Werner Riegel

Homocysteine, cystathionine, methylmalonic acid and B-vitamins in patients with renal disease.

Abstract Moderate hyperhomocysteinemia is very frequent in renal patients. Aside from homocysteine (HCY) itself, the metabolites methylmalonic acid (MMA) and cystathionine (CYS) supply further information about disturbances in HCY metabolism. In two groups of renal patients, transplant and hemodialysis patients, we measured HCY, MMA and CYS and evaluated their diagnostic value for impaired HCY metabolism due to vitamin deficiency and renal insufficiency. We investigated serum samples from 63 transplant patients and 38 patients undergoing hemodialysis. HCY, MMA and CYS were assayed by gas chromatography-mass spectrometry, vitamin B6 by HPLC, B12 and folate by chemiluminescence immunoassay. The determination of HCY, MMA, and CYS in renal patients provides specific information about intracellular disturbances of HCY metabolism. The frequency of increased metabolite levels in renal patients was much higher than the frequency of lowered vitamin concentrations in serum. Furthermore, the metabolite levels in transplant patients were only moderately increased, whereas they were strongly increased in patients on hemodialysis (HCY 19.2 vs. 28.8 μmol/l, MMA 292 vs. 1025 nmol/l, CYS 733 vs. 2711 nmol/l). Our findings may support the use of MMA determination in the diagnosis of vitamin B12 deficiency in renal patients. Compared to vitamin B12 deficiency, renal dysfunction itself appears to cause only a modest elevation in serum MMA. Regression analysis revealed that the moderate elevation of HCY and CYS in transplant patients is mainly a consequence of impaired remethylation of HCY to methionine with activated transsulfuration, whereas the mildly elevated MMA level is attributable to renal dysfunction. In patients on hemodialysis, all three metabolites were markedly elevated, indicating a strongly disturbed HCY metabolism. Based on a backward regression, we discovered that the HCY metabolism was strongly disturbed by renal insufficiency and vitamin deficiency. The markedly elevated HCY level was mainly attributable to functional vitamin B12 deficiency indicated by high MMA, and the strong CYS elevation was due to renal dysfunction and inhibition of this pathway by low levels of vitamin B6. In conclusion, besides HCY, the determination of MMA and CYS levels supports an early diagnosis of B-vitamin deficiency in renal patients. MMA is a more sensitive indicator of intracellular vitamin B12 deficiency than vitamin B12 in serum.

In vivo effects of dialysate flow rate on Kt/V in maintenance hemodialysis patients

It is generally assumed that hemodialysis adequacy is only minimally affected by increasing the dialysate flow rate (Qd). Recent in vitro studies showed that dialyzer urea clearance (Kd(urea)) may increase substantially more than expected in response to an increase in Qd. Because these studies implied that dialysis efficacy may benefit from greater Qds, we studied in vivo the effects of various Qds on the delivered dose of dialysis in 23 maintenance hemodialysis (MHD) patients. Hemodialysis was performed at Qds of 300, 500, and 800 mL/min for at least 3 weeks each, whereas specific dialysis prescriptions (treatment time, blood flow rate [Qb], ultrafiltration volume, and type and size of dialyzer) were kept constant. Delivered dose of dialysis, assessed by single-pool Kt/V (Kt/V(sp)) and double-pool Kt/V (Kt/ V(dp)), was measured at least three times for each Qd (218 measurements). Mean +/- SEM Kt/V(sp) was 1.19 +/- 0.03 at Qd of 300 mL/min, 1.32 +/- 0.04 at 500 mL/min, and 1.45 +/- 0.04 at 800 mL/min. The relative gains in Kt/V(sp) for increasing Qd from 300 to 500 mL/min and 500 to 800 mL/min were 11.7% +/- 8.7% and 9.9% +/- 5.1%, respectively. Kt/V(dp) increased at a similar percentage (11.2% +/- 8.9% and 10.3% +/- 5.1%, respectively). The observed gain in urea clearance by increasing Qd from 500 to 800 mL/min was significantly greater than the increase in Kd(urea) predicted from mathematical modeling (5.7% +/- 0.4%; P = 0.0008). Removal ratios for creatinine and the high-molecular-weight marker, beta(2)-microglobulin, were not affected by increasing Qd from 500 to 800 mL/min. The proportion of patients not achieving adequacy (Kt/V(sp) >/= 1.2) was reduced from 56% at Qd of 300 mL/min to 30% at 500 mL/min and further to 13% at 800 mL/min. It is concluded that increasing Qd from 500 to 800 mL/min is associated with a significant increase in Kt/V. Hemodialysis with Qd of 800 mL/min should be considered in selected patients not achieving adequacy despite extended treatment times and optimized Qbs.

An Increased Serum Level of Free Apo(a) in Renal Patients Is More Striking than that of Lp(a) and Is Influenced by Homocysteine

Lipoprotein(a) [Lp(a)] excess combined with hyperhomocysteinaemia and hyperfibrinogenaemia may contribute to the high incidence of vascular diseases in dialysis patients. This study is aimed at investigating the role of free apolipoprotein(a) [fapo(a)] in renal patients. We have been able to show that, as compared with controls (0.53 mg/l), the median serum concentrations of fapo(a) in patients with nephrotic syndrome (2.58 mg/l) and with peritoneal dialysis (3.40 mg/l) were strongly elevated (5- to 7-fold), while the fapo(a) levels in patients undergoing haemodialyis (1.02 mg/l) and after renal transplantation (0.90 mg/l) were about doubled. The observed differences in fapo(a) levels indicate that several mechanisms may increase the level of fapo(a), i.e., reduced renal clearance, enhanced hepatic synthesis, or homocysteine releasing apolipoprotein(a) from Lp(a). In the study collective, the median total homocysteine levels were significantly elevated in all patient groups, stronger in patients on haemodialysis (31.4 µmol/l) and peritoneal dialysis (31.2 µmol/l) than in patients with nephrotic syndrome (19.7 µmol/l) and after renal transplantation (19.5 µmol/l). In transplant patients with adequate renal function and without other apolipoprotein(a)-increasing factors, fapo(a) was significantly increased when total homocysteine exceeded 22 µmol/l. In conclusion, our findings let us presume that an increased fapo(a) level in renal patients possibly could be one of the reasons contributing to the high incidence of vascular diseases in these patients, because fapo(a) not covalently linked with Lp(a) is even more easily able to inhibit the fibrinolytic system than the complete Lp(a). These preliminary results have to be confirmed by further investigations.

Effect of cyclosporin A on carbohydrate metabolism in the rat

Abstract. Liver and kidney carbohydrate metabolism was investigated in rats treated with daily doses of 15 mg/kg body weight cyclosporin A (CyA) for 2 and 8 weeks or of 50 mg/kg body weight CyA for 2 weeks. The higher dosage caused significantly reduced liver glycogen and liver glycogen synthetase activity (of both active I‐form and total enzyme activity), whereas the activity of the glycogen‐degrading enzyme phosphorylase (active a‐form and total activity) remained unchanged. Plasma glucose and glucagon levels, as well as blood ketone bodies of these animals, increased significantly and plasma insulin decreased. In contrast, kidney glycogen and glucose content were higher in rats treated with 50 mg CyA, probably due to enhanced ketone body utilization. Reduced liver glycogen synthetase activity was also found in rats treated with 15 mg CyA. Our data suggest that hypoinsulinemia, induced by CyA, might be a contributing factor to the hyperglycemia, which is mainly due to inhibition of liver glycogen synthesis.

Effects of Acidosis on Acute Phase Protein Metabolism in Liver Cells

Metabolic acidosis has been shown to act as a causative factor in muscle protein breakdown and negative nitrogen balance, as well as in decreased albumin synthesis. Albumin and other acute phase proteins (APP) are mainly synthesized in the liver following induction by interleukins, hormones and other mediators. Acute phase proteins have been shown to be predictors of cardiovascular mortality in the general population and in patients with end stage renal disease (ESRD). Clinical investigation gives evidence that albumin is reduced by acidosis in ESRD patients. The aim of our study was to investigate the role of the liver in acidosis, i.e. the influence of acidosis on metabolic activity and secretion of APP by liver cells (HepG2). Cells were cultured in a medium containing different amounts of bicarbonate. Metabolic activity was significantly diminished when the bicarbonate concentration of the extracellular medium was reduced (86.13±1.90% (pH 7.0) vs. 99.53±90% (pH 7.4); p<0.01). While cellular release of negative APP was significantly decreased (albumin: 4.6±0.41 (pH 7.0) vs. 7.54±0.62 (pH 7.4) [ng/µg protein], p<0.001, transferrin: (0.78±0.08 (pH 7.0) vs. 1.07±0.07 (pH 7.4) [ng/µg protein], p<0.05), no significant influence of acidosis (pH 7.0) on the positive APP, α1-acid glycoprotein (AGP) (1.69±0.25) (pH 7.0) vs. 1.62±0.23 (pH 7.4) [ng/µg protein]), could be shown. Our data indicate that acidosis results in inhibition of liver cell metabolic activity and in reduced secretion of the negative acute phase proteins albumin and transferrin. In contrast, secretion of the positive acute phase protein AGP seems to be unchanged at pH 7.0 as compared to pH 7.4. We conclude that negative and positive APP in liver cells (HepG2) appear to be differently regulated by acidosis.

Rückbildung der Retroperitonealfibrose durch eine Kombinationstherapie von Tamoxifen und Steroiden

Zusammenfassung□ HintergrundDie idiopathische Retroperitonealfibrose ist gekennzeichnet durch eine fortschreitende Proliferation und Fibrosierung retroperitonealen Gewebes. Durch eine zunehmende Kompression und Ummauerung benachbarter Strukturen kommt es dabei im Verlauf der Erkrankung zu zahlreichen Komplikationen.□ FallbeschreibungEs wird über zwei Patientinnen mit einer idiopathischen Retroperitonealfibrose berichtet. Bei beiden Patientinnen mußte im Verlauf der Erkrankung wegen persistierender Harnabflußstörungen eine Harnleiterlateralisation durchgeführt werden. Zusätzlich entwickelte, sich bei den Patientinnen eine Thrombose der Vena iliaca communis bzw. der Vena cava inferior. Aufgrund des fortschreitenden Charakters der Erkrankung wurde eine Therapie mit Tamoxifen in Kombination mit niedrigdosierten Steroiden eingeleitet. Hierunter kam es bei beiden Patientinnen zu einer Regression der retroperitonealen Veränderungen sowie zu einem Rückgang zuvor bestehender Entzündungszeichen.□ SchlußfolgerungBei Patienten mit einer idiopathischen Retroperitonealfibrose scheint Tamoxifen den Verlauf der Erkrankung günstig zu beeinflussen und eine Regression der bindegewebigen Massen induzieren zu können. Bei den von uns beschriebenen Fällen, insbesondere bei Patienten mit persistierender entzündlicher Aktivität der Erkrankung halten wir eine zusätzliche, niedrigdosierte Steroidmedikation zur Vermeidung einer Bindegewebsneubildung für erforderlich.Summary□ BackgroundIdiopathic retroperitoneal fibrosis is characterized by proliferation and fibrosis of retroperitoneal tissue. It is complicated by obstruction and encasement of retroperitoneal structures.□ Case ReportWe describe two female patients with idiopathic retroperitoneal fibrosis. Both had to undergo lateralization of the ureter because of ureteral obstruction. Also both patients developed thrombosis of the inferior vena cava resp. the common iliac vein. Because of the eventful course of the disease a combined tamoxifen and steroid therapy was started. Hereafter there was a marked regression of the retroperitoneal fibrotic masses and the previous inflammatory signs disappeared.□ ConclusionTamoxifen seems to be effective in the treatment of idiopathic retroperitoneal fibrosis by inducing a regression of the fibrotic masses. Especially in patients with continuous activity of the disease we recommend an additional steroid therapy to prevent a regeneration of the fibrosis.BACKGROUND Idiopathic retroperitoneal fibrosis is characterised by proliferation and fibrosis of retroperitoneal tissue. It is complicated by obstruction and encasement of retroperitoneal structures. CASE REPORT We describe two female patients with idiopathic retroperitoneal fibrosis. Both had to undergo lateralization of the ureter because of ureteral obstruction. Also both patients developed thrombosis of the inferior vena cava resp. the common iliac vein. Because of the eventful course of the disease a combined tamoxifen and steroid therapy was started. Hereafter there was a marked regression of the retroperitoneal fibrotic masses and the previous inflammatory signs disappeared. CONCLUSION Tamoxifen seems to be effective in the treatment of idiopathic retroperitoneal fibrosis by inducing a regression of the fibrotic masses. Especially in patients with continuous activity of the disease we recommend an additional steroid therapy to prevent a regeneration of the fibrosis.

Reduction of degranulation of polymorphonuclear leukocytes by immunosuppression in patients following cadaveric renal transplantation

Plasma levels of main granulocyte components of patients after cadaveric renal transplantation were compared 9 days postoperative with the plasma levels of patients undergoing aortofemoral and iliacofemoral bypass operation or abdominal surgery. Lactoferrin values were significantly lower in patients under immunosuppression with cyclosporine and prednisolone, whereas plasma levels of myeloperoxidase were comparable in all 3 groups of patients. Plasma E-alpha 1 PI values were significantly lower in patients undergoing bypass operation compared to abdominal surgery but did not differ from patients undergoing cadaveric kidney transplantation. Within 22 days postoperatively, there was no difference in the plasma levels of main granulocyte components in patients after kidney transplantation with and without postoperative complications. In vitro incubation of heparinized whole blood and isolated granulocytes obtained from healthy subjects in the presence of CsA, azathioprine, or prednisolone were performed. Only CsA caused inhibition of spontaneous degranulation of polymorphonuclear neutrophils showing significant lower elastase and lactoferrin release. However, in vivo administration of CsA and prednisolone in transplant patients displayed no effect on in vitro degranulation of both whole blood samples and isolated granulocytes. Our data demonstrate that CsA after in vitro incubation inhibits spontaneous granulocyte degranulation but not after in vivo administration. However, in vivo administration of CsA and prednisolone reduces lactoferrin release under certain conditions, e.g., postoperative stress or during hemodialysis therapy.

Therapeutischer Plasmaaustausch 1996

Zusammenfassung□ Der therapeutische Plasmaaustausch (TPA) ist ein extrakorporales Blutreinigungsverfahren zur Entfernung großmolekularer Plasmabestandteile. Seit Ende der siebziger Jahre wurde die Plasmapherese bei einer Vielzahl von Erkrankungen eingesetzt, in deren pathophysiologischem Verständnis humoralen Faktoren eine wesentliche Bedeutung zugeschrieben wird.□ Aus heutiger Sicht ist der Plasmaaustausch als adjuvante Therapie nur bei wenigen Entitäten in bestimmten Krankheitssituationen anerkannt: Antibasalmembranerkrankung, TTP/HUS, Guillain-Barré-Syndrom, Hyperviskositätssyndrom, chronische Polyneuropathie bei IgG- und IgA-Gammopathie, chronisch inflammatorische demyelinisierende Polyneuropathie und Myasthenia gravis.Summary□ Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique to remove large molecular weight substances. Since the late seventies TPE was used in a variety of diseases in which humoral factors may play a part in the pathogenesis.□ Today, accepted indications only exist for a few entities in defined situations: Anti-glomerular basement membrane antibody mediated disease, TTP/HUS, Guillain-Barré-syndrome, hyperviscosity syndrome, chronic polyneuropathy associated with IgG and IgA gammopathy, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis.Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique to remove large molecular weight substances. Since the late seventies TPE was used in a variety of diseases in which humoral factors may play a part in the pathogenesis. Today, accepted indications only exist for a few entities in defined situations: Anti-glomerular basement membrane antibody mediated disease, TTP/HUS, Guillain-Barré-syndrome, hyperviscosity syndrome, chronic polyneuropathy associated with IgG and IgA gammopathy, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis.

Was ist geischert in der Prävention der Kontrastmittelnephropathie

Nephropathy is one of the most important side effects of radiocontrast in patients with impaired renal function. Incidence is reported from 20% to 100% depending on underlying disease. For prevention of radiocontrast nephropathy a large number of substances were investigated in experimental and clinical studies. Clinical relevance of this findings will be assessed by this article. In summary of these studies hydration is the most relevant and significant measure for prevention of radiocontrast nephropathy in patients at risk (i.e. serum creatinine > 1.5 mg/dl). 1 ml/kg body weight/h with 0.45% NaCl 12 h before and after administration of radiocontrast should be supplied. Hemodialysis is recommended if impaired renal function (serum creatinine > 3.5 mg/dl) is accompanied by additional risk factors, e.g. diabetes mellitus. The impact of dialysis therapy is not clarified by clinical studies.ZusammenfassungEine der wichtigsten Kontrastmittelnebenwirkungen ist die akute Verschlechterung einer bereits bestehenden Nierenfunktionseinschränkung. Die Inzidenz liegt in Abhängigkeit der Grunderkrankung zwischen 20% und 100%. In experimentellen und klinischen Studien wurden zahlreiche medikamentöse Therapieansätze zur Prävention der Kontrastmittelnephropathie untersucht. In der vorliegenden übersicht werden diese Maßnahmen hinsichtlich ihrer klinischen Relevanz bewertet. Als Schlußfolgerung dieser Studien kann als einzig gesicherte Maßnahme zur Protektion der Kontrastmittelnephropathie bei Risikopatienten (Ausgangskreatinin > 1,5 mg/dl) eine ausreichende Hydratation empfohlen werden. Sie wird mit 1 ml/kg KG/h mittels 0,45% NaCl zwölf Stunden vor und nach Kontrastmittelapplikation durchgeführt. Bei Patienten mit höhergradiger Nierenfunktionseinschränkung (Serumkreatinin > 3,5 mg/dl) und gleichzeitigem Vorliegen einer zusätzlichen Risikokonstellation (zum Beispiel Diabetes mellitus) wird eine Hämodialysebehandlung nach Kontrastmittelgabe empfohlen. Der Wertr der Dialysebehandlung ist allerdings nicht durch kontrollierte Studien gesichert.SummaryNephropathy is one of the most important side effects of radiocontrast in patients with impaired renal function. Incidence is reported from 20% to 100%, depending on underlying disease. For prevention of radiocontrast nephropathy a large number of substances were investigated in experimental and clinical studies. Clinical relevance of this findings will be assessed by this article. In summary of these studies hydration is the most relevant and significant measure for prevention of radiocontrast nephropathy in patients at risk (i. e. serum creatinine > 1,5 mg/dl). 1 ml/kg body weight/h with 0,45% NaCl 12 h before and after administration of radiocontrast should be supplied. Hemodialysis is recommended if impaired renal function (serum creatinine > 3,5 mg/dl) is accompanied by additional risk factors, e. g. diabetes mellitus. The impact of dialysis therapy is not clarified by clinical studies.