Richard A. Robson

Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia.

In an ambulatory population of diabetic subjects (Type 1 and Type 2), the urine excretion of the renal osmolyte, glycine betaine, was compared to known markers of glycemic control, renal dysfunction and to the excretion of related betaines, including trigonelline, proline betaine, carnitine and acetyl-carnitine. Of the 85 subjects, 20 patients had urine glycine betaine concentrations above the reference range for normal subjects. Plasma glycine betaine concentrations were within reference ranges for normal subjects. Patients with elevated glycine betaine excretion tended to have lower plasma glycine betaine concentrations, but this did not reach statistical significance. One way analysis of variance found excretion is independent of treatment, duration of diagnosed diabetes, blood pressure and body mass index (BMI). An association between glycine betaine excretion and glycemic control was observed with statistically significant correlations occurring with both plasma glucose (r = 0.43, P < 0.001) and glycated haemoglobin (HbA1c) (r = 0.35, P < 0.005). The excretion of carnitine, acetyl-carnitine and proline betaine were related to glycine betaine excretion (r = 0.49, P < 0.001; r = 0.40, P < 0.001; r = 0.27, P < 0.05, respectively). Urine carnitine and acetyl-carnitine concentrations were also related to plasma glucose concentrations (r = 0.30, P < 0.01). Increased urine retinol binding protein concentrations (RBP), a marker of proximal tubular dysfunction, correlated with elevated urine glycine betaine excretion and plasma HbA1c (r = 0.28, P < 0.01). These results suggest poor glycemic control is associated with the increase in urine glycine betaine, carnitine, acetyl-carnitine and RBP excretion in diabetic patients. However, < 50% of the observed increase in glycine betaine excretion has been accounted for by the variables measured, suggesting other unidentified processes may also be involved.

End-Stage Reflux Nephropathy

Forty-two of 371 patients (11.3%) entering a dialysis-transplant program had end-stage reflux nephropathy. Thirteen of these 371 patients were under 16 years of age, with 6 of them having reflux nephropathy. Most patients presented with severely impaired renal function, hypertension, and proteinuria. Documented urinary tract infections occurred in only 4 of the 18 male and 14 of the 24 female patients. Thirty-five patients had hypertension, which in 22 had not been detected before presentation. Five presented with accelerated hypertension. Eight of the 24 women presented during a pregnancy. Twenty-nine patients are still alive, 20 with a functioning renal transplant. Reflux nephropathy is an important cause of end-stage renal failure, particularly in younger people. All patients presenting with renal insufficiency and proteinuria, with or without urinary tract infections or hypertension, should have reflux nephropathy excluded.

Abnormal glycine betaine content of the blood and urine of diabetic and renal patients

In normal human plasma the concentrations of the renal osmolyte, glycine betaine, are usually between 20 and 70 mumol/l, in adult males (median 44 mumol/l) higher than in females (34 mumol/l). Concentrations are lower in renal disease (median 28 mumol/l) and normal in diabetes. Urinary excretion of glycine betaine shows no sex difference and is frequently elevated both in renal disease and in diabetes (medians: normal, 6.2, renal 12.3 and diabetes, 39.7 mmol/mol creatinine). The elevation in diabetes does not strongly correlate with known renal disease, nor with either urinary microalbumin or plasma creatinine. There is no correlation with glycated haemoglobin. The positive correlation with the excretions of another renal osmolyte, sorbitol, was highly significant in diabetic subjects. In the diabetic group there was also a significant negative correlation between plasma glycine betaine and urine microalbumin.

Anemia and angiotensin-converting enzyme inhibition in renal transplant recipients

The renin-angiotensin system has been shown to have an effect on erythropoietin synthesis and hemoglobin concentration. We present a retrospective study of stable renal transplant recipients who received an angiotensin-converting enzyme (ACE) inhibitor as treatment of hypertension. Fifteen patients were eligible, with a mean hemoglobin concentration of 130.7 ± 22.7 g/L (SD). Within 6 months of ACE-inhibitor therapy, the mean hemoglobin had fallen significantly to 110.5 ± 23.2 g/L (p < 0.001). No parallel change in leukocyte or platelet counts was evident. Prospective studies are needed to clarify the effect of inhibition of the renin-angiotensin system on erythropoietin synthesis and release.

Comparison of ciprofloxacin with netilmicin for the treatment of acute pyelonephritis.

A prospective, randomised trial was undertaken to compare the efficacy of ciprofloxacin and netilmicin for the treatment of acute pyelonephritis. Forty-three patients were enrolled and 34 (29 women) completed the protocol. Fifteen of 17 patients treated with ciprofloxacin and 15 of 17 treated with netilmicin were cured. All patients were treated for five days. One patient relapsed after ciprofloxacin and another had a reinfection, while two relapsed after netilmicin. Five of six patients with a urinary tract abnormality were cured. Side effects were generally mild and rapidly reversible. Patients treated with ciprofloxacin spent a mean of 3.7 days in hospital compared with 5.3 days for those treated with netilmicin. The difference in duration of hospital stay was statistically significant (p less than 0.01). Both drugs proved highly effective and safe for the treatment of severe acute pyelonephritis.

The effects of quinolones on xanthine pharmacokinetics

Caffeine, theobromine, and theophylline are among the most widely consumed compounds in beverages and in pharmaceutical preparations. These methylxanthine alkaloids are metabolized by similar pathways involving demethylation and hydroxylation that are predominantly cytochrome P-450 mediated. In vivo and in vitro evidence suggests that the cytochrome P-450 isozymes involved in the demethylation pathways are distinct from the cytochrome P-450 isozymes involved in the hydroxylation pathways. Although distinctions can be made between demethylation and hydroxylation pathways, the evidence suggests that these different cytochrome P-450 isozymes are under common regulatory control. Any drug inhibiting the family of cytochrome P-450 isozymes involved in the metabolism of the methylxanthines would, therefore, be expected to have a similar effect on theophylline, theobromine, and caffeine. A number of quinolones, including enoxacin, pipemidic acid, ciprofloxacin, norfloxacin, and pefloxacin, have been shown to reduce the clearance of theophylline, while lomefloxacin has no effect on theophylline or caffeine clearance. It has been hypothesized that only fluoroquinolones that form a 4-oxo-metabolite inhibit theophylline clearance. Lomefloxacin, which does not form a 4-oxo-metabolite, would therefore not be expected to inhibit the clearance of theophylline or caffeine. In contrast, ciprofloxacin, which does form a 4-oxo-metabolite, has been shown to reduce theophylline and caffeine clearances by about one third. Another hypothesis for the differences among quinolones suggests that quinolones that have a greater impact on theophylline clearances are more stereochemically similar to theophylline. Substitutions at position 8 on the quinolone nucleus (as in lomefloxacin) would result in stearic hindrance and decrease the structural similarity to theophylline.

Effect of hemodialysis and recombinant human erythropoietin on determinants of blood viscosity.

Blood viscosity (hemorheology) is a major determinant of the rate of blood flow, and increases in viscosity are known to be involved in the etiology of vascular diseases. This placebo-controlled study investigated the independent and combined effects of hemodialysis and recombinant human erythropoietin (rHuEpo) on determinants of blood viscosity in patients with chronic renal failure and related any changes to the normal physiological range. Hemodialysis patients were shown to have a high incidence of rheological abnormalities although the degree of anemia associated with chronic renal failure compensated for these changes. The main effect of both hemodialysis and rHuEPO treatment was an increase in hematocrit associated with a rise in blood viscosity and inconsistent changes in red blood cell (RBC) deformability. The rise in viscosity was significant only following rHuEPO treatment. Hemodialysis-induced increases in blood and plasma viscosity correlated strongly with the degree of hemoconcentration. Although hemodialysis patients have inherent hemorheological abnormalities, correction of renal anemia with rHuEPO to a hematocrit level of < 0.35 in conjunction with dialysis-induced hemoconcentration did not result in adversely high blood viscosity levels in any patient.

Hemorheology and Fistula Function in Home Hemodialysis Patients following Erythropoietin Treatment: A Prospective Placebo-Controlled Study

The beneficial effect of correcting anemia in end stage renal failure using recombinant human erythropoietin (rHuEPO) is sometimes complicated by thrombosis of the arteriovenous fistula. This placebo-controlled study investigated the relationship between hemorheological changes caused by rHuEPO and alterations in fistula function and heparin requirements in home hemodialysis patients. Erythropoietin induced a rise in high shear rate blood viscosity, a determinant of blood flow in large vessels. Doppler assessment of brachial artery blood flows, tests of fistula function and heparin requirements were similar in the two patient groups. These findings indicate that rHuEPO treatment of renal anemia resulted in the expected rise in red blood cell mass and blood viscosity although these changes did not cause problems with arteriovenous access or alter fistula function in the short term.

Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia

Diabetes mellitus subjects, type 1 and type 2, have increased glycine betaine excretion compared to normal subjects that correlated with plasma glucose and HbA(1C) concentrations. The current study was undertaken to determine whether elevated glucose concentration directly increases glycine betaine excretion in an animal model. Non-pregnant female Coopworth sheep received an intravenous glucose load (12.5,25 and 50% w/v; rate 200 ml/h) for 6 h followed by a 12 h physiological saline washout (0.9% w/v). Plasma and urine samples were analyzed for glycine betaine and glucose. Urine volumes and osmolality were also measured. Using the non-parametric Kruskal Wallis analysis of variance test we found no difference in glycine betaine excretion between glucose loaded and saline infused control animals (P=0.861). However, a significant negative correlation (r=-0.28, P<0.001) was observed between urine osmolality and glycine betaine excretion independent of treatment. We conclude that acute elevations of plasma glucose concentrations did not result in increased glycine betaine excretion and is therefore unlikely to be directly responsible for elevated glycine betaine excretion observed in diabetes mellitus subjects.

OKT3 for the Treatment of Steroid-Resistant Acute Renal Allograft Rejection

OKT3 (Orthoclone) was first used in this unit on February 25, 1987. Up until March 31, 1996, 153 patients had a total of 163 transplants. Fifty of these patients who received 53 transplants (28 male, mean age 37.5 years, 48 cadaveric donors), were treated with OKT3 for steroid-resistant acute rejection. Forty-nine graft biopsies were undertaken and 47 showed acute rejection. In the other 4 episodes a clear-cut clinical and laboratory diagnosis of severe rejection was made. OKT3 (5 mg i.v.) was started at a median of 19 days following transplantation and was successful in reversing 43 of 51 (84%) episodes of steroid-resistant acute rejection. Of those treated, the patient and graft survival at 1 year was 86 and 69%, at 3 years 82 and 64% and at 5 years 79 and 61%, respectively. Adverse effects were common. Four patients died from sepsis within the first 3 months after transplantation. OKT3 was effective in reversing 84% of steroid-resistant acute rejection episodes.