[Antiphospholipid antibody syndrome: a priori a contraindication to kidney transplantation?]. / Antiphospholipidantikörpersyndrom: a priori eine Kontraindikation zur Nierentransplantation?

BACKGROUND: The antiphospholipid antibody syndrome (APLS) is characterised by the presence of antiphospholipid antibodies in association with thrombotic disorders of the arterial and/or venous system, spontaneous abortion and thrombocytopenia. Several studies have shown that end-stage renal disease patients with APLS are at extremely high risk for graft thrombosis and graft loss after kidney transplantation. MATERIAL AND METHODS: We report on the treatment and clinical courses of 6 APLS renal transplant patients. RESULTS: Of 3 patients treated with low-dose subcutaneous heparin two had early graft loss due to venous graft thrombosis; of those patients treated by systemic heparin (PTT goal 45-55 s) and followed by coumadin (INR 2.5-3.0) only one had early graft loss whereas 2 grafts are doing well 2 years post-transplant. CONCLUSION: Our experience as well as recently published data suggest that kidney transplantation can be performed successfully in APLS patients if anticoagulation therapy is performed consistently. A general APL antibody screening prior to kidney transplantation does not seem to be justified at present. A prospective, randomised multicenter study is warranted to evaluate the management of these patients with respect to intensity, type and duration of anticoagulation therapy.

Haemodynamic effects of valsartan in acute renal ischaemia/reperfusion injury.

BACKGROUND: Acute deterioration of renal function is an important side-effect of angiotensin-converting enzyme (ACE) inhibitors, especially if accompanied by other nephrotoxic events. Angiotensin II receptor(1) blockers (ARB) are thought to have fewer side-effects on renal perfusion and function. We examined the effects of valsartan (VAL) on kidney function as well as the contribution of the nitric oxide (NO) system in a rat model of ischaemic acute renal failure (ARF). METHODS: ARF was induced by 40 min of clamping of both renal arteries in female Sprague-Dawley rats. Renal haemodynamic and tubular parameters were determined during post-ischaemic infusion of vehicle, VAL, VAL and the NO-synthase substrate L-arginine, and VAL together with inhibition of NO synthases (NOS) by L-NMMA. RESULTS: Clamping induced acute renal failure with marked decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) accompanied by a rise in renal vascular resistance (RVR) and fractional sodium excretion. Valsartan caused a slight but significant improvement of GFR and RPF without full recovery of renal function and caused a lowering of RVR and tubular sodium loss. L-arginine-co-administration had no additive beneficial effect. Valsartan-induced changes were not significantly depressed by unspecific inhibition of NOS. CONCLUSIONS: Inhibition of the angiotensin II-receptor(1) diminishes the deleterious effects of ischaemia and reperfusion on glomerular function and on the renal microcirculation. An involvement of the NO system could not be demonstrated.

Hormonal changes in brain death and immune activation in the donor.

Kidneys obtained from brain dead donors show inferior graft survival compared to living donation. The effects of brain death itself are thought to be partly responsible for these results. We, therefore, examined levels of catecholamines, the vasoconstricting hormones AT II, ET-1 and renin activity, pituitary hormones, and their correlation to pro-inflammatory cytokines and cytokine receptors. In 17 brain dead patients and 19 preoperative neurosurgical patients, these parameters were measured by HPLC, RIA and ELISA. Brain death resulted in massive increases in serum catecholamines, AT II and ET-1, as well as PRA, whereas thyroid and adrenal hormone levels remained unchanged. We found a significant correlation with rises in IL-6 and soluble TNF and IL-2 receptors as markers for the activation of immunological cascades. We concluded that these effects could be directly and indirectly responsible for the impaired organ perfusion and function observed in brain death.

Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics?

Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.

The calcium-parathyroid hormone regulation in chronic renal failure investigation of its dynamic secretion pattern.

In patients with secondary hyperparathyroidism (HPT) caused by chronic renal failure (CRF), the pulsatility of parathyroid hormone (PTH) secretion and the relation of PTH to plasma Ca2+ concentrations were investigated. Intermittent hyper- and hypocalcemia was induced to study the deterministic reaction of the parathyroid glands. Compared to normal behaviour in CRF the pulsatility is lost. Yet the deterministic coupling between PTH and Ca2+ concentrations remains qualitatively the same though quantitatively it is exaggerated and varies depending on the subjects.

[Cardiovascular risk factors in diabetic nephropathy]. / Kardiovaskuläre Risikofaktoren bei diabetischer Nephropathie.

BACKGROUND: Diabetic nephropathy is associated with increased cardiovascular mortality. This may be contributed to by changes in plasma lipids, fibrinogen and hemorheology. Cardiovascular autonomic dysfunction, which is related to an increased incidence of arrhythmic death, may also play a role. PATIENTS AND METHODS: Therefore, we investigated in 58 IDDM-patients with none (n = 28), incipient (albuminuria 30 to 300 mg/day, n = 11) and overt clinical nephropathy (albuminuria > 300 mg/day, n = 19) plasma concentrations of lipoproteins and fibrinogen, plasma viscosity, erythrocyte aggregation and erythrocyte rigidity. Assessments of neuropathy included tibial nerve motor conduction velocity, perception of vibration, beat-to-beat variation during rest and during forced respiration, heart-rate response to Valsalva maneuver and heart-rate response to standing (30:15). RESULTS: Patients with clinical overt nephropathy had, compared to those without nephropathy, significantly higher concentrations of LDL-cholesterol, triglycerides and fibrinogen, significantly lower concentrations of HDL-cholesterol and significantly higher plasma viscosity, erythrocyte aggregability and erythrocyte rigidity. Regarding the assessments of neuropathy we found in patients with nephropathy, compared to those without nephropathy, significantly reduced tibial nerve motor conduction velocity, reduced perception of vibration thresholds and reduced heart rate variability during rest, during forced respiration, in response to Valsalva maneuver and in response to standing. In diabetic patients with microalbuminuria erythrocyte aggregability and erythrocyte rigidity were significantly higher and heart rate variability during rest was significantly lower than in patients without nephropathy. CONCLUSION: In clinical overt nephropathy there is an aggregation of different cardiovascular risk factors, namely, disturbances in lipoprotein concentrations, increased fibrinogen concentration and disturbances in hemorheology. Furthermore marked deterioration in peripheral and autonomic cardial nerve function in these patients is evident accounting for a part of the greatly increased cardiovascular mortality of these patients.

Hemorheology, plasma protein composition and von Willebrand factor in type I diabetic nephropathy.

Patients with IDDM, especially those with albuminuria are at high risk for macrovascular and microvascular complications. Besides the major classic risk factors altered hemorheology may also play a role. Plasma viscosity, erythrocyte aggregation and erythrocyte deformability are the major determinants of blood flow in the microcirculation. Therefore, these hemorheological parameters and plasma protein composition were evaluated in 58 IDDM-patients with none (N0), incipient (N1: albuminuria 30-300 mg/day) and overt clinical nephropathy (N2: albuminuria > 300 mg/day). As an estimate of endothelial injury plasma levels of von Willebrand Factor (vWF) were investigated. Patients with incipient and clinical nephropathy exhibited increasing blood levels of fibrinogen (N0 = 2.47 +/- 0.09, N1 = 2.71 +/- 0.15, N2 = 3.49 +/- 0.24 g/l, p < 0.001), alpha 2-macroglobulin (N0 = 257 +/- 11, N1 = 251 +/- 21, N2 = 382 +/- 43 mg/100 ml, p < 0.01) and haptoglobin (N0 = 174 +/- 16, N1 = 216 +/- 39, N2 = 278 +/- 36 mg/100 ml, p < 0.05), whereas serum albumin concentration decreased (N0 = 5.1 +/- 0.1, N1 = 4.7 +/- 0.1, N2 = 4.1 +/- 0.2 g/100 ml, p < 0.001). In the same patients erythrocyte aggregation (N0 = 10.0 +/- 0.4, N1 = 12.1 +/- 0.5, N2 = 12.9 +/- 0.6, p < 0.001), plasma viscosity (N0 = 1.34 +/- 0.01, N1 = 1.38 +/- 0.02, N2 = 1.40 +/- 0.02 mPas, p < 0.05) and erythrocyte rigidity (N0 = 0.05 +/- 0.01, N1 = 0.15 +/- 0.05, N2 = 0.09 +/- 0.02, p < 0.05) were increased, predominantly in those with overt clinical nephropathy. Erythrocyte aggregation was positively correlated with plasma concentrations of fibrinogen (r = 0.65, p < 0.001) and alpha 2-macroglobulin (r = 0.35, p < 0.05), but negatively with plasma albumin concentration (r = -0.49, p < 0.001). Plasma viscosity was positively correlated with plasma concentrations of fibrinogen (r = 0.46, p < 0.001) and haptoglobin (r = 0.46, p < 0.001). Von Willebrand Factor levels were higher in patients with overt clinical nephropathy (N0 = 126 +/- 8, N1 = 136 +/- 12, N2 = 163 +/- 14%, p < 0.09, PN0-N2 < 0.05). A significant correlation between vWF and the rheological determinants could not be detected. These data demonstrate that blood rheology is profoundly altered in patients with IDDM and nephropathy. Elevated levels of vWF may indicate endothelial damage, and changes in plasma viscosity as well as erythrocyte aggregability seem to be the result of altered plasma protein composition due to proteinuria. These abnormalities in hemorheology may be an aggravating factor promoting microvascular and macrovascular damage in patients with type I diabetes mellitus and nephropathy.

Endotoxin-induced acute renal failure in the rat: effects of urodilatin and diltiazem on renal function.

Acute renal failure (ARF) due to endotoxins is a common problem in clinical medicine. Endotoxins are released from the outer membrane of the gram-negative bacterial envelope and are composed of lipopolysaccharides (LPS). Although systemic hypotension often is present, LPS-induced ARF is characterized by marked intrarenal vasoconstriction. Both calcium channel blockers and natriuretic peptides are able to antagonize vasoconstricting signals and have been reported to exert beneficial effects in toxic and ischemic ARF: We investigated the effects of diltiazem (Dil, 300 micrograms/kg) or urodilatin (Uro, 40 micrograms/kg) or a combination of both (same doses) on renal function in early LPS-induced ARF: One hour after induction of ARF by i.v. injection of LPS glomerular filtration rate (GFR, clearance of fluorescence-marked inulin) was distinctly reduced to about 54% of basal values. In the following infusion period (60 min) a significant increase of GFR was observed with diltiazem (1.54 +/- 0.11 ml/min), urodilatin (1.60 +/- 0.10 ml/min) and the combination of both drugs (1.66 +/- 0.04 ml/min) compared to controls (1.17 +/- 0.08 ml/min). Combined administration did not cause additive effects. Also 60 and 120 minutes after stopping of drug infusion elevated GFR could be maintained in all experimental groups. Due to their vasorelaxing activity both Uro and Dil induced a decrease of mean arterial blood pressure in comparison with controls and revealed remarkable diuretic and natriuretic activity. In conclusion our results underline that marked intrarenal vasoconstriction in LPS-induced ARF can be antagonized by the well known relaxing potency of Uro and Dil towards vascular smooth muscle and mesangial cells. Both Uro and Dil were capable of improving suppressed renal function in the early phase of LPS-induced ARF in the rat as long as severe systemic hypotension is absent.

Influence of nitric oxide on renal function in toxic acute renal failure in the rat.

Besides other mechanisms, nitric oxide (NO) plays a major role in maintaining the high renal blood flow (RBF) and is also involved in the regulation of glomerular hemodynamics and contractility of mesangial cells. We examined the hypothesis that L-arginine-derived NO exerts beneficial effects in toxic acute renal failure (ARF) in the rat. To induce ARF uranyl nitrate (UN) was given intravenously as a bolus injection (25 mg/kg over 5 min) following a basal period. After the initiation phase of ARF (3 h) saline in the control group (C) and drugs in the experimental groups (I-III, each n = 8) were administered for 60 min. Group I: Arg (= L-arginine, 300 mg/kg), group II: MeArg (= N-methyl-L-arginine, 30 mg/kg), group III: Arg + MeArg (300 mg/kg, 30 mg/kg respectively). The experiments were continued for additional 60 min following the infusion period. Glomerular filtration rate (GFR, inulin clearance) was reduced 3 h after UN to about 50% of normal values in group I-III and control group. After infusion of Arg GFR had significantly improved, but remained unchanged after MeArg in relation to control. One hour after the infusion period these effects were even more pronounced. We conclude that NO exerts beneficial effects on renal function in this animal model of ARF. These results underline the regulatory role of the L-arginine/NO pathway for renal function not only under basal conditions but also in ARF.

Parathyroid hormone secretion and serum calcium concentration--a deterministic view of its regulation.

In seven normal men we investigated the basal secretion of PTH by blood sampling in 30 sec intervals for estimation of intact PTH and at 2-min intervals for measurement of ionized calcium. In 4 of these subjects we also investigated the PTH-secretion under conditions of intermittent hypercalcemia and hypocalcemia. Our measurements demonstrate the existence of three time scales in the secretion of PTH, viz. short-term pulses (faster than 2 min), an intermediate pattern of adjusting PTH levels to changed Ca2+ averages, and finally a long-term coupling between PTH and Ca2+ averages after 20 min. Ionized calcium controls the long-term regulation and intermediate adaptation mechanisms, but the short-term fluctuations seem to be due to spontaneous secretion.

Effects of urodilatin and diltiazem on renal function in ischemic acute renal failure in the rat.

In humans as well as in experimental models the hallmark of ischemic acute renal failure (ARF) is a profound diminution in glomerular filtration rate (GFR) and renal blood flow. Both calcium antagonists and a-ANP have been reported to exert beneficial effects in ischemic ARF. No data, however, exist about combined administration of the natriuretic peptide urodilatin and calcium channel blockers. We therefore investigated the effects of urodilatin (URO, 40 micrograms/kg/h, i.v.) and diltiazem (DIL, 300 micrograms/kg/h, i.v.) in the rat given immediately after clamping of both renal arteries for 40 min. Compared to controls (0.07 +/- 0.01) depressed GFR (ml/min/100 g) was clearly elevated with URO (0.16 +/- 0.03), DIL (0.13 +/- 0.03) and URO + DIL (0.14 +/- 0.02) after the ischemic lesion. After cessation of drug delivery the beneficial effects were blunted in the URO group, in contrast to the DIL and URO + DIL group, where GFR was significantly elevated compared to controls even 3 h after starting reperfusion. Besides that also urine flow, sodium excretion and blood pressure were examined. In conclusion both URO and DIL exert beneficial effects in ischemic ARF in the rat while infused. In contrast to URO DIL showed prolonged beneficial effects even after cessation of drug delivery. An additional effect of both drugs could not be observed.

Role of L-arginine-derived NO in ischemic acute renal failure in the rat.

Nitric oxide (NO) is involved in the regulation of renal perfusion and glomerular hemodynamics under basal conditions. We examined the hypothesis that L-arginine-derived NO modifies ischemic acute renal failure (ARF) in the rat. After a basal period ischemia was induced by clamping of both renal arteries (40 min). Thereafter, in the reperfusion period, we intravenously infused L-arginine (Arg, 300 mg/kg/60 min), or L-monomethylarginine (MeArg, 30 mg/kg/60 min), or Arg + MeArg (300 mg/kg/60 min, 30 mg/kg/60 min, resp.). Besides monitoring of urinary flow rate and arterial blood pressure, and determination of sodium excretion, glomerular filtration rate (GFR, mL/min/100 g) was estimated at the end of the infusion period and again after another 30 and 120 min by inulin clearance (fluorescence-marked inulin). In the basal period GFR showed no differences between the groups (Arg: 0.86 +/- 0.07, MeArg: 0.92 +/- 0.06, Arg + MeArg: 0.89 +/- 0.08, control: 0.84 +/- 0.07). At 180 min after the beginning of the reperfusion period, GFR was 0.13-0.02 in the control group. After administration of Arg, a remarkable and persistent increase in GFR was observed (0.28 +/- 0.03), whereas infusion of MeArg showed no significant effects (0.13 +/- 0.04). Combined administration of Arg + MeArg revealed a moderate increase of GFR (0.19 +/- 0.05), ranging between the Arg and the control group. Also, 60 and 90 min after the beginning of the reperfusion period, the highest values for GFR were obtained in the Arg group. We conclude that in this model of ischemic ARF in the rat, L-arginine-derived NO is capable of improving renal function. These data underline the regulatory role of the L-Arg-NO pathway for renal function, not only under normal conditions, but also in ARF.

Toxic acute renal failure in the rat: effects of diltiazem and urodilatin on renal function.

Beneficial effects of natriuretic peptides have been reported in different models of acute renal failure (ARF). Calcium antagonists can also improve renal function, especially in ischemic models of ARF. The aim of our study was to investigate the effects of urodilatin and diltiazem alone and in combination in uranyl nitrate-induced toxic ARF in the rat. Three hours after induction of ARF glomerular filtration rate (GFR) was clearly diminished to about 50% compared to basal values. Intravenous infusion of diltiazem and urodilatin revealed a significant increase of GFR that even continued after cessation of drug delivery. Combined administration of urodilatin and diltiazem had no additional effect, probably due to a more pronounced fall in blood pressure in this group. Besides their vasorelaxing and blood pressure lowering effects both drugs also revealed diuretic activity. In conclusion both urodilatin and diltiazem are able to elevate GFR in the early phase of toxic ARF in the rat.

Toxic acute renal failure in the rat: effects of L-arginine and N-methyl-L-arginine on renal function.

Nitric oxide (NO) is generated from L-arginine (Arg) by different isoforms of nitric oxide synthase (NOS) and plays a major role in maintaining the high basal renal blood flow. NO also is involved in the regulation of glomerular haemodynamics and contractility of mesangial cells. We examined the hypothesis that L-arginine-derived NO modifies toxic ARF in the rat. After a basal period uranyl nitrate (UN) was given intravenously as a bolus injection (25 mg/kg over 5 min) to induce ARF. After the initiation phase of ARF (3 h) saline in the control group (C) and drugs in the experimental groups (I-III, each n = 8) were administered for 60 min. Group I, Arg (300 mg/kg); group II, MeArg (30 mg/kg); group III, Arg + MeArg (300 mg/kg, 30 mg/kg resp.). The experiments were continued for further 60 min following the infusion period. Glomerular filtration rate (GFR, inulin clearance) was reduced 3 h after UN to about 50% of normal values in groups I-III and control group (I, 0.52 +/- 0.06; II, 0.51 +/- 0.05; III, 0.49 +/- 0.05; C, 0.50 +/- 0.07 ml/min). After infusion of Arg GFR had significantly improved (0.64 +/- 0.07), but further declined after MeArg (0.46 +/- 0.06) in relation to control (0.47 +/- 0.07). This negative effect could be overcome by combined administration of Arg + MeArg (0.59 +/- 0.07). One hour after the infusion period these effects were even more pronounced (Arg, 0.71 +/- 0.06; MeArg, 0.43 +/- 0.05; Arg + MeArg, 0.65 +/- 0.07; C, 0.46 +/- 0.05). We conclude that the L-arginine/NO pathway is involved in toxic ARF of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hantavirus infection with acute kidney failure]. / Hantavirus-Infektion mit akutem Nierenversagen.

Hantavirus infection was confirmed by history, symptoms and biochemical changes, as well as immunofluorescence test in 29 patients (24 men, 5 women; mean age 36.9 +/- 11.5 years) with nontraumatic renal failure (ANF), retrospectively in 15 patients. Cardinal symptoms were acute onset (n = 29), fever (n = 27), pain in the flanks, abdomen or head (n = 27), reduced glomerular filtration rate (n = 29), proteinuria (n = 25) and thrombocytopenia (n = 16). Normal renal function was restored in all patients. Follow-up examination of 15 patients 6-7 years after the acute illness revealed normal blood pressure, normal serum creatinine, absent proteinuria and normal inulin clearance in all, thus confirming the favourable prognosis of the infection in Western Europe. Nonetheless, because Hantavirus infection is by no means rare, it should be included in the differential diagnosis of acute renal failure.

[Pharmacokinetics of gadolinium-DTPA in chronic renal insufficiency requiring dialysis]. / Pharmakokinetik von Gadolinium-DTPA bei dialysepflichtiger chronischer Niereninsuffizienz.

MRT with gadolinium-DTPA (0.1 mmol/kg body weight) was performed in 10 patients with renal insufficiency requiring dialysis and the clearance of gadolinium-DTPA was studied. After 3 dialysis on 3 successive days more than 97% of the initial concentration of gadolinium-DTPA had been eliminated. Average half-life was 1.87 hours. There were no side effects in any of the patients. Close laboratory observation of liver function showed no significant changes during the period of study. No contra-indication for the use of this contrast medium in patients with renal insufficiency requiring dialysis was found during this study.