Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia?

Reactive oxygen species: general aspects Reactive oxygen species, including superoxide radicals, hydrogenperoxide, nitric oxide, peroxynitrite, hydroxyl radicals andhypochlorous acid are by-products of normal metabolic processesin cells. Reactive oxygen species can be found in several cellsincluding macrophages and vascular smooth muscle cells. At lowconcentrations reactive oxygen species can act as physiologicalmediators of cellular responses whereas higher concentrationsmay cause cell damage [1,2]. The major sources of reactive oxygenspecies are leakages from the electron transport chains of mitochondriaand endoplasmic reticulum. Cellular energy metabolism is basedon the production of ATP through the electron transport reactionin which O₂ accepts electrons and H⁺ and then is eventuallyreduced to water. Only 1–2% of the electrons are leakedto generate superoxide radicals in reactions mediated by coenzymeQ and ubiquinone and its complexes. During ageing (and probablyin patients     

Dialysis Arthropathy, {beta}2-Microglobulin and the Effect of Dialyser Membrane

Patients with dialysis arthropathy had the greatest mean serumß₂-microglobulin (59.5 mg/l) but there was no thresholdconcentration of ß₂-microglobulin above which allpatients developed dialysis arthropathy. Haemodialysis patientswithout dialysis arthropathy and patients on continuous ambulatoryperitoneal dialysis (CAPD) also had grossly elevated valuesof ß₂-microglobulin (47.9 mg/l and 30.7 mg/l respectively).There was a significant positive correlation between durationof treatment and serum ß₂ for the patients treatedby haemodialysis, but this was not the case for patients onCAPD. There was a significant negative correlation between residualurinary volume and serum ß₂-microglobulin for thepatients on haemodialysis without dialysis arthropathy, andalso for patients on CAPD. This was not true for the patientswith dialysis arthropathy. Both duration of treatment and residualurine volume correlated with serum ß₂-microglobulin,and therefore an analysis of covariance was used to take accountof this in comparing the groups. This showed that there wasno difference between serum ß₂-microglobulin in haemodialysispatients with and without dialysis arthropathy. However, CAPDpatients had a significantly lower corrected mean serum ß₂-microglobulinHaemodialysis with cuprophane membranes was associated withan increase in ß₂-microglobulin of 11.5%, whereashaemodialysis with polycarbonate was associated with a decreaseof 6.8% at 6 h. Our results provide circumstantial evidencethat repeated haemodialyses with cupro phane membranes may predisposelong-term haemo dialysis patients to dialysis arthropathy. CAPDpatients have lower ß₂-microglobulin concentrationsand may be less likely to develop dialysis a Long-term prospectivestudies are needed to confirm these assertions.     

HYPOXIC VENTILATORY DRIVE IN THE DOG UNDER ALTHESIN ANAESTHESIA

Althesin was administered i.v. to eight dogs, using two differentrates of infusion (6.55 +mn; 2.13 µl kg^–1 min and12.80 +mn; 2.00 µl kg^–1 min). Ventilation (T_I, T_E,RR, T_I/T_tot, V_T, V_E, V_T/T_I) and arterial blood-gas tensionswere measured in air and during a 10-min period of 100% oxygenbreathing. For both rates of Althesin infusion the ventilatoryresponse to oxygen was identical: there was significant depressionof ventilation (decrease in V_E and of the ventilatory drive,V_T/T_I) from the 1st min of inhalation lasting up to the 10thmin. This decrease in ventilation was more marked and persistentthan the decrease noticed in the unanaesthetized dog. We concludethat the hypoxic ventilatory drive persists in the dog underAlthesin anaesthesia.     

Regulation of phosphoinositide hydrolysis and cytosolic free calcium induced by endothelin in human glomerular epitheial cells

The regulation of the inositide signalling pathway and [Ca²⁺]_iby endothelin (ET) peptides was investigated in human glomerularepithelial cells in culture. Endothelin-1 and -2 induced anaccumulation of inositol phosphates in a time- and dose-dependentmanner. The baseline of [Ca²⁺]_i, in glomerular epithelial cellswas 109±2.8 nmol/l, n=60. Endothelin-l (ED₅₀: approx.3x10 mol/l) caused a rapid and transient rise in [²⁺]_i as detectedby fura-2 microfluorimetry studies. The endothelin-l-inducedinositol phosphate accumulation was inhibited by the selectiveET_A recep tor antagonist BQ123. Endothelin-3 and BQ3020, a selectiveET_B receptor agonist, showed no effect. The results suggestan ETA-mediated pathway. This study demonstrates an ET_A-mediatedtransmembrane signalling via phospholipase C with consecutiveelevation of inositol phosphates and intracellular calcium.Since endothelin peptides contribute to both normal renal functionand renal dysfunction, this study adds further knowledge onglomerular cell regulation.     

Pyruvate anions neutralize peritoneal dialysate cytotoxicity

A new peritoneal dialysate containing pyruvate anions was developedin order to avoid cytotoxic effect of conventional lactate-baseddialysate. The dialysate has a final pH of 5.4 to 5.6 and iscomposed of 1.36–3.86% glucose-monohydrate; 132 mmol/lsodium; 1.75 mmol/l calcium; 0.75 mmol/l magnesium; 102 mmol/lchloride and 35 mmol/l pyruvate. For cytotoxicity testing peritonealmacrophages, and mesothelial cells (MC) were exposed to conventionallactate dialysate, and pyruvate dialysate. We investigated theO₂^– generation and cytokine synthesis after endotoxinstimulation in peritoneal macrophages and the proliferationof mesothelial cells of cultured human MC. After exposure tolactate dialysate O₂^– generation and cytokine synthesisin peritoneal macrophages and proliferation of mesothelial cellswere inhibited when compared to solution containing pyruvateand the control solution. After preincubation with 3.86% glucosecontaining solutions, all negative effects became even morepronounced in the lactate group whereas after pre-exposure topyruvate containing solution the toxic effects were absent.These results suggest that the acute toxic effects of commerciallyavailable peritoneal dialysates can be avoided by the use ofsodium pyruvate instead of sodium lactate.     

Changed excretion of urinary proteins and enzymes by chronic exposure to lead

Fifteen various serum and urine parameters were evaluated asindicators of renal alterations induced by lead in 82 male workersof a battery plant chronically exposed to lead (median of bloodlead concentration: 2.03 µmol/1). The control group comprised44 non-exposed healthy volunteers (0.34 µmol/1). High-molecular-massproteins (transferrin, immunoglobulin G (IgG), (albumin)) weredetermined in urine as markers of glomerular integrity; lowmolecular-weightproteins and parenchymal enzymes (₁-microglobulin, ß₂-microglobulin,retinol-binding protein, lysozyme, ribonuclease, N-acetyl-ß-D-glucosaminidase(NAG), alanine aminopeptidase (AAP), alkaline phosphatase (AP),-glutamyltransferase (GGT)) as indicators of changes in theproximal tubule; Tamm-Horsfall glycoprotein and kallikrein asmarkers of the distal tubule. There was a positive correlationbetween tubular indicators and blood lead concentration as wellas the erythrocyte protoporphy-rin (EPP). About 30% of the lead-exposedworkers showed an increased excretion of ₁-microglobulin, NAG,ribonuclease, and/or Tamm-Horsfall protein, whereas the glomerularindicators remained unchanged. The combined determination ofNAG and ₁-microglobulin in urine could be helpful in the earlydetection of lead-induced changes in the nephron.     

Contrasting renal haemodynamic effects of protein in normal subjects and glomerulonephritic patients with impaired renal function

The effects of a protein load on renal haemo-dynamics in patientswith renal failure are controversial. We measured insulin clearance( C_in and PAH clearance (C_PAH) by constant infusion techniquein six healthy subjects and 13 patients with biopsy-confirmedglomerulonephritis and chronic renal failure. The subjects were pre-equilibrated on their usual diet and studiedbefore and 2 h after 1 g protein/kg as cooked red meat. In healthysubjects this caused a significant increase of C_in (from l36±7.2(SD) to 148±7.9 ml/min/1.73 m²) and of C_PAH (from 547±142to 639±89). In contrast C_in decreased from 72.7±7.7to 60.3±8.4 in patients with chronic renal failure, whereasC_PAH showed no significant change (from 275±67.8 to 278±72.7).A similar decrease of C_in was also seen with acute infusionof amino acids (AA). The change in C_in was not related to changesof PRA or concentrations of plasma amino acids. While absoluteand fractional Na excretion increased in controls, they decreasedin patients in parallel with the decrease of C_in. The decreaseof C_in after infusion of AA was amplified by pre-equilibrationon low-sodium diet (20 mmol Na/day). The effect of meat ingestionon C_in was not obliterated, however, by pretreatment with captopril(25 mg b.i.d. for 7 days). In conclusion, in patients with chronic renal failure, a paradoxicaldecrease in C_in is seen both after oral protein and after amino-acidinfusion.     

Bedside stereomicroscopy of renal biopsies may lead to a rapid diagnosis of Fabry's disease.

Case A 43-year-old female Fabry patient presented with asymptomaticslight albuminuria (0.043 g/l), normal glomerular filtrationrate (120 ml/min/1.73 m²) and normal echocardiography. In youngerage she had complained of typical burning pains in her extremities.A renal biopsy was done in     

Myoglobinuria: round up more than the usual suspects.

Case A 72-year-old man was referred to the nephrology service becauseof myoglobinuria. The referring physicians were concerned thathe might develop acute renal failure. Indeed, the myoglobinconcentration in a sample of urine was 4757 µg/l, whereashis creatine kinase activity was 6287 U/l and his lactic aciddehydrogenase was 936 U/l. Anti-nuclear antibody titres weremarkedly elevated at a titre of 1:20 000 while anti-double-strandedDNA antibodies were not present. Serum creatinine concentrationand cystatin C concentrations were not elevated     

A well-meant present from a friend.

Case A 70-year-old female was admitted to hospital because of a generalweakness and a high creatinine level. On admission she was hypotensive(105/55 mmHg) and complained of chronic back pains. During theweeks preceding the hospitalization she was taking fosinopril10 mg qd, amitryptiline 50 mg qd and paracetamol as required(not >1000 mg per day). She had raised urea (35.1 mmol/l),creatinine (889 µmol/l), potassium     

Lymphadenopathy and proteinuria.

Case A 79-year-old Vietnamese woman was hospitalized with a 2-monthhistory of progressive fatigue and dyspnoea. Her past historyincluded hypertension, hypercholesterolemia and cholecystectomy.Her physical examination revealed dyspnoea at rest, bilateralcrepitus, ascites, peripheral leg oedema, hypertension (150/100mmHg), ecchymosis, left subconjunctival haemorrhage jugulo-carotidianand axillary lymphadenopathies and barely palpable liver andspleen. Laboratory data are presented in Table 1; among them were serumcreatinine of 85 mmol/l, blood urea nitrogen 9.4 mmol/l, proteinuria(2.5–6 g/l) and     

Ear and kidney malformations with renal failure in an infant: what is the link?

Case A male term newborn was admitted because of neonatal renal failureleading to the diagnosis of left hypodysplastic kidney and aplasiaof the right kidney on ultrasound. The serum creatinine was500 µmol/l. There was no history of fetal urological malformation.He     

A man with a serum creatinine near 10 mg/dl with an intravenous pyelogram showing normally functioning kidneys.

Case A 29-year-old male Brazilian Indian was admitted to our hospital2 days after having been mugged and heavily beaten by strangerswhile drunk. On admission he had no fever and was normotensive.The main positive physical finding was a somewhat tense abdomenwith evidence of free intraperitoneal fluid. Of note, the serumvalues of creatinine, urea nitrogen (BUN) and     

Nephroquiz: a woman with renal failure, ureteric obstruction and vasculitic rash.

Case A 57-year-old housewife presented to the emergency departmentwith seizures. She was drowsy and disorientated, febrile, tachypnoeic,tachycardic and tender in the left loin. There were a few brownmacules on her ankles. Recent history revealed low back pain,ankle swelling, a purpuric rash and haematuria. Two years earlier,a nodular lesion on her left leg was diagnosed and treated aspyoderma gangrenosum. Laboratory studies on admission showed: white cell count 23.8x 10⁹/l, haemoglobin 7.2 g/dl, potassium 7.4 mmol/l, urea     

Urinary prostaglandins (PGE2 and PGI2) in hyporeninaemic hypoaldosteronism in diabetic patients with chronic renal failure

The present work studies the urinary excretion of PGE₂ and PGI₂(6-keto PGF 1) in 11 insulin-dependent diabetic patients withchronic renal failure with a glomerular filtration rate of 33.9±9.03 ml/min who had hyporeninaemic hypoaldosteronismto evaluate the influence of these prostaglandins on the appearanceof this latter process. The results obtained in this group ofpatients were compared with those of a control group of healthyindividuals, another group of nine non-diabetic patients withCRF, and a last group of eight insulin-dependent diabetic patientswith normal renal functión to evaluate to what extentthe possible variations in prostaglandin excretion could berelated to the diabetes, CRF, or a conjunction of both processes. The results of the groups of diabetic patients with CRF wereC_cr 33.9 ±9.03 ml/min, decreased (P< 0.0001) withrespect to the control group and with no difference with theCRF group without diabetes; plasma potassium (4.7 ±0.4mEq/l), increased P<0.005) with respect to the values foundin the control group; plasma bicarbonate (17.8 ± 1.8mEq/l), decreased (P< 0.005) with respect to the controlgroup and also, though not significantly, with respect to thegroup of non-diabetic patients with CRF. Plasma aldosterone(pg/ml): resting 44.3±14.9; standing 65.7 ±63.5and post-frusemide 65.5 ±58.6, decreased (P<0.01)with respect to the other three groups. Plasma renin activity(PRA) (ng/ml/h): resting 0.34±0.3; standing 0.6 ±0.4, post-fmsemide 0.9 ±0.5, decreased significantlywith respect to the other three groups. PGE₂ (pg/mg Cr): basal1720±397; post-frusemide 2636±462, increased (P<0.05)with respect to the control group and that of the diabetic patientswithout CRF, but with no differences compared with the non-diabeticpatients with CRF. PGI₂ (pg/mg cr): basal 369 ±45 andpost-frusemide 699 ± 103, increased (P<0.01) withrespect to the controls and diabetic patients with normal renalfunction and with no differences compared with the non-diabeticpatients with CRF. Our findings indicate that patients with diabetes mellitus andCRF showing hyporeninaemic hypoaldosteronism have high urinaryexcretion of PGE₂ and PGI₂. The increase in the urinary prostaglandinsis related to CRF. The data rule out the hypothesis that thehyporeninaemic hypoaldosteronism of these patients is due toa deficit of prostaglandins.     

Crystals from fat. Acute oxalate nephropathy.

Case A 69-year-old man was admitted with acute renal failure. Pastmedical history included chronic pancreatitis caused by heavyalcohol intake, diagnosed in 1972, with an ensuing requirementfor enzyme replacement therapy and development of non-insulindependent diabetes mellitus. In February 1999 his serum creatinine(SCr) was 80 µmol/l. One month later, he stopped pancreaticenzyme therapy and experienced fatty diarrhoea. At the end     

Effects of histamine on inositol phosphates and intracellular Ca2+ in human glomerular epithelial cells

The effect of histamine on the phosphoinositide turnover andintracellular free calcium activity [Ca²⁺]_i was examined inhuman glomerular epithelial cells in culture. Addition of histamineto glomerular epithelial cells resulted in formation of inositolphosphates in a time- and dose-dependent manner. A transientmaximum of inositol trisphosphate (InsP₃) was observed within10 s. Stimulation of protein kinase C by short-term pretreatment(15 mm) of glom erular epithelial cells with phorbol 12-mynstate13-acetate caused a dose-dependent inhibition of the histamine-inducedinositol phosphate accumulation. The baseline of [Ca²⁺]_i inthe cells was 115 ±2.7 nmol/l (n=103). Histamine (ED₅₀:approx. 2x10^–7mol/l) caused a rapid and transient increasein [Ca²⁺]_i, as detected by fura-2 microfluorimetry studies.In a calcium-free extracellular solution the rapid increaseof [Ca²⁺]_i was still present. The H₁ receptor antagonist mepyramine(IC₅₀: approx. 8 x 10^–9 mol/l) inhibited the histamine(10^–6 mol/l) response on [Ca²⁺]_i Cimetidine, a potentH₂ receptor antagonist, showed no effect. This data indicates that H₁ receptor activation causes hydrolysisof phosphatidylinositol 4, 5-bisphosphate by phospholipase Cactivation, and consecutive mobil ization of intracellular calcium.Since histamine is a mediator of inflammation, antigen responseand cellular injury, these findings could be of importance forthe understanding of glomerular epithelial cell pathology.     

Back pain in chronic renal failure.

Back pain in chronic renal failure Patient SK, a 40-yr-old female, resident of Bhagalpur villagein Bihar, India, was operated for gallstones 3 years previously.On pre-operative checkup, mild renal dysfunction was detected.She was asymptomatic for renal disease with serum creatinineof 159 µmol/l (1.8 mg/dl), bland urinary sediment     

Safety of patient-maintained propofol sedation using a target-controlled system in healthy volunteers{dagger}

We investigated the safety of a patient-maintained system thatallows individuals to operate a target-controlled infusion ofpropofol to achieve sedation. Ten healthy volunteers were recruitedand instructed to try to anaesthetize themselves with the system.A target-controlled infusion of propofol was set to delivera target propofol concentration of 1 µg ml^–1,and the subjects allowed to increase the target in incrementsof 0.2 µg ml^–1 by pressing a control button twicein 1 s. There was a lockout time of 2 min and a maximum permittedtarget concentration of 3 µg ml^–1. Heartrate and pulse oximetry oxygen saturation (Sp_O2) were monitored continuously,and non-invasive arterial pressure, ventilatory frequenciesand sedation scores were measured every 5 min. Sedation wascontinued until the subject stopped pressing the button. A keywordwas then read for the individual to remember and sedation discontinued.There were no instances of significant decrease of Sp_O2 or lossof airway control. Maximum target blood concentration of propofolrecorded ranged from 1.4 to 3 µg ml^–1.Two subjects became oversedated, one of whom was unrousablewith loss of eyelash reflex. No subject could recall the keyword,although one recognized it from a list of 10 words. We concludethat the patient-maintained sedation system described couldnot be guaranteed to produce only conscious sedation in all patients,and that close clinical supervision by an anaesthetist would stillbe required for safe operation. Br J Anaesth 2000; 85: 299–301 Footnotes ^* Corresponding author: Department of Anesthesiology, Duke UniversityMedical Center, Box 3094, Durham, North Carolina 27710, USA