Evidence for a role of antilaminin-producing B cell clones that escape tolerance in the pathogenesis of HgCl2-induced membranous glomerulopathy

In Brown-Norway rats HgCl₂ induces an autoimmune disease dueto a T-dependent B cell polyclonal activation. This diseaseis marked by the production of numerous antibodies includingantiglom-erular basement membrane (GBM) antibodies. Rats exhibita biphasic glomerulopathy with heavy pro-teinuria. Initiallyanti-GBM antibodies are found linearly deposited; they precedethe appearance of membranous glomerulopathy. Rats recover spontaneouslyeven if HgCl₂ injections are pursued, but mechanisms at playare unclear. We have assessed the effects of transplanting thespleen from a BN rat, either at the acme of the disease or atthe time of convalescence, into naive BN rats, some of whichwere then injected with HgCl₂- Transplantation of a spleen fromHgCl₂-injected rats at the acme of the disease dramaticallyprotects BN rats from all the manifestations of the mercurydisease. BN rats transplanted with a spleen from HgCl₂-injectedrats at the time of convalescence only exhibited a typical membranousglomerulopathy with heavy proteinuria but without circulatinganti-GBM antibodies. Antilaminin antibodies were eluted fromthe glomeruli. This study shows that spleen cells from HgCl₂-injectedrats are able to confer tolerance to HgCl₂-induced autoimmunity.It also shows that some B cell clones escape this tolerance.Finally, this study strongly suggests that membranous glomerulopathy,responsible for proteinuria in this model, is related to thepresence of antilaminin antibodies.     

Reduced Deposition of Aluminium in Trabecular Bone of Uraemic Rats Treated with Dihydroxylated Vitamin D Metabolites

The rate of aluminium accumulation in bone may be related tothe presence of vitamin D metabolites. The present study investigatedthe effect of 1,25(OH)₂D₃ (24 pmol/d s.c.) and 24R,25(OH)₂D₃(480 pmol/day), combined or alone, on the deposition of aluminium(119 µmol/kg per day) in bone of uraemic rats during concomitantparenteral administration of aluminium for 9 weeks. Bone histomorphometryof trabecular bone revealed a severe low-turnover osteodystrophyin aluminium-treated uraemic rats, as evidenced by a decreasein osteoblastic osteoid surfaces and mineral apposition rates.1,25(OH)₂D₃ as well as 24R,25(OH)₂D₃ decreased stainable bonealuminium and the aluminium content of trabecular bone and,in parallel, the number of osteoblasts and osteoclasts increased.Additional treatment with one or both vitamin D metabolites14 days prior to the aluminium load further improved these results.Despite these effects, dynamic histomorphometric parametersremained suppressed and osteoidosis persisted. Serum PTH concentrationswere significantly elevated in aluminium-loaded uraemic ratstreated with 24R,25(OH)₂D₃ alone compared to controls. In conclusion,administration of 1,25(OH)₂D₃ or 24R,25(OH)₂D₃ reduces the accumulationof aluminium in trabecular bone in uraemic rats and preventssome of its excess toxicity. The mechanism of action may bedifferent for either vitamin D metabolite; however, combinedtreatment does not result in further reduction of the accumulationrate of aluminium in bone in this model.     

Enhanced Gastrointestinal Absorption of Aluminium in Uraemia: Time Course and Effect of Vitamin D

The present study examines the time course of aluminium absorptionin uraemic rats vs controls and investigates the effect of vitaminD. Following an oral load of 410 µmol aluminium there wasa significant increase in the urinary excretion rate of aluminiumas early as 60 min in uraemic rats. Compared with controls thisincrease was significantly greater in uraemic animals and maximumexcretion rates (77±49 vs pre-load 2±1 nmol Al/h)were achieved after 2 h. When vitamin-D-deficient rats with normal renal function werecompared with vitamin-D-replete controls, the latter excreteda significantly greater amount of the oral dose of aluminiumin their urine (727±361 vs 359±l40nmol Al/5d;P<0.02) and the post-load increase in the serum aluminiumconcentration was more pronounced in the vitamin-D-replete animals. Aluminium administered i.v. resulted in similar urinary aluminiumexcretion rates in both groups. In uraemicrats, however, regardlessof their vitamin D status, adminis tration of 1,25(OH)₂D₃ hadno effect on the amount of urinary aluminium excretion afteroral or i.v. loads. These findings suggest that although in rats with normal renalfunction aluminium absorption appears to be partly vitamin Ddependent, 1,25(OH)₂D₃ does not further augment the enhancedgastrointestinal absorption of aluminium in uraemia.     

Plasma Exchange in a Rat Model of Autoimmune Glomerulonephritis

Using an original technique permitting repeated plasma exchangein the rat, we have tested this therapeutic approach in animalsactively immunised with horseradish peroxidase, and in ratswith HgCl₂-induced autoimmune glomerulonephritis. Plasma exchangeeffectively removes circulating JgG anti-horseradish peroxidaseantibodies from the sera of immunised rats. When applied tothe model of HgCl₂ antiglomerular basement membrane glomerulonephritisin Brown-Norway rats, this technique is also remarkably effective.In these rats, proteinuria is abolished during the plasma exchangetreatment period and no circulating antiglomerular basementmembrane antibodies can be detected. These antibodies are, however,found in the ultrafiltrates of exchanged rats. Serum IgE, characteristicallyelevated in HgCl₂-treated rats, is also markedly diminishedin exchanged rats. Control rats treated with infusions of freshfrozen plasma or with heparin alone did not show any improvementin disease severity. These results suggest that plasma exchangealone can attenuate antiglomerular basement membrane nephritisin HgCl₂-treated rats. This observation may be of relevancefor the treatment of human antiglomerular-basement membrane-mediatedglomerulonephritis.     

Prevention of cyclosporin nephrotoxicity with a platelet-activating factor (PAF) antagonist

BACKGROUND.: Cyclosporin (CsA) is a potent immunosuppressive drug whose mainside-effect is nephrotoxicity. In the kidney, CsA induces vasoconstrictionwith a decrease in renal blood flow (RBF) and glomerular filtrationrate (GFR) and a significant increase in renal vascular resistance(RVR). CsA enhances platelet-activating factor (PAF) synthesisin mesangial cells in vitro. PAF, a secondary mediator of anaphylaxisand inflammation, exhibits vasoactive properties in the kidneysimilar to those of CsA. METHODS.: The in situ autoperfused rat kidney model was used to investigatewhether PAF plays a role in the haemodynamic injury inducedby CsA. RESULTS.: In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced a significantdecrease in RBF and in GFR and an increase in RVR. BN 52021,a potent and specific PAF antagonist (20 mg/kg i.v. bolus dose)induced a significant increase in GFR (137±32% of initialvalue, P<0.05). BN 52021 (20 and 10 mg/kg) also significantlyprevented the decline in RBF and GFR induced by CsA. CONCLUSIONS.: We have demonstrated that the PAF antagonist BN 52021 can minimizethe alteration of renal function induced by CsA.     

Selective downregulation of ETA receptor mRNA in renal transplant recipients on cyclosporin A revealed by quantitative RT-PCR

Despite intensive investigation, a pathophysiological role forthe endogenous vasoconstrictor peptide endothelin (ET) remainselusive. The kidney is particularly sensitive to the effectsof ET, which are mimicked by the administration of cyclosporinA (CsA), and animal models suggest a role for ET in the vasoconstriciveeffects of CsA. Using a recently validated novel fluorescentquantitative RT-PCR assay to enable the direct study of humanrenal biopsies, we have quantified mRNA for the two known ETreceptor subtypes ET_A and ET_B in cortical tissue from threegroups of patients: renal transplant recipients on CsA (n=7),those with native renal disease (n=5) and normal controls (n=7).Median mRNA levels (amol/µg total RNA) were 0.024, 0.17and 0.2 respectively for ET_A and 0.57, 0.64 and 0.96 for ET_B.These values indicate significant downregulation of ET_A (P=0.003)but not ET_B (P=0.104) mRNA in the transplant group. These resultsprovide the first demonstration of a perturbation in the humanET system at tissue level in a pathophysiological situation,and suggest that the deleterious renal vasoconstrictor effectsof CsA might be ameliorated by selective ET_A receptor antagonismin the future. This study also illustrates the feasibility ofex vivo analysis of human diagnostic material at the molecularlevel.     

Highly sulphated glycosaminoglycans in articular cartilage and other tissues containing {beta}2 microglobulin dialysis amyloid deposits

BACKGROUND: Highly sulphated glycosaminoglycans (GAGs) are a common constituentof amyloid deposits and an integral component of articular connectivetissues where ß₂-microglobulin (ß₂M) amyloidis most often found. METHODS: Using alcian blue, magnesium chloride, critical electrolyteconcentration, mucin histochemistry, and immunohistochemistry,the GAGs composition of ß₂M amyloid deposits in jointcapsule and cartilage, carpal, and heart tissues of 22 uraemicpatients was determined. RESULTS: Highly sulphated GAGs were found in ß₂M amyloid depositsnot only within cartilage, where such GAGs are normally foundin high concentration, but also in other articular and extra-articularconnective tissues. Keratan sulphate was often specificallylocalized to ß₂M amyloid deposits in articular cartilageand to a lesser extent in periarticular tissues, with one caseshowing colocalization with systemic vascular amyloid deposition.Other sulphated GAGs, chondroitin 4 and 6 sulphate, dermatansulphate, and heparan sulphate were also identified in tissuescontaining ß₂M amyloid deposits, but with the exceptionof heparan sulphate (identified by mucin histochemistry) werenot specifically localized to the deposits themselves. CONCLUSION: These findings suggest that qualitative or quantitative changesin the composition of highly sulphated GAGs may play a rolein localization of ß₂M amyloid deposits in articularand extra-articular tissues.     

Gastric mucosal end-tidal PCO2 difference as a continuous indicator of splanchnic perfusion

Gastric mucosal and arterial blood PCO₂ must be known to assessmucosal perfusion by means of gastric tonometry. As end-tidalPCO₂ (PE'_CO2) is a function of arterial PCO₂, the gradient betweenPE'_CO2 and gastric mucosal PCO₂ may reflect mucosal perfusion.We studied the agreement between two methods to monitor gutperfusion. We measured the difference between gastric mucosalPCO₂ (air tonometry) and PE'_CO2 (=DPCO_2gas) and the differencebetween gastric mucosal PCO₂ (saline tonometry) and arterialblood PCO₂ (=DPCO_2sal) in 20 patients with or without lung injury.DPCO_2gas was greater than DPCO_2sal but changes in DPCO_2gas reflectedchanges in DPCO_2sal. The bias between DPCO_2gas and DPCO_2salwas 0.85 kPa and precision 1.25 kPa. The disagreement betweenDPCO_2gas and DPCO_2sal increased with increasing dead space.We propose that the disagreement between the two methods studiedmay not be clinically important and that DPCO_2gas may be a methodfor continuous estimation of splanchnic perfusion. Br J Anaesth 2000; 85: 563–9 ^* Corresponding author: Department of Anesthesiology and IntensiveCare, Division of Critical Care, Kuopio University Hospital,PO Box 1777, FIN-70211 Kuopio, Finland     

Serum {alpha}2-macroglobulin in haemodialysis patients: baseline and kinetic studies

The pathogenesis of dialysis related amyloidosis remains unresolveddespite the identification of ß₂-microglobulin (ß₂M)as the major protein constituent, as well as other proteinsbeing present in the deposits. Among the latter we have assessedthe serum concentrations of ₂-macroglobulin (₂M) both in thebaseline stage and during the haemodialysis (HD) procedure.We have also assessed the influence of the membrane on ₂M kinetics. Fifteen HD patients with histologically proven dialysis-relatedamyloidosis (DRA group) and 15 HD patients clinically and radiologicallyconsidered dialysis-related amyloidosis free (control group)were included in the baseline study. Blood was sampled the daybefore the second dialysis of the week and ₂M, ß₂Mand ₁, antitrypsin were determined along with the routine biologicalanalysis of these patients. Serum ₂M was greater in dialysis-relatedamyloidosis than in control patients (t = 2.35; P<0.026).Serum ß₂M was similar in both groups. The serum ₂Mand ß₂M correlated in patients with dialysis-relatedamyloidosis (r = 0.64; P<0.01), while no correlation wasfound in controls (r = 0.17; NS). Stepwise analysis taking thepresence of dialysis-related amyloidosis as the dependent variableretained the serum ₂M concentration as the first variable inthe model (F = 4.4; partial r = 0.38; P<0.046). The sameproteins were determined in another group of seven patients,before and hourly during HD as well as 2 and 8 h after the endof HD during nine consecutive dialyses (3 cycles of 3 HD eachusing AN69 and cuprophane membranes in a crossover design).Serum ₂M significantly increased from hour 3 and continued toincrease 2 hours post-HD (+11% and +9% with AN69 and cuprophanerespectively; P<0.001). Total proteins peaked at hour 4 (+4% and +3% P<0.01) and decreased after HD. Serum ß₂Msignificantly decreased with AN69 HD ( – 29% P<0.001)and remained unchanged during cuprophane HD. In conclusion, significant increases in serum ₂M are observedimmediately after and during the early post-dialysis periods,regardless of the membrane used. Further, serum ₂M correlateswith ß₂M only in patients with dialysis-related amyloidosis,and this variable was retained in the multivariate regressionanalysis to predict dialysis-related amyloidosis. Although thebaseline results require confirmation with larger studies, wepostulate that the present results are of relevance for dialysis-relatedamyloidosis pathogenesis since ₂M, previously identified indialysis related amyloid deposits, is closely related to acute-phasereactant proteins, and interacts with the main infiltratingcells of the deposits (macrophages). ₂M modifications couldrepresent a new manifestation of the inflammatory response tothe haemodialysis procedure.     

Differential effects of probucol on two distinct experimental rat nephrosis models

We compared an antiproteinuric effect of a lipid‐lowering agent probucol on two distinct types of experimental nephrosis in rats, i.e. mercuric–chloride (HgCl₂)‐induced autoimmune glomerulonephritis in Brown Norway (BN) rats and puromycin aminonucleoside (PA)‐nephrosis in Wistar rats. The rats were fed either standard rat chow or chow containing 5% probucol. BN rats were treated with HgCl₂ according to a standard protocol (HgCl₂ 1 mg/kg subcutaneously three times/week). Probucol treatment did not ameliorate proteinuria, renal histology or a strong linear staining for IgG and an intercellular adhesion molecule, ICAM‐1, in glomeruli. Wistar rats were made nephrotic with an intraperitoneal injection of PA (100 mg/kg). In this model, in contrast to the BN rat model, no glomerular deposition of IgG or ICAM‐1 was observed. Probucol treatment ameliorated proteinuria significantly. These findings suggest that the response to probucol differs in different experimental nephrosis models. As probucol only affects PA‐nephrosis, in which ICAM‐1 expression is negative, the ICAM‐1 attenuation is not likely to be involved in the antiproteinuric effect of probucol.     

Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity

Hypomagnesaemia with magnesuria are common findings in cyclosporin-(CsA)-treatedpatients and have been proposed as both a cause and a consequenceof nephrotoxicity. To investigate the role of Mg depletion inthe pathogenesis of acute CsA nephrotoxicity, rats kept on alow-salt diet were maintained on plain water (Mg(–)group)or water supplemented with 2% MgCl₂ (Mg(+) group) and randomlyassigned to treatment with CsA 15mg/kg (CsA) or vehicle (VH)s.c. for 7 days. Water and food ingestion in VH animals wasadjusted to the intake of CsA animals. CsAMg(–)group showeda significant plasma magnesium (PMg) reduction as compared tobaseline (1.13 versus 1.53 mg/dl, P<0.001) or VH values (versus1.60 mg/dl, P< 0.001) and a significantly greater post-treatmentfractional excretion of magnesium (FeMg) as compared to VH (9.4versus 5.4%, P<0.0l). Magnesium supplementation increasedPMg (2.11 versus 1.57 mg/dl P<0.001) and FeMg (13.6 versus6.2%, P<0.001) but did not prevent a reduction in GFR withCsA treatment. Alanine aminopeptidase (AAP) excretion at 7 dayswas significantly greater than baseline (130 versus 44 IU/gCr,P<0.05) or VH (36 IU/gCr, P<0.05) values only in the CsAMg(–)rats. No differences were observed in intraerythrocyte Mg, bloodpressure, and urinary excretion of N-acetyl ß-D-glucosaminidaseamong groups. Renal histology was similar in CsA rats independentof magnesium supplementation: mild vacuolization and tubularcollapse in proximal tubules. In conclusion, Mg depletion couldnot be implicated in the pathogenesis of acute CsA-induced glomerulardysfunction, but Mg replacement may protect from some of thetubular toxicity of CsA.     

In vivo prostanoid formation during acute renal allograft rejection

Vasoconstriction during acute renal allograft rejection maybe regulated by increased formation of vasoactive prostanoids.To address this hypothesis we investigated the biosynthesisof thromboxane (Tx)A₂, a potent vasoconstrictor and plateletagonist, of prosta-cyclin (PGI₂), a vasodilator and plateletantagonist, and of prostaglandin (PG)E₂, a mediator of saltand water excretion, in nine children with 12 acute rejectionepisodes, prospectively during the first 7 weeks after renaltransplantation. We used physicochemical analysis of stableurinary prostanoid index metabolites. Rejection crises wereassociated with an increase in TxB₂ excretion from baselinemedian 9.2 (range 1.9–18.6) ng/h/1.73m² to 21.2 (range10.0–133.0) ng/h/1.73m² (P<0.005) during acute rejectionepisodes. Methylprednisolone pulse therapy resulted in a partialreduction, but not normalization of TxB₂ excretion. Urinary2,3-dinor-TxB₂ was slightly stimulated during allograft rejection,urinary 1 l-dehydro-TxB₂ did not change significantly. RenalPGI₂ and PGE₂ biosynthesis remained essentially unchanged. Incontrast to acute graft rejection, patients with chronic graftrejection and those with stable graft function on differentimmunosuppressive regimens with or without cyclosporin A didnot present stimulated renal TxA₂ formation. Increased renalTxA₂ formation in acute renal allograft rejection is likelyto mediate vasoconstriction and potentiate the loss of renalblood flow and glomerular filtration rate, in the absence ofan adequate response of the renoprotective prostanoids PGI₂and PGE₂.     

Acute effect of oral, intraperitoneal, and intravenous 1{alpha}-hydroxycholecalciferol on markers of bone metabolism

OBJECTIVE: To study the acute effect of 1-hydoxycholecalciferol (1-OHD₃)on serum levels of alkaline phosphatase, Ca²⁺, osteocalcin,parathyroid hormone (PTH), phosphate and type I and III procollagens(PICP and PIIINP respectively) in patients undergoing peritonealdialysis. Also, 1,25-(OH)₂D₃ was measured. DESIGN: Single doses of 1-OHD₃ (80 ng/kg body wt) were given in randomizedcross-over fashion, orally, intraperitoneally (i.p.) and intravenously(i.v.) on three occasions. Blood was sampled at 0, 1, 6, 12,and 24 h after administration of 1-OHD₃. MAIN RESULTS: Following oral administration of 1-OHD₃, a decrease in serumalkaline phosphatase was seen when levels at 1 and 6 h werecompared to baseline (P<0.05). Oral and i.v. drug administrationsresulted in an increasing trend in serum Ca²⁺ throughout thestudy (P<0.05). Moreover, a difference in serum Ca²⁺ wasfound when 24-h levels after oral 1-OHD₃ dose was compared tobaseline (P<0.05). Serum osteocalcin at 12 and 24 h afteroral 1-OHD₃ compared to baseline were increased (P<0.05).Intact PTH followed a circadian rhythm after all three routesof drug delivery. After 24 h, significant decreases of intactPTH were observed in the oral and i.v. group. No changes inserum phosphate and serum PICP levels were observed over timeafter oral, i.p., and i.v. delivery of 1-OHD₃However, serumPIIINP following oral and i.p. administration of 1-OHD₃ decreasedat 1 and 6 h (P<0.05). CONCLUSION: Oral and iv. administration of 1-OHD₃ does influence serum levelsof osteocalcin, PTH, and PIINP. Noticeable is the significantincrease in serum osteocalcin after oral administration of 1-OHD₃,the remarkable increase (22.6%) in osteocalcin 24 h after i.v.1-OHD₃, though not statistically significant, the increase inserum PTH levels 12 h following oral and i.v. doses of 1-OHD₃and the moderate effect on serum Ca²⁺ levels.     

Beta2 adrenergic antagonist inhibits cerebral cortical oxygen delivery after severe haemodilution in rats

Background. Haemodilution has been associated with neurologicalmorbidity in surgical patients. This study tests the hypothesisthat inhibition of cerebral vasodilatation by systemic ß₂adrenergic blockade would impair cerebral oxygen delivery leadingto tissue hypoxia in severely haemodiluted rats. Methods. Under general anaesthesia, cerebral tissue probes wereplaced to measure temperature, regional cerebral blood flow(rCBF) and tissue oxygen tension (P_BrO₂) in the parietal cerebralcortex or hippocampus. Baseline measurements were establishedbefore and after systemic administration of either a ß₂antagonist (10 mg kg^–1 i.v., ICI 118, 551) or saline vehicle.Acute haemodilution was then performed by simultaneously exchanging50% of the estimated blood volume (30 ml kg^–1) with pentastarch.Arterial blood gases (ABGs), haemoglobin concentration (co-oximetry),mean arterial blood pressure (MAP) and heart rate (HR) werealso measured. Data were analysed using a two-way ANOVA andpost hoc Tukey's test [mean (SD)]. Results. Haemodilution reduced the haemoglobin concentrationcomparably in all groups [71 (9) g litre^–1]. There wereno differences in ABGs, co-oximetry, HR and MAP measurementsbetween control and ß₂ blocked rats, either beforeor 60 min after drug or vehicle administration. In rats treatedwith the ß₂ antagonist there was a significant reductionin parietal cerebral cortical temperature, regional blood flowand tissue oxygen tension, relative to control rats, 60 minafter haemodilution (P<0.05 for each). These differenceswere not observed when probes were placed in the hippocampus. Conclusion. Systemic ß₂ adrenergic blockade inhibitedthe compensatory increase in parietal cerebral cortical oxygendelivery after haemodilution thereby reducing cerebral corticaltissue oxygen tension.     

Effects of Cyclosporin on Renal Microcirculation

To evaluate renal microcirculation during acute cyclosporin(CsA) administration (50 mg/kg, i.v.), seven euvolaemic Munich–Wistarrats were studied. CsA infusion caused a significant decreasein total glomerular filtration rate (GFR) (0.96±0.04vs 0.47±0.07 ml/min) and in single-nephron GFR (SNGFR)(27.90±3.4 vs 14.02±3.5 nl/min). The efferentarteriolar resistance increased substantially (P<0.05) whilethe afferent resistance rose moderately. Consequently, therewas an increase (P<0.05) in mean glomerular capillary hydraulicpressure (_GC), from 45±1to 55±4 mmHg, together with an important decrease inmean glomerular plasma flow rate (Q_A), from 100±17 to44±13 nl/min. Since tubular hydraulic pressure was maintainedunaltered, an elevated transglomerular hydraulic pressure differencewas observed (P<0.05). The lower values of SNGFR were accountedfor by both the decrease in Q_A and in the glomerular ultrafiltrationcoefficient (K_f). The latter was reduced from 0.096±0.03to 0.031±0.010 nl/sec per mmHg(P<0.05) by CsA Additionally, three groups of Munich–Wistar rats werepreviously treated with captopril (2 mg/kg per h, i.v.), verapamil(20 µg/kg per min, i.v.) or indomethacin (2 mg/kg, i.v.).Both captopril and verapamil minimised the renal effects ofCsA, with a decline of 25% instead of 50%on GFR and RPF. Thus CsA infusion caused a decline on SNGFR due to an importantreduction in Q_A and K_f with an impressive increase on arteriolarresistance, a mark of angiotensin II stimulation. However, indomethacinwas unable to prevent glomerular haemodynamic changes, suggestingthat prostaglandins have a minor effect, if any, in impairingglomerular haemodynamics during acute CsA treatment.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renalfunction. The degree of renal dysfunction is usually estimatedfrom the clearance of creatinine (C_Cr). Theoretically however,a fall in C_Cr can be caused by a decrease of GFR, an inhibitionof the tubular secretion of creatinine, or the combination ofboth. CsA has convincingly been shown to decrease GFR, but detailedinformation on the effects of CsA on tubular secretion of creatinineis lacking. METHODS: We performed two studies to investigate the influence of CsAon tubular creatinine secretion. In study A we simultaneouslymeasured C_Cr and GFR (using inulin) immediately before and 4weeks after cessation of CsA therapy in 17 renal transplantpatients. In study B, the rise in serum creatinine after administrationof cimetidine, which blocks the tubular secretion of creatinine,was compared in renal transplant patients treated with eitherCsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR(54±15 vs 63± 16 ml/min/1.73 m²; P>0.01) andof C_Cr (71±21 vs 82±23 ml/min/1.73 m²; P>0.01),but the ratio between C_Cr and GFR (a measure of the relativecontribution of tubular secretion to the clearance of creatinine)did not change significantly (1.33±0.21 vs 1.32±0.30).Study B: In nine couples of patients matched for GFR the relativerises in serum creatinine after administration of cimetidinewere 26±21% and 22±7% for the CsA and azathioprinetreated patients respectively (NS). CONCLUSIONS: CsA does not substantially inhibit the tubular secretion ofcreatinine. A rise in serum creatinine after administrationof CsA can thus be attributed completely to a fall in GFR.     

Effect of diltiazem and methyldopa on gestation-related renal complications in rats with adriamycin nephrosis. Relationship to glomerular prostanoid synthesis

BACKGROUND: In the presence of pre-existing renal disease, occurrence ofhypertension during pregnancy may compromise renal functionand aggravate proteinuria. In pregnant rats with early adriamycinnephropathy, this is associated with an increase in the glomerularTxB₂:PGE₂ ratio. In the present study we evaluated the effectof blood-pressure control on renal function and its relationshipwith glomerular prostanoid synthesis. DESIGN OF THE STUDY: Pregnant Wistar rats with adriamycin nephropathy received diltiazem,30 mg/kg/day or methyldopa, 400 mg/kg/day from mid-gestation.Mean arterial pressure (MAP), inulin clearance (C_IN), urineprotein excretion (UP) and glomerular prostanoid synthesis weremeasured. Results were compared with (i) untreated pregnantrats with adriamycin nephropathy, (ii) virgin rats with adriamycinnephropathy, and (iii) normal virgin or (iv) pregnant normalrats. RESULTS: MAP increased in untreated pregnant rats with adriamycin nephropathy(P<0.01 versus virgin rats with adriamycin nephropathy),contrasting with the physiological decrease observed in normalpregnant rats. Diltiazem and methyldopa decreased MAP to normalvalues. In untreated pregnant rats with adriamycin nephropathy C_IN decreasedand proteinuria increased significantly at the end of gestation.Treatment with diltiazem and methyldopa augmented GFR, but onlydiltiazem decreased UP significantly. It was associated withan increased glomerular PGE₂ synthesis. CONCLUSIONS: We conclude that in rats with adriamycin nephropathy, antihypertensivetreatment improved GFR. Diltiazem also decreased urinary proteinexcretion, associated with a normalization of the glomerularTxB₂: PGE₂ ratio.     

Effect of autonomic neuropathy on ventilatory response to progressive hypercapnia in dialysis patients

The impact of autonomic neuropathy (common in patients on haemodialysis)on ventilatory response to hypercapnia has been studied. We investigated cardiac reflex tests in 20 patients on chronichaemodialysis (8 patients were found with and 12 without neuropathyof the autonomic nervous system). Using the hyperoxic CO₂-rebreathingmethod (according to Read), we tested the above-mentioned twogroups of patients and compared them with 14 healthy controlsubjects. Accumulation of CO₂ in blood with hyperoxic CO₂ rebreathingstimulates central chemoreceptors, and therefore causes a progressiverise in minute ventilation. In patients with autonomic neuropathy (n=8), ventilatory responseto increasing pCO₂ was significantly lower than that in thecontrols (1.7±0.3 versus 3.2±0.5 l/min/mmHg, P<0.001).On the other hand ventilatory response in patients without autonomicdamage (n=12) showed no significant difference when comparedto controls (3.1±0.8 l/min/mmHg). There were no differencesin lung function, arterial blood gas analysis, blood chemistry,duration on dialysis, and demographic data when comparing thepatients with and those without autonomic damage. Our analysis shows different patterns of ventilatory responseto increasing pCO₂ in patients on haemodialysis. Autonomic neuropathyhas to be considered when rebreathing tests are interpreted.The clinical relevance of these findings needs further investigation.     

ON-LINE Po2 AND PN2o ANALYSIS WITH AN IN VIVO CATHETER ELECTRODE

A technique was developed for the in vivo determination of Po₂and PN₂o with a catheter electrode using double-pulse polarography.The method was evaluated in dog studies comparing readings fromthe electrode with those from a mass spectrometer employingan in vivo probe. The oxygen readings obtained from the catheterelectrode were also compared with values obtained by conventionalblood-gas analysis. Good agreement was observed between theelectrode and the mass spectrometer for both Po₂ and PN₂o. Similaragreement was found between the electrode readings and blood-gasanalysis for Po₂. In the presence of halothane, the electrodeover-read for both Po₂ and PN₂O; a remedy is suggested. Thein vivo electrode provides an effective, less expensive, alternativeto the mass spectrometer for the on-line measurement of Po₂,and PN₂o in vivo. ^*Also Physical Chemistry Laboratory, University of Oxford.