Biomedical subjects
Publications and source records attributed to K L Lynn.
A grossly obese (149 kg) man with the sleep apnea syndrome was found to have proteinuria and a supernormal glomerular filtration rate. Renal histology showed glomerulomegaly and focal glomerulosclerosis. It is suggested that obesity may induce glomerular hyperfiltration and in turn glomerulosclerosis.
The clearance of drugs excreted entirely unchanged by the kidneys is assumed to relate directly to renal function. The clearance of drugs which are entirely metabolized is usually not altered in patients with renal impairment, although there are examples of both increased and decreased metabolic clearance rates. The clearance of metabolites which are excreted unchanged through the kidneys is also directly related to renal function. The angiotensin converting enzyme (ACE) inhibitors enalapril, ramipril, cilazapril and quinapril are prodrugs that are rapidly converted to active metabolites which are excreted unchanged through the kidneys. Studies have consistently demonstrated reduction in the apparent oral clearance of the active metabolites, in proportion to the degree of impairment of renal function. In addition, for quinapril at least, the metabolic clearance of the parent drug is slightly reduced in renal impairment. The activity of captopril and lisinopril lies in the parent molecule itself. Lisinopril is excreted renally unchanged, while captopril is both metabolized and excreted renally unchanged. The duration of ACE inhibition after administration of any of the ACE inhibitors is prolonged in proportion to the degree of renal impairment. From these pharmacokinetic and pharmacodynamic properties, it follows that the dose rate of the ACE inhibitors should be reduced in direct proportion to the degree of reduction in renal function. Reducing the dose, rather than prolonging the dose interval, is more logical for compliance and for maintaining a consistent degree of ACE inhibition over 24 h.
Between January 1973 and December 1986 a total of 47 children (32 boys) under the age of 16 years had a total of 60 renal biopsies. The commonest indication for biopsy was the nephrotic syndrome, followed by macroscopic haematuria, Henoch-Schönlein nephritis and lupus nephritis. The children have been followed prospectively for a mean period of five and one-half years. One-half of the children are now in a full remission, five have reached end-stage renal failure, two have died of sepsis, two have chronic renal failure and the remainder continue to have proteinuria and/or macroscopic haematuria. Renal biopsy by an experienced operator using ultrasonic control and having the facilities of an expert histopathological service was a safe diagnostic procedure which has enabled important prognostic and therapeutic decisions to be made.
Two patients who had taken overdoses of theophylline were treated initially with oral activated charcoal. Owing to continued toxic plasma levels of theophylline, haemoperfusion was used to reduce rapidly theophylline levels. Both patients recovered rapidly.
1. Eight women with acute pyelonephritis were treated with i.v. enoxacin for 5 days. All were clinically cured and five had a bacteriological cure. Five women reported side effects. 2. During treatment there was no significant accumulation of enoxacin and the total clearance of the drug did not alter with repeated dosing. Drug elimination half-life (mean 4.3 h, s.d. 2.1) was similar to that reported in healthy volunteers. 3. Enoxacin should be compared with the aminoglycosides and beta-lactam antibiotics for the treatment of severe or complicated urinary tract infections.
From August 1974 to January 1985, 53 patients (26 men; seven Maoris) mean age 45 (SD 15) years, with diabetes mellitus for a mean of 12 (SD nine) years had a renal biopsy and were followed. Indications for biopsy were nephrotic syndrome, proteinuria, renal impairment (five) and hematuria (one). Mean plasma creatinine concentration was 0.22 (SD 0.18) mmol/L and protein excretion 3.4 (SD 2.5) g/24 h. Diabetic nephropathy was demonstrated in 39 patients and significantly associated with retinopathy and insulin dependent diabetes mellitus (IDDM). Of the 39 patients followed for 25.7 (SD 22.8) months, 18 had died (nine myocardial infarction, six uremia, two sepsis, one stroke) and nine had begun dialysis. The five-year cumulative renal survival was 28%. The presence of the nephrotic syndrome and the plasma creatinine concentration at presentation were the best predictors of survival. Diabetics with IDDM of 20 years duration, retinopathy and heavy proteinuria, who survive the other complications of their disease, are likely to have diabetic nephropathy requiring renal replacement therapy.
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1. Binding between the radiolabelled loop-acting diuretics ([14C]frusemide, [14C]ethacrynic acid and [3H]bumetanide) and human Tamm-Horsfall glycoprotein or human serum albumin in vitro was evaluated by equilibrium dialysis. 2. The diuretic action and binding to urinary Tamm-Horsfall glycoprotein of the radiolabelled diuretics in vivo, after intravenous administration, were examined in rabbits. 3. In vitro, all three radiolabelled diuretics bound strongly to human serum albumin, but not to Tamm-Horsfall glycoprotein. 4. Radiolabelled frusemide and bumetanide, but not ethacrynic acid, caused a diuresis in rabbits, but no binding between the drugs and Tamm-Horsfall glycoprotein was seen in vivo. 5. Binding to Tamm-Horsfall glycoprotein does not appear to be an important mechanism in the action of loop diuretics.
1. A role has been suggested for anti-Tamm-Horsfall protein (THP) antibodies in renal disease based on the results of immunoassays of pathological sera. The putative autoantibodies have not been isolated from such sera nor have definitive inhibition studies of their binding been carried out. We have carried out such studies using rabbit anti-THP antibodies as control reagents. 2. Urinary THP prepared by salt precipitation was used to prepare four immunoabsorbent columns by covalent coupling to CNBr-activated Sepharose 4B. After washing with a variety of dissociating agents to remove any non-covalently bound subunit THP, each column was incubated with normal and immune rabbit serum. Fractions washed and eluted from columns were tested for anti-THP antibodies by enzyme-linked immunosorbent assay (ELISA) and THP antigen by radioimmunoassay, and showed NH4SCN (3 mol/l) and guanidine hydrochloride (GuHCl) (6 mol/l) equivalent and sodium dodecyl sulphate (20 g/l) to be inferior in their capacity to produce immunoabsorbent THP capable of isolating specific antibodies from immune rabbit serum. 3. The column treated with GuHCl (6 mol/l) was used further in attempts to isolate putative anti-THP antibodies from five patients, who had a history of urinary tract infections and whose sera showed strong binding by ELISA. 4. Results from direct and inhibition ELISA experiments on fractions collected after washing and elution with all sera suggested that the putative human anti-THP antibodies were of very low affinity and/or directed against non-subunit THP. 5. The pathological relevance of human anti-THP antibodies measured by ELISA remains to be established.
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Over a 13-year period 42 patients (35 women) with systemic lupus erythematosus and renal disease had a renal biopsy. Renal involvement as the first and only manifestation of systemic lupus erythematosus was common in men. The commonest reason for renal biopsy (23/42) was the finding of proteinuria with or without haematuria. One-half of all patients had diffuse proliferative glomerulonephritis. Twenty-seven patients were treated with both prednisone and azathioprine and 10 with prednisone alone at some stage during follow-up. The renal biopsy findings were useful in assessing the severity of renal involvement and prognosis. A five-year renal survival of 72% was observed. Diffuse proliferative glomerulonephritis with renal insufficiency was associated with a poor prognosis. Those patients who were established on the dialysis/transplant programme became symptom free on no treatment.
Glomerulonephritis is the main determinant of mortality in the Henoch Schönlein syndrome. We report a prospective study on 17 patients with the Henoch Schönlein nephritis who underwent a renal biopsy during a 12-year period. Three patients have developed end-stage renal failure, 13 are alive with normal renal function and one was lost to follow-up. We recommend that patients with Henoch Schönlein nephritis be followed up, with urinalysis and assessment of renal function, for at least five years.
An enzyme-linked immunosorbent assay (ELISA) has been established using Nunc polystyrene immunoplates coated with a monoclonal antibody to human Tamm-Horsfall urinary glycoprotein (THP) to detect and measure THP in human serum. Optimal reaction conditions for both the monoclonal capture antibody and the affinity-purified rabbit anti-human THP second antibody were established to produce standard curves which showed linearity between 20-90 ng/ml with a sensitivity of 2-3 ng/ml. The plate-to-plate standard curve mean coefficient of variation (CV) was 5.9 +/- 2.9% on assays performed on the same day while day to day mean CV was 13.3 +/- 2.4%. The specificity of the ELISA was demonstrated by inhibition of binding after preincubation of both urinary THP standards and serum with monoclonal anti-THP antibody. Sera from 195 blood donors tested by the ELISA had a mean concentration of THP antigenic determinants of 260 +/- 105 ng/ml. Results from three control sera run on all plates used in the survey showed mean CV less than 7.6% while no binding was observed with sera from an anephric patient.
A randomised trial was undertaken to compare the efficacy of netilmicin and ceftriaxone for the treatment of severe or complicated urinary tract infections. Forty-seven patients completed the study. Twenty-three of 24 patients treated with netilmicin and 21 of 23 treated with ceftriaxone were cured. One patient treated with netilmicin had a mild, reversible disturbance of renal function. Six patients developed diarrhoea after ceftriaxone treatment.
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The pharmacokinetics of morphine were measured using gas chromatography-mass spectrometry (GCMS) with specific ion monitoring after the intramuscular administration of papaveretum to four patients with renal failure (one anephric) and three normals. The apparent t1/2 of absorption and t1/2 of elimination were significantly shorter in the patients with renal failure (P less than 0.05). Morphine glucuronides are eliminated slowly in these patients as expected. Renal failure does not impair the elimination of morphine.