Geoffrey Boner

Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease

BACKGROUND Pruritus is a common disabling problem in patients with advanced end-stage renal disease. Few studies have evaluated the clinical characteristics of uremic itch. OBJECTIVES The aim of this multicenter study was to provide a comprehensive description of the prevalence and clinical characteristics of pruritus affecting patients with end-stage renal disease who are undergoing hemodialysis. METHODS A detailed questionnaire recently developed was used to evaluate pruritus in 219 patients undergoing hemodialysis treatment in 3 dialysis units. We examined the relationship of the quality of dialysis and various factors and medical parameters to itch. RESULTS Pruritus was a common symptom in the study population. Approximately 66% of the patients had pruritus at some point, and 48% were affected by it at the time of the study. There was no correlation between the occurrence of pruritus and demographic or medical parameters (type of kidney disease, medical management, dialysis efficacy as expressed by Kt/V) of the patient. The data suggest that uremic pruritus tends to be prolonged, frequent, and intense, and it can impair the patients quality of life including a negative effect on sleep and mood. Major factors found to exacerbate pruritus include rest, heat, dry skin, and sweat. Major factors found to reduce pruritus include activity, sleep, hot and cold shower, and cold. Treatment with angiotensin inhibitors seemed to be more common among those with uremia who had itch (P =.02) whereas furosemide was more commonly used among those who never itched (P =.002). CONCLUSION This study provides a detailed description of uremic pruritus with new data on its characteristics including affective and sensory dimensions and associated symptoms.

Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat

Introduction Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor β1 (TGF-β1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-β1 in diabetic rats. Materials and methods Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days. Results Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-β1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-β1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). Conclusions Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-β1.

Thromboxane Production in Human Lung During Cardiopulmonary Bypass: Beneficial Effect of Aspirin?

BACKGROUND Increased systemic levels of thromboxane (Tx) during cardiopulmonary bypass (CPB) in humans have been reported. It is not known whether this reflects a general systemic response to the surgical procedure or an increased pulmonary production of Tx in response to ischemia and reperfusion. METHODS Thromboxane B2 levels were measured in the right atrium and left atrium of 14 patients undergoing coronary artery bypass grafting for angina. Eight patients (group 1) were without aspirin for at least 15 days before operation, and 6 patients (group 2) were treated with aspirin (100 mg/day) for at least 1 month before operation. Levels of TxB2 were determined by enzyme immunoassay after lipid extraction and separation. RESULTS Thromboxane B2 levels were elevated throughout CPB. In group 1, left atrial TxB2 levels were significantly higher (p < 0.05) than right atrial levels at all study points during CPB. After pulmonary reperfusion, TxB2 levels in both atria increased significantly (p < 0.02) compared with the levels before cross-clamping of the aorta, and there was an increasing gradient between the two atria (p < 0.05). Mean plasma TxB2 levels during CPB in group 2 were significantly reduced (p < 0.0001) in the right atrium (by 73%) and in the left atrium (by 69%) compared with levels in group 1. CONCLUSIONS The rise in TxB2 levels in the left atrium after CPB in humans reflects production of Tx mainly in the lungs, most probably by ischemic pulmonary tissue and intravascular hematologic components. Aspirin markedly reduces Tx production during CPB, and it might play a major role in preventing pulmonary injury after operations with CPB in humans.

Insulin treatment reduces the increased serum and lung angiotensin converting enzyme activity in streptozotocin-induced diabetic rats

Serum and lung angiotensin-converting enzyme (ACE) activity is increased in the streptozotocin (STZ)-diabetic rat. In the present study, the effect of insulin treatment on this increased ACE activity in the STZ-diabetic rat was investigated. Serum and tissue ACE activity was determined by radiometric assay using [3H]-Hippuryl-glycyl-glycine as substrate. Fifteen days after onset of diabetes (n = 16), 8 rats received insulin daily (6-12 units/kg, s.c.) for 33 days, 8 diabetes rats remained untreated. Control, non-diabetic, rats (n = 8) received saline. The baseline serum ACE activity in the control group was 595 +/- 13 nmol/ml/min and did not change significantly throughout the study. However, serum ACE activity in the untreated diabetic rats increased significantly as of day 14 post-STZ (650 +/- 24 nmol/ml/min, p < 0.001) compared to the corresponding values of the control group and compared to baseline values. Insulin administration to diabetic rats starting on day 15 post-STZ caused a gradual reduction in serum ACE activity to basal values, being (527 +/- 22 nmol/ml/min) at day 47. ACE activity in lungs of untreated diabetic rats was increased by 46%, 47 days post-STZ. Insulin treatment reduced lung ACE activity to values similar to those observed in non-diabetic rats. These changes were associated with reduced kidney weight and urine volume. In summary, insulin administration to hyperglycaemic rats resulted in a reduction in the enhanced serum and lung ACE activity to values seen in non-diabetic rats. Normalizing the activity of the renin-angiotensin system may slow or prevent the glomerular hypertension, a major factor in the development of diabetic nephropathy.

Factors associated with primary and secondary graft failure following cadaveric kidney transplant

Abstract:  The risk profile for primary renal graft failure is largely unknown because of its inclusion with secondary failures or its exclusion from analysis. This study compares characteristics of the cadaveric transplant recipients who experienced primary failure, secondary failures or survived with a functioning graft for at least 6 months. Medical records of all cadaveric kidney‐transplant patients performed in Israel over a 3‐yr period 1997–2000 were reviewed. Fishers exact test and multinomial regression models were used to assess the association of demographic, pre‐operative and operative risk factors with the two types of failure outcomes. Of 325 grafts, 54 (16.6%) failed of which half were primary failures. Univariate analysis demonstrated a significant trend of increasing proportion of patients with specific risk factors from the functioning grafts group to the secondary and to the primary graft failure groups. Independent risk factors for primary graft failure included ‘surgical complications’, ‘donors age ≥60 yr’, ‘waiting for transplant ≥6 yr’, and ‘human leukocyte antigen‐DR (HLA‐DR) mismatch’, based on the multivariate model. These factors may reflect the scarcity of organ donations in Israel, which leads to a prolonged waiting time, higher tolerance for HLA‐DR mismatches, and utilization of kidneys from elderly donors.

The Effect of an Angiotensin Converting Enzyme Inhibitor on Skin Microvascular Hyperaemia in Microalbuminuric Insulin‐dependent Diabetes Mellitus

Patients with longstanding insulin‐dependent (Type 1) diabetes mellitus (IDDM) are reported to have microvascular complications in most capillary beds. The microvascular hyperaemia of the skin in normoalbuminuric and microalbuminuric IDDM patients and healthy volunteers was measured with laser Doppler flowmetry. The effect of 3 and 9 months of treatment with captopril, an angiotensin converting enzyme inhibitor, on hyperaemia in the microalbuminuric patients was studied. Mean (±SD) pretreatment duration of skin postocclusive reactive hyperaemia was longer in microalbuminuric than in both normoalbuminuric patients and healthy volunteers (118.2 ± 34.4 vs 57.8 ± 16.0 vs 63.3 ± 18.3 sec, respectively, p < 0.00001). After 3 and 9 months of captopril treatment the prolonged hyperaemia was shortened to 78.6 ± 45.6 s (p < 0.01) and 62.3 ± 55.6 s (p < 0.03), respectively. Urinary albumin excretion decreased from 63.9 ± 43.5 to 33.4 ± 28.1 mg 24 h−1 at 3 months treatment (p < 0.002) and 43.1 ± 38.5 mg 24 h−1 at the end of the study period (p <0.02). A positive correlation between changes in urinary albumin excretion and the shortening of the skin postocculsive reactive hyperaemia was found. Blood pressure remained in the same range throughout. These results show that captopril affects skin blood flow, independent of its hypotensive effect. This action may reflect the influence of angiotensin converting enzyme inhibitor on vascular beds other than those of the kidneys.

Negative impact of ‘old‐to‐old’ donations on success of cadaveric renal transplants

Abstract:  The effect of ‘old‐to‐old’ cadaveric renal transplants on operative complications and graft survival was assessed in all 325 patients undergoing solitary cadaveric renal transplantations in Israel during a 3‐yr period. Preoperative information and hospital course data were abstracted from the charts. Results were analyzed using Kaplan–Meyer survival curves, univariate and multivariate Cox models. Overall, 62 (19.1%) grafts failed within a year. Failure rate was 46.2% for ‘old‐to‐old’ transplants compared with 15.5% for all other donor/recipient age combinations (p < 0.0001). ‘Old‐to‐old’ transplants remained independently associated with graft failure in a multivariate Cox model after controlling the effect of other risk factors. ‘Old‐to‐old’ transplants were also associated with increased operative complications relative to other age combinations. The decision to use ‘old‐to‐old’ transplants, even when donors are scarce, is problematic and should be reconsidered.

Insulin and losartan reduce proteinuria and renal hypertrophy in the pregnant diabetic rat

This study was designed to investigate the effect of hyperglycemia and angiotensin II (AngII) on renal hypertrophy and proteinuria in the pregnant diabetic rat. Secondary objectives were to evaluate changes in components of the renin-angiotensin axis and the effects of administration of losartan on pregnancy outcome. Fifty-three pregnant rats were allocated to 6 groups (1) nondiabetic controls (n = 12), (2) nondiabetic controls administered losartan (70-80 mg/kg/day; n = 10), (3) rats in which intravenous streptozotocin (STZ) was used to induce diabetes (55 mg/kg on day 10 of pregnancy; n = 10), (4) diabetic rats treated with losartan (n = 7), (5) diabetic rats treated with insulin (4 U/day; n = 7), and (6) diabetic rats treated with insulin and losartan (n = 7). Urinary protein excretion measured 4 days after STZ was 4 times greater in the rats with STZ-induced diabetes and significantly less in diabetic rats given losartan, insulin, or both. Postpartum kidney weight was greater in the rats with STZ-induced diabetes (2.04 +/- 0.21 g) than in the controls (1.37 +/- 0.14 g; P <.05) and reduced in the diabetic rats given losartan, insulin, or both (1.57 +/- 0.22, 1.73 +/- 0.13, and 1.51 +/- 0.14 g, respectively; P <.05). Plasma levels of angiotensin II in rats given losartan were more than 3.5 times greater than those in controls (749 +/- 436, 596 +/- 323, 567 +/- 349, and 159 +/- 28 pg/mL; P <.001). Postpartum activity of angiotensin-converting enzyme was increased in the untreated diabetic rats compared with that in control rats (162 +/- 12 vs 117 +/- 16 nmol/mL/min; P <.05). This increase was abolished by treatment with losartan or insulin. The number of newborns and mean weight of each newborn was similar in all groups. In summary, administration of losartan or insulin prevented, in part, kidney hypertrophy and protein excretion in the diabetic pregnant rat. Losartan did not affect the number or weight of newborns. Because angiotensin II receptor-blockers are contraindicated in pregnancy, good control of diabetes through the use of insulin should be advantageous.

Should the use of short acting angiotensin-converting enzyme inhibitors be abandoned?

Background Angiotensin-converting enzyme inhibitors (ACE-I) have different modes of action and different durations of inhibition. The effects of ACE-I on the various components of the renin-angiotensin system (RAS) at trough hours were studied in patients with diabetes mellitus receiving long-term ACE-I treatment. Methods Out of 86 Type 1 and 2 diabetic patients, 49 were untreated, 25 received captopril and 12 received enalapril as chronic treatment. Blood for the determination of plasma renin activity (PRA), serum ACE activity and plasma angiotensin II (Ang II) was drawn in the morning (0700—0900 hours) after an overnight fast, about 12 hours after the last dose. PRA and Ang II were measured by RIA and serum ACE activity was assayed by a radiometric assay using 3H-hippuryl-glycyl-glycine as a substrate. Results Mean age was significantly greater in the enalapril-treated patients. Systolic and diastolic blood pressures were not different between the captopril-treated and untreated groups. Serum ACE activity in the captopril-treated diabetic patients was 101.5±42.5 nmol/mL/min, values obtained in untreated diabetic patients (101.4±25.2 nmol/mL/min). In contrast, ACE activity in the enalapril-treated patients was significantly reduced (5.5±7.5 nmol/mL/min) compared with untreated and captopril-treated patients (p<0.00001). PRA values in the ACE-I treated patients were significantly increased. Plasma Ang II levels were significantly increased in the captopril-treated vs. untreated patients (65.1±50.2 vs. 36.2±31.7 pg/mL, p=0.006), whereas the values in the enalapril-treated patient were slightly, but not significantly, reduced (23.8±21.4 pg/mL). Conclusion Trough serum ACE activity is not suppressed in diabetic patients receiving captopril, compared with those receiving enalapril and we thus question the use of short acting ACE-I in these patients.