Recently, a novel heterozygous missense mutation c.T1421G (p. L474R) in the PODXL gene encoding podocalyxin was identified in an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. However, this PODXL mutation appeared not to impair podocalyxin function, and it is necessary to identify new PODXL mutations and determine their causative role for FSGS. In the present study, we report the identification of a heterozygous nonsense PODXL mutation (c.C976T; p. Arg326X) in a Chinese pedigree featured by proteinuria and renal insufficiency with AD inheritance by whole exome sequencing (WES). Total mRNA and PODXL protein abundance were decreased in available peripheral blood cell samples of two affected patients undergoing hemodialysis, compared with those in healthy controls and hemodialysis controls without PODXL mutation. We identified another novel PODXL heterozygous nonsense mutation (c.C1133G; p.Ser378X) in a British–Indian pedigree of AD-FSGS by WES. In vitro study showed that, human embryonic kidney 293T cells transfected with the pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower mRNA and PODXL protein compared with cells transfected with the wild-type plasmid. Blocking nonsense-mediated mRNA decay (NMD) significantly restored the amount of mutant mRNA and PODXL proteins, which indicated that the pathogenic effect of PODXL nonsense mutations is likely due to NMD, resulting in podocalyxin deficiency. Functional consequences caused by the PODXL nonsense mutations were inferred by siRNA knockdown in cultured podocytes and podocalyxin down-regulation by siRNA resulted in decreased RhoA and ezrin activities, cell migration and stress fiber formation. Our results provided new data implicating heterozygous PODXL nonsense mutations in the development of FSGS.

The morphology of gastrocnemius muscles was examined in RFPs (renal failure patients) being treated using HD (haemodialysis) and CAPD (continuous ambulatory peritoneal dialysis). RFPs ( n =24) volunteered to participate in the present study. Twelve RFPs (five women and seven men; mean age, 55 years) were undergoing CAPD treatment and 12 RFPs (two women and ten men; mean age, 62 years) were undergoing HD treatment. Muscle biopsies from gastrocnemius muscles were found not to differ ( P >0.05) in fibre type distribution, MyHC (myosin heavy chain) expression or fibre CSA (cross-sectional area) between the two groups. There were, however, significant differences ( P <0.05) in CC/F (capillary contact/fibre), C/F (capillary to fibre ratio) and cytochrome c oxidase activity. The HD group had 33% more CC/F, with a 19% higher C/F and 33% greater cytochrome c activity in glycolytic fibres (II) than the CAPD group. There were no apparent differences in age, gender, co-morbidity, self-reported physical activity or physical functioning between the two groups, which could account for the difference in muscle capillarity between the groups. The HD patients were, however, administered heparin as a routine part of the dialysis therapy. The possibility is discussed that heparin in combination with mild anaemia and acidosis may have augmented angiogenesis in the HD patients.

Congestive heart failure is a common and serious complication in patients undergoing chronic dialysis. However, there have been no studies on preferential medical therapies to improve left ventricular function in haemodialysis patients. β-Blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy; moreover, plasma levels of noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The present study investigated whether β-blocker treatment could improve left ventricular function in haemodialysis patients with a dilated left ventricle. Our study group comprised 14 haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and after 4 months of treatment with the β-blocker metoprolol: left ventricular dimension at end-systole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and haemoglobin concentration showed no significant change after compared with before treatment with metoprolol. Heart rate decreased significantly, from 79±9 beats/min to 69±9 beats/min, but systolic blood pressure remained unchanged. The left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly. Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide and brain natriuretic peptide decreased markedly [from 100±89 pg/ml to 46±29 pg/ml ( P = 0.0051) and from 549±516 pg/ml to 140±128 pg/ml ( P = 0.0035) respectively]. In conclusion, β-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left ventricle.

Metabolic acidosis frequently complicates end-stage renal failure. In haemodialysis patients its severity is usually monitored by measurement of the total CO 2 (TCO 2 ) level. Samples from ‘satellite dialysis’ patients are often stored prior to analysis. We investigated the affect of storage of 21 samples for 24 h under different conditions prior to analysis. If samples were stored at room temperature the TCO 2 fell from 22.7±4.2 mmol/l to 21.6±3.7 mmol/l ( P = 0.001). If the same samples were spun and stored at 4 °C the TCO 2 was 22.4±3.9 mmol/l ( P = not significant). We conclude that the magnitude in the fall of TCO 2 stored at room temperature for 24 h is unlikely to be clinically significant and can be prevented by spinning the sample and refrigerating it.

Nabumetone, a newer non-steroidal anti-inflammatory drug (NSAID) which preferentially blocks cyclo-oxygenase-2 activity, may be less nephrotoxic than indomethacin. This study tested whether nabumetone has effects different from those of indomethacin on exercise-induced changes in renal function and the renin–aldosterone system. In a randomized fashion, ten subjects were studied after indomethacin (100 mg), nabumetone (1 g) or no medication (control) administered orally at 22.00 hours on the day before each study day, and again at 8.00 hours upon arrival at the laboratory. Renal function was studied at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone. Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F 1α (6-oxo-PGF 1α ) and thromboxane B 2 in all study periods. Nabumetone decreased 6-oxo-PGF 1α excretion during and after exercise. Excretion rates for PGE 2 did not change. Neither indomethacin nor nabumetone changed baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin decreased the plasma renin concentration. Thus, during exercise, nabumetone may decrease the excretion of 6-oxo-PGF 1α by inhibition of cyclo-oxygenase-1 or by inhibition of specific exercise-induced activation of cyclo-oxygenase-2, or both. None of the drugs changed the renal response to exercise. Inhibition by indomethacin of angiotensin II and thromboxane A 2 synthesis may, during exercise, counterbalance renal vasoconstriction caused by blockade of vasodilatory prostaglandins.

1. Adrenomedullin is a potent vasodilating peptide first isolated from phaeochromocytoma and adrenal medulla but also found in the heart, lungs and kidneys. It may also be a paracrine factor because endothelial and smooth muscle cells synthesize adrenomedullin as well as express the receptors. Adrenomedullin induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of nitric oxide. 2. We have developed a specific radioimmunoassay and measured the immunoreactivity of human adrenomedullin in the plasma of 58 male subjects: eight with essential hypertension, 12 with heart failure, 10 with ascites due to cirrhosis, 12 with chronic renal failure, four with hypoxia due to chronic obstructive pulmonary disease and 12 control subjects. 3. Plasma levels (mean ± SEM) in patients with essential hypertension (16.3 ± 1.9 pmol/l), congestive heart failure (17.5 ± 2.8 pmol/l) and renal failure (17.7 ± 2.5 pmol/l) were raised compared with control subjects (7.8 ± 1.4 pmol/l, P < 0.05), confirming previous reports. 4. In addition, we observed that plasma levels of adrenomedullin were significantly raised in patients with ascites due to liver cirrhosis (15.5 ± 1.9 pmol/l) and chronic obstructive pulmonary disease with hypoxia (20.0 ± 1.5 pmol/l). 5. We concluded that the plasma level of adrenomedullin is raised in a variety of diseases.

1. Erythrocyte choline transport was studied in 10 haemodialysis patients immediately before and after a haemodialysis session and in 10 control subjects. Choline uptake was measured in erythrocytes from normal and uraemic patients after washing in vitro and subsequent incubation in autologous plasma. Amines present in uraemic plasma were examined for their effect on choline transport in normal erythrocytes. 2. NMR spectroscopy was used to measure choline, trimethylamine and dimethylamine in erythrocyte extracts from nine control subjects, 32 subjects with renal impairment and nine samples from haemodialysis patients. 3. The increased choline influx in uraemic erythrocytes is significantly decreased by prior haemodialysis (mean V max pre-dialysis 146±20 μmol h −1 I −1 , postdialysis 113±13 μ/mol h–1 I −1 ( P < 0.005). After in vitro washing there is a fall in V max , and no longer any significant difference between pre- and post-dialysis samples. There remains a significant difference in the erythrocyte choline V max between samples from patients with chronic renal failure and from normal subjects ( P < 0.005). 4. Human plasma was found to contain factors capable of increasing choline uptake. Trimethylamine and dimethylamine were found to inhibit choline uptake. Trimethylamine and trimethylamine- N -oxide transstimulated choline efflux, but the major transport substrate present in erythrocyte extracts from all groups was choline, which was higher in those with renal impairment (71 ± 10 μmol/l) than in haemodialysis patients (47 ± 10 μmol/l) and control subjects with normal renal function (40 ± 9 μmol/l). 5. Our data suggest that erythrocyte choline transport is increased in uraemia as a consequence of increased transporter number or activity, rather than the presence of intracellular substrate.

1. C-type natriuretic peptide is a neuropeptide, which is also produced by the vascular endothelial cells. Plasma immunoreactive C-type natriuretic peptide concentrations in patients with various diseases have not yet been studied. 2. Plasma immunoreactive C-type natriuretic peptide concentrations were studied by radioimmunoassay in normal subjects, patients with congestive heart failure, non-dialysed patients with chronic renal failure and haemodialysis patients with chronic renal failure. The C-type natriuretic peptide levels were compared with the levels of atrial natriuretic peptide and brain natriuretic peptide. 3. Plasma immunoreactive C-type natriuretic peptide concentrations were greatly elevated in patients with chronic renal failure [non-dialysed, 13.0 ± 4.2 pmol/l (mean ± SEM), n = 9, P < 0.01) compared with normal subjects (4.4 ± 0.4 pmol/l, n = 26); haemodialysis, 16.1 ± 2.1 pmol/l, n = 13, P < 0.01], but not in patients with congestive heart failure (New York Heart Association Class II-IV, 3.0 ± 0.7 pmol/l, n = 11, P > 0.05). Plasma immunoreactive atrial natriuretic peptide and brain natriuretic peptide concentrations were elevated both in patients with congestive heart failure and in haemodialysis patients with chronic renal failure. 4. Reverse-phase high performance liquid chromatography showed that immunoreactive C-type natriuretic peptide in plasma from normal subjects and haemodialysis patients was eluted in the positions of C-type natriuretic peptide −22 and −53. 5. These findings suggest that C-type natriuretic peptide is a non-cardiac circulating hormone and participates in the cardiovascular regulation in a different manner from atrial natriuretic peptide and brain natriuretic peptide.

1. The relationship between vasopressin and the progression of renal failure has been proposed, but not intensively investigated because of a lack of orally available, selective vasopressin antagonists. 2. The effects of novel, orally available vasopressin V 1 and V 2 receptor antagonists on several indices of the progression of chronic renal failure, i.e. blood pressure, urinary protein excretion, sodium balance and renal histopathology, were investigated by using Wistar rats with adriamycin-induced nephropathy accelerated by deoxycorticosterone acetate-salt hypertension. Groups 2 and 3 were treated with V 1 and V 2 antagonists, respectively, while the untreated group 1 served as the control. To block the effects of vasopressin efficaciously, V 1 and V 2 antagonists were simultaneously administered (group 4). 3. At week 6, 2 weeks after the beginning of administration of deoxycorticosterone acetate-salt and vasopressin antagonists after the second injection of adriamycin, V 1 and V 2 antagonists given either alone or in combination significantly reduced the systolic blood pressure as compared with the control, and urine volume was increased in groups 3 and 4. The proteinuria was also decreased at week 10 in groups 2, 3 and 4. Differences in sodium excretion between all groups were not significant. Histopathological alterations in the kidneys of group 4 were significantly ameliorated. 4. These results suggest that a combination of V 1 and V 2 antagonists can have therapeutic effects in certain types of chronic renal failure.

1. Dopamine β-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine β-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine β-hydroxylase, we applied a homologous human dopamine β-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine β-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine β-hydroxylase deficiency. 2. Authentic, physically stable dopamine β-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 ± 1.4 ng/ml (range: 18.5–52.5 ng/ml), but at a 283 ± 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine β-hydroxylase concentrations were correlated ( r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine β-hydroxylase was suggested by incomplete correlation with plasma dopamine β-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine β-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine β-hydroxylase was not changed by the central α 2 -agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine β-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine β-hydroxylase concentration was not closely linked either pharmacologically or biochemically to central noradrenergic neuronal activity. 4. Cerebrospinal fluid dopamine β-hydroxylase was not changed in essential hypertension. In Parkinson's disease, cerebrospinal fluid dopamine β-hydroxylase was markedly diminished (16.3 ± 2.9 versus 31.3 ± 1.4 ng/ml, P < 0.001) and rose by 58 ± 21% ( P = 0.02) after adrenal-to-caudate chromaffin cell autografts. In congenital dopamine β-hydroxylase deficiency, lack of detectable dopamine β-hydroxylase immunoreactivity in cerebrospinal fluid or plasma suggests absent enzyme (rather than a catalytically defective enzyme) as the origin of the disorder. 5. We conclude that cerebrospinal fluid dopamine β-hydroxylase immunoreactivity, while not closely linked to central noradrenergic neuronal activity, is at least in part derived from the central nervous system, and that its measurement may be useful in both the diagnosis and treatment of neurological disease.

1. The present study was designed to determine the changes in renal function in two models of experimental pancreatitis in rats, in an attempt to assess the possible pathogenic role of reactive oxygen species and to elucidate a possible therapeutic role for somatostatin. 2. Mild pancreatitis was induced by low blockade of the biliary duct and severe pancreatitis was evoked by retrograde infusion of bile salts. Renal function was studied by clearance techniques in rats with pancreatitis, treated or not treated with somatostatin. Plasma and glomerular malonyldialdehyde levels were measured by the thiobarbituric acid method. 3. Renal function did not change in rats with low blockade of the biliary duct, but animals receiving a retrograde infusion of bile salts showed a significant decrease in glomerular filtration rate and renal plasma flow with respect to sham-operated animals. 4. Plasma malonyldialdehyde levels increased significantly in rats treated with bile salts with respect to control animals, whereas no changes were detected in glomerular malonyldialdehyde levels. Thus, the renal dysfunction does not seem to be related to an increased production of reactive oxygen metabolites at the glomerular level. 5. Somatostatin infusion significantly improved renal function in rats with severe pancreatitis (retrograde infusion of bile salts) by increasing glomerular filtration rate, renal plasma flow and filtration fraction. These results support a possible therapeutic role for somatostatin in the renal dysfunction associated with the severe forms of pancreatitis.

1. We have developed a radioimmunoassay for the measurement of immunoreactive brain natriuretic peptide (1–32) in human plasma. Simultaneous measurements of atrial natriuretic peptide have also been carried out to allow for direct comparison between circulating brain natriuretic peptide and atrial natriuretic peptide. Plasma levels of immunoreactive brain natriuretic peptide (means ± sem ) were 1.1 ± 0.1 pmol/l in 36 normal healthy subjects and were significantly elevated in cardiac transplant recipients (18.8 ± 3.9 pmol/l, n = 12) and in patients with dialysis-independent (8.8 ± 1.5 pmol/l, n = 11) or dialysis-dependent (41.6 ± 8.8 pmol/l, n = 14) chronic renal failure. Similarly, in these groups of patients plasma levels of atrial natriuretic peptide were also significantly raised when compared with those in the group of normal healthy subjects. 2. The plasma level of atrial natriuretic peptide was significantly higher than that of brain natriuretic peptide in normal subjects and in patients with dialysis-independent chronic renal failure, with ratios (atrial natriuretic peptide/brain natriuretic peptide) of 2.8 ± 0.2 and 2.2 ± 0.3, respectively. However, in both cardiac transplant recipients and patients on dialysis plasma levels of atrial natriuretic peptide and brain natriuretic peptide were similar, with ratios of 1.3 ± 0.2 and 1.0 ± 0.1, respectively, in these two groups. 3. Plasma levels of brain natriuretic peptide and atrial natriuretic peptide were significantly correlated in the healthy subjects and within each group of patients. When all groups were taken together, there was an overall correlation of 0.90 ( P <0.001, n = 73). 4. Patients on dialysis had the highest plasma levels of both brain natriuretic peptide (41.6 ± 8.8 pmol/l, n = 14) and atrial natriuretic peptide (41.3 ± 9.4 pmol/l, n = 14) and the levels of both peptides declined significantly after maintenance haemodialysis. However, the overall percentage decrease in the plasma level of atrial natriuretic peptide (43.6 ± 7.5%) after dialysis was significantly greater than that observed for brain natriuretic peptide (15.9 ± 5.3%, P <0.005). 5. Displacement curves of iodinated atrial natriuretic peptide from bovine adrenal membranes by human atrial natriuretic peptide (99–126) and human brain natriuretic peptide (1–32) gave a median inhibitory concentration of 144 pmol/l for atrial natriuretic peptide and 724.4 pmol/l for brain natriuretic peptide. The cross-reactivity of human brain natriuretic peptide with the atrial natriuretic peptide receptor preparation was 19.5% of that of atrial natriuretic peptide, indicating that human brain natriuretic peptide has a lower binding affinity for the atrial natriuretic peptide receptor/binding site on bovine adrenal membranes. 6. These results suggest that brain natriuretic peptide is co-secreted with atrial natriuretic peptide and may also be an important factor in the adaptive mechanisms to impairment of renal function. However, whether brain natriuretic peptide has an independent and fundamentally important role in man remains to be investigated.

1. Platelets from patients on haemodialysis showed a loss of sensitivity to nitric oxide, reflected by a reduction in the ability of nitric oxide both to inhibit thrombin-induced aggregation and to increase intraplatelet cyclic GMP levels. Responses of platelets from patients on continuous ambulatory peritoneal dialysis were slightly, but not significantly, impaired. Platelets from both groups of uraemic patients showed normal sensitivity to the cyclic AMP-dependent inhibitor prostacyclin. 2. Reduced levels of cyclic GMP in response to nitric oxide in platelets from patients on haemodialysis were due to a defect in its generation, rather than to accelerated breakdown. 3. Basal levels of intra-platelet cyclic GMP were significantly increased in both patients on haemodialysis and patients on continuous ambulatory peritoneal dialysis. 4. The activity of nitric oxide was more stable in plasma than in buffer; its survival in plasma from patients on haemodialysis was similar to that in plasma from healthy control subjects.

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5′-mono-phosphate decarboxylase by oxypurinol-7-ribotide.

1. Cardiac index, oxygen uptake and haemoglobin concentration have been measured in eight patients with end-stage renal failure, and the values compared with those in eight healthy control subjects. Assuming the arterial blood to be 97% saturated, the oxygen saturation of mixed venous blood has been calculated. 2. Cardiac index was lower in the patients (2.45 ± 0.42 litres min −1 m −2 ) compared with the control subjects (3.74 ± 0.17 litres min −1 m −2 ). Oxygen uptake was reduced from 147 ± 16 ml STP min −1 m −2 in the control subjects to 112 ± 9 ml STP min −1 m −2 in the patients. 3. Oxygen saturation of mixed venous blood was 53 ± 8% in the patients compared with 79 ± 2% in the control subjects, suggesting some degree of tissue hypoxia. If oxygen uptake were not reduced in renal failure, then the mixed venous blood oxygen saturation would be as low as 40%. 4. The oxygen saturation of blood sampled from the superior vena cava of patients with renal failure was 57 ± 6%. 5. The data on oxygen uptake and venous oxygen saturation suggest that in the patients with end-stage renal failure, the low values of cardiac index, previously measured by impedance cardiography, are accurate.

1. Plasma levels of immunoreactive N -terminal pro-atrial natriuretic peptide ( N -terminal ANP) have been measured in 25 normal subjects, 29 patients with essential hypertension, six cardiac transplant recipients, seven patients with dialysis-independent chronic renal failure and 11 patients with haemodialysis-dependent chronic renal failure. Plasma was extracted on Sep-Pak cartridges and N -terminal ANP immunoreactivity was measured using an antibody directed against pro-ANP (1–30). 2. Plasma levels of TV-terminal ANP (means ± sem) were 235.3 ± 19.2 pg/ml in normal subjects and were significantly raised in patients with essential hypertension (363.6 ± 36.3 pg/ml), in cardiac transplant recipients (1240.0 ± 196.2 pg/ml), in patients with chronic renal failure not requiring dialysis (1636.6 ± 488.4 pg/ml) and patients with chronic renal failure on maintenance haemodialysis (10 336.1 ± 2043.7 pg/ml). 3. There were positive and significant correlations between the plasma levels of TV-terminal ANP and α-human ANP (α-hANP) with individual correlation coefficients of 0.68 within the normal subjects, 0.47 in patients with essential hypertension, 0.78 in patients with dialysis-independent chronic renal failure and 0.68 in patients with haemodialysis-dependent chronic renal failure ( P < 0.05 in every case). 4. Gel filtration behaviour on Sephadex G-50 of the immunoreactive N -terminal ANP from Sep-Pak extracts of plasma from normal subjects or patients was consistent with a single peak having an elution volume corresponding to that of human pro-ANP (1–67) standard. 5. These studies demonstrate that the N -terminal pro-ANP peptide is co-secreted with α-hANP in both normal subjects and patients with cardiovascular/renal disease. The higher levels of the N -terminal ANP may reflect differences in the rate of elimination from the circulation but the exact structure and functional significance of the circulating N -terminal ANP remains to be established.

1. Studies were conducted to test the hypothesis that glycerol-induced acute renal failure in rats may be mediated by 5-hydroxytryptamine. 2. The tryptophan hydroxylase inhibitor, β-chlorophenylalanine, or saline was administered for 4 days before performance of 24 h clearance studies after glycerol administration. 3. p -Chlorophenylalanine significantly reduced the nephrotoxic effect of glycerol, as evidenced by improved glomerular filtration rate, urine volume excretion and absolute sodium excretion, and reduced plasma creatinine concentration. 4. These results suggest that glycerol-induced acute renal failure may be mediated by the renovascular and/or tubular actions of 5-hydroxytryptamine.

1. To examine whether insulin resistance in uraemia extends to amino acid metabolism, the effect of physiological hyperinsulinaemia on plasma amino acid concentrations was studied in 17 chronically uraemic and 28 healthy subjects by using the euglycaemic insulin clamp technique. 2. In six uraemic and seven control subjects, splanchnic and leg exchange of amino acids was quantified with hepatic and femoral venous catheterization, and in five uraemic and eight control subjects intracellular free amino acid concentrations were determined in muscle tissue obtained by needle biopsy. 3. In response to hyperinsulinaemia the plasma concentrations of all amino acids except alanine decreased by 10–50% in both uraemic and control subjects. Splanchnic alanine uptake declined by 20% and leg amino acid release tended to decrease in both groups. 4. The intracellular levels of all measured amino acids except alanine fell significantly and to a similar extent in uraemic and control subjects. 5. These results indicate that insulin-mediated alterations in regional amino acid exchange and in plasma and intracellular amino acid concentrations are similar in uraemic and control subjects. 6. It is concluded that tissue insensitivity to insulin in uraemia does not extend to uptake or release of amino acids and that resistance to insulin can be selective in its effect on different metabolic functions.

1. We examined the effects of various levels of dietary protein on the course of adriamycin-induced nephropathy in rats fed with high (30%), intermediately low (10%) or strictly low (5%) protein diets for 24 weeks. 2. In the rats fed on the 30% protein diets, there were massive proteinuria, progressive increases in serum creatinine and focal glomerular sclerosis associated with severe tubulo-interstitial changes. 3. With the 5% dietary protein, proteinuria was decreased, the levels of serum creatinine were preserved within normal ranges and renal histological changes diminished. Weight loss and hypoproteinaemia were more marked. 4. With intermediate protein restriction (10% protein), renal function and plasma protein were preserved but body weight did not increase normally. 5. Aggregated human immunoglobulin G, which had been intravenously injected at weeks 12 and 24, accumulated in the glomeruli more densely in rats fed on the 30% protein diet than in those fed on the 10% or 5% protein diets. 6. We tentatively conclude that functional and histological deterioration of focal glomerular sclerosis can be prevented by appropriate restriction of dietary protein; however, severe protein restriction does aggravate nutritional states.

1. The response of circulating 1,25-dihydroxyvitamin D [l,25-(OH) 2 D] to challenge with vitamin D treatment both before and after 7–10 days of prednisone therapy (25 mg/day) was investigated in five anephric subjects, six patients with chronic renal failure (CRF), two patients with vitamin D intoxication and four patients with hypoparathyroidism. 2. In anephric subjects serum 25-hydroxyvitamin D [25-(OH)D] rose from 58 ± 48 ( sd ) to 377±221 ( sd ) nmol/l after administration of 150 μg of 25-(OH)D 3 for 1 month. Serum l,25-(OH) 2 D, which was barely detectable in only two out of five patients under basal conditions, rose to 30 ± 21 pmol/l after 2 weeks of therapy with 25-(OH)D 3 , but fell to 10 ± 5 pmol/l during prednisone treatment. 3. In CRF patients circulating l,25-(OH) 2 D rose from 37 ± 24 to 58 ± 24 pmol/l during 25-(OH)D 3 therapy, but fell to 41 ± 31 pmol/l during prednisone treatment. In two patients with rheumatoid arthritis, hypercalcaemia due to vitamin D intoxication was associated with raised levels of 1,25-(OH) 2 D (288 and 317 pmol/l). Administration of prednisore resulted in suppression of l,25-(OH) 2 D levels (132 and 96 pmol/l respectively) and reduction of serum calcium to within the normal range. 4. In the hypoparathyroid patients prednisone therapy did not affect circulating 25-(OH)D levels but serum l,25-(OH) 2 D fell from 192 ± 42 to 117 ± 23 pmol/l and serum calcium from 2.41 ± 0.21 to 2.20 ± 0.05 mmol/l. 5. These findings indicate that a steroid sensitive extrarenal production of l,25-(OH) 2 D may occur in all subjects with a threshold serum concentration of the precursor 25-(OH)D.

1. Rats were studied 7 days and 17 days after the onset of renal failure which was induced by a surgical technique. 2. Plasma urea, creatinine ( P Cr ) and potassium had increased after 7 days; plasma potassium increased much more after 17 days but P Cr was slightly lower. 3. Renal failure caused resetting of erythropoietic control to a lower level of packed cell volume (PCV). After 7 days renal failure some rats had a low PCV, whereas others still had a normal PCV apparently due to slower erythrocyte destruction of pre-renal failure cells. 4. After 7 days renal failure, rats with a normal PCV had an increased erythrocyte membrane leak to potassium that resulted in a low erythrocyte potassium [K + ] RBC . This was accompanied by an increase in active sodium pump units [increased ouabain sensitive sodium flux ( F o ) and its rate constant ( k o )] that caused erythrocyte sodium ([Na + ] RBC ) to fall. The increased active pump units retarded the fall in [K + ] RBC and may have extended the life of the normal erythrocytes in the renal failure environment. 5. The PCV was below normal in all rats after 17 days renal failure. [K + ] RBC was increased and since k o was normal there appeared to be compensation to produce erythrocytes with reduced membrane leak to potassium with longer standing renal failure. 6. P Cr was only related to PCV after 17 days renal failure and not in the earlier phase of erythrocyte destruction. The changes in erythrocyte membrane permeability were very significantly related to PCV after 17 days.

1. The present report focuses on some aspects of the intra-erythrocytic cation metabolism (e.g. the maximal velocity of the Na + –Li + countertransport and Na + /K + /Cl −1 cotransport) in uraemic patients on different dialysis treatments. 2. Patients undergoing dialysis treatment [continuous ambulatory peritoneal dialysis (CAPD) or haemodialysis (HD)] overall showed higher Na + –Li + countertransport than controls. With regard to Na + /K + /Cl −1 cotransport, CAPD patients and controls did not differ and both showed, on average, higher values than HD patients. 3. A subgroup of HD patients was studied before and after dialysis. No significant overall changes were detected as a result of the dialysis process with regard to Na + /K + /Cl −1 cotransport. Na + -Li + countertransport was significantly reduced by dialysis and a distinctly different response to dialysis was evident according to predialysis values. Patients with high values of Na + –Li + countertransport showed a significant reduction in this parameter while patients with normal values showed no effect. No distinct association was detected between alteration in either Na + –Li + countertransport or Na + /K + /Cl −1 cotransport and the clinical characteristics of the patients. 4. It is concluded that uraemia and/or dialysis influences the maximal velocity of the parameters under investigation. The effect on Na + –Li + countertransport seems to be similar for both CAPD and HD, while Na + /K + /Cl −1 cotransport is not altered in CAPD patients.

1. Metabolites of vitamin D 3 were measured in the circulation of four patients on chronic haemodialysis (three of whom were surgically anephric) before and during daily ingestion of 40000 i.u. of cholecalciferol. 2. Circulating 24,25-dihydroxyvitamin D 3 [24,25-(OH) 2 D 3 ] was measurable, but abnormally low before treatment; its circulating concentration rose in a substrate dependent manner when serum 25-hydroxyvitamin D 3 (25-OHD 3 ) increased, but the response was reduced when compared with the normal relationship. 3. Serum 1,25-hydroxyvitamin D 3 [1,25-(OH) 2 D 3 ] and calcidiol lactone (25-OHD 3 -lactone) were consistently unmeasurable in sera from these patients before administration of cholecalciferol. However, when serum 25-OHD 3 rose with treatment, 1,25-(OH) 2 D 3 became detectable in the sera of three of the four patients and 25-OHD 3 -lactone could be measured in all of them. 4. These data indicate that extrarenal sites of synthesis of 24,25-(OH) 2 D 3 , 25-OHD 3 -lactone and 1,25-(OH) 2 D 3 exist in chronically dialysed patients but require large amounts of substrate to be significant.

1. We have measured the rate of purine synthesis de novo in blood mononuclear cells in vitro and the activities of the purine salvage enzymes [hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8), adenine phosphoribosyltransferase (APRT; EC 2.4.2.7)] and ribosephosphate pyrophosphokinase (PP-ribose-P synthetase;EC 2.7.6.1)] and the concentration of phosphoribosylpyrophosphate (PP-ribose-P) in the erythrocytes of affected family members. 2. These subjects belong to families where hyperuricaemia and renal failure occur together early in life, and the genetic transmission follows an autosomal dominant mode of inheritance. We term this syndrome, familial hyperuricaemic nephropathy. 3. No significant differences were detected in either the rates of purine synthesis de novo in vitro between the index patients and the control subjects with respect to the enzyme activities or the PP-ribose-P concentrations. Two groups of controls were used, healthy individuals and patients with a comparable degree of renal failure due to non-immune complex renal disease. 4. Mononuclear cells from patients with Lesch-Nyhan syndrome (congenital HPRT deficiency) showed the expected acceleration of purine synthesis de novo in vitro. 5. The accelerated purine synthesis de novo in vitro associated with phytohaemagglutinin-induced lymphocyte transformation was detectable by the method used. 6. We conclude that familial hyperuricaemic nephropathy is not due to a metabolic lesion which causes accelerated purine synthesis de novo. This suggests that the primary abnormality may be a failure of the renal tubular net excretion of urate.

1. In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations following an oral load of rubidium chloride. The changes in plasma rubidium concentration are related to the distribution of rubidium to all the body tissues and the changes in intra-erythrocytic rubidium concentrations provide an example of rubidium uptake by one particular tissue. 2. In eight healthy volunteers pretreatment with a loading dose of digoxin (20 μg/kg) enhanced the rise in plasma rubidium concentrations and attenuated the rise in intra-erythrocytic rubidium concentrations after the oral load of rubidium chloride. 3. Ten patients with chronic renal failure, compared with a well-matched control group, were found to have changes similar to, but more marked than, those caused by digoxin, i.e. a much greater rise in plasma rubidium concentrations and a much smaller rise in intra-erythrocytic rubidium concentrations, after the oral load of rubidium chloride. 4. These findings are consistent with widespread reduction in Na + ,K + -ATPase activity in subjects who have taken a loading dose of digoxin and patients with chronic renal failure. They are, therefore, consistent with the findings of previous studies in vitro and show that it is possible to demonstrate changes in cation transport in vivo .

1. We have measured the plasma oxalate concentration (P Ox ), urinary oxalate excretion (U Ox ), oxalate equilibrium distribution volume (ODV), oxalate metabolic pool size [(ODV) × (P Ox )], total plasma oxalate clearance (PC Ox ), renal (or dialyser) oxalate clearance (RC Ox ), non-renal oxalate clearance (NRC Ox ) and the tissue oxalate accretion rate (TOA)= [(NRC Ox ) × (P Ox )] in three patients with severe renal failure due to primary hyperoxaluria who were being treated by peritoneal dialysis or haemodialysis, or by renal transplantation. The clearance (either GFR or dialyser) of [ 99m Tc]diethylenetriaminepenta-acetate (DTPA) and the extracellular fluid volume (ECF) measured as [ 99m Tc]DTPA distribution volume were also determined. 2. Negligible amounts of 14 C were found in faeces or as 14 CO 2 in expired air and hence (NRC Ox ) = (PC Ox -RC Ox ). 3. Haemodialysis removed oxalate more efficiently than peritoneal dialysis in the patient where a direct comparison was possible. Neither treatment could keep up with the TOA when performed for clinically acceptable times. 4. The plasma oxalate concentrations calculated from 14 C clearance through the dialyser and the chemically determined concentration of the oxalate in the dialysate were in the range 111–146 μmol/l. This is higher than in normals and in hyperoxaluric patients who are not in renal failure. Hence, although the ODV and ECF are similar to those of hyperoxaluric patients without renal failure and normal control subjects, the oxalate metabolic pool (ODV × P Ox ) is grossly enlarged. 5. In the patient treated by renal transplantation, the oxalate pool size diminished concurrently with the resumption of oxalate excretion but expanded again as renal function decreased due to oxalosis. 6. The quantitative data show that dialysis procedures can only be a temporary holding operation and the prognosis with transplantation remains bad unless excessive oxalate production can be controlled.

1. There is clinical and experimental evidence to imply that urinary immunoglobulin light chains are nephrotoxic yet some patients pass large amounts for years with little renal damage. Animal experiments suggest that a light chain is more nephrotoxic if it has a high isoelectric point (i.e. is cationic in relation to urine pH). 2. We studied 23 patients with multiple myeloma, measuring light chain excretion rate, light chain isoelectric point (pI) and creatinine clearance. 3. Light chain excretion rate was independent of light chain isoelectric point and did not correlate with creatinine clearance. 4. Light chain isoelectric point correlated with creatinine clearance, suggesting that this characteristic may be an important determinant of the nephrotoxic effect of these immunoglobulin constituents.

1. The effect of rapid intravenous infusion of 25 ml of isotonic sodium chloride solution (saline)/kg body weight on extracellular fluid volume (ECFV, 82 Br distribution volume), plasma volume ( 131 I-labelled albumin distribution volume) and blood volume (from plasma volume and packed cell volume) was studied in nine normal subjects and a group of 11 patients with end-stage renal disease (ESRD). 2. Immediately after the infusion, the increases in ECFV were equal in the two groups but the increases in plasma and blood volumes were significantly larger in the patients with ESRD. .3. Ninety minutes after the end of the infusion, the blood volume/ECFV ratio was significantly decreased from the control value in the normal subjects, but slightly increased in the patients with ESRD. 4. It is concluded that in severe renal failure the control of fluid distribution is changed in a way which leads to a preferential distribution of rapidly infused saline into the intravascular compartment.

1. We have studied purine metabolism in renal failure using high-pressure liquid chromatography to determine metabolite concentrations in erythrocytes and plasma, and microradiochemical assays of enzyme activity in erythrocytes. 2. the mean activities of some of the enzymes involved in purine metabolism were raised in renal failure. Significant elevations of adenylate kinase (EC 2.7.4.3), purine nucleoside phosphorylase (EC 2.4.2.1), hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) and adenosine deaminase (EC 3.5.4.4) but not of adenine phosphoribosyltransferase (EC 2.4.2.7) and ribosephosphate pyrophosphokinase (phosphoribosylpyrophosphate synthetase; EC 2.7.6.1) activities were demonstrated. However, there was an overlap between results from patients with renal failure and normal (control) subjects. Erythrocyte phosphoribosylpyrophosphate levels were also unchanged. 3. Erythrocyte nucleotide concentrations especially those of inosine were raised in renal failure. 4. the plasma inosine was reduced in renal failure. 5. the significance of these changes is discussed.

1. Homocysteine which is formed during the metabolism of methionine is readily oxidized and is measured by the amino acid analyser as cysteine—homocysteine mixed disulphide and homocystine. We measured plasma amino acid concentrations after an overnight fast in 27 stable long-term renal transplant recipients and 25 age-and sex-matched normal subjects with particular emphasis on sulphur-containing amino acids. 2. Plasma cysteine—homocysteine mixed disulphide was increased in the patients (mean 6.0 ± sd 3.2 μmol/l; normal 3.1 ± 0.9 μmol/l, P < 0.001) and homocystine was detectable in low concentration (< 1.0 μmol/l) in 24; the elevation in cysteine—homocysteine was related to serum creatinine ( r = 0.60, P < 0.002). Cystine was also increased (91.6 ± 29.3 μmol/l; normal subjects 64.0 ± 16.7 μmol/l, P < 0.001), but methionine concentrations were normal. 3. When pyridoxine, folic acid and vitamin B 12 , cofactors for homocysteine metabolism, were administered sequentially to 11 arbitrarily selected transplant recipients cysteine—homocysteine decreased from 7.3 ± 2.1 to 4.3 ± 0.8 μmol/l ( P < 0.001) and homocystine became undetectable. the response coincided with the giving of folic acid and occurred without alteration in serum creatinine and with normal serum folate and vitamin B 12 concentrations. 4. in eight patients in whom pretreatment erythrocyte folate was measured, folic acid therapy reduced cysteine—homocysteine from 9.0 ± 3.1 to 5.4 ± 1.6 μmol/l over a 4 week period ( P < 0.001), the largest response being in the one patient with subnormal erythrocyte folate; values were in the low-normal or normal range in the other seven. 5. We conclude that plasma homocysteine is increased in renal transplant recipients when serum creatinine is only moderately elevated and that the homocysteine concentrations are decreased by treatment with folic acid, suggesting that both reduced homocysteine excretion and relative shortages of folic acid are responsible.

1. Plasma sulphur-containing amino acids were measured in 19 patients with renal failure on chronic haemodialysis and in 22 normal subjects, to determine the rate of accumulation of these amino acids in chronic azotaemia. 2. Cysteine-homocysteine mixed disulphide was significantly increased in patients before dialysis and homocystine was detected in low concentration in 10 patients. Cystine and taurine were also increased. Changes in other neutral and acidic amino acids were similar to those reported in chronic renal insufficiency. 3. In 3–4 h of dialysis serum creatinine was decreased by a mean of 55%, cysteine-homocysteine by 41%and cystine by 58.5%( P <0.001 for each). Methionine concentrations were normal throughout. 4. We conclude that sulphur-containing amino acids, except methionine, accumulate in chronic renal failure as rapidly as creatinine.

1. The metabolism of glycerol by isolated rat-kidney tubules was investigated. 2. Indomethacin, at a concentration of 0.1 mmol/l, markedly inhibited the utilization of glycerol and its conversion into glucose and CO 2 . 3. The glycerol 3-phosphate production rose significantly when indomethacin was present, indicating a fall in the rate at which glycerol 3-phosphate was oxidized. 4. The results are discussed in relation to the observation that indomethacin increases the severity of glycerol-induced acute renal failure.

1. The fall in blood pressure produced by a test dose of prazosin was greater in a group of patients with chronic renal failure than in a group with normal renal function. 2. This difference could not be attributed to increased reactivity, measured as the slope of the regression line relating mean blood pressure and plasma prazosin concentration, nor to retarded elimination of the drug. 3. The enhanced antihypertensive effect of prazosin in renal failure appears to reflect changes in the bioavailability or distribution of the drug, which result in higher drug concentrations for a given dose.

1. The distribution of intact parathyroid hormone-(1–84) [PTH-(1–84)] and of its COOH-terminal fragments was determined in human serum by column chromatography. In addition to PTH-(1–84) (peak I), COOH-terminal fragments having molecular weights of approximately 4000–7000 (peak II) and immunoreactive components co-eluting with human PTH-(1–12) (peak III) were observed. 2. Mean concentrations of intact PTH-(1–84) and of its COOH-terminal fragments were significantly raised in chronic renal failure as compared with those of normal subjects. Mean amounts of peak II were higher in patients with chronic renal insufficiency than in nutritional vitamin D deficiency, in pseudohypoparathyroidism and in primary hyperparathyroidism, despite comparable amounts of PTH-(1–84). 3. In chronic renal failure as well as in a group of patients with vitamin D deficiency, pseudohypoparathyroidism and primary hyperparathyroidism and in controls, significant linear relations were found between the serum concentrations of calcium and log (peak II/peak I). Our findings suggest that the conversion of intact PTH-(1–84) into COOH-terminal fragments by the parathyroid glands (resulting in a raised secretion of fragments) and/or in peripheral organs may be directly related to the serum concentration of calcium. However, the degradation of the fragments may also be suppressed in a calcium-dependent manner.

1. The mucus glycoproteins in meconium from normal infants and from infants having cystic fibrosis with meconium ileus have been studied. 2. Whereas normal meconium contained about 50% protein-bound carbohydrate, the meconium from cystic fibrosis contained only about 10%. 3. Glycopolypeptides were prepared from the mucus glycoproteins. The oligosaccharide units from this material were released and fractionated. The fractions ranged widely in size and composition. 4. The fractions from cystic fibrosis specimens had a significantly higher content of fucose than those from normal specimens.

1. Plasma 25-hydroxy-vitamin D concentration was measured in 40 normal subjects, 19 patients with terminal renal failure, 137 patients who had been on dialysis up to 11 years and in 17 renal transplant patients. 2. The mean plasma concentration of 25-hydroxy-vitamin D was below normal in patients with terminal renal failure and in patients who had been on maintenance haemodialysis for less than 1 year. The mean concentration in patients who had been on dialysis for more than 1 year and in renal transplant patients was normal. 3. The seasonal variation of plasma 25-hydroxy-vitamin D concentration found in the 58 patients on maintenance haemodialysis for more than 2 years is similar to that reported in normal subjects.

1. A relationship between bacterial endotoxin absorbed from the gut and acute renal failure has been postulated. Experiments employing either the endotoxin-tolerant state or the enhancement of endotoxin injury were undertaken to test this relationship in rats. 2. Endotoxin tolerance was induced by the administration of increasing doses of Escherichia coli 026 lipopolysaccharide. The severity of renal injury was assessed at various times after glycerol administration in endotoxin-tolerant and control animals. At 48 h, endotoxin-tolerant rats had higher urine volume and creatinine clearance than the non-tolerant control animals. In rats studied 72 h after glycerol, functional and anatomical assessment showed the endotoxin-tolerant rats to have lower serum urea concentrations and also less renal histological injury than the non-tolerant, control animals. 3. Lead acetate, which potentiates endotoxin injury, or diluent alone was administered to rats after glycerol. At 2, 3 and 10 days later there was a twofold increase in mortality in the lead acetate-treated animals. 4. A small dose of endotoxin (0·1 mg) was shown to be innocuous in control rats. Also, all rats given glycerol alone were alive 24 h later. In contrast, administration of the same dose of endotoxin simultaneously with glycerol resulted in an 80% mortality at 24 h. 5. These studies demonstrate enhancement of glycerol-induced renal injury by endotoxin and support a possible role for endotoxin in this model of acute renal failure.

1. To evaluate potential alterations in hepatic metabolism of drugs occurring in patients with renal insufficiency the fate of aminopyrine was studied in 17 patients with chronic renal failure and in 27 normal subjects. 2. Although patients with chronic renal failure exhibited large variations, their aminopyrine plasma disappearance times (mean 0·62 ± sd 0·24 h −1 ) were significantly higher than those found in normal subjects (0·30 ± 0·07 h −1 , P < 0·002). 3. 14 CO 2 derived from [ dimethylamine - 14 C]aminopyrine disappeared from breath more rapidly in patients with chronic renal failure and a history of analgesic abuse (0·40 ± 0·04 h −1 ) than in control subjects (0·22 ± 0·03 h −1 , P < 0·01) and in other patients with chronic renal failure (0·24 ± 0·04 h −1 ). 4. Dialysis treatment and serum creatinine concentrations were not correlated with the rates of aminopyrine metabolism. Two additional patients, however, with combined renal and hepatic disease, exhibited markedly slowed rates of aminopyrine demethylation. 5. Although chronic renal failure by itself might not alter microsomal drug metabolism it is concluded that, in patients with a history of abuse of phenacetin-containing analgesics, marked acceleration in aminopyrine N -demethylation may be observed.

1. Young, sub-totally nephrectomized rats were used to study the altered mineral metabolism of renal failure and its effects on bone growth and mineral maturation. 2. Rats killed at 4 weeks after sub-total nephrectomy demonstrated less bone growth than the age-matched control animals. These differences diminished in successive 4 week periods and were not significant at 12 weeks after operation. 3. The major differences in bone mineral composition between the uraemic rats and the control rats were: (i) lower CO 2 3 ; − concentrations, and (ii) higher PO 3 4 ; − and HPO 2 4 ; − concentrations. 4. These differences are consistent with the view that bone mineral matures by the conversion of an acidic calcium phosphate precursor into a carbonate-containing apatite, an essential feature of this conversion being the replacement of PO 3 4 ; − or HPO 2 4 ; − by CO 2 3 ; − . By this definition, uraemic rats at 4 weeks after operation contained more immature bone mineral than the control rats. These differences corresponded to the changes in bone weight, and were similarly unaffected at 12 weeks after operation. 5. The effects observed were transient and were reversed as renal function recovered. If renal failure is sustained, however, as in patients with end-stage renal disease, the maturation defect could become a feature of renal bone disease. Specific aetiological factors are discussed, but not identified.

1. Plasma concentrations of human calcitonin were measured in groups of patients with chronic renal failure, treated either conservatively or by haemodialysis, and compared with a normal group of persons. 2. Plasma calcitonin was statistically significantly elevated in both groups with renal failure. 3. When the data from the three groups were pooled, plasma calcitonin was found to be inversely correlated with total calcium and directly correlated with plasma creatinine.

1. Five patients with the osteomalacia of chronic renal failure were given 50–100 nmol of 25-hydroxy vitamin D 3 intravenously per day for 24–28 days. 2. In all five patients, during administration of 25-hydroxy vitamin D 3 there was a substantial rise in the plasma concentration of 25-hydroxy vitamin D from initially abnormally low values. 3. Significant improvement in bone mineralization, intestinal calcium absorption and muscle strength occurred in the three patients with the greatest rise in plasma 25-hydroxy vitamin D.

1. Relationships between labelled albumin disappearance rate (LADR), plasma volume, blood volume, plasma renin activity (PRA) and blood pressure (BP) were studied in normotensive control subjects and patients with hypertension of different aetiology and severity. In essential hypertensive patients without complications an inverse linear relationship was found between blood pressure and plasma or blood volume. 2. Very close inverse correlations were found between LADR and PRA in both normotensive subjects and patients with uncomplicated essential hypertension. LADR appears to be an excellent reference standard for PRA. 3. It is postulated that LADR mainly reflects the relation between circulating fluid and vascular capacitance tone. LADR is increased in hypertension and blood volume may still be inappropriately high.

1. The functional integrity of the adrenal cortex has been tested in a case of selective hypoaldosteronism by adrenocorticotrophin (ACTH) and angiotensin II (AII) infusion. 2. During ACTH infusion a normal functioning zona fasciculata was indicated by the impressive increase of the ACTH-dependent plasma steroids; the aldosterone response was moderate. 3. During AII infusion the plasma aldosterone response was blunted with an unexpected dose-dependent increase in pregnenolone, resulting in abnormal decreasing progesterone/pregnenolone ratios during the infusion, suggesting a slow-down in the conversion of pregnenolone into progesterone. 4. This defect, a probable consequence of chronic renin deficiency on the zona glomerulosa, could be a contributing factor to the hypoaldosteronism.

1. Five normal subjects were given 100 ml of aluminium hydroxide gel per day for 28 days. 2. The phosphorus balance became more positive in one subject, less negative in two and changed from negative to positive in the other two subjects. This was accompanied by a rise in the concentration of the fasting morning plasma phosphorus. Calcium balance did not change. 3. The normal subjects absorbed 0·3–3·6 mmol of aluminium/day, which is significantly less than that absorbed by five patients with chronic renal failure, three of whom were studied before, and two after, the observations on the normal subjects had been completed. 4. In a further five normal subjects on 100 ml of aluminium hydroxide gel/day the 08.00 hours concentration of plasma phosphorus did not fall, though there was a fall at 11.00, 14.00 and 17.00 hours.

1. High plasma immunoreactive calcitonin concentrations were observed in ten of eleven patients with acute renal failure, particularly in the oliguric phase. 2. Immunoreactive calcitonin decreased progressively with time, independently of recovery of renal function. 3. Radioimmunoassay curves obtained with serial dilutions of plasma from these patients were parallel to or superimposed upon those obtained with calcitonin standards.

1. Platelet survival was measured in patients with acute proliferative glomerulonephritis or chronic renal failure and also in control subjects. 2. Platelet survival is markedly reduced in acute proliferative glomerulonephritis as compared with control subjects; it was slightly reduced in patients in chronic renal failure due to interstitial renal disease and maintained on dialysis.

1. Measurements of lung volumes, airway resistance, maximal expiratory flow rates and closing volume were made in twelve patients with chronic renal insufficiency and fluid overload, before and after haemodialysis. 2. Before dialysis, these measurements were within normal limits, except for peak expiratory flow rate, which was significantly lower, and closing volume, which was significantly higher than predicted values. 3. After dialysis body weight decreased significantly and the removal of excess of fluid was accompanied by a significant decrease of closing volume. 4. Measurements of closing volume and the other pulmonary tests were made in six healthy subjects, the same timing being observed as in the patients. Mean as well as individual values of closing volume did not alter, thus excluding the possibility that the changes observed in the patients were due to a circadian rhythm. 5. It is suggested that the higher than predicted closing volume was due to the accumulation of fluid in the dependent areas of the lung, promoting a premature airway closure. Removal of excess of fluid allowed airways to close at a lower lung volume.

1. The histological appearances of cancellous bone from the ilium have been quantified in thirteen patients with osteomalacia due to chronic renal failure. 2. There was an excess of osteoid tissue and a reduction in the extent of the calcification front in that osteoid lamella lying next to calcified bone. 3. Administration of calcium compounds orally produced an increase of punctate calcification within the osteoid, but there was no change in the extent of the calcification front. 4. Administration of vitamin D produced a marked rise in the extent of the calcification front but no increase of punctate calcification within the osteoid. 5. This rise in the extent of the calcification front was not dependent on a rise in plasma calcium × plasma phosphorus product. 6. It is concluded that vitamin D has a direct action on the bone in patients with the osteomalacia of chronic renal failure.

1. The effect of haemodialysis on blood pressure was assessed in forty-six patients with end-stage kidney disease, in relation to measurements of plasma renin concentration (PRC), plasma renin substrate (PRS) and blood volume. Parallel measurements of PRC and blood volume were carried out before and during the period of regular dialysis treatment. PRS was measured during this period only. 2. Both before and during regular dialysis PRC was higher in relation to blood volume in patients whose hypertension persisted after fluid withdrawal than in cases who became normotensive. PRS levels were similar in both groups. 3. The decrease of blood volume by regular dialysis led to a rise in plasma renin both in patients with controllable hypertension and in those with persistent hypertension. After at least 5 months of regular dialysis, the acute removal of 1.5 litres of body fluid caused a similar percentage rise in PRC in six patients with persistent hypertension and twelve patients with controllable hypertension. In three other patients with controllable hypertension and very low PRC, PRC was unresponsive both to the acute and the chronic volume depletion. 4. The pressor response to exogenous angiotensin in anephric patients, in whom no renin could be detected in the plasma, was decreased after ultrafiltration. This was caused by an increase in the threshold dose and not by a decrease in the slope of the dose-response relationship. This effect of ultrafiltration was due to fluid loss itself rather than to a rise in endogenous angiotensin. 5. The results indicate that the presence of hypertension in the face of fluid loss reflects a disturbance in renin release which is rather associated with the pathologic state of the kidney than with an excessive stimulus to the kidney. The decrease in sensitivity to angiotensin caused by fluid loss is presumably overridden by the effect of a high renin level.

1. Stabilized hypertensive haemodialysis patients, as well as those with normotension, had a greatly elevated cardiac index (CI) that was not due to hypervolemia, but was most likely secondary to their anaemic condition. The hypertension itself was not accompanied by hypervolaemia, but was associated with a relatively very high total peripheral resistance. 2. In eight patients with successfully transplanted kidneys the following results were found. (a) Five were clearly hypertensive and had supine mean arterial pressure between 117 and 143 mmHg. It is noted that they were receiving prednisone at the time of the studies. (b) CI was normal in seven. (c) Total blood volume was normal in all. (d) The presence of wide-open arterio-venous fistulae was not associated with an increase in CI.