Co-administration of co-trimoxazole does not augment tacrolimus-induced impairment in kidney function in rats

Co-trimoxazole is an antibiotic that is frequently used in organ transplant patients. Our objective was to determine the effect of co-trimoxazole on tacrolimus-mediated functional impairment of the kidney in rats. Sprague Dawley rats were divided into three groups. Group 1 (dextrose) received 5% dextrose and Group 2 (tacrolimus) received tacrolimus (1 mg/kg/day) as a continuous intravenous infusion for seven days. Group 3 (combination) received tacrolimus as above and co-trimoxazole (30 mg/kg/day trimethoprim and 150 mg/kg/day sulfamethoxazole) intraperitoneally for six or seven days. Biochemical and functional parameters were measured pre- and post-drug infusion. On day 7, glomerular filtration rate (GFR) was evaluated using 3H-inulin while the effective renal plasma flow (ERPF)/cationic tubular secretion was assessed using 14C-tetraethylammoniumbromide(TEA). GFR (mL/min/kg) as measured by inulin clearance was higher (p < or = 0.05) in the dextrose (12.0 +/- 1.4) group as compared to tacrolimus group (6.0 +/- 1.3) and combination group (6.4 +/- 1.6), but there was no difference between the tacrolimus and combination group. ERPF/cationic tubular secretion (mL/min/kg) was also significantly higher in the dextrose group (62.6 +/- 10.3) as compared to the other two groups. ERPF/cationic tubular secretion was not different between the combination (33.3 +/- 5.9) and the tacrolimus (35.1 +/- 6.7) groups when there was no co-trimoxazole in the body. However, in the presence of co-trimoxazole ERPF/cationic tubular secretion was significantly reduced in the combination (23.1 +/- 3.5) group as compared to the tacrolimus group (35.1 +/- 6.7). These results indicate that co-trimoxazole does not further potentiate tacrolimus induced impairment in kidney function but is likely to further inhibit cationic tubular secretion in patients on tacrolimus therapy.     

A randomized cross‐over comparison of short‐term exposure of once‐daily extended release tacrolimus and twice‐daily tacrolimus on renal function in healthy volunteers

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once‐daily tacrolimus extended release (Tac‐ER) includes equivalent exposure [AUC_(0–24 h)] but lower C_max versus twice‐daily tacrolimus immediate release (Tac‐IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once‐daily Tac‐ER and twice‐daily Tac‐IR in a prospective, randomized, two period, cross‐over study. Tacrolimus was titrated to achieve trough levels of 8–12 ng/ml. Twenty four hours ERPF and GFR estimated by para‐aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10‐day dosing period. Mean Tac C₀ was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac‐ER and Tac‐IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac‐ER compared with Tac‐IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m², P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac‐ER at 114.5 ± 13.6 ml/min/1.73 m² compared with 108.9 ± 9.7 ml/min/1.73 m² for Tac‐IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac‐ER compared with Tac‐IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).     

Fish oil and cyclosporin A-induced renal hypoperfusion in kidney-transplanted patients

BACKGROUND.: Dietary supplementation with fish oil has been said to improverenal function in cyclosporin A (CsA)-treated subjects. METHODS.: Renal function and the acute renal haemo-dynamic and tubularresponse to an oral CsA-dose (3 mg/kg) were investigated beforeand after 12 weeks of fish oil supplementation (6 g/day) in12 low-dose CsA-treated kidney-transplanted patients (s-creatinine,124 ± 24 µmol/l, mean ± SD). After an overnightfast, ten 1-h renal clearance periods were performed, two periodsbefore and eight after CsA-ingestion. An additional controlclearance study without CsA intake was performed in six subjects. RESULTS.: Fish oil did not change baseline values of the effective renalplasma flow (ERPF) or the glomerular filtration rate (GFR).Compared to the control study, CsA decreased GFR and ERPF significantlyon aver-age 20 ± 3% (P<0.01) and 23 ± 3% (P<0.01)respectively, 4–6 h after peak CsA blood concentrationwith no additional effect of fish oil. CsA also significantlydecreased the renal clearance of lithium, used as an index ofproximal tubular outflow, with no impact of dietary fish oil. CONCLUSION.: Fish oil supplementation had no effect on baseline renal functionor CsA-induced hypoperfusion in stable renal transplant recipientstreated with a low maintenance dose of CsA.     

Co-administration of ketoconazole and tacrolimus therapy: a transplanted rat model

Background/aim The aim of this work is to study the effect of addition of ketoconazole to experimental kidney transplanted rat treated with tacrolimus and precludes the percentage of tacrolimus dose reduction. Material and methods The material of this work included 60 male Sprague Dawely rats subjected to renal allotransplantation. They were equally divided into five groups: Group I: served as control group, Group II: received FK506 3.2 mg/kg/bw, Group III: received FK506 2 mg/kg/bw, Group IV: received FK506 1 mg/kg/bw, Group V: received FK506 1 mg/kg/bw plus ketoconazole 20 mg/kg/day. FK506 trough level and laboratory investigations were determined at 0, 3, 7, 10, 14, and 27 days post-transplantation. Results In all groups loss of body weight was observed at day 27 after treatment compared to that before transplantation. Serum creatinine significantly increased at day 27 compared to the basal level in groups treated with 1.0 mg and 3.2 mg FK506 (1.80 ± 0.50 vs. 0.39 ± 0.06 P = 0.001) and (1.03 ± 0.26 vs. 0.50 ± 0.07 P = 0.001) respectively. While for 2.0 mg or 1.0 mg plus keto groups, no significant differences in serum creatinine levels over time (0.56 ± 0.22 vs. 0.44 ± 0.10 P = 0.106) and (0.55 ± 0.30 vs. 0.42 ± 0.08 P = 0.160) were observed. Conclusion Concomitant administration of ketoconazole and FK506 is safe and results in increase blood trough level concentration of FK506 with 50% dose reduction in transplanted rat model.     

Nifedipine improves immediate,and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients

To investigate the effect of oral nifedipine, a calcium channel blocker known not to modify cyclosporin A (CyA) pharmacokinetics, on immediate transplant function and CyA nephrotoxicity, 68 adult renal transplant recipients were pre-operatively randomized to one of three regimes: A (high-dose CyA, initial dose 17 mg/kg per day, maintenance dose 7 mg/kg per day); B (regime A plus oral nifedipine); C low-dose CyA, initial dose 10 mg/kg per day, maintenance 4 mg/kg per day plus azathioprine 1 mg/kg per day). All three groups received identical steroid regimes. Calcium channel blockers of all types were avoided in groups A and C. Delayed graft function (dialysis dependence by day 4) was seen least frequently in group B (P < 0.02). Group B had improved graft function at 6 months compared with group A, identified by differences in serum creatinine (P < 0.05), GFR (P < 0.01) and ERPF (P < 0.05). Similar differences in serum creatinine (P < 0.05) and GFR (P < 0.05) were also identified at 12 months. Group C also had better 6- and 12-month GFR values than group A (P < 0.05 each). The three groups did not differ in donor or recipient age, HLA matching, ischaemic or anastomosis times, frequency of early rejection or whole-blood CyA levels. These results indicate that nifedipine significantly improves immediate and medium-term graft function.     

Clopidogrel reduces post‐transplant obliterative bronchiolitis

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2^b) donor tracheas were orthotopically transplanted into CBA.J(H2^k). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real‐time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL‐12, IL‐4, IL‐6, TNF‐α, TGF‐β, PDGFβ, MCP1, P‐/E‐selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor‐specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.     

Predictive Value of Bedside Effective Renal Plasma Flow for Renal Recovery in Severe Acute Renal Failure

Single injection, single blood sample, effective renal plasma flow (ERPF) estimated by^l3lI-orthoiodohippurate can be performed accurately and conveniently without urine collection at the bedside. The purpose of this study was to determine if ERPF early in the course of severe acute renal failure (ARF) predicts recovery of renal function in hemodynamically stable patients. Over 18 months, ERPF was determined in 33 such patients with ARF in whom an etiologic diagnosis could be established. Eight patients died within 2 months of onset and while on dialysis, did not have an autopsy, and were not considered further. Six patients (Group A) either remained on dialysis after at least 6 months follow-up or had irreversible renal disease at autopsy. In Group B (19 patients, 13 of whom were dialyzed), serum creatinine returned to less than 2.0 mg/dL (n = 16) or was decreasing without dialysis. Peak serum creatinine (Group A 11.2 ± 1.4; Group B 10.1 ± 1.3 mg/dL) did not differ between groups. Oliguria was present in 75% of Group A patients and in 25% of Group B patients. Initial ERPFs differed (p < 0.001) between Group A (90 ± 11) and Group B (204 ± 20 mL/min). Initial ERPF was greater than 125 mL/min in 15 Group B patients but in no Group A patients; the false-positive rate was 21% and the false-negative rate was 0%. We conclude that at a time when the etiology of ARF is often not established, an initial ERPF of 125 mL/min or greater predicts recovery of renal function and less than 125 mL/min suggests that renal function will not recover. Serial studies improve the diagnostic accuracy of this test.     

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     

Co-administration of Ketoconazole and Tacrolimus Therapy: A Transplanted Rat Model

Background/Aim: The aim of this work is to study the safety and the effect of addition of ketoconazole to experimental kidney transplanted rat treated with tacrolimus and predicts the percentage of tacrolimus dose reduction. Material and Methods: The material of this work included 60 male Sprague Dawely rats subjected to renal allotransplantation. They were equally divided into five groups: Group I: served as control group, Group II: received FK506 3.2 mg/kg/bw, Group III: received FK506 2 mg/kg/bw, Group IV: received FK506 1 mg/kg/bw, Group V: received FK506 1 mg/kg/bw plus Ketoconazole 20 mg/kg/day. FK506 trough level and laboratory investigations were determined at 0, 3, 7, 10, 14, and 27 days post-transplantation. Results: In all groups loss of body weight was observed at day 27 after treatment compared to that before transplantation. Serum creatinine significantly increased at day 27 compared to the basal level in groups treated with 1.0 and 3.2 mg FK506 (1.80 ± 0.50 versus 0.39 ± 0.06 P = 0.001) and (1.03 ± 0.26 versus 0.50 ± 0.07 P = 0.001) respectively, while for 2.0 mg or 1.0 mg plus keto groups, no significant differences in serum creatinine levels over time (0.56 ± 0.22 versus 0.44 ± 0.10 P = 0.106) and (0.55 ± 0.30 versus 0.42 ± 0.08 P=0.160) were observed. Conclusion: Concomitant administration of Ketoconazole and FK506 in transplanted rat model is safe and results in increase of blood trough level concentration of FK506 with 50% reduction of its dose.     

Verapamil prevents the apoptotic and hemodynamic changes in response to unilateral ureteral obstruction

Introduction: Obstruction of the urinary tract has marked effects on renal blood flow, glomerular filtration rate (GFR), and tubular function. Moreover, ureteral obstruction results in an injury response that can progress to irreversible renal fibrosis and tubular atrophy by apoptosis. Methods: We examined the effect of a calcium channel blocker (verapamil) on renal functions and the abundance of apoptotic (p53, Fas, proliferating cell nuclear antigen [PCNA]) markers 1 week after Unilateral Ureteral Obstruction (UUO). Results: Immunohistochemistry studies revealed that UUO was markedly associated with up-regulation in the expression of p53 (1550 ± 82 vs 100 ± 23%), Fas (657 ± 48 vs 100 ± 31%), and proliferating cell nuclear antigen (945 ± 70 vs 100 ± 17% of sham levels). Administration of verapamil normalized the up-regulation of apoptotic markers p53 (724 ± 116 vs 1550 ± 82%); Fas (162 ± 38 vs 657 ± 48%) and PCNA (353 ± 54 vs 945 ± 70%). Furthermore, tubular diameter, as an important marker for detecting tubular atrophy was significantly decreased compared to those in UUO rabbits. The percent area of interstitial fibrosis in UUO kidneys was significantly greater than that in Verapamil-treated kidneys. Importantly, Verapamil reduced the development of interstitial fibrosis in UUO rabbits. We measured the GFR and renal blood flow in UUO. Short-term Verapamil challenge partially prevented the decrease in GFR (non-treated UUO: 62 ± 14; Verapamil + UUO: 119 ± 7; Sham: 127 ± 23 μL·min⁻¹·kg body wt⁻¹, P < 0.05) and renal blood flow (non-treated UUO: 1.1 ± 0.4; Verapamil + UUO: 5.0 ± 0.2; sham: 6.3 ± 0.2 mL·min⁻¹·kg body wt⁻¹, P < 0.05). Conclusion: Verapamil significantly prevents impairment in renal function and also prevents the up-regulation of p53, Fas, and PCNA during UUO, demonstrating a marked renoprotective effect of Verapamil treatment in conditions with urinary tract obstruction.     

Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis in murine aortic allografts

Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopidogrel has a beneficial effect on the development of transplant arteriosclerosis. Fully MHC mismatched C57Bl/6 (H2^b) donor aortas were transplanted into CBA.J (H2^k) recipients and mice received either clopidogrel alone (1 mg/kg/day) or in combination with cyclosporin (2 mg/kg/day) or everolimus (0.05 mg/kg/day). Grafts were analysed by histology and morphometry on day 30 after transplantation. In mice treated with clopidogrel alone, transplant arteriosclerosis was significantly reduced [intima proliferation 56 ± 11% vs. 81 ± 7% (control)/n = 7]. Daily application of everolimus reduced the development of transplant arteriosclerosis compared with untreated controls [intima proliferation of 29 ± 9% vs. 81 ± 7% (control)/n = 7]. Strikingly, combination of clopidogrel and everolimus almost abolished the formation of transplant arteriosclerosis [intima proliferation: 11 ± 8% vs. 81 ± 7% (control)/n = 7]. By contrast, combination of cyclosporin and clopidogrel compared with clopidogrel alone showed no additive effect. These results demonstrate that combination of platelet‐ and mammalian target of Rapamycin‐inhibition can dramatically reduce the development of transplant arteriosclerosis.     

Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome

Although therapy with intravenous (IV) rituximab and tacrolimus reduces the relapse rate in steroid-dependent nephrotic syndrome (SDNS), studies on comparative efficacy are lacking. We retrospectively reviewed the records of patients with difficult-to-treat SDNS who had previously received levamisole, cyclophosphamide and/or mycophenolate mofetil, then treated with either rituximab or tacrolimus and followed for 12 months. Between January 2009 and April 2010, ten patients received two to three doses of IV rituximab (375 mg/m²/week) and 13 received tacrolimus (0.1–0.2 mg/kg/day) for 12 months; none had previously received either agent. Patients received tapering doses of alternate-day prednisolone; other immunosuppressive agents were discontinued. The mean age of the patients at treatment initiation with rituximab and tacrolimus was 12.2 ± 2.3 and 12.3 ± 3.0 years, respectively. The respective pre-treatment relapse rates (3.1 ± 1.1 and 3.5 ± 1.6 relapses per year) and cumulative prednisolone dose (137.2 ± 69.4 and 140.5 ± 59.0 mg/kg/year) were similar. Therapy resulted in a decline in relapse rate in both groups (P < 0.001). The number of relapses in the rituximab and tacrolimus groups was similar at 6 months (0.3 ± 0.5 vs. 0.3 ± 0.6 episodes, respectively), 12 months (0.8 ± 1.0 vs. 0.9 ± 1.1 episodes) and last follow-up (1.2 ± 1.0 vs. 1.5 ± 1.3 episodes). There were no differences in relapse-free survival at 6, 12 and 18 months. Therapy resulted in a significant decline in the cumulative prednisolone dose (67.2% in the rituximab group and 43.6% in the tacrolimus group) and a reduced body mass index. These findings suggest that in our patients with difficult-to-treat SDNS, treatment with two to three doses of rituximab was as effective as 12 months of therapy with tacrolimus in terms of steroid sparing and reduction in the relapse rate.     

Is Bariatric Surgery Necessary after Intragastric Balloon Treatment?

Background: The use of the Bio-Enterics intra-gastric balloon (BIB) has been shown to be a safe and effective procedure for the temporary treatment of morbid obesity. We conducted a retrospective comparative analysis of the weight loss in patients that after BIB removal underwent bariatric surgery and those who did not wish surgery. Methods: From January 2000 to March 2004, 182 BIBs were positioned in 175 patients (104 F / 71 M; mean age 37.1±11.6 years, range 16-67; mean BMI 54.4 ± 8.1 kg/m², range 39.8-79.5; mean %EW 160.8±32.9% range 89-264). Patients were excluded from this study who had emergency BIB removal for balloon rupture (n=2, 1.1%) and for psychological intolerance (n=7, 7.8%). All patients were scheduled for a bariatric operation, before BIB positioning. After BIB removal, a number of patients now declined surgery. Consequently, patients were allocated into 2 groups: Group A in whom BIB removal was followed by bariatric surgery (Lap-Band^?, laparoscopic gastric bypass, duodenal switch) (n=86); Group B patients who after BIB removal refused any surgical procedure (n=82). Both groups were followed for a minimum of 12 months. Results were reported as mean BMI and %EWL ± SD. Statistical analysis was done by Student t-test or Fisher's exact test, with P<0.05 considered significant. Results: Mean BMI and mean %EWL in the 166 patients at time of removal were 47.3 ± 8.1 kg/m² and 32.1±16.6%, respectively. At the same time, mean BMI was 47.6±6.9 and 48.1±6.5 kg/m² in group A and B (P=NS). At 12 months follow-up (100%), mean BMI was 35.1 kg/m² in Group A (BIB + surgery) and 51.7 kg/m² in Group B (BIB alone) (P<0.001). Conclusions: After BIB removal, half (49.4%) of the patients scheduled for surgery refused a bariatric operation. These patients returned to their mean initial weight at 12 months follow-up. Therefore, bariatric surgery after BIB removal is highly recommended.     

Histological Features of Acute Tubular Necrosis in Native Kidneys and Long-Term Renal Function

There are few studies on the relationship between the morphology of acute tubular necrosis (ATN) in native kidneys and late functional recovery. Eighteen patients with acute renal failure (ARF) who had undergone renal biopsy were studied. All had the histological diagnosis of ATN and were followed for at least six months. Clinical characteristics of ARF were analyzed, and histological features were semi-quantitatively evaluated (tubular atrophy, interstitial inflammatory infiltrate, interstitial fibrosis, and ATN). According to the maximal GFR achieved during the follow-up, patients were divided into two groups: complete recovery (GFR ≥ 90 mL/min/1.73 m²) and partial recovery (GFR < 90 mL/min/1.73 m²). Only 39% of the patients achieved complete recovery. Patients with partial recovery achieved their maximal GFR (63 ± 9 mL/min/1.73 m²) 37 ± 14 months after ARF, a period of time similar to those patients with complete recovery (i.e., 54 ± 22 months). Patients with partial recovery had more severe ARF: oliguria was more frequent (90 versus 17%, p < 0.01), and they had higher peak creatinine (13.85 ± 1.12 versus 8.95 ± 1.30 mg/dL, p = 0.01), and longer hospitalization (45 ± 7 versus 20 ± 4 days, p = 0.03). No single histological parameter was associated with partial recovery, but the sum of all was when expressed as an injury index [4.00 (2.73–5.45) versus 2.00 (1.25–3.31), p < 0.05]. In conclusion, among patients with atypical ATN course, those with more severe ARF and tubule-interstitial lesions are more prone to partial recovery.     

The effects of nifedipine on cyclosporine nephrotoxicity in rats

We have investigated the effect of nifedipine on cyclosporine nephrotoxicity in the Sprague-Dawley rat employing a repeatable, single-shot, isotopic technique of measuring the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Groups of 10 rats received either cyclosporine 5 mg/kg daily or cremaphor with either nifedipine 0.5 mg/kg daily or its vehicle for 14 days. In the cyclosporine group the GFR (P < 0.001, paired t-test), ERPF and filtration fraction (FF) (P < 0.01) all fell significantly. The cyclosporine plus nifedipine group underwent an increase in the ERPF (P < 0.01), the GFR remained unchanged, and the FF fell significantly (P < 0.0001). In this model, nifedipine completely abolished the renal arteriolar vasospasm produced by cyclosporine. That the FF fell in the cyclosporine plus nifedipine-treated animals indicates that cyclosporine has an effect which is not mediated by arteriolar vasoconstriction. This action may be at the glomerular level and is resistant to calcium channel blockade.     

Aminoglutethimide stimulates extra adrenal delta-4-androstenedione production

The source of androgens was investigated in dogs (mean weight 17.9 kg) during aminoglutethimide (AG) adrenal blockade because it has been found that AG treated postmenopausal patients maintain androgen concentrations in plasma while estrogens are suppressed. Treatment started 2 days following bilateral oophorectomy (sterile conditions). Group 1 (N = 5) received no drug, Group 2 (N = 5) received AG (20 mg/kg b.i.d. × 7 days, 10 mg/kg b.i.d. × 7 days), and Group 3 (N = 5) received AG plus Cortisol 0.5 mg/kg/day. At a second laparotomy (Na pentobarbital 35 mg/kg iv, 98% O₂/2% CO₂ controlled volume ventilation, anticoagulation, Na heparin), aortic and venous monitoring catheters and a left adrenal vein to femoral vein T-shaped silastic catheter for total left adrenal vein blood flow diversion were inserted. Five adrenal vein flow determinations with simultaneous aortic and adrenal vein blood samplings occurred over an hour. Radioimmunoassay (cortisol, 17-OH-progesterone and δ-4-androstenedione [D-4-A]) of pooled aortic and adrenal plasma of each dog with flow values allowed mean adrenal secretion rate calculations for each steroid determined. Treatments suppressed adrenal secretion of D-4-A (P ? 0.004) (Group 1: 24,000 pg/min ± 11,300 (1 SD); Group 2: 5300 ± 1299; Group 3: 9800 ± 5100), but aortic concentrations of D-4-A were comparable (Group 1: 116 pg/ml ± 27; Group 2: 114 ± 70; Group 3: 92 ± 73) in observed and treated groups (analysis of variance). Linear regression correlation of adrenal D-4-A secretion to aortic concentration (r = 0.89, P ? 0.04) in controls was absent in treated groups. Insignificant suppression of adrenal secretion of cortisol and 17-OH progesterone corresponds to the low AG dose required to avoid lethal obtundation in treated groups. AG treatment depressed the linear regression correlation of adrenal secretion to aortic concentrations of 17-OH progesterone. The results indicate a peripheral source of D-4-A. It can be hypothesized that AG induces hepatic enzymes of steroidogenesis for δ-4-androstenedione.     

Renal function during and after childhood acute poststreptococcal glomerulonephritis

It is still debatable whether acute poststreptococcal glomerulonephritis (APSGN) can lead to permanent renal impairment. The clinical, immunological, and histological findings during the acute disease have been described thoroughly, however, the hemodynamic events are still poorly understood. In this retrospective study, the inulin and p-aminohippurate clearances were measured to evaluate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) within a month of onset of the disease (acute stage) in 26 children, and 2–12 months after onset (follow-up) in 22 children with APSGN. During the acute stage, the mean GFR was 77±23 (SD) ml/min per 1.73 m², the mean ERPF 537±138 ml/min per 1.73 m², and the filtration fraction (FF) 14%±3%, compared with values for controls of 115±11 ml/min per 1.73 m², 607±72 ml/min per 1.73 m², and 19%±2%, respectively (n=42). At follow-up, GFR was 114±15 ml/min per 1.73 m², ERPF 600±68 ml/min per 1.73 m², and FF 19%±3%. Thus, during the disease both GFR and ERPF fell below values for controls, but later were restored. The GFR, however, was more reduced than the ERPF, as indicated by the reduced FF. This might reflect a relative hyperperfusion of individual nephrons, which might start processes later deleterious to the nephrons. This finding, however, needs to be further investigated and we have therefore started a long-term follow-up of these patients. Received: 24 June 1998 / Revised: 4 December 1998 / Accepted: 7 December 1998     

Effect of systemic insulin on protein kinetics in postoperative cancer patients

Background: Cancer cachexia is a significant cause of postoperative morbidity and mortality in patients with tumors of the upper gastrointestinal tract. Standard parenteral nutrition (TPN) has failed to alter this. The anabolic effect of insulin has been well documented, and its positive effect on protein economy in cancer patients has been recently demonstrated. This study examines the effect of high-dose insulin and parenteral nutrition on protein kinetics in postoperative cancer patients. Methods: Eleven patients underwent surgery for pancreatic, esophageal, or gastric carcinoma. Postoperatively, patients received standard TPN for 4 days (1 g/kg/day amino acids, 1,000 kcal/day dextrose, 100 g/day lipid), and hyperinsulinemic parenteral nutrition for 4 days (same as standard TPN plus 1.44 U/kg/day regular human insulin) in a crossover design. All patients received both treatments, and the order of treatment was determined randomly. Euglycemia was maintained during insulin infusion via a variable 30% dextrose infusion. Patients underwent protein metabolic studies after each treatment period and rates of whole body and skeletal muscle protein synthesis, breakdown, and net balance were determined by radioisotopic tracer methods using¹⁴C-leucine and³H-phenylalanine. Results: Compared with standard TPN (STD), hyperinsulinemic TPN (INS) resulted in a significant increase in skeletal muscle protein synthesis (INS: 52.04±10.22 versus STD: 26.06±6.71 nmol phe/100 g/min, p<0.05) and net balance of protein (INS: 7.75±4.61 versus STD: −15.10±6.44 nmol phe/100 g/min, p<0.01), but no difference in skeletal muscle protein breakdown (INS: 44.29±11.54 versus STD: 41.17±5.89 nmol phe/100 g/min). Whole-body net balance of protein also significantly increased with insulin-based TPN, compared with standard TPN (INS: 0.04±0.05 versus STD: −0.08±0.07 μmol leu/kg/min, p<0.05), but no difference in whole-body protein synthesis (INS: 2.52±0.15 versus STD: 2.49±0.15 μmol leu/kg/min) or whole-body protein breakdown (INS: 2.48±0.16 versus STD: 2.58±0.19 μmol leu/kg/min) was observed. Patients received significantly more calories during the hyperinsulinemic TPN period than during the standard TPN period. There was no difference in total, essential, or branched-chain amino acids, and no difference in serum free fatty acids, triglycerides, or cholesterol was observed between the two treatment periods. Conclusion: High-dose insulin in conjunction with hypercaloric parenteral nutrition causes improved skeletal muscle protein synthesis, skeletal muscle protein net balance, and whole-body protein net balance compared with standard TPN in postoperative cancer patients. Results of this study were presented at the 46th Annual Meeting of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993. Dr. Pearlstone is recipient of the Resident's Clinical Prize.     

The effect of small bowel bypass and subsequent resection on gastric acid secretion and serum gastrin

Evaluation of gastric acid secretion and serum gastrin response to proximal or distal intestinal bypass and subsequent resection was undertaken. Ten dogs with gastric fistulas underwent control secretory studies consisting of basal acid output (BAO), maximal vagal stimulation (2 deoxy-d-glucose (2DG) 150 mg/kg iv), maximal histamine stimulation (160 μg/kg/hr iv), and test meal stimuli. Serum gastrin was measured basally and following gastric stimulation. Dogs were then divided into two bypass groups: Group I, distal bypass, leaving 40 cm jejunum and 4 cm ileum; and Group II, proximal bypass, leaving 4 cm jejunum and 40 cm ileum. Postoperatively, repeat studies were performed. Both groups then underwent resection of the bypassed segments followed by repeat secretory and gastrin tests. BAO was significantly increased in Group I dogs. BAO increased from a control of 0.04 ± 0.02 to 0.51 ± 0.19 meq H⁺/60 min (±SEM). No significant changes in BAO were observed in Group II following bypass. Acid secretion to maximal vagal or maximal histamine stimulation was not significantly different in either group. Serum gastrin response was unchanged in either group following a test meal. In Group I dogs, resection of the previously bypassed bowel produced a further significant increase in BAO (1.44 ± 0.4 meq H⁺/60 min). After resection of the bypassed bowel, there was no significant change in basal or stimulated gastrin. Gastric fistula BAO increased following 90% distal but not proximal bypass; subsequent resection of the bypassed segment produced a further increase in BAO. Acid secretory responses to both histamine and 2DG were not influenced by either bypass or resection. An increase in BAO without a change in the background of serum gastrin may suggest the presence of a gastric secretory inhibitor in the distal small bowel.     

Conversion from twice‐daily to once‐daily tacrolimus formulation in pediatric liver transplant recipients – a long‐term prospective study

To assess the safety and efficacy of conversion from twice‐daily tacrolimus to once‐daily tacrolimus in pediatric liver transplant recipients. Conversion from twice‐daily to once‐daily tacrolimus was made in stable pediatric liver transplant recipients. Doses and serum levels of tacrolimus, liver, and renal function were recorded on the day before the conversion and at days 5, 30, 90, and 180 postconversion. Patients were controlled every 2–3 months thereafter. Fifty‐five patients were enrolled in the study. The mean age at conversion was 10.2 ± 3.6 years. The mean tacrolimus trough level was 4.7 ± 1.9 ng/dl preconversion, followed by a significant decline to 4.2 ± 1.7 30 days after the switch (P < 0.004). Mean daily tacrolimus dose was 0.09 ± 0.046 mg/Kg preconversion with a significant increase to 0.11 ± 0.060 3 months postconversion (P < 0.001). Fifteen patients with calculated glomerular filtration rate between 60 to 80 ml/min/m² preconversion showed a significant improvement one and 3 years after the switch (73 ± 4.1, 83 ± 4.3 and 90.3 ± 7.3 ml/min/m², respectively (P < 0.001). The mean follow‐up was 5.2 ± 2.4 years. Conversion to once‐daily tacrolimus is safe and effective in a cohort of stable pediatric liver transplant patients.