapy. Two months later, hypercalcemia (11.8–13.2 mg/dl) and hypophosphatemia (2.5–3.0 mg/dl) were noted without any bone symptoms. The serum intact-parathyroid hormone (PTH) and serum alkaline phosphatase levels were 240 pg/ml and 2483 IU/l, respectively. Ultrasound studies revealed enlargement of the two parathyroid glands. Under the diagnosis of ter-tiary hyperparathyroidism, he underwent percutaneous ethanol injection (PEIT) into the left parathyroid gland. Although levels of serum calcium and phosphorus returned to normal ranges and the intact PTH level decreased to 95 pg/ml with the three injections, another injection was needed to normalize recurrent hypercalcemia 2 months later. The patient experienced only transient mild dysphonia and local pain after PEIT. Although PEIT is believed less effective than parathyroidectomy, it has some advantages such as applicability to high-risk patients, repeatability of treatment, low incidence and severity of side effects. Received: 26 June 2001 / Revised: 21 November 2001 / Accepted: 24 November 2001     

Creatinine excretion rates for renal clearance studies

A total of 637 timed-urine collections for creatinine excretion rates obtained from 295 children over 14 years have been analyzed. The children ranged in age from 2.8 to 21.7 years at the time of the clearance study. The data analyzed included only one study from a child during any 6-month period. The objective is to provide data defining the expected range of creatinine excretion for renal clearance studies. One hundred forty-two studies were conducted on children not pretreated with cimetidine and 495 on those pretreated with cimetidine. Analysis showed that pretreatment with cimetidine for creatinine clearance studies does not alter creatinine excretion rates (P=0.080; 95% CI –0.03 to 1.61). Creatinine excretion rates in urine collections obtained at home (roughly 24-h collections) were compared with 2-h supervised collections in the Children’s Kidney Center. The supervised urine collections resulted in creatinine excretion rates 1.38 mg/kg/24 h greater than home collections (P=0.001; 95% CI 0.76–2.00). Using regression equations for creatinine excretion rate with age, tables have been prepared showing the expected rate of creatinine excretion for renal clearance studies in children 3–21 years of age. Received: 7 December 2000 / Revised: 20 March 2001 / Accepted: 22 March 2001     

Adult liver transplantation and steroid-azathioprine withdrawal in cyclosporine (Sandimmun)-based immunosuppression – 5 year results of a prospective study

New immunosuppressants are said to be superior to cyclosporine due to their higher incidence of steroid sparing and to the reduced incidence of side-effects. From May 1992 to February 1995, 79 adults underwent primary liver transplantation using cyclosporine A (Sandimmun)-based triple drug immunosuppression. Nine patients who died early after liver transplantation due to reasons unrelated to immunological problems were excluded from this analysis. The long-term outcome of the remaining 70 patients was prospectively studied in relation to steroid and azathioprine withdrawal. They were re-evaluated 6-monthly in relation to liver and kidney function; cholesterolemia, infection, de novo diabetes mellitus and arterial hypertension, malignancy, ophthalmological and osteomuscular diseases. In case of rejection occurring during or after steroid tapering, patients were switched, by protocol, to tacrolimus therapy. Median follow-up was 81 months (range 60–96). Forty-four patients (62.8 %) were biopsied 5 years after transplant; 20 patients (28.6 %) were biopsied at a median follow-up of 32 months (range 7.8–47). Six patients (8.6 %) who refused biopsies more than 1 year after liver transplantation had normal liver values throughout the whole follow-up period. Five-year actual patient and graft survivals were 75 % and 65.8 %, respectively, for the whole group (n = 79) and 85.7 % and 74.3 % for the studied group (n = 70). Steroids could be withdrawn in all but two patients (97.1 %) at a median time of 7 months (range 3–42). Steroids were restarted in six patients (8.6 %) for extrahepatic reasons. Freedom from steroids was thus observed in 62 patients (88.6 %). Seven patients (10 %) had rejection after steroid tapering; six were switched to tacrolimus. Two patients (2.9 %) needed retransplantation because of acute and chronic rejection whilst still being on full immunosuppression. In total, three patients (4.3 %) had histological signs of chronic rejection during follow-up. At 5 years post-transplant, 66.6 % and 13.3 % of the 60 patients at risk were on cyclosporine and tacrolimus monotherapy, respectively; 93.3 % were steroid-free. Mean creatinine and cholesterol levels were 1.56 ± 1.3 mg/dl and 193.5 ± 56.6 mg/dl; incidences of de novo arterial hypertension, insulin dependent diabetes mellitus were 26.6 % and 13.3 %. Two patients (2.8 %) developed post-transplant lymphoproliferative disease, two (2.8 %) had skin cancer. Cyclosporine-based immunosuppression allows safe steroid withdrawal in most patients and cyclosporine monotherapy can be achieved in two-thirds without compromising graft and patient survival. Results of new immunosuppressive strategies should be approached with caution, especially when considering steroid sparing and the incidence of side-effects. Received: 12 July 2000 Revised: 15 December 2000 Accepted: 11 September 2001     

Use of anti-CD25 monoclonal antibody in combination with rapamycin to eliminate cyclosporine treatment during the induction phase of immunosuppression.

BACKGROUND: Cyclosporine and tacrolimus are associated with drug-induced renal dysfunction that may exacerbate recovery from ischemic injuries during the first month posttransplant. We sought to use anti-CD25 (anti-interleukin-2 receptor) monoclonal antibodies in combination with sirolimus (rapamycin) to avoid cyclosporine therapy during the early postoperative period in six renal transplant recipients deemed to be at high risk for delayed graft function. METHODS: Six consecutive patients deemed to be at high risk for delayed graft function were treated with rapamycin (2-12 mg/day), anti-CD25 monoclonal antibodies, and steroids, withholding inception of cyclosporine therapy until the serum creatinine fell below 3.0 mg/dl. RESULTS: During the first 2 months posttransplant, none of the patients displayed clinical or histopathological evidence of acute allograft rejection episodes, cytokine release syndrome, or hypersensitivity reactions. None of the patients received even empiric bolus or high-dose steroid therapy for a presumed rejection episode. All patients recovered renal graft function within 8 weeks posttransplant. To date all patients have stable renal graft function. Five patients have serum creatinine levels between 0.8 to 1.3 mg/dl at 6 months and the other patient has a serum creatinine level of 1.7 mg/dl at present follow-up of 2 months posttransplant. CONCLUSION: During the early posttransplant period anti-CD25 monoclonal antibodies combined with rapamycin and steroids offer a promising baseline therapy to avoid cyclosporine exposure and facilitate recovery from ischemic/reperfusion injuries.     

Renal allograft rejection with normal renal function in simultaneous kidney/pancreas recipients: does dissynchronous rejection really exist?

BACKGROUND: Between July 1, 1994 and December 1, 1998, 147 simultaneous kidney/pancreas transplantations were performed at our center. Of 95 patients who experienced at least one acute renal allograft rejection episode after transplantation, 7 (7.4%) developed rejection in the presence of stable and normal or near-normal renal function. METHODS: The indication for renal allograft biopsy was a rising serum lipase, i.e., suspected pancreatic rejection. All seven patients were treated with steroids and augmentation of the tacrolimus dose, with a fall in the serum lipase and no change in the serum creatinine. RESULTS: The serum creatinine levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1.4+/-0.4, 1.3+/-0.3, 1.2+/-0.2, and 1.2+/-0.2 mg/dl. The serum lipase levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1022+/-1157 mg/dl, 874+/-996 mg/dl, 243+/-260 mg/dl, and 94+/-75 mg/dl. The tacrolimus dosages and levels at the time of the biopsy and 1 week later were 14.9+/-5.0 mg/day and 15.0+/-4.0 ng/ml, and 16.4+/-6.3 mg/day and 15.1+/-6.8 ng/ml. CONCLUSIONS: These findings suggest that, in patients undergoing simultaneous kidney/pancreas transplantation, the entity of dissynchronous pancreatic allograft rejection without renal allograft rejection may not really exist. These data also make an additional fundamental point that acute rejection may occur in patients with normal and stable renal function.     

Tacrolimus versus cyclosporin A: a comparative study on rat renal allograft survival

Although tacrolimus has been studied in a wide variety of experimental animal models, we are the first group to systematically study the effect of tacrolimus on rat renal allograft survival, as primary therapy and as anti-rejection therapy, in comparison with cyclosporin A (CyA). Renal grafts were transplanted from BN to LEW rats. Tacrolimus and CyA were administrated orally from day 0 for 50 days as primary therapy after grafting. Allografts were rejected after a median survival time (MST) of 8 days. Both tacrolimus und CyA significantly prolonged renal allograft survival, in a dose-dependent manner compared with the allograft controls. The most effective dose was 3.2 mg/kg, per day for tacrolimus, and 10 mg/kg per day for CyA. There was no significant difference in renal function between the group treated with the most effective dose of tacrolimus and the CyA-treated group. The percentage of detectable serum IL-2 level was 45 % in the allograft control group, but was undetectable in groups treated with the most effective dose of tacrolimus or CyA at days 3 and 6 after grafting. On the other hand, no side effects were noted in recipient rats by daily inspection, body weight change, and histological studies, although minimal tubular vacuolation was encountered in the group treated with CyA 32 mg/kg per day. In addition, the most effective doses of tacrolimus and CyA were studied as anti-rejection therapy. All of the 5 recipients treated with tacrolimus from days 2–14, and 3 of the 5 treated from days 4–16 after grafting, survived for more than 50 days. However, the MST was 19 days for recipients treated with CyA from days 2–14, and 13 days for those treated from days 4–16 after grafting. In summary, tacrolimus as primary therapy induced rat renal allograft survival with renal function and side effects comparable with those of CyA. Interestingly, when both agents were used as anti-rejection therapy, tacrolimus, but not CyA, could significantly overcome ongoing renal allograft rejection in the rat. Received: 31 March 1998 Received after revision: 9 September 1998 Accepted: 12 October 1998     

European randomised trial of dual versus triple tacrolimus-based regimens for control of acute rejection in renal allograft recipients

Two large multicentre studies have shown superiority of tacrolimus-based immunosuppressive regimens compared with standard cyclosporine-based therapy in renal transplantation. In these studies, tacrolimus was used in a triple drug regimen of tacrolimus, corticosteroids, and azathioprine. The present study aimed to determine whether a tacrolimus-based dual regimen achieves a similar efficacy and safety profile compared with conventional triple therapy. In this prospective, open, multicentre trial, 249 patients were randomised to receive either dual therapy (n = 125) of oral tacrolimus (initial daily dose of 0.2 mg/kg) and oral prednisone or additionally, as a triple therapy (n = 124), oral azathioprine. The primary endpoint was the incidence of acute rejection at month 3. In addition, all patients were included into a follow-up evaluation at 1 year after transplantation. Both treatment groups had similar baseline characteristics. At month 3, patient survival was 97.6 % (dual) and 96.7 % (triple); graft survival was 92.7 % (dual) and 91.7 % (triple). The incidence of treated acute rejection confirmed by biopsy was 27.4 % (dual) and 24.8 % (triple); difference 2.6 %, 95 % CI [–9.4 %–12.9 %], P = 0.755. The incidence of corticosteroid-resistant rejection (biopsy-confirmed) was 9.7 % (dual) and 10.7 % (triple). The overall adverse events profile was similar; leukopenia (1.6 % vs 11.6 %, P = 0.002) was more frequent with triple therapy. Between months 4 and 12, six (dual) and eight (triple) patients had a rejection. At month 12, patient survival was 95.6 % (dual) and 93.6 % (triple); graft survival was 91.8 % (dual) and 90.7 % (triple). Tacrolimus proved to be efficacious and safe with both dual and triple low-dose regimens. The addition of azathioprine to a tacrolimus/corticosteroid-based therapy did not result in an increased efficacy. Received: 6 March 2000 Revised: 26 June 2001 Accepted: 18 July 2001     

Can daclizumab reduce acute rejection and improve long‐term renal function in tacrolimus‐based primary renal transplant recipients?

SUMMARY: Aims: To evaluate the efficacy and safety of a tacrolimus‐based immunosuppressive regimen with and without induction therapy using daclizumab in first cadaveric renal transplant recipients. Methods: Since January 2001, we studied the effect of daclizumab in a non‐randomized and prospective study of 36 sequential first cadaveric renal transplant recipients. They were compared with a historical control group of 21 sequential first cadaveric renal transplant recipients without induction therapy. All patients received tacrolimus, azathioprine and corticosteroids as concomitant immunosuppressive therapy. Daclizumab was given at 1 mg/kg infusion 2 h before transplantation and then every 14 days for four more doses. Outcomes measured included incidence of acute rejection, patient survival, graft survival, annualized change in creatinine clearance (CrCl), cardiovascular risk profile, infection and malignancy. Results: Fewer biopsy proven acute rejections were observed in the induction treatment group: 11.1% (4/36) versus 19% (4/21) but the rejection free survival was similar (P = 0.37). The patient survival and graft survival were comparable. The renal function was similar in both groups. There were also no significant difference in infection, malignancy and cardiovascular risk profile in both groups. Conclusion: Adding daclizumab to a tacrolimus‐based therapy is safe but cannot further improve clinical efficacy.     

Anti-lymphocyte antibodies late in the course of pediatric renal transplantation

 Beyond the immediate post-transplant period, physicians are often reluctant to use anti-lymphocyte preparations to treat episodes of acute renal functional deterioration attributable to acute rejection. This is due to the perception that such episodes are less likely to be reversible, and to concern regarding the potential adverse effects of anti-lymphocyte antibodies, including opportunistic infections, lymphoproliferative disorders, and the development of human anti-mouse antibodies. Records were reviewed for all 365 renal transplants performed in 267 patients at our center from 1971 to 1996. Anti-lymphocyte antibodies were used in an attempt to reverse 6 episodes of corticosteroid-resistant acute rejection in 5 children at a mean interval of 24.5 months following transplantation. The mean serum creatinine at initiation of therapy with the anti-lymphocyte agents was 2.9 mg/dl. Following treatment, the mean serum creatinine decreased to 1.3 mg/dl (P=0.03, Student’s t-test). Two patients developed uncomplicated opportunistic infections after completion of anti-lymphocyte therapy; none have developed lymphoproliferative disorders or antibodies to OKT3. We conclude that in the correct clinical setting with corticosteroid-resistant acute rejection, the use of anti-lymphocyte antibodies should not be withheld solely on the basis of length of time since transplantation. Received: 27 January 1998 / Revised: 19 May 1998 / Accepted: 6 July 1998     

Mycophenolat Mofetil und niedrigdosiertes Cyclosporin A verbessern die eingeschr?nkte Nierenfunktion von Herzempf?ngern

Zusammenfassung Cyclosporin (CSA) Nephrotoxizität ist ein häufiges Problem nach Herztransplantation. Wir untersuchten den Effekt einer CSA-Dosisreduktion in Verbindung mit einer Mycophenolat Mofetil (MMF) Behandlung auf die Nierenfunktion von Herzempfängern mit CSA-Nephrotoxizität (Serum-Kreatinin >2mg/dl).¶ Methoden: 14 herztransplantierte Patienten (12 Männer, 2 Frauen; 111 bis 1813 Tage nach HTX) mit CSA-basierter Immunsuppression (plus Azathioprin und/oder Steroide) und einem Serum Kreatinin >2mg/dl wurden mit einer Tagesdosis von 2000mg MMF behandelt. Eine dilatative Kardiomyopathie war bei 10 Patienten die Grunderkrankung, eine ischämische Kardiomyopathie bei 4. Das mittlere Patientenalter betrug 57 Jahre (44-69 Jahre). Azathioprin wurde abgesetzt und CSA langsam reduziert. Kreatinin-Clearance, Serum Kreatinin, Harnstoff-N und Harnsäure wurden kontrolliert. Cyclosporin-Spiegel wurden gemessen und die Dosis auf Zielspiegel von 70-1207g/l eingestellt. 12 Patienten hatten Endomyokardbiopsien, 2 nur noch echokardiographische Kontrollen. ¶ Ergebnisse: Zwei Abstoßungen Grad 1B nach ISHLT wurden beobachtet innerhalb von einem Jahr nach Wechsel zu MMF. ¶ Parameter Ausgangswert (N=14) Langzeit-Verlauf (N=14) P¶ Serum Kreatinin (mg/dl) 2,5 - 0,8 1,8 - 0,6 0,001 Harnstoff-N (mg(dl) 51 - 18 41 - 17 0,008 Harnsäure (mg/dl) 9,9 - 2,1 8,1 - 2,3 0,005 Kreatinin-Clearance (ml/min) 45 - 20 60 - 36 0,01 CSA-Spiegel (7g/l) 177 - 54 106 - 28 <0,001 Schlußfolgerungen: Die Umstellung von Azathioprin auf MMF mit konsekutiver Reduktion von CSA bei Herztransplantierten mit CSA-induzierter Nephropathie verbessert die Nierenfunktion belegt durch niedrigeres Serum-Kreatinin, Harnstoff-N, Harnsäure und höhere Kreatinin-Clearance. Summary Cyclosporin A (CSA) nephrotoxicity is a common problem after cardiac transplantation. We have studied the impact of CSA dose reduction in association with mycophenolate mofetil (MMF) treatment on renal function in heart transplant recipients with suspected CSA nephrotoxicity (serum creatinine >2mg/dl). Methods: 14 heart transplant recipients (12 men, 2 women; 111 to 1813 d post transplant) with CSA-based immunosuppression (plus azathioprine and/or steroids) and a serum creatinine >2mg/dl were started on a daily dose of MMF of 2000mg. Dilated cardiomyopathy was the underlying disease in 10 pts, ischemic cardiomyopathy in 4. Mean patient age was 57 yrs (range 44-69 yrs). Azathioprine was discontinued and CSA slowly tapered. Creatinine clearance, serum creatinine, urea nitrogen, and uric acid were monitored. Cyclosporine levels were measured and CSA dose adjusted for whole blood levels of 70-1207g/l. 12 pts still had endomyocardial biopsies while 2 had echocardiographic controls only.¶ Results: Two rejection episodes grade 1B acc. to ISHLT were observed until one year after switch to MMF. Results: Two rejection episodes grade 1B acc. to ISHLT were observed until one year after switch to MMF. ¶ Parameter Baseline¶(N=14) Late Follow-Up (N=14) P¶ Serum creatinine (mg/dl) 2.5 - 0.8 1.8 - 0.6 0.001 Blood urea nitrogen (mg/dl) 51 - 18 41 - 17 0.008 Uric acid (mg/dl) 9.9 - 2.1 8.1 - 2.3 0.005 Creatinine clearance (ml/min) 45 - 20 60 - 36 0.01 Whole blood CSA level (7g/l) 177 - 54 106 - 28 <0.001 Conclusions: Conversion from azathioprine to MMF with consecutive reduction of CSA in heart transplant recipients with CSA-induced renal impiarment improves renal function as evidenced by lower serum creatinine, urea nitrogen, uric acid, and higher creatinine clearance.     

High-and Low-dose Regimens of Cyclosporin in Renal Transplantation: Immunosuppressive Efficacy and Side-effects

The immunosuppressive effectiveness and nephrotoxic side-effectsof either high-dose cyclosporin (CsA) (16 mg/kg per day) orlow-dose (9mg/kg per day) in combination with azathioprine (Aza)(1 mg/kg per day) were studied in 80 renal transplant patientswho also received low-dose corticosteroids. At 3 months, patientswho received high-dose CsA were randomly assigned to eithercontinuation of CsA or conversion to Aza, whereas in the triple-therapygroup either CsA or Aza was discontinued. No differences inpatient (97.5%) or graft survival (90%–92.5%) were foundat 1 year. There were no differences in the incidence of primarynon-functioning kidneys. The incidence of acute rejection episodeswas 45% in the high-dose CsA group and 55% in the group treatedwith low CsA doses together with Aza (not significant). At 3months the mean creatinine clearance was 60±4ml/min (mean±SEM)in the high-dose group (mean cumulative CsA dose 0.96 g/kg)compared with 55±3 ml/min in the low-dose group (meancumulative CsA dose 0.60 g/kg). At 1 year no differences inthe degree of proteinuria or the incidence of hypertension wasfound between the different groups. The best mean creatinineclearance at 1 year (77±5 ml/min) was found in patientswho received high doses of CsA for 3 months followed by conversion.     

Calcitriol pulse therapy is not more effective than daily calcitriol therapy in controlling secondary hyperparathyroidism in children with chronic renal failure

Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism, but its efficacy and safety are still under discussion. The present randomized multicenter study compares the effect of an 8-week course of daily versus intermittent (twice weekly) calcitriol therapy on parathyroid hormone (PTH) suppression in 59 children (mean age 8.4±4.7 years) with chronic renal insufficiency (mean C_cr 22.4±11.6 ml/min per 1.73 m²) and secondary hyperparathyroidism. After a 3-week washout period, the patients were randomly assigned to treatment with daily oral calcitriol (10 ng/kg per day) or intermittent oral calcitriol (35 ng/kg given twice a week). The calcitriol dose was not changed throughout the study period of 8 weeks. At start of the study, the median intact PTH (iPTH) level was 485 pg/ml (range 83–2032) in the daily group (n=29) and 315 pg/ml (range 93–1638) in the intermittent group (n=30). After 8 weeks, the respective median iPTH concentrations were 232 pg/ml (range 63–1614) and 218 pg/ml (range 2–1785) (ns). The mean iPTH decrease from baseline was 19.2±57.8% and 13.7±46.7% respectively (not significant). Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group. One episode of hypercalcemia (>11.5 mg/dl) was observed in both groups and a single episode of hyperphosphatemia (>7.5 mg/dl) was observed in the daily group. It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis. Received: 29 September 1999 / Revised: 2 February 2000 / Accepted: 9 February 2000     

Erythropoietin treatment in children with renal failure

 Erythropoietin (EPO) treatment dramatically changes the life of a child with end-stage renal disease. The administration of recombinant human (rHu)EPO is beneficial and safe in the predialysis period, during hemodialysis or peritoneal dialysis, and after renal transplantation. The goal of hemoglobin correction should be the level at which normal quality of life is possible without adverse events: in children this is usually 10–11 g/dl. rHuEPO is administered once to twice a week subcutaneously to children before dialysis, during peritoneal dialysis, and after transplantation. There is no real benefit of intraperitoneal administration. In children on hemodialysis two to three times a week IV administration is preferred. Among the many reasons for non-response to rHuEPO, iron deficiency (absolute or functional), infections, and hyperparathyroidism are the most common in the pediatric renal patient. Hypertension is the most-frequent side effect of rHuEPO treatment and needs careful monitoring. Iron should be supplemented orally or IV. No significant beneficial effect of rHuEPO on growth has been demonstrated. However, the association with recombinant human growth hormone therapy is not detrimental in children. Received: 4 May 1998 / Revised: 31 July 1998 / Accepted: 31 July 1998     

Long-term beneficial effect of tacrolimus conversion on renal transplant recipients

OBJECTIVE: Acute rejection, chronic allograft nephropathy, and cyclosporine (CsA) toxicity remain serious problems for renal transplant recipients and may lead to graft loss. We retrospectively analyzed 34 patients whose biopsies revealed acute and/or chronic allograft rejection, or CsA nephrotoxicity, and who converted from CsA to tacrolimus. PATIENTS AND METHODS: From July 1996 through September 2003, CsA was converted to tacrolimus in 34 renal transplant recipients (26 male, 8 female) with renal biopsy at our hospital. Blood pressure and serum creatinine levels were checked monthly and serum cholesterol, triglyceride, and glutamic-pyruvic transaminase (GPT) levels were checked every three months. RESULTS: A consistently stable and better function after conversion was obtained in a significant portion (24, 71%) of patients. A statistically significant decline in serum creatinine and an improvement in the glomerular filtration rate were found at 3 m, 6 m, 12 m, 36 m, and 72 m after tacrolimus conversion. In 85.7% (12/14) of patients with acute rejection and in 35.7% (5/14) of patients with chronic allograft nephropathy (concomitant with acute rejection in 5), improved or stabilized graft function was noted. In addition, the systolic blood pressure and diastolic BP dropped significantly (P<0.05), while there was no significant change in cholesterol, triglyceride, and GPT levels. CONCLUSION: The beneficial effect of tacrolimus conversion on patients with acute rejection, chronic allograft nephropathy, or CsA nephrotoxicity was demonstrated in long-term follow up. The improvement in both renal function and blood pressure may be of paramount importance in reducing long-term cardiovascular morbidity and mortality.     

Body growth of children with steroid-resistant nephrotic syndrome

Whilst it is assumed that body growth is retarded in children with steroid-resistant nephrotic syndrome (NS), the degree of growth failure and the pathomechanisms involved are poorly understood. We collected serial growth data in 45 children (24 males) with steroid-resistant NS usually from onset to end-stage renal disease (ESRD) during childhood (n=10) or until final height was attained (n=27). Mean follow-up time was 9 (2–19) years. Mean initial standardized height was –0.3±1.2 standard deviation scores (SDS). Mean final height was +0.4 SDS in males and –1.0 SDS in females (sex difference not significant). In 16 patients with serum creatinine levels consistently <1.2 mg/dl, mean final height SDS was 0.3 SDS higher than that obtained within 6 months of onset. In contrast, 9 children who entered ESRD lost an average of 1.3 SDS from the initial record to ESRD (P=0.017). In prepubertal patients without renal insufficiency, mean height SDS decreased during corticosteroid treatment by 0.3 SDS, followed by a partial catch-up after discontinuation of treatment; the change from initial to final height SDS was inversely correlated with the total prednisone dose given (r=–0.50, P=0.03). In 16 prepubertal children with serial height and serum protein measurements who were off steroids and maintained normal creatinine levels, mean individual albumin concentrations correlated with the change in height SDS per year (r=0.65, P=0.0006) and in boys with final height (r=0.73, P=0.03). In conclusion, growth in steroid-resistant NS depends on the preservation of renal function, the cumulative dose of steroids applied, and the severity of hypoproteinemia. Received: 15 July 1998 / Revised: 30 November 1998 / Accepted: 11 December 1998     

Etiology and outcome of chronic renal failure in Indian children

A prospective analysis of all new pediatric cases of chronic renal failure (CRF) was performed at our hospital over a 1-year period. The diagnosis of CRF was based on serum creatinine >2 mg/dl with supportive clinical, laboratory, and radiological findings. There were a total of 48 patients with CRF with a median age of 13 years (range 10 days to 16 years). The causes of CRF included glomerulonephritis (37.5%), obstruction and interstitial (52%), hereditary (6.3%), and undetermined (4.2%). Patients were symptomatic for a mean of 33.2 months (range 10 days to 11 years) at presentation. Eight patients (16.7%) had acute reversible deterioration of renal function at presentation. This was due to accelerated hypertension in 2, infection in 3, volume depletion in 2, and nonsteroidal antiinflammatory drugs in 1 patient. At presentation, 22 (46%) children had mild to moderate renal failure and 26 (54%) had end-stage renal disease. Twenty-one children (43.7%) had associated illness at presentation. Mean follow-up was 22.9 weeks (range 2–126 weeks). At the end of the study period, 10 (21%) patients were on conservative treatment, 7 (14.6%) on maintenance dialysis, 8 (16.7%) patients had functioning allografts, 4 (8.3%) patients had died, and 19 (39.6%) opted against further therapy. We conclude that CRF in Indian children carries a poor prognosis due to late referral and the limited availability and high cost of renal replacement therapy. Received: 31 July 1998 / Revised: 7 December 1998 / Accepted: 13 December 1998