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Background Determination of glomerular filtration rate (GFR) using plasma disappearance curves requires the injection of a filtration marker and repeated timed blood collections. Gadolinium-containing contrast media are excreted exclusively by glomerular filtration and could provide a novel approach to quantifying GFR using magnetic resonance (MR) imaging. The aim of this study was to demonstrate the feasibility of measuring GFR by the clearance of gadolinium-containing contrast medium in patients with chronic kidney disease (CKD). Methods Informed consent was obtained from stable CKD patients in stages 1, 2 or 3 (n=16; 5 women, 11 men; median age 54 years). GFR was measured after a bolus injection of gadobutrol (4 mL, approximately 0.05 mmol/kg) and calculated from the washout of the signal intensity obtained over the liver. The obtained MR-GFR was compared with simultaneously measured plasma clearance of inulin and gadobutrol. Results Technical failure occurred in 2 patients. The mean obtained MR-GFR was 71 ± 25 (SD) mL/min per 1.73 m² and agreed well with the mean inulin-GFR (70 ± 24 mL/min per 1.73 m²). Pearson's correlation coefficient was r=0.91. The mean of the paired differences was 1 ± 10 mL/min per 1.73 m² and not significantly different from zero. GFR obtained from gadobutrol plasma clearance also agreed well with inulin-GFR and MR-GFR (r=0.92 and r=0.75, respectively). Conclusions We describe a novel method of determining GFR from MR imaging using a low dose of gadobutrol in patients with reduced GFR that enables the absolute quantification of GFR after routine contrast-enhanced MR imaging.

Background/Aims: Serum- and glucocorticoid-inducible kinase 1 (SGK1) stimulates the epithelial sodium channel (ENaC), renal outer medullary K+ channel 1, Na+/K+-ATPase and presumably the Na+-Cl– cotransporter (NCC). SGK1-deficient mice (sgk–/–) show a compensated salt-losing phenotype with secondary hyperaldosteronism. The present experiments explored the role of SGK1 in the response to diuretics. Methods:sgk1–/– mice and their wild-type littermates (sgk1+/+) were treated with the ENaC blocker triamterene (200 mg/l), the Na+-K+-2Cl– cotransport inhibitor furosemide (125 mg/l), the NCC blocker hydrochlorothiazide (400 mg/l) and the mineralocorticoid receptor blocker canrenoate (800 mg/l) for 8 days. Renal SGK1 expression was studied using quantitative RT-PCR and immunofluorescence. Results: Diuretic treatment increased SGK1 mRNA and protein expression in the kidney of wild-type sgk1+/+ mice. The responses to furosemide, hydrochlorothiazide or canrenoate were not different between sgk1+/+ and sgk1–/– mice, and were accompanied by moderate increases in plasma aldosterone and urea concentrations. However, treatment with triamterene in sgk1–/– mice (but not in sgk1+/+ mice) led to severe, eventually lethal, body weight loss as well as increases in plasma aldosterone, urea and K+ concentrations. Conclusions: SGK1 is required for diuretic tolerance to triamterene. The observations confirm the impaired kaliuretic potency of sgk1–/– mice and point to a role of SGK1 in renal Na+ reabsorption by mechanisms other than ENaC.

HISTORY AND ADMISSION FINDINGS A 54-year-old female patient presented with increasing somnolence since two days. Furthermore, the patient reported left-sided mid-abdominal pain and obstipation for one week. Immediately prior to admission, the patient had returned from a 14-day beach holiday on the Azores. Physical examination of the somnolent patient revealed a sun-tanned skin, signs of exsiccosis, and tachycardia with 116 beats per minute. INVESTIGATIONS Laboratory studies showed marked hypercalcemia due to primary hyperparathyroidism and acute renal failure. Neck ultrasonography revealed a hypoechogenic, 5.8 x 3.5 x 3.1 cm-measuring mass behind the lower pole of the right thyroid lobe. DIAGNOSIS, TREATMENT AND COURSE Serum calcium levels significantly decreased after immediate rehydration, bisphosphonate administration, and continuous hemodialysis that was also indicated because of acute renal failure with anuria. After knowledge of increased parathormone levels the patient underwent rapidly resection of the parathyroid adenoma which was histologically confirmed. CONCLUSIONS Hypercalcemic crisis is often associated with acute renal failure due to calcium-induced polyuria.

With a daily maintenance dose of 0.1 mg digitoxin a mean steady state digitoxin serum concentration of 17.0 +/- 3.2 ng/ml was measured in 10 male probands. When 750 mg of quinidine bisulphate were administered at the same time digitoxin concentration increased significantly to 22.4 +/- 4.2 ng/ml (P less than 0.0005). The serum half life of digitoxin during quinidine treatment was significantly increased to 10.8 +/- 2.1 days compared to a control group with 7.6 +/- 1.6 days (P less than 0.0025). Protein binding of digitoxin, renal digitoxin excretion and renal digitoxin clearance were equally uninfluenced by quinidine as were endogenous creatinine clearance and sodium and potassium excretion in urine. In two patient with cardiac insufficiency there was likewise a significant increase in digitoxin serum concentration. For clinical application of combined therapy of quinidine and digitoxin the danger of digitalis intoxication seems to be less in comparison to digoxin as increase of digitoxin concentration in serum is lower than of digoxin.

Two hundred digitalized patients under nine freely practising physicians were investigated. One hundred and ninety-six patients received digoxin or one of its derivatives. Of these, 50% did not have therapeutic serum glycoside concentrations, 48% were in the mostly subtherapeutic range and 2% were in the potentially toxic range. Signs of glycoside intoxication were not found. A substantiated indication for glycoside therapy was found in the final analysis in 55% of the patients. In 128 patients, the methyldigoxin dose calculated (0.16 +/- 0.030 mg/d) was markedly in excess of that actually prescribed (0.13 +/- 0.050 mg/d; p less than 0.001), so that there were indications of a general underdigitalization. In addition, it was not possible to anchor the restrictive kidney function as a reason for reduction of digoxin dosage in the prescription behavior. In the long run, only 36% of the patients with justified indication and therapeutic serum glycoside concentration as well as (with reservations) the 3% with potentially toxic serum glycoside concentration profited from the glycoside therapy.

A prospective, randomized efficacy study of low-dose enalapril was undertaken in 38 outpatients (24 men, 14 women; mean age 58 [41-69] years) with chronic heart failure (NYHA functional class III-IV). All patients were pretreated with digitalis and diuretics, some also with conventional vasodilators. 19 patients (group E) received in addition to their previous medication, 5 mg enalapril daily, while the other 19 (group K) continued with their previous therapy. Three months later, 15 patients in group E improved by at least one NYHA functional class and none died (P less than 0.02). Four patients in group K died and only one patient improved by one class. After three months, left ventricular ejection fraction was significantly higher (P less than 0.0001) in group E (39 +/- 19%) compared to group K (30 +/- 14%). In group E, plasma aldosterone concentration decreased significantly (P less than 0.0001) by 33.4 +/- 6.5 ng/dl, while in group K no significant change occurred (delta 1.1 +/- 1.2 ng/dl). Thus, low-dose enalapril in addition to conventional therapy may improve the clinical status of patients in severe chronic heart failure. This improvement is associated with an increase in left ventricular ejection fraction and reduction in secondary hyperaldosteronism.

Amyloidosis with renal involvement was diagnosed in a 52-year-old man with Crohn's disease for 15 years. A severe nephrotic syndrome developed (proteinuria 40 g daily) with oedema and arterial hypotension (80/60 mm Hg). As adequate substitution treatment was not possible an attempt at medical renal ablation was made with a combination of captopril (25 mg daily), frusemide (80 mg daily) and indomethacin (200 mg daily). The proteinuria decreased to 18 g daily, but serum creatinine concentration rose to 5.8 mg/dl so that chronic haemodialysis had to be undertaken. Yet the patient's clinical state hardly improved and, because of his poor general condition, bilateral nephrectomy was contraindicated. In consequence bilateral catheter embolization of the renal arteries was performed. The urinary protein loss fell at once to 0.5 g daily. Serum protein rose from 3.1 g/dl under substitution to 5.7 g/dl without. During the following six months, while on chronic haemodialysis, the nephrotic syndrome did not recur. However, cardiac involvement in the amyloidosis was demonstrated so that the prognosis is poor. Permanent bilateral embolization of the renal arteries is a feasible method of managing a treatment-resistant nephrotic syndrome in selected patients.

An ultrasound investigation was undertaken of the neck region of 42 patients with normal neck anatomy in order to determine whether the results of ultrasound-gained topographical data provided pointers to the choice of entry site to the internal jugular vein (IJV). In addition, the IJV was punctured under ultrasound control in 23 patients in an intensive care unit in whom there was a problem of increased bleeding tendency, anatomical difficulty or previously failed "blind" puncture. In all of them a central venous catheter was placed without complication by the Seldinger technique via the primary chosen point for puncture. An approach through the sternocleidomastoid muscle, between the cricoid level and the "central" place of puncture between the two bellies of the sternocleidomastoid muscle proved to be the most satisfactory compromise between easy application of the ultrasound head, large vein diameter and reduction of any risk of mistakenly puncturing artery or pleura. This approach has to be varied according to the ultrasound findings. It is concluded from this experience that ultrasound is suitable for the placement of central venous catheters. But since the equipment is bulky it cannot be used in an emergency.

BACKGROUND AND OBJECTIVE In patients with chronic glomerular nephropathy associated arterial hypertension and proteinuria are considered to be cardinal risk factors in the progressive deterioration of renal function. Treatment regimens which reduce proteinuria and hypertension improve prognosis. The effect of the new beta-receptor blockers compared to common ACE-Inhibitors is of special interest. PATIENTS AND METHODS The studied cohort consisted of 11 patients with CGN, hypertension and proteinuria > 400 mg/24 h. Four drugs were given for 4 weeks, doubly blinded and randomized according to a "Latin-square design": Celiprolol (beta-1-antagonist, beta-2-agonist, 200 mg/d), Atenolol (selective beta-1-antagonist, 50 mg/d), Ramipril (ACE-inhibitor, 2.5 mg/d) and placebo. There was a two-week wash-out phase between each of the four treatment phases. At the end of each treatment phase glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and para-amino-hippuric acid (PAH) clearance. Proteinuria was determined in the course of a three-day collection period at the end of each treatment phase. During this period blood pressures were measured with a continuous 24-hour blood pressure monitor. RESULTS Mean arterial blood pressure (MAP) was significantly reduced, compared with placebo, by all three antihypertensives (108 +/- 9 mm Hg with placebo, 98 +/- 12 mg Hg with atenolol, 101 +/- 11 mm Hg with celiprolol and 98 +/- 8 mm Hg with ramipril; P < 0.01). Celiprolol produced a significant rise In ERPF (322 +/- 109 ml/min with placebo, 391 +/- 110 ml/min with celiprolol: P < 0.05). GFR was slightly, but not significantly, reduced by celiprolol and atenolol. Filtration fraction remained unchanged with atenolol and celiprolol, while it was slightly, but not significantly, reduced with ramipril. Compared with the placebo, all three drugs significantly reduced proteinuria (P < 0.05): 1.8 +/- 1.3 g/24 h with placebo, 1.2 +/- 1.2 g/24 h with atenolol, 1.2 +/- 1.1 g/24 h with celiprolol and 1.4 +/- 1.4 g/24 h with ramipril. CONCLUSION These data indicate that, in addition to ACE inhibitors, the new generation of beta-receptor blockers in particular, because of their vasodilator action, favourably influence proteinuria and renal blood flow in patients with CGN and arterial hypertension.

The relationship between blood-lipid levels and severity of proteinuria was examined retrospectively in 30 patients (12 males, 18 females; mean age 39 [18-58] years). All patients had histologically confirmed glomerulonephritis (minimal change: n = 7, perimembranous: n = 8, focal sclerosing: n = 6, rapid progressive: n = 3, mesangio-proliferative: n = 4, membrano-proliferative: n = 1, diabetic glomerulosclerosis: n = 1). None was taking lipid-lowering drugs. Patients were classified according to the degree of proteinuria. In group 1 (proteinuria less than 5 g/d, n = 13) the LDL-HDL ratio averaged 4.4; in group 2 (proteinuria 5.0-10.0 g/d, n = 10) the average ratio was 8.8, and in group 3 (proteinuria greater than 10.0 g/d, n = 7) 13.3. Total cholesterol concentration also rose with increasing proteinuria (to 300 +/- 87 mg/dl, 375 +/- 168 mg/dl and 464 +/- 143 mg/d, respectively). The size of the LDL-HDL ratio and the level of total cholesterol did not correlate with the degree of excretory renal failure. These results point to an impressive correlation between the degree of proteinuria and the level of LDL-HDL ratio as a measure of atherogenic risk for a given patient.

The effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.

Several studies have implicated a remarkable dysfunctional apoptotic state and/or response in ESRD patients. Previously published studies are controversial with respect to acute effects of haemodialysis (HD) treatment on up- or downregulation of apoptotic genes. Twenty-eight chronic HD patients were haemodialysed for 4 hours with a 4008 dialyser using high-flux membranes. For subgroup analysis, patients were separated into a low (up to 0.5 mg/dl) and a high (0.5 to 5.0 mg/dl) CRP group. Blood was drawn prior to HD and 240 min after initiation of HD. Acute changes of transcript levels encoding pro- or anti-apoptotic genes were analyzed in RNA immediately isolated from blood leukocytes using quantitative real-time PCR. In the present study, we detected a significant elevation of the death receptor CD95/Fas (induction factor (IF) 1.55 +/- 0.16), the death receptor 5 (DR5) (IF 1.17 +/- 0.08), and caspase 8 (IF 1.37 +/- 0.14) gene expression during HD. mRNA levels of the respective ligands (CD95L, TRAIL), of the caspase 5 and anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl2l2 were slightly, but not significantly, increased after HD treatment. An additional anti-apoptotic molecule, BAG3, was found to be slightly, but significantly, induced after HD (IF 1.16 +/- 0.07). In addition to being an activator of immune cells, CD40L has been shown to be strongly induced after HD treatment (IF 1.70 +/- 0.20). Subgroup analysis revealed no significant differences between low vs. high CRP patient groups or diabetic vs. non-diabetic patients. These results indicate a marked influence of routine haemodialysis treatment on the transcription of pro- and anti-apoptotic molecules and the involvement of the extrinsic pathway for apoptosis through the activation of death receptors and the initiator caspase 8. Furthermore, following dialysis, lymphocytes seem to be activated by CD40L, which represents an early T-cell activation marker.

Background. Renal anaemia is caused by a relative erythropoietin (EPO) deficiency. Due to difficult interpretation of serum EPO concentrations adapted to anaemia and renal function, the diagnostic value of measuring serum EPO concentrations is limited. Methods. We retrospectively analysed the relationship between haemoglobin and serum EPO concentrations routinely measured in in- and out-patients of our university hospital from 2001–04. Patients under EPO substitution or those with acute renal failure, polycystic kidney disease, renal carcinoma or polycythaemia due to pulmonary disease were excluded. The study population (n ¼ 500) was then stratified according to the presence or absence of chronic kidney disease (CKD) and to the stage if CKD was present. EPO concentrations were expressed in percentiles corrected for the severity of anaemia and based on the EPO response in patients without CKD. Results. In patients without CKD (n ¼ 167) there was a strong parametric correlation between severity of anaemia and increase in EPO (r ¼� 0.81). Linear regression of the log-transformed EPO values revealed the equation log EPO (mIU/ml) ¼� 0.135 � Hb (g/dl) þ 2.821 (r 2 ¼ 0.65). With increasing stages of CKD the correlation between haemoglobin and EPO concentrations was gradually attenuated and was completely lost in CKD stage four and five. In anaemic patients with Hb < 11 g/dl, relative EPO deficiency defined as EPO concentrations below the 25th percentile was present in 38%, 67%, 93% and 100% of the patients with CKD stages 1–5, respectively. Conclusions. Expression of EPO concentrations in percentiles improves the diagnostic value of measuring EPO concentrations for diagnosing relative EPO deficiency and renal anaemia.

PURPOSE In this volunteer study, 2 navigator-gated strongly T1-weighted saturation-recovery (SR) sequences, a turbo fast low angle shot (TurboFLASH) and a new true fast imaging in steady precession (TrueFISP) readout technique, were compared for suitability in dynamic magnetic resonance nephrography. MATERIALS AND METHODS Ten healthy volunteers (mean age 26.1 +/- 3.6) were equally divided into 2 subgroups. After bolus-injection of 3.75 mL of gadobutrol (approximately 0.05 mmol/kg body weight), slightly obliqued coronal single-slice images of the kidneys were recorded every 4-5 seconds during free breathing using 1 of the 2 sequences. Time-intensity curves were determined from manually drawn regions-of-interest over the kidney parenchyma. Both sequences were subsequently evaluated with regard to linearity of signal, signal to noise ratio (SNR), and time-dependent behavior of signal intensity curves. RESULTS : The TurboFLASH readout showed better linearity of the signal behavior as compared with the TrueFISP technique (TurboFLASH: no deviation from linearity down to T1 = 400 milliseconds; TrueFISP at T1 = 700 milliseconds: 12% deviation, at T1 = 400 milliseconds: 19%). The time-intensity curves of the TrueFISP sequence exhibited distinctly lower variability than the TurboFLASH approach. The SNR increased with TrueFISP by 3.4 +/- 0.5-fold for native renal parenchyma and by 3.3 +/- 0.9 for contrast-enhanced renal parenchyma. For split renal function evaluation, the linear regression to the signal increase in the first minutes after the first pass could be performed with higher reliability using the TrueFISP technique (increase of correlation coefficient by 17.1%). CONCLUSION A SR navigator-gated TrueFISP sequence seems most favorable for dynamic magnetic resonance nephrography due to the high signal yield and low curve variability.

Syphilitic disease is uncommon, but its incidence has increased worldwide in the last few years. An unusual manifestation of secondary syphilis after orthotopic liver transplantation is described which confirms that lues should be considered in patients with immune deficiency and abnormal liver function tests.

Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality.To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice.In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m2, systolic BPor= 140 mmHg and/or diastolic BPor= 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks.At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of beta-blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT-I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline (p0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (1% of patients) were dry cough and nausea.The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.

Mineralocorticoids stimulate renal tubular Na(+) reabsorption, enhance salt appetite, increase blood pressure, and favor the development of renal fibrosis. The effects of mineralocorticoids on renal tubular Na(+) reabsorption and salt appetite involve the serum- and glucocorticoid-inducible kinase 1 (SGK1). The kinase is highly expressed in fibrosing tissue. The present experiments thus explored the involvement of SGK1 in renal fibrosis. To this end, SGK1-knockout mice (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)) were implanted with desoxycorticosterone acetate (DOCA)-release pellets and offered 1% saline as drinking water for 12 weeks. The treatment led to significant increases in fluid and Na(+) intake and urinary output of fluid and Na(+) in sgk1 (+/+) mice, effects blunted in sgk1 (-/-) mice. Blood pressure increased within the first 7 weeks to a similar extent in both genotypes, but within the next 5 weeks, it increased further only in sgk1 (+/+) mice. Creatinine clearance did not change significantly but albuminuria increased dramatically in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. Histology after 12 weeks treatment revealed marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys from sgk1 (+/+) mice, but not from sgk1 (-/-) mice. In conclusion, a lack of SGK1 protects against DOCA/high-salt-induced albuminuria and renal fibrosis.

Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and acute renal failure. Lack of complement inactivating factor H predisposes to the development of atypical HUS. Little is known about mechanisms linking complement activation with loss of erythrocyte integrity during HUS. Recent studies disclosed that increased cytosolic Ca2+ activity and cellular ceramide trigger programmed erythrocyte death or eryptosis, characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. In the present study, we investigated whether eryptosis occurs during the course of HUS. To this end, erythrocytes from healthy volunteers were exposed to plasma from a patient with severe idiopathic recurrent HUS secondary to factor H depletion. Phosphatidylserine exposure (Annexin binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence), and ceramide formation [anti-ceramide antibody and enzymatic (diacylgycerol kinase) analysis] were determined. Exposure of erythrocytes to plasma from the patient, but not to plasma from healthy individuals, triggered Annexin binding. The effect of plasma on erythrocyte Annexin binding was abolished by plasmapheresis or filtration at 30 kDa. It was paralleled by formation of ceramide and increase of cytosolic Ca2+ activity. Enhanced Annexin binding of erythrocytes from healthy individuals was observed after exposure to plasma from three other patients with HUS. The proeryptotic effect of patient plasma was mimicked by exposure to the Ca2+ ionophore ionomycin, and eryptosis was potentiated in the presence of cell membrane-permeable C6-ceramide. Furthermore, in vitro complement activation similarly triggered erythrocyte phosphatidylserine exposure, an effect which was blunted by the addition of factor H. In conclusion, our present observations disclose a novel, pathophysiological, factor-H dependent mechanism leading to injury of erythrocytes during the course of hemolytic uremic syndrome.

Serum- and glucocorticoid-inducible kinase (SGK) 1 and SGK3 share the ability to upregulate several ion channels, including the epithelial Na+ channel. Whereas SGK1 is under genomic control of mineralocorticoids and glucocorticoids, SGK3 is constitutively expressed. The SKG1-knockout ( sgk1−/−) mouse is seemingly normal when it is fed a standard diet, but its ability to retain NaCl is impaired when it is fed a salt-deficient diet. In the SGK3-knockout ( sgk3−/−) mouse fed standard and salt-deficient diets, hair growth is strikingly delayed but NaCl excretion is normal. Thus the possibility was considered that SGK1 and SGK3 could mutually replace each other, thus preventing severe NaCl loss in sgk1−/− and sgk3−/− mice. We crossed SGK1- and SGK3-knockout mice and compared renal electrolyte excretion of the double mutants ( sgk1−/−/ sgk3−/−) with that of their wild-type littermates ( sgk1+/+/ sgk3+/+). Similar to sgk3−/− mice, the sgk1−/−/ sgk3−/− mice display delayed hair growth. Blood pressure was slightly, but significantly ( P < 0.03), lower in sgk1−/−/ sgk3−/− (102 ± 4 mmHg) than in sgk1+/+/ sgk3+/+ (114 ± 3 mmHg) mice, a difference that was maintained in mice fed low- and high-salt diets. Plasma aldosterone concentrations were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− than in sgk1+/+ sgk3+/+ mice fed control (511 ± 143 vs. 143 ± 32 pg/ml) and low-salt (1,325 ± 199 vs. 362 ± 145 pg/ml) diets. During salt depletion, absolute and fractional excretions of Na+ were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− (1.2 ± 0.2 μmol/24 h g body wt, 0.12 ± 0.03%) than in sgk1+/+/ sgk3+/+ (0.4 ± 0.1 μmol/24 h g body wt, 0.04 ± 0.01%) mice. The sgk1−/−/ sgk3−/− mice share the delayed hair growth with sgk3−/− mice and the modestly impaired renal salt retention with sgk1−/− mice. Additional lack of the isoform kinase does not substantially compound the phenotype for either property.

Clinical assessment of glomerular filtration rate (GFR) mainly relies on single determinations of serum creatinine (crea) which is commonly insensitive to mild renal dysfunction. Serum cystatin C (cysC) has been proposed as an alternative endogenous marker of GFR showing higher correlation to standard clearance methods such as inulin or iohexol clearance. We compared serum crea and cysC levels in n=127 patients undergoing cardiac catheterization. The clearance of the iodinated contrast dye iopromide served as reference method for GFR. Serum cysC was determined by a particle-enhanced immunonephelometric method. CysC showed higher non-parametric correlation (r=0.805) to the iopromide clearance compared to crea (r=0.652) and to the estimated GFR according to the Cockcroft-Gault formula (r=0.690), which underestimated true GFR systematically. Receiver operating curves revealed a greater area-under-the-curve (AUC) for cysC (0.957 vs. 0.801, p0.05). At a cut-off level of1.3 mg/l cysC exhibited an 88% sensitivity and a 96% specificity for detecting renal dysfunction which was defined as an iopromide clearance less than 80 ml/min/1.73 m2; best values for crea were 63% for sensitivity and 80% for specificity at a cut-off of1.2 mg/dl. In conclusion, cysC detected reduced GFR more reliably and at an earlier stage in patients undergoing cardiac catheterization allowing a better identification of patients with renal dysfunction and those at risk for contrast damage.

Background. The activation of both the renin–angiotensin–aldosterone and endothelin (ET) system in uremia contributes to the development of cardiovascular disease. The combination of ET receptor antagonists and inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II type 1 (AT1) receptor could therefore inhibit atherogenesis. We studied the effects of different medications on growth-factor-induced proliferation of vascular smooth muscle cells (VSMC) isolated from uremic rats. Methods. Subtotally nephrectomized rats (SNX) were treated with an ETA receptor antagonist, losartan, trandolapril, or the combinations of an ETA receptor antagonist and losartan or trandolapril for 12 weeks. Proliferation induced by different growth factors in isolated aortal SMC was measured using a BrdU-ELISA. Results. Maximum proliferation in response to PDGF-BB, bFGF, and TNF-α which was higher in untreated SNX than in controls (PDGF-BB: 486.60 ± 8.27% versus 346.74 ± 4.60%, n = 8), was reduced after monotherapy ...

Background. Cardiovascular disease is the most important cause of death in patients with end-stage renal disease. In uraemia, the renin–angiotensin– aldosterone and endothelin (ET) systems are activated. It is not known whether inhibition of these systems attenuates the proliferation of isolated smooth muscle cells of uraemic rats. Methods. Subtotally nephrectomized (SNX) rats were treated with an ETA receptor antagonist, an ETAB receptor antagonist, the angiotensin type 1 (AT1) receptor antagonist losartan (all 10 mg/kg body weight/day) or the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.1 mg/kg body weight/ day) or received no medication (SNX) for 12 weeks. Then, aortal smooth muscle cells (SMCs) were isolated and cultivated. After incubation of SMCs with different growth factors (5–7 days), proliferation was measured using a bromodeoxyuridine enzyme-linked immunosorbent assay (BrdU ELISA). Results. Higher maximum levels of proliferation were found in SMCs from untreated SNX rats than in SMCs from control animals [platelet-derived growth factor-BB (PDGF-BB) 486.60±8.27 vs 346.74±4.60%, basic fibroblast growth factor (bFGF) 176.68±6.50 vs 123.71±1.49%, tumour necrosis factor-a (TNF-a) 153.38±10.16 vs 122.27±1.41%]. Treatment with ET receptor antagonists or losartan attenuated growth factor-stimulated proliferation (PDGF-BB: ETA receptor antagonist, 135.71±1.08%; ETAB receptor antagonist, 122.72±0.58%; losartan: 103.69±1.83%, n ¼ 8). SMCs from trandolapril-treated rats showed an increased response (PDGF-BB 663.48±7.00%, n ¼ 8). Conclusions. Treatment of SNX rats with ET receptor antagonists or losartan reduced growth factor-induced SMC proliferation in vitro. However, further investigations with uraemic patients have to clarify whether angiotensin or ET receptor antagonists inhibit the development of atherosclerosis.

Background. There is an ongoing discussion about the risks of di(2-ethylhexyl) phthalate (DEHP) exposure for the general population as well as for specific subgroups in various medical settings. Haemodialysis patients certainly belong to the group with the highest exposure taking into account the repeated treatments over a long period of time. Many studies have shown that DEHP metabolites are more active with regard to cellular responses than DEHP itself. Although 4-heptanone has been shown to be a DEHP metabolite in rats, this has never been tested in humans. On the other hand, 4-heptanone was reported to be associated with diabetes mellitus. Methods. After establishing analytical methods for all postulated metabolites, we analysed (i) plasma samples from 50 patients on haemodialysis and 50 controls; (ii) urine samples from 100 diabetic patients and 100 controls; and (iii) urine samples from 10 controls receiving DEHP intravenously. Results. 4-Heptanone concentrations in urine did not differ between controls (128.6±11.4mg/l, mean± SEM) and diabetic patients (131.2±11.6mg/l) but were significantly elevated in plasma from haemodialysis patients (95.9±9.6mg/l) compared with controls (10.4±0.5mg/l). Exposure to DEHP led to a significant increase (P

Background. To determine whether gadolinium-based contrast media (CM) could be used safely for angiographies in patients with renal dysfunction we investigated renal function after gadobutrol exposure and compared the results with standard iodinated CM (iohexol) in a randomized clinical study. Methods. Twenty-one patients (aged 67±11 years, nine female and 12 male) with severely impaired renal function [mean serum creatinine 3.2±1.3 mg/dl, mean glomerular filtration rate (GFR) 31±16 ml/ min/1.73 m 2 ] who needed to have angiography because of severe peripheral vascular disease, renal artery stenosis or aortic aneurysms were randomized to receive in a blinded manner either gadobutrol (Gadovist 1.0 mmol/ml) or iohexol (Omnipaque 350) as contrast agents. GFR was measured by CM clearance (Renalyzer) at baseline and 48 h after CM administration. The primary end point was the mean change of GFR from baseline at 48 h, the secondary one the incidence of CM-induced acute renal failure, defined as a decrease in GFR of >50% from baseline within 48 h of CM administration. Results. In the gadobutrol group (n ¼ 10) we observed a statistically significant decrease in GFR of 10.6± 13.8 ml/min/1.73 m 2 within 48 h after CM administration (P

BACKGROUND Hydration is a commonly used method to prevent the decline in GFR after contrast media (CM) application. So far, there have been no controlled, randomized trials investigating the most effective route of fluid administration. METHODS Thirty-nine patients with normal renal function (65 +/- 9 years, serum creatinine 0.9 +/- 0.2 mg/dl, GFR = 110 +/- 31 ml/min/1.73 m2) receiving at least 80 ml of low-osmolality CM during an angiographic procedure were randomized to one of the following hydration regimens: Group 1: volume expansion with 300 ml saline during CM administration (n = 20, serum creatinine 0.8 +/- 0.1 mg/dl, GFR 119 +/- 27 ml/min/1.73 m2); Group 2: intravenous administration of at least 2,000 ml saline within 12 h before and after CM application (n = 19, serum creatinine 0.9 +/- 0.2 mg/dl, GFR 101 +/- 32 ml/min/1.73 m2). GFR was measured by CM clearance (Renalyzer) at baseline and 48 hours after CM administration. The primary end point was the mean change in the GFR after 48 hours, the secondary one was the incidence of CM-induced nephropathy (CMIN), defined as a decrease in GFR of more than 50% from the baseline GFR within 48 hours. RESULTS Patients of group 1 showed a significantly (p < 0.05) higher decline in GFR (delta GFR 34.6 +/- 25.7 ml/min/1.73 m2) compared to patients receiving the intravenous prehydration regimen (delta GFR 18.3 +/- 25.0 ml/min/1.73 m2). The incidence of CMIN was lower in prehydrated patients (5.3%) compared to the other group (15%). CONCLUSION In patients with normal renal function, intravenous prehydration seems to be a very effective and feasible method to prevent the decline in GFR after contrast media exposure. Volume expansion given only during the CM exposure appears not to be sufficient enough to prevent renal damage.

Blood pressure, together with proteinuria, represents one of the most important factors in the progression of chronic renal failure (CRF). Antihypertensive therapy is beneficial to slow down the progression of a variety of chronic renal diseases, no matter what the cause. Intraglomerular hypertension, increased glomerular permeability and proteinuria should be identified, since they can be treated to prevent or minimize further glomerular injury. But not all antihypertensive drugs are equally effective to prevent the progression of CRF. Recent large trials indicate that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in diabetic and nondiabetic renal diseases. In nondiabetic patients, the AIPRI and REIN studies support that angiotensin-converting enzyme (ACE) inhibitors have a long-term renoprotective effect. The benefits of ACE inhibitors can be demonstrated even in patients who are not hypertensive. Angiotensin II receptor antagonists are shown to be renoprotective in type 2 diabetics (RENAAL and IDNT). However, whether these renoprotective effects are due to blood pressure reduction or due to the specific pharmacologic RAAS blockade is still a matter of debate. This discussion is still open, because the reduction in blood pressure levels was lower in patients treated with a drug that interferes with the RAAS compared with other antihypertensive regimens. It is concluded that both ACE inhibitors and AT II receptor antagonists are lowering the intraglomerular pressure independent of any change in systemic blood pressure by dilatation of the efferent arteriole of the glomerulus. These additional nonpressure-related effects may protect renal function by their antiproteinuric effect. In addition, beneficial effect of ACE inhibitors are related to reduction of AT II, which has potent proinflammatory effects independent of its hemodynamic influences. Other drugs, such as diuretics, beta blockers, and hydralazine, do not induce efferent dilatation and, therefore, may be less likely to reverse intraglomerular hypertension. For example, hydralazine and nifedipine appear to produce prominent afferent or preglomerular arteriolar dilatation. This will allow more of the systemic pressure to be transmitted to the glomerulus. Therefore, short-acting dihydropyridine calcium channel blockers (CCB) are not recommended. By comparison, long-acting dihydropyridines such as diltiazem and verapamil are less potent vasodilators and may primarily decrease the resistance of the efferent arteriole, similar to the ACE inhibitors. They may have an antiproteinuric activity. Yet, there is lack of large prospective randomized trials.A beta blocker as antihypertensive agent is indicated as second- or third-line drug especially in patients with additional cardiovascular disease. Other antihypertensive drugs can be added as necessary to achieve the treatment goals for arterial hypertension. The use of a diuretic will often be helpful in patients who already have renal insufficiency, since fluid overload is an important cause of hypertension and may also enhance the effectiveness of drugs that interfere with the RAAS. alpha(1)-receptor or sympathetic blockers are further possible drugs for combination antihypertensive therapy.

Background: The therapy of nephrotic syndrome in focal segmental glomerulosclerosis (FSGS) is still a matter of controversy. Methods: We performed a prospective randomized study of the treatment of nephrotic syndrome due to FSGS. We compared 2 specific treatment protocols to assess the effect of treatment on proteinuria and renal function. Fifty-seven patients were randomly assigned to 2 groups: group 1 (n = 34) received steroids and cyclosporine, and group 2 (n = 23) received steroids and chlorambucil for 6 months. When treatment was refractory to chlorambucil, the patients in this group were treated with cyclosporine. Creatinine, blood urea nitrogen, proteinuria, lipids, and arterial hypertension were monitored at regular intervals. Results: Patients showed a mean serum creatinine of 1.5 ± 0.2 mg/dL (132.6 ± 17.7 μmol/L) and proteinuria of 4.8 ± 2.8 g/24 h with no differences between the groups. At the end of the chlorambucil therapy, patients in group 2 had creatinine levels of 1.8 ± 0.6 mg/dL (159.1 ± 53 μmol/L) and proteinuria levels of 3.4 ± 1 g/24 h. All patients in this group were given cyclosporine. After 4 years the mean creatinine level in group 1 was 1.7 ± 0.4 mg/dL (150.3 ± 35.4 μmol/L) and the proteinuria level was 2.5 ± 1 g/24 h. In group 2, the mean creatinine level was 1.9 ± 0.6 mg/dL (168 ± 53 μmol/L) (not significant [NS]) and the mean proteinuria level was 2.3 ± 1.1 g/24 h (NS). Full remission occurred in 23% of the patients in group 1 (n = 8) and 17% of the patients in group 2 (n = 4; NS). Partial remission was observed in 38% of the patients in group 1 (n = 13) and 48% in group 2 (n = 11; NS). The number of patients who developed end-stage renal disease was comparable in both groups: 4 of 34 patients in group 1 after 2.5 ± 0.8 years, and 5 of 23 patients in group 2 (NS). Conclusion: Additional treatment with chlorambucil was found to be ineffective in FSGS. Patients responded to treatment with steroids or cyclosporine, but additional treatment with chlorambucil did not improve the patient's outcome. Future studies must focus on the long-term prognosis of these patients.

Background: Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with chronic renal failure undergoing dialysis therapy. Aim of the study was to evaluate whether there is a correlation between a past infection with Chlamydia pneumoniae inducing antibody production and the manifestation of symptomatic atherosclerotic disease in patients with chronic renal failure on hemodialysis. Methods: A retrospective study was designed including 151 dialysis patients with a clinical apparent atherosclerotic disease (case subjects) and 116 dialysis patients without any symptomatic atherosclerotic manifestation (control group). An ELISA was used to measure seropositivity for IgA and IgG titers. Results: Elevated IgA titers against Chlamydia pneumoniae were found in 67% of the case subjects, but only in 29% of the controls (OR 5.34, CI 2.98 - 9.56). Forty-five patients of the case subjects had a history of myocardial infarction (OR 5.14, CI 2.38 -11.09). Prior stroke was found in 30 patients in case subjects (OR 4.37, CI 1.73 -- 11.01). The follow-up after 3 years showed that only 20 patients died from cardiovascular disease in the control group in comparison to 57 patients in the case group (OR 2.51). IgG seropositivity revealed an OR of 1.02 (CI 1.0 - 2.1 ). Conclusion: These results indicate that IgA seropositivity is associated with an increased frequency of symptomatic atherosclerotic manifestations. Especially an increased number of patients was found with prior myocardial infarction or stroke when elevated IgA titers were detected. IgA positivity seems to be a separate prospective risk factor in patients with chronic renal failure and hemodialysis for premature cardiovascular death.

Hintergrund: Die sympathische Aktivitat stellt einen negativen Pradiktor der chronischen Herzinsuffizienz dar und ist mit einer erhohten Mortalitat verbunden. Die Verabreichung der β-Rezeptoren-Blocker Carvedilol, Metoprolol oder Bisoprolol fuhrt zu einer Verbesserung der Prognose dieser Patienten. Ziel: Ziel dieser Pilostudie war, die Vertraglichkeit und die Veranderung der linksventrikularen Ejektionsfraktion unter einer Behandlung mit dem β-Blocker Nebivolol bei Patienten mit chronischer Herzinsuffizienz zu untersuchen. Patienten und Methodik: Zwolf Patienten mit Herzinsuffizienz und einer Ejektionsfraktion zwischen 13 und 39% wurden in einer doppelblinden, plazebokontrollierten, randomisierten Studie entweder mit Nebivolol oder Plazebo zusatzlich zu einer Standardtherapie behandelt. Bestimmt wurden die Vertraglichkeit, die korperliche Belastungsdauer und Leistung, der Blutdruck, die Herzfrequenz, das NYHA-Stadium und die linksventrikularen Funktionsparameter mittels Echokardiographie. Die Untersuchungen wurden bei Einschluss in die Studie und 3 Monate nach oraler Therapie mit Nebivolol (2,5–5 mg, n = 6) oder Plazebo (n = 6) durchgefuhrt. Ergebnisse: Nebivolol wurde sehr gut vertragen, die NYHA-Klassifikation verbesserte sich bei vier Patienten. Die Herzfrequenz sank, wahrend die maximale Dauer der Belastung sowie die Leistungsstufe konstant blieben. Die linksventrikulare Funktion war nach 12-wochiger Therapie mit Nebivolol verbessert (Ejektionsfraktion Nebivolol: Anstieg von 29,8 ± 10,66% auf 41,2 ± 10,53%, p = 0,007; Plazebo: Anstieg von 29,7 ± 5,01% auf 35,7 ± 9,54%; n. s. Der linksventrikulare endsystolische Diameter sank nach Nebivololbehandlung von 56,5 ± 9,40 mm auf 50,2 ± 9,43 mm (p ≤ 0,02). Schlussfolgerung: Diese Daten weisen darauf hin, dass Nebivolol gut vertragen wird und moglicherweise die linksventrikulare Funktion bei Patienten mit chronischer Herzinsuffizienz verbessert.

Apheresis has been effective as rescue therapy in patients with severe, therapy-resistant, systemic lupus erythematosus (SLE). Its benefit in patients with less severe but therapy-resistant SLE is not known. Dextran sulfate apheresis was applied as a rescue therapy for therapy-resistant vasculitic skin lesions in a 30 year old female patient with a 9 year history of SLE in combination with antiphospholipid syndrome and Raynaud's phenomenon. Partial remission was achieved after 9 immunoadsorption sessions, as documented by marked improvement of skin lesions and an increase of capillary density in the nailfold area. Further improvement was noted with maintenance therapy using mycophenolate mofetil. Dextran sulfate apheresis can be applied safely in patients with moderate therapy-resistant SLE disease activity when severe immunodeficiency and cytotoxic adverse effects should be avoided.

Die Therapie der Glomerulonephritis ist kompliziert, weil das klinische Bild sehr unterschiedlich sein kann. Eine akute Nephritis, ein nephrotisches Syndrom oder lediglich eine geringe Proteinurie oder Hamaturie konnen Ausdruck einer Glomerulonephritis sein. Die Indikation zu einer symptomatischen Therapie kann vom klinischen Bild abgeleitet werden, eine immunsuppressive Therapie setzt eine histologische Diagnose voraus, um die mogliche Differenzialtherapie abzudecken. Die sofortige Therapie einer rapid-progressiven Glomerulonephritis kann den Patienten vor der Dialyse bewahren. Ein nephrotisches Syndrom wird entsprechend dem klinischen Verlauf zuerst symptomatisch; bei histologischen oder klinischen Anzeichen fur eine Progression in die Niereninsuffizienz ist meist eine definierte Immunsuppression zusatzlich indiziert. Die durch Studien untersuchten Therapieschemata werden detailliert vorgestellt.

Glomerulonephritis is paralleled by excessive formation of transforming growth factor-beta (TGF-β), which participates in the pathophysiology of the disease. Recently, a novel downstream target of TGF-β has been identified, i.e. the human serum and glucocorticoid-dependent kinase 1 (hSGK1), a serine/threonine kinase participating in the regulation of Na+ transport. The present study was performed to elucidate transcriptional regulation of hSGK1 in glomerulonephritis. To this end, in situ hybridization was performed in biopsies from patients with clinical diagnosis of glomerulonephritis. hSGK1 transcript levels were moderately enhanced in 5 out of 9 patients and strongly enhanced in 4 out of 9 patients. Distal nephron epithelial cell hSGK1 transcript levels were low or absent in 7 of the 9 patients but markedly enhanced in 2 of the 9 patients. In conclusion, glomerulonephritis leads to glomerular and in some cases to epithelial up-regulation of hSGK1 transcription.

BACKGROUND AND OBJECTIVE Radiographic contrast media (CM) administration causes a decline in renal function, especially in patients with pre-existing renal impairment. The value of CM removement by dialysis to prevent radiocontrast-induced nephropathy (RCIN) has not been established yet. The present study was designed to investigate the influence of haemodialysis on renal function in patients with preexisting renal failure receiving CM for various purposes. PATIENTS AND METHODS 15 patients with reduced renal function (mean serum creatinine concentration 2.7 +/- 0.2 mg/dl) were randomly assigned to receive either haemodialysis for 2-3 hours, started as early as possible after administration of CM (106 +/- 25 minutes), or conservative treatment. Serum creatinine and iodine concentrations were measured over 5 days. RESULTS The percentile creatinine increase on days 2 and 3 after CM application was higher in the dialysed group. The rate of RCIN (defined as a serum creatinine increase of greater than or equal to 0.5 mg/dl within 48 h after administration of CM) was significantly higher in the dialysed group (43% in the haemodialysis group and 13% in the group on conservative treatment, respectively). Iodine concentration declined earlier in the dialysed group. CONCLUSION Our data indicate that haemodialysis performed within two hours after CM application did not prevent the occurrence or the outcome of RCIN in patients with renal failure. In some patients haemodialysis even seems to have worse effects regarding the development of RCIN.

Background. The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results. Methods. We conducted an open long-term randomized prospective multi-centre study comparing the combination of ramipril (R) and felodipine ER (F) with either drug alone in non-diabetic renal disease. Included were patients with uncontrolled hypertension (diastolic blood pressure (DBP)) P95 mmHg on treatment with a diuretic and a beta-blocker. Fiftyone patients received the combination of R and F, 54 patients R, and 53 patients F. The treatment goal was aD BP-90 mmHg and a similar BP reduction in the three groups. Mean doses at the last visit were 5q5, 10 and 9 mg, respectively, after a mean treatment time of nearly 2 years. The progression of renal impairment was studied by serial measurements of serum creatinine, iohexol clearance, and albuminuria. Results. The reduction in supine systolic (S) BP and DBP expressed as median values were 19.0u14.5, 14.3u15.0 and 13.5u13.3 mmHg in the RqF, R, and F groups, respectively. There was no significant difference between the groups. When correction for the acute drug effect was performed the RqF group had a slower progression rate of the renal disease (loss of glomerular filtration rate (GFR) mluminuyear) compared with the F group (P-0.05) but not to the R group (P)0.20). There was a rise in albuminuria after 2 years in the F group (P-0.05), but no significant change was found in the other groups. Conclusions. In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics, tended to cause a better BP reduction as each drug per se. The RqF treatment also caused a slower progression of the renal disease compared with F alone. The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension.

Several studies have recently suggested a principal role of adenosine in the pathogenesis of radiocontrast media-induced nephropathy. In the present experiments, we therefore investigated the renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a potent and selective adenosine A1 receptor antagonist, on radiocontrast media-induced nephropathy in the model of the N-ϖ-nitro- l -arginine methyl ester ( l -NAME) hypertensive, chronic nitric oxide (NO)-depleted rat. Chronic NO depletion was induced by pretreatment with l -NAME, 50 mg/ml, added to drinking water for 8 weeks. Clearance experiments were performed in anesthetized rats and glomerular filtration rate was assessed prior to and following the application of high osmolar radiocontrast media (sodium diatrizoate, 3 ml/kg, i.v.) or an equivalent volume of isoosmolar mannitol to examine the role of hyperosmolarity in radiocontrast media-induced nephropathy. Subgroups received KW-3902 (0.1 mg/kg, i.v.), 20 min prior to radiocontrast media administration. Age-matched, untreated rats served as controls. Radiocontrast media application induced a significant decline in glomerular filtration rate in l -NAME hypertensive animals, whereas no effects were observed in control rats. KW-3902 fully prevented the drop in glomerular filtration rate in response to radiocontrast media in l -NAME hypertensive rats. No renal hemodynamic alterations were observed in mannitol-infused animals. The present experiments demonstrate that the decrease in glomerular filtration rate following radiocontrast media occurred independently of the osmotic load, and that KW-3902 effectively prevented the radiocontrast media-induced deterioration in renal function. KW-3902 may be especially beneficial in patients at high risk for developing acute renal failure following radiocontrast media application or in patients in which extracellular fluid volume expansion is limited by clinical conditions such as congestive heart failure.

Reduction of pathological autoantibodies and circulating immune complexes can be useful in the treatment of autoimmune disease. Plasmapheresis has been shown to reduce autoantibody levels in systemic lupus erythematosus (SLE), but its effect on patients' outcome was not better compared with conventional immunosuppression in the past.Immunoadsorption as a selective extracorporeal immunoglobulin elimination technique was evaluated as rescue therapy in patients suffering from SLE.Eight patients with severe, therapy-resistant SLE underwent immunoadsorption onto protein A sepharose without concomitant immunosuppressants.Remission of the disease was achieved in seven patients. Therapy had to be stopped in one patient because of side-effects. The best results were obtained when immunoadsorption was carried out daily, without supplementary intravenous immunoglobulin therapy. Oral cyclophosphamide for 3-6 months during follow-up was used to suppress relapse. Autoantibodies and circulating immune complexes were effectively eliminated regardless of their IgG subclass.Immunoadsorption onto protein A might be used as an extracorporeal treatment option in SLE when other therapies are ineffective.

Summary Immunoadsorption is a new extracorporeal treatment for immunologicaly-mediated diseases. This review deals with the primary plasma separation for immunoadsorption, the various immunoadsorbers and the technique of immunoadsorption itself. Primary plasma separation can be performed either by plasma membrane filtration or by centrifugation depending on the quantity of processed plasma. Currently, there are non-selective, semi-selective and highly selective adsorbers commercially available. Adsorbers can be subdivided into single-use and reusable devices. The choice of the adsorber is dependent on the clinical situation of the patient. An adapted anticoagulant regimen must be used to avoid complications in the patient and to obtain optimal adsorber performance. Thus, immunoadsorption is an effective and safe extracorporal treatment in severely ill patients suffering from autoimmune diseases.

Transforming growth factor β (TGF-β) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-β stimulates the expression of a distinct serine/threonine kinase (hSGK) which had previously been cloned as an early gene transcriptionally regulated by cell volume alterations. The present study was performed to elucidate transcription and function of hSGK in diabetic nephropathy. As shown by Northern blotting, an increase of extracellular glucose concentration increased hSGK mRNA levels in cultured cells, an effect qualitatively mimicked by osmotic cell shrinkage or treatment with TGF-β (2 μg/liter), phorbol 12,13-didecanoate (1 μM), or the Ca 2+ ionophore ionomycin (1 μM) and blunted by high concentrations of nifedipine (10 and 100 μM). In situ hybridization revealed that hSGK transcription was markedly enhanced in diabetic nephropathy, with particularly high expression in mesangial cells, interstitial cells, and cells in thick ascending limbs of Henle's loop and distal tubules. According to voltage clamp and tracer flux studies in Xenopus oocytes expressing the renal epithelial Na + channel ENaC or the mouse thick ascending limb Na + ,K + ,2Cl − cotransporter BSC-1, coexpression with hSGK stimulated ENaC and BSC-1 11-fold and 6-fold, respectively, effects reversed by kinase inhibitors staurosporine (1 μM) and chelerythrine (1 μM) and not elicited by inactive hSGK. In conclusion, excessive extracellular glucose concentrations enhance hSGK transcription, which in turn stimulates renal tubular Na + transport. These observations disclose an additional element in the pathophysiology of diabetic nephropathy.

BACKGROUND Radiographic contrast media (CM) application causes a decline in renal function, especially in patients with pre-existing renal dysfunction. In addition to hydration, several vasodilating substances have been evaluated for their ability to prevent renal damage after CM application. In a prospective, double-blind, placebo-controlled study we investigated the effect of the oral administration of theophylline, an adenosine receptor antagonist, on changes in renal haemodynamics and tubular injury induced by CM in well-hydrated patients with mild-to-moderate renal insufficiency. METHODS We studied 80 patients with pre-existing chronic renal insufficiency (creatinine > 1.5 mg/dl) who received more than 100 ml iopromide. Hydration (either oral or intravenous) started at least 24 h before and lasted until 24 h after CM application. In addition, patients were randomly assigned to receive either theophylline (810 mg daily) or placebo. Serum creatinine and creatinine clearance were measured before and for 3 days after CM application. Urine was collected to measure N-acetyl-beta-glucosaminidase (NAG) enzymuria for the same period. Sixty-four patients completed the entire study protocol (theophylline, n = 35 and placebo, n = 29). RESULTS During the study period serum creatinine concentration and creatinine clearance did not change significantly in either group. Acute renal failure (increase of serum creatinine of at least 0.5 mg/dl) could be observed in two patients from the theophylline group (5.7%) and one from the placebo group (3.4%). The increase in NAG excretion reached statistical significance (P < 0.05) in the placebo group on days 2 and 3 after CM application. CONCLUSIONS Our results indicate a role for adenosine in CM-induced tubulotoxicity. However, the glomerular filtration rate is preserved by hydration alone in these patients. The application of theophylline did not bring an additional benefit. The use of adenosine antagonists may be beneficial in patients where sufficient hydration may be impossible or in patients with a concomitant decrease in renal blood flow (e.g. congestive heart failure).

One of the hallmarks of apoptosis is cell shrinkage which appears to be important for cell death. The mechanisms mediating cell volume decrease have, however, not been addressed. Mechanisms employed by swollen cells to decrease their cell volume include activation of ion transport pathways, such as ion channels and KCl cotransport, and release of cellular osmolytes, such as taurine, sorbitol, betaine and inositol. The present study has been performed to test for release of taurine. To this end Jurkat human T-lymphocytes were loaded with [3H]taurine and apoptotic cell death induced by triggering the Fas(CD95) receptor with monoclonal crosslinking antibody. Triggering the Fas(CD95) receptor led to a release of 60+/-5% of cellular taurine within 90 min. The release did not occur prior to 45 min. The release coincided with cell shrinkage as evidenced from forward scatter in FACS analysis and preceeded DNA fragmentation according to propidium iodide staining. The delay of taurine release was not influenced by exchange of medium and thus was not due to extracellular accumulation of a stimulator. The Fas(CD95)-induced taurine release, cell shrinkage and DNA fragmentation were blunted by lowering of ambient temperature to 23 degreesC. Following pretreatment of cells with Fas(CD95) antibody at 23 degreesC rewarming led to rapid taurine release, cell shrinkage and DNA fragmentation, indicating that the temperature-sensitive step is distal to the mechanisms accounting for the delay. Osmotic cell swelling led to an immediate release of taurine. In conclusion, Fas(CD95) triggering leads to delayed taurine release through a temperature-sensitive mechanism.