Urinary excretion of endothelin-1 in children with absorptive idiopathic hypercalciuria

Urinary excretion of endothelin-1 (ET-1) and plasma ET-1 were measured in 21 children with absorptive idiopathic hypercalciuria (AIH) and 22 controls. The absorptive type of idiopathic hypercalciuria was determined by a calcium loading test. Daily urinary excretion of ET-1 and urinary ET-1/creatinine ratio were significantly increased (P=0.005 and P=0.007, respectively) in patients with AIH (9,274±6,444 pg/24 h and 14.04±9.52 pg/mg, respectively) compared with controls (4,699±2,120 pg/24 h and 7.36±4.71 pg/mg, respectively). Plasma ET-1 levels were significantly lower in patients with AIH (0.84±0.64 pg/ml) than in controls (1.54±0.54 pg/ml, P=0.0001). In conclusion, patients with AIH had increased urinary ET-1 excretion and decreased plasma ET-1 levels. This is most likely due to the decreased reabsorption of ET-1 in the renal tubule and increased renal production.     

Atrial natriuretic peptide and cyclic 3′5′-guanosine monophosphate as indicators of fluid volume overload in children with chronic renal failure

Plasma atrial natriuretic peptide (ANP) and cyclic 35-guanosine monophosphate (cGMP) were investigated as indicators of fluid volume overload in children and adolescents with chronic renal failure. Plasma ANP and cGMP were measured in both paediatric patients with chronic renal failure (n=17, mean serum creatinine 371±242 mol/l) and those with end-stage renal disease on haemodialysis (n=18). cGMP was higher in children with chronic renal failure than in 45 healthy controls (1.0±0.4 vs 2.1±0.8 nmol/l,P<0.01), whereas plasma ANP was similar (26.9±9.7 vs 34.0±12.3 pmol/l). Both ANP and cGMP were markedly elevated in children with end-stage renal disease before haemodialysis and fell significantly during dialysis. During dialysis body weight decreased by 1.6±0.7 kg, corresponding to 4.5±2.1% of body weight. Plasma ANP correlated positively with plasma cGMP in haemodialysed patients (r=0.43,P<0.05). Reduction in body weight and in mean arterial pressure correlated more closely with plasma ANP than with cGMP. Therefore, elevation of plasma ANP appears to indicate volume overload in children undergoing haemodialysis, but whether it can be used also in children with chronic renal failure requires further investigation     

Sequential changes of biochemical bone parameters after kidney transplantation

Background. Persistant hyperparathyroidism after renal transplantation (Rtx) has been reported in several studies. However these studies evaluated biochemical bone parameters either only during a short time period (up to 6 months) or for a longer time period, but with long intervals in between. Therefore, we prospectively evaluated biochemical bone parameters of kidney transplant recipients at short intervals for 2 years after surgery. Methods. Biochemical bone parameters were prospectively investigated in 129 patients 2, 3, 5, 8, 12, 18 and 24 months after Rtx. All patients received prednisone and cyclosporin A as immunsuppressive therapy, and 75 patients was treated with calcium, phosphorus, or vitamin D preparations. Results. Serum creatinine levels decreased from 166.8±5.4 &mgr;mol/l to 140.0±4.9 two years after Rtx; (data are expressed as mean±s.e.m.). Serum phosphorus levels increased slightly from 0.9±0.022 mmol/l to 0.98±0.025 (12m), but remained within the lower normal range. We observed a rise in total and albumin adjusted calcium concentrations 3 months after Rtx. 52% of all patients had serum calcium levels above 2.62 mmol/l (upper normal limit in our laboratory) 3 months after renal transplantation with a gradual decrease thereafter. There was no correlation of calcium and PTH levels. We observed a significant rise in biochemical bone parameters from 2 to 5 months after renal transplantation (P<0.001): alkaline phosphatase (AP) increased from 164.3±9.4 to 236±12.7 U/l (normal 50-180), bone specific alkaline phosphatase (BAP) rose from 17.7±1.36 to 23.2±1.7 ng/ml (normal:4-20) and osteocalcin (OC) increased from 20.2±1.5 to 26.7±1.9 ng/ml (normal 4-12). AP and BAP levels values normalized 12 months after renal transplantation, whereas OC was still above normal throughout the study period. Patients were subdivided into two groups: those with good and those with impaired graft functions. Patients with good graft function had stable serum creatinine levels (⩽132 &mgr;mol/l or ⩽1.5 mg/dl) well below the mean serum creatinine concentration during the study period. The significant changes in AP, BAP, and OC occurred irrespective of renal function. However, patients with impaired graft function (n=65) had significantly higher PTH-levels (70 pg/ml higher) than patients with good graft function (n=64), P<0.01. PTH was positively correlated with serum creatinine (r=0.0.001). Moreover, patients with low 25(OH) vitamin D levels (n=63) had significantly higher PTH concentrations (between 40 and 80pg/ml, P<0.01) throughout the sudy period compared to patients (n=66) with a sufficient 25(OH)D supply irrespective of graft function. There was a negative correlation of 25(OH)D levels and PTH; (r=-0.49, P<).001). 1,25(OH)2D3 (evaluated in 24 patients) levels increased from 46.5±6.6 to 76.9±7.6pg/ml (normal: 35-90) at 12 months. Conclusion: Hypercalcaemia is a common phenomenon in the early period after kidney transplantation and occurs in the presence of low normal phosphorus levels. It is most probably related to improved PTH action and 1-hydroxylation of vitamin D. The rise in biochemical bone parameters between 3 and 5 months occurs irrespective of graft function and normalization is only achieved 1 year after transplantation. PTH is constantly elevated for up to 2 years after kidney transplantation and is most probably related (a)to impaired graft function and (b) to suboptimal 25 OH vitamin D supply. Keywords: hypercalcaemia; biochemical bone parameters; renal transplantatiom; secondary hyperparathyroidism; vitamin D      

The immune status of uraemic children/adolescents with chronic renal failure and renal replacement therapy

In adults with chronic renal failure (CRF) and/or renal replacement therapy (RRT) various immunological abnormalities have been described, but few data are available for the paediatric age group. We performed basic in vitro immunological studies in 26 patients 10 months–19 years of age with advanced renal failure, 11 with CRF (creatinine clearance 16.8±5.2 ml/min per 1.73 m²), 15 on RRT with haemodialysis (HD;n=9) and continuous ambulatory peritoneal dialysis (CAPD;n=6) as well as in 16 healthy controls. None had clinical evidence of deranged immune function. No significant differences were found in the percentages of B- and T-cells, T-cell subsets CD3, CD4, CD8 and mitogenic responses to phytohaemagglutinin and concanavalin A (Con A) between RRT patients (HD=CAPD) and control children. Most parameters in CRF patients were also normal, although they had a low percentage of B-cells (12.1±4.1; RRT: 19.7±6.5; controls: 18.5±7.1;P<0.01), relatively low levels of serum immunoglobulin G (948.4±209.4 mg/dl; HD: 1374.7±235.2 mg/dl;P<0.01; CAPD: 966.3±430.2 mg/dl, NS) and a high normal response to Con A (34.3±13.6 cpm ×10^–3; RRT: 34.5±11.3 cpm ×10^–3; controls: 23.4±9.9 cpm ×10^–3,P<0.01). All these values were, however, well within the normal accepted range. These data indicate that children/adolescents with CRF and/or RRT have no significant basic in vitro immunological defects. This study did not test the functional immune status of the young uraemic patients.     

Advanced glycation end products in children with chronic renal failure and type 1 diabetes

Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nɛ-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P<0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P<0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabe-tic children showed significantly elevated pentosidine levels (P<0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics. Received: 25 July 2001 / Revised: 14 November 2001 / Accepted: 18 November 2001     

Measurement of erythropoietin in anephric children

Serum erythropoietin (Ep) levels were measured using a highly sensitive radioimmunoassay in 69 children undergoing chronic dialysis; 31 were anephric, whereas 38 were non-nephrectomized (nephric). Twenty-nine normal children were studied as controls. Serum Ep levels in the anephric group were much higher than anticipated (mean 19.7±1.8 mU/ml), albeit significantly lower than those measured in normal children (mean 26.2±2.4 mU/ml,P<0.05), or in nephric children on dialysis (33.0±2.9 mU/ml,P<0.001). Anephric children on peritoneal dialysis (PD) had significantly (P<0.05) higher serum levels of Ep (22.7±2.4 mU/ml,n=19) than anephric children on hemodialysis (HD) (15.1±2.3 mU/ml,n=12). There was no significant difference between Ep levels in anephric patients dialyzed for less than or equal to 1 year (19.6±2.0 mU/ml,n=20) compared with anephric patients dialyzed for more than 1 year (20.0±3.9 mU/ml,n=11). Although serum Ep levels showed a tendency to increase with time after nephrectomy, the mean values for <3 months (14.7±1.9), 3 months–12 months (21.0±2.7), and >12 months (21.6±6.0) were not significantly different from each other. This demonstration of relatively normal levels of serum Ep in anephric children suggests that extrarenal sites of Ep production are able to exert a significant response to severe anemia in patients who are devoid of renal parenchyma.Table of SPNSG centers and investigators, and source of patients studied: Offprint requests to: R. J. Hogg, Department of Pediatrics, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX, 75246, USA     

Cadaveric renal transplantation in children under 5 years of age

From March 1987 to August 1990 23 cadaveric renal transplants were performed in 19 children under the age of 5 years at the time of transplantation. The mean age of the recipients was 3.3 years (range 1.3–4.7) and the mean weight 13.0 kg (range 9.3–19.2). The mean donor age was 7.8 years (range 1.5–25). All children received triple immunosuppression with prednisolone, cyclosporin A and azathioprine, and 4 who had 2 grafts during this period also received antithymocyte globulin at the time of the second transplant. Patient survival is 100%. Actuarial first cadaveric graft survival was 57% at 1 year and remains unchanged at 3 years. There were 10 graft losses, 4 were associated with renal venous thrombosis without apparent rejection. Two were lost due to acute vascular rejection with associated renal venous thrombosis, and the remaining 4 losses followed cellular or chronic vascular rejection. The mean glomerular filtration rate ±SD was 51.4±23.6 ml/min per 1.73 m² (n=11) at 1 year and 43.5±25.3 at 2 years (n=6). The mean height standard deviation score improved from –2.2±1.1 at the time of transplantation to –1.3±1.0 1 year post transplant (n=11). The immunosuppression was well tolerated with a low incidence of side effects. Cadaveric renal transplantation remains a difficult but rewarding undertaking in children under 5 years of age.     

Urinary ET-1, AVP and sodium in premature infants treated with indomethacin and ibuprofen for patent ductus arteriosus

The relative potency and interrelationship between vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. The relationship between urinary vasoactive factors and sodium excretion has not been adequately addressed in premature infants receiving indomethacin and ibuprofen for therapy of patent ductus arteriosus. Excretion rates of AVP, ET-1 and sodium were measured in premature infants with RDS receiving indomethacin or ibuprofen. Forty-four RDS premature infants (<34-week gestation) with PDA received either ibuprofen (n=22) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 h or 3 doses at 12-h intervals of indomethacin (n=24), 0.2 mg/kg, infused continuously over a period of 15 min. Urinary ET-1, AVP and sodium excretion were measured before and after treatment. Indomethacin treatment caused a significant decrease in urinary ET-1 and AVP excretion (UET-1/Ucr 0.14±0.01 vs. 0.10±0.05 fenton/mmol; P<0.05; 24.42±6.18 vs. 12.63±3.06 pg/mmol; P<0.05, respectively), along with a significant reduction in urinary sodium (92.1±36.1 vs. 64.8±35.6 mmol/l; P<0.01), fractional excretion of sodium (6.8±37.1 vs. 4.5±37.1%; P<0.01) and urinary osmolality (276.2±103.9 vs. 226.4±60.3 mOsmol/kg; P<0.05). Ibuprofen treatment caused a significant decrease in urinary AVP (UAVP/Ucr 24.5±3.4 vs. 16.3±2.04 pg/mmol; P<0.01), along with a significant decrease in urinary sodium (78.0±8.4 vs. 57.0±8.0 mmol/l; P<0.05) and in fractional excretion of sodium (7.5±1.3 vs. 3.9±3.0%; P<0.05), while it did not modify urinary ET-1 excretion. The association of renal ET-1 and AVP activity with sodium excretion in premature infants treated with indomethacin and ibuprofen supports the hypothesis that these factors may play a role in the physiologic changes in sodium excretion.     

The production and clearance of endothelin and its influence on kidney function after liver transplantation in rats

To assess the involvement of endothelin-1 (ET-1) in rat liver allograft rejection, we evaluated ET-1 expression in tissues obtained from BN (RT1ⁿ) to BN rats (group 1), and DA (RT1^a) to BN rats (group 2). The ET-1 levels in group 1, determined by radioimmunoassay, remained low in the serum, liver, and bile, but in group 2, they peaked on postoperative day (POD) 5 in the liver, kidney, bile, and urine, at 344 ±31.6pg/gwet, 306 ± 97.4pg/gwet, 1008 ± 258 pg/day, and 156 ± 45 pg/day, respectively, whereas levels in the serum peaked on POD 7 at 38.7 ± 13.1 pg/ml. In the portal vein (PV) ET-1 showed extremely high levels without statistical difference between groups 1 and 2, at 93.0 ± 15.5, and 83.0 ± 9.84 pg/ml on POD 7, respectively. However, in the suprahepatic vena cava (SHVC) and the abdominal aorta (AO), the ET-1 levels were statistically higher in group 2 compared to group 1 (P < 0.01). Immunohistochemical staining showed decreased staining of the liver and kidney in group 2 on POD 7. In conclusion, increasing levels of ET-1 were released from the liver and kidney during the early stage of rejection, resulting in the high ET-1 levels in these tissues, which were cleared promptly. However, an increased production of ET-1 was not observed in association with the release of ET-1.     

Growth hormone for children with chronic renal failure and on dialysis

We studied all children with CRF who received recombinant human growth hormone (rhGH) for more than a year (mean±SD duration of therapy 3.7±2.5 years) over an 11-year period. There were 32 children. Twenty-one children were conservatively managed, with a mean glomerular filtration rate (GFR) of 24±12 mL min^–1/1.73 m² at the start of rhGH. Their height standard deviation score improved from –2.5±1.4 to –2.1±0.7 at 1 year (P=0.3), –2.0±0.7 at 2 years (P=0.01), and –1.6±0.6 at 3 years (P=0.001). After that there was no improvement. Eleven children were on dialysis, six on haemodialysis (HD) and five on peritoneal (PD). Ht SDS improved from –2.7±0.5 to –2.3±0.5 at 1 year (P=0.02). Thereafter there was no further improvement. RhGH was stopped because of transplantation in 29 patients at a mean±SD age of 12.1±4.0 years. Mean Ht SDS was –1.8±0.8 at transplant and there was no change over the following 5 years. In conclusion, treatment with rhGH resulted in improvement in Ht SDS in conservatively managed CRF for up to 3.0 years and for 1 year in children on dialysis. Discontinuation of rhGH after transplantation resulted in little change in Ht SDS.     

Acute and long-term changes in plasma levels of atrial natriuretic factor in patients with renal replacement therapy

In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6–12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32–634. Weight loss during dialysis was 1.5±1.1 kg (mean±SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P=0.02, n=12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3.7 to 17.81 (mean 6.6; r=0.65, P=0.02). On day 2, mean 24 h diuresis decreased to 3.3±1.41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34–88 ml/min per 1.73 m² body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2–6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.     

Renal handling of uric acid under cyclosporin A treatment

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567±156 mol/l) compared with the AZA group (378±98), the CRF group (415±119) and the N group (290±68). Mean uric acid clearances in each group measured 3.9±2.8 ml/min per 1.73 m² (CyA), 5.6±3.4 (AZA), 4.0±2.2 (CRF) and 8.4±3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53±0.15 mol/ml in the CyA group (P<0.01) compared with 0.34±0.08, 0.29±0.15 and 0.27±0.07 mol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.     

Bone mineral density and bone turnover markers in children with chronic renal failure

Bone mineral density (BMD) at lumbar spine (L₂-L₄) was measured by dual-energy X-ray absorptiometry (DEXA) in 21 children with predialysis chronic renal failure (CRF) and 44 children with end-stage renal failure (ESRF) on regular hemodialysis. BMD results were expressed as Z-scores. Osteopenia was documented in 13 predialysis patients (61.9%) and 26 patients (59.1%) with ESRF. No significant correlation was observed between Z-scores and the duration of CRF or estimated creatinine clearance. In osteopenic children there was a negative correlation between Z-scores and serum phosphorus (r=–0.61, P=0.004), intact parathyroid hormone (iPTH) (r=–0.47, P=0.03), and bone-specific alkaline phosphatase (r=–0.52, P=0.02) and a positive correlation with total calcium (r=0.41, P=0.07) and 25-hydroxycholecalciferol (r=0.53, P=0.02). Osteopenic children who had iPTH values 200 pg/ml were more osteopenic than those who had lower iPTH levels (P=0.006). In conclusion, osteopenia, assessed by DEXA, is frequent in children with CRF. It occurs early irrespective of the duration or the severity of CRF. In children with ESRF the degree of osteopenia is correlated with laboratory markers of renal osteodystrophy and patients with biochemical findings of secondary hyperparathyroidism are more osteopenic than the others.     

Urinary endothelin excretion in the neonate: influence of maturity and perinatal pathology

The present study was undertaken to establish the developmental pattern of urinary endothelin-1 (ET-1) excretion and to define its possible role in mediating pathophysiological changes related to perinatal asphyxia/infection and dopamine treatment. Urinary ET-1 levels were measured by radioimmunoassay in 7 full-term neonates (mean gestational age 39.3 weeks) on days 1, 3 and 5, and in 9 pre-term neonates (mean gestational age 30.8 weeks) on days 1, 3, 5, 7 and weekly thereafter for 5 consecutive, weeks. The results were compared with those of three age-groups of 30 normal children (4–8 years, 9–12 years and 13–18 years); each group, consisted of 10 children. The influence of severe cardiopulmonary distress (n=16, mean gestational age 33.9 weeks, post-natal age 3.3 days) and dopamine administration in a dose of 2 g/min per kg (n=10, mean gestational and post-natal ages 32.1 weeks and 5.6 days, respectively) were also studied. In full-term infants, ET-1 concentration fell from 34.3±1.8 pmol/l on day 1 to 21.5±1.5 pmol/l on day 5 (P<0.01). In premature infants its absolute value and its post-natal fall were similar in the 1st week and no further change occurred in weeks 2–5; it stabilized at levels between 17.1±2.2 and 16.7±1.7 pmol/l. These concentrations tended to be lower than those of 25.5±1.3, 23.0±1.0 and 26.2±0.7 pmol/l measured in three groups of older children. During the 1st week, daily ET-1 excretion remained unchanged in term infants (3.1±1.0 vs. 3.7±1.5 pmol/m² per day), but there was a significant increase from 6.5±1.0 to 12.4±0.7 pmol/m² per day (P<0.01) in premature infants. During weeks 2–5, preterm infants excreted more ET-1 than older children (P<0.01). In response to perinatal ashphyxia/infection and dopamine therapy, urinary ET-1 excretion markedly rose and there was a significant positive correlation between urine flow rate and ET-1 excretion (P<0.001). We conclude that ET-1 concentration rather than excretion rate may have a role in mediating the changes in renal functions that occur soon after birth. The pathophysiological significance of the flow-dependent increase in urinary ET-1 excretion needs to be further studied.     

Liberation of vasoactive substances and its prevention with thromboxane A2 synthase inhibitor in pig liver transplantation

There are multiple causes of liver graft nonfunction in the early post-transplant period. Since a severe microcirculatory disturbance based on ischemia-reperfusion liver injury is considered to be the main underlying pathophysiology, it is suspected that various vasoactive substances are liberated after reperfusion of the graft. In order to investigate this matter, we conducted an experimental study with pig liver allotransplantation. Two groups of animals received donor grafts with or without thromboxane synthase inhibitor (sodium ozagrel), 1.25 mg/kg body weight intravenously, given at the time of liver harvesting. All of the recipient animals in the treatment group (n=10) survived longer than 7 days whereas three of ten animals in the control group died within 7 days. Serum lactate dehydrogenase (LDH) in the recipient serum at 1 h after reperfusion was significantly lower in the treatment group (915.1±167.3 U/l) than in the control group (1264.4±134.7 U/l). Serum thromboxane B₂ (2261.7±1055.7 pg/ml) and endothelin-1 (6.3±2.2 pg/ml) after reperfusion in the treatment group were significantly lower than those in the control group (4220.0±1711.0 pg/ml and 11.2±3.1 pg/ml, respectively). Although serum angiotensin II after reperfusion tended to be lower in the treatment group than in the controls serum renin activity was less than 3 ng/ml in both groups of animals. There were no differences in the plasma endotoxin levels between the two groups. We conclude that the administration of sodium ozagrel to the donor animals provided better graft function in recipients than no such treatment. We speculate that the inhibition of thromboxane A₂ production suppresses the liberation of other vasoconstrictive substances, preventing microcirculatory disturbance and, thereby, contributing to improved graft function after liver transplantation.     

Acute effects of recombinant human erythropoietin on plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients

Background: The pathogenesis of rHuEpo-induced hypertension in haemodialysis (HD) patients still remains uncertain. Endothelin-1 (ET-1) is produced from proendothelin-1 (proET-1) by an endothelin-converting enzyme. Since proET-1 is known to have approximately 1/100 the potency of ET-1 for contracting an isolated blood vessel, the change in the activity of endothelin-converting enzyme (ECE) has been proposed as an important factor in the pathophysiology of various hypertensive diseases. However there is no report on whether a change in the rate of conversion of proET-1 to ET-1 may be involved in the pathogenesis of rHuEpo-induced hypertension. The purpose of this study was to ascertain the potential role of ECE in the development of rHuEpo-induced hypertension. Methods: The levels of plasma erythropoietin, proET-1, ET-1, and mean arterial blood pressure (MAP) were measured following a single dose of rHuEpo (100 U/kg) in HD patients with 24-h ambulatory blood pressure monitoring. Different routes of administration (19 intravenous group, 10 subcutaneous group) were compared to a placebo-injected control group (10 HD patients). Results: Plasma erythropoietin levels reached maximal value 5 min after i.v injection of rHuEpo (13.1±2.4 vs 2780.9±290.1 mU/ml, P<0.01), whereas it was 6h in the s.c. group (14.7±3.8 vs 38.8±17.7 mU/ml, P<0.05). A significant increase in MAP was noted 30 min after rHuEpo injection, which lasted for 3 h in the i.v. group. However, no significant changes in MAP were noted in patients given rHuEpo subcutaneously. Both the plasma concentrations of proET-1 and ET-1 started to increase from 10 min after i.v. rHuEpo administration, with the pro-ET-1 reaching a peak level at 30 min (13.5±7.4 vs 21.6±3.8 pg/ml, P<0.05) and the ET-1 at 1 h (4.2±2.6 vs 9.9±4.8 pg/ml, P<0.05). In patients with significant interdialysis hypertension following a single i.v. injection of rHuEpo, the molar ratio of ET-1 over proET-1 (ET-1/proET-1) was significantly higher than in patients without hypertension. In addition, the increase in ET-1 levels was significantly greater in patients with interdialysis hypertension, while changes in proET-1 level were similar in both hypertensive and non-hypertensive groups. Changes in interdialysis MAP (Dgr;IDMAP) was significantly correlated with &Dgr;ET-1 during the interdialysis period, but not with &Dgr;proET-1. Conclusion: Differences in ET-1/proET-1 ratio in relation to changes in MAP after a single intravenous administration of rHuEpo suggest a potential role for ECE in the pathogenesis of rHuEpo-induced hypertension. Key words: endothelin-1; endothelin-converting enzyme; haemodialysis; proendothelin-1; rHuEpo-induced hypertension      

Impact of ACE I/D gene polymorphism on congenital renal malformations

To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo- /dysplasia, obstructive uropathy, reflux nephropathy; n=59), other congenital or hereditary diseases (n=23), or acquired glomerular disorders (n=13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal ’survival’ analysis was performed, using a GFR loss of 10 ml/min per 1.73 m² as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n=163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P<0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P<0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P<0.001) and gross proteinuria (RR 4.7, P<0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria. Received: 25 August 2000 / Revised: 10 December 2000 / Accepted: 15 December 2000     

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective,matched cohort study

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).     

Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients—an international CTS registry analysis

Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12–23 years (n = 964) with a 1-year tacrolimus trough level between 4.0 and 10.9 ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0 ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P < 0.001). This association was not apparent in young children aged 0–11 years (n = 455) and less pronounced in adults aged 24–34 years (n = 1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P < 0.001 and P = 0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.     

Measurement of the vasoconstrictive substances endothelin,angiotensin II,and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults

In a rat model, the left kidney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro-Collins (EC) solution (n=12) or University of Wisconsin (UW) solution (n=6) for 10 min. Each kidney was then harvested and stored at 4°C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A-II), thromboxane (B₂) (TxB₂), and prostaglandin I₂ (PGI₂). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64±0.3 pg/ml vs 0.82±0.1 pg/ml (P0.009); A-II 20.8±6.2 pg/ml vs 7.75+2.3 pg/ml (P0.007); TxB₂ 100.8±17.7 pg/ml vs 40.1±11.7 pg/ml (P0.04); PGI₂ 638.3±41.1 pg/ml vs 318.3±36.4 pg/ml (P0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB₂ and prostacyclins during the 24–48 h period. In the UW solution, basal levels of ET and A-II were lower than those in EC solution, but similarly increased after initial ischemia. At 24 h, the concentrations produced by the left and right kidneys were as follows: ET 0.66±0.1 pg/ml vs 0.48±0.1 pg/ml (P0.14); A-II 10.36±3.7 pg/ml vs 2.14±0.7 pg/ml (P0.006); TxB₂ 178±53 pg/ml vs 52±23.1 pg/ml (P0.001); and PGI₂ 448.3±49 pg/ml vs 323±44.3 pg/ml (P0.01), respectively. After 48 h, the range of concentrations of each substance was similar to that obtained after 24 h. In further studies, the concentrations of ET and A-II were measured in solution previously used to preserve human kidneys (n=7). The mean concentration of ET and A-II in these samples was 3.82±1.14 pg/ml and 21.3±9.2 pg/ml, respectively, whereas in control media both substances were below the limits of detection. These results demonstrate that vasoconstrictive substances can be measured in the preservation media after a kidney has been stored cold and that higher concentrations are found when the organ has been subjected to prior normothermic ischemia. The measurement of these vasoactive substances before transplantation may reveal that the kidney has been subjected to previous ischemic events. Moreover, these vasoactive substances could be involved in the early recovery of renal function after kidney transplantation.