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Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 +/- 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 78) and group B (fast progressors, n = 49). TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-beta1, 92.3%; TNFalpha, 25.6%; IL-6, 74.4%; fast progressors: TGF-beta1, 85.7%; TNFalpha, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.

Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

Background: While cyclosporine A (CsA) is an effective therapy for nephrotic syndrome, it has nephrotoxic side effects. We compared the anti-proteinuric effects and nephrotoxicity in rats with passive Heymann nephritis (PHN) of CsA and mycophenolate mofetil (MMF)., Methods: PHN was induced in female Wistar rats. Two treatment groups consisting of 8 rats each received either 25 mg of CsA or 25 mg of MMF/kg body weight/day and were compared with untreated controls. Kidney function and proteinuria were monitored over 4 weeks. Western blots were used for densitometric analysis of renal cyclooxygenase-2 (COX-2) protein expression. Thromboxane B2 (TxB2) and 6-keto-PGF(1alpha) were determined by radioimmunoassays (RIAs) in renal tissue and urine., Results: Rats with PHN exhibited a marked proteinuria of 12.76 +/- 4.42 vs. 0.73 +/- 0.28 mg/24 h (p < 0.01) and showed increased glomerular concentrations of TxB2 and 6-keto-PGF(1alpha) (992.6 +/- 216.9 and 1,187.0 +/- 54.2 pg/mg protein, respectively) compared with healthy controls (595 +/- 196.17 and 729 +/- 297.84, respectively) and a strongly induced COX-2 protein expression. CsA and MMF treatment reduced PHN-related proteinuria to 2.10 +/- 1.47 and 1.47 +/- 7.2 mg/24 h, respectively. In rats with PHN, CsA induced a significant deterioration of renal function and enhanced urine excretion of thromboxane A2, paralleled by a significant, twofold increase in COX-2 protein expression and renal prostaglandins. By contrast, MMF treatment in rats with PHN was not nephrotoxic and had no effect on prostaglandin production. COX-2 protein expression under MMF was suppressed., Conclusion: While the antiproteinuric efficacy of MMF and CsA in PHN was comparable, the absence of nephrotoxicity might favor MMF in the treatment of nephrotic syndrome. The CsA-induced increase in COX-2 expression and COX-2-dependent prostacyclin may indicate a mechanism that compensates nephrotoxicity in the diseased and CsA-exposed kidney.

Despite all the medical progress, the mortality rate in intensive care units for patients with acute renal failure (ARF) remains high, among specific patient populations, up to 88% [Letourneau I, Dorval M, Belanger R, Legare M, Fortier L, Leblanc M. Acute renal failure in bone marrow transplant patients admitted to the intensive care unit. Nephron Apr 2002; 90 (4), 408-412.]. Recent trial results indicate that patient survival may be improved by adequate renal replacement therapy. In particular, the dose of intermittent and continuous renal replacement therapies has proved to be a significant factor affecting patient survival. Daily intermittent hemodialysis, e.g., is superior to alternate-day intermittent hemodialysis, and with continuous therapies, survival is related to the filtration rate. Further relevant factors include early initiation of renal replacement therapy, choice of biocompatible membranes and the application of bicarbonate-buffered replacement solutions for defined patient groups. The advantages offered by continuous techniques could be demonstrated for individual patient groups; in meta-analyses, advantages were shown for the total population of patients with ARF. Other than for patients with chronic renal failure (NKF-DOQI. Clinical practice guidelines for hemodialysis adequacy. Am J Kid Dis 1997; Vol. 30, 515-566.), there are no current clinical guidelines for a standard treatment of intensive care patients with ARF. Therefore, such a treatment standard still needs to be determined.

Background: In experimental glomerulonephritis, inhibition of cyclooxygenase 2 (COX-2) enhances the renocortical expression of pathogenic alpha(v) integrins., Aims: To study whether this effect is mediated by prostaglandin E(2) (PGE(2)) acting through its EP(3) receptor in cultured rat mesangial cells (MCs)., Methods: MCs were incubated with lipopolysaccharide (LPS), celecoxib, PGE(2), or the selective EP(3) agonist, MB28767. The expression of COX-2, EP(3), and alpha(v) integrin mRNA was measured by reverse transcriptase polymerase chain reaction., Results: LPS upregulated COX-2 expression 2.8-fold and alpha(v) integrin expression twofold. The COX-2 inhibitor celecoxib increased alpha(v) integrin mRNA expression twofold. Both exogenous PGE(2) and the specific EP(3) receptor agonist, MB28767, reduced constitutive alpha(v) integrin mRNA expression to half normal values. COX-2 dependent PGE(2) suppressed the expression of alpha(v) integrin mRNA mediated by the EP(3) receptor in MCs., Conclusions: These results suggest that COX-2 suppresses the expression of alpha(v) integrins by an increased production of PGE(2) activating its EP(3) receptor in glomerulonephritis.

Background: Renal cyclooxygenases (COX) produce the prostaglandins (PG) E2, I2 and thromboxane (TxA2), which interact with distinct G protein-coupled receptors. We investigated the expression of the three EP receptors EP2, EP3 and EP4 and the receptors for PGI2 (IP) and TxA2 (TP) in rats with passive Heymann nephritis (PHN). We studied their regulation by COX-2 inhibition with celecoxib., Materials and Methods: Four groups of Wistar rats were studied: healthy rats (group A), healthy rats treated with celecoxib (group B), rats with PHN (group C), and rats with PHN receiving celecoxib (group D). Expression of the mRNA for all receptors in the renal cortex and for the EP3 receptor in cultured mesangial cells (MCs) was determined by semiquantitative reverse transcriptase polymerase chain reaction. Stable prostaglandin metabolites were measured in the urine by radioimmunoassay., Results: Rats with PHN (group C) showed an 1.8-fold increase of cortical EP3 receptor mRNA expression as compared with controls (group A). In celecoxib-treated PHN rats (group D) the mRNA expression of the EP3 and EP4 receptors was significantly reduced to 1.0-fold and 0.7-fold induction, respectively. Furthermore, the excretion of bicyclo-prostaglandin E2 (PGE2) was inhibited by celecoxib. No changes were observed in the expression of the other PG-receptors. In cultured MC, PGE2 enhanced the EP3 mRNA expression., Conclusions: These data suggest a predominant role of the EP3 receptor in the transduction of PGE2-actions in PHN. It was concluded that COX-2-dependent PGE2 is able to potentiate its effects in the kidney by up-regulating its own receptors.

History and Clinical Findings: A 26-year-old woman presented with fatigue, muscle cramps and weakness. Since the age of 8 years she had moderate hypokalemia of unknown origin that was confirmed on multiple occasions. There was no family history of disease., Investigations: Laboratory tests showed moderate to severe hypokalemia with a serum potassium concentration of 2.7 to 3.0 mmol/l, hypomagnesemia, metabolic alkalosis and pronounced stimulation of the renin-angiotensin-aldosterone system. Despite normal serum calcium levels, urinary calcium excretion was below the detection threshold. Increased natriuresis was observed after administration of furosemide, but not after administration of hydrochlorothiazide. This finding pointed to the presence of a non-functional thiazide-sensitive sodium/chloride cotransporter in the distal convoluted tubule, characteristic for Gitelman's syndrome. Genetic analysis confirmed the diagnosis of Gitelman's syndrome and documented two heterozygous mutations in the gene encoding the sodium/chloride cotransporter., Treatment and Course: The patient was treated with 160 mmol potassium and 30 mmol magnesium supplementation per day. Serum potassium was normalized and magnesium serum levels increased. Weakness and fatigue improved markedly., Conclusion: Gitelman's syndrome is an important differential diagnosis in the evaluation of the normotensive patient with hypokalemia.

Objective: We evaluated the variable Kt/V, which has become established in the therapy of end-stage renal disease in acute renal failure, to assess the influence of the filtration volume of continuous venovenous hemofiltration on Kt/V. We measured the variables of acid-base balance and uremia control., Design: Prospective interventional pilot study., Setting: Medical intensive care unit of a university hospital., Patients: Fifty-six patients with acute renal failure and continuous venovenous hemofiltration treatment., Interventions: The patients were consecutively treated with a filtration volume of either 1 L/hr (group 1) or 1.5 L/hr (group 2)., Measurements and Main Results: Patients with a filtration volume of 1.5 L/hr achieved a Kt/V of 0.8 per day, which was significantly higher than in the patient group treated with 1 L/hr (0.53, p <.05). The filtration volume of 1.5 L/hr led to a markedly better control of blood urea nitrogen concentrations, 69.3 +/- 6.6 mg/dL vs. 52.1 +/- 5.2 (p <.05), and to a much quicker and longer lasting compensation of acidosis. Both groups had acidotic pH at the beginning of therapy (group 1, 7.29 +/- 0.02; group 2, 7.29 +/- 0.02, nonsignificant). In group 2, a significantly higher pH value than in group 1 was measured after 24 hrs of continuous venovenous hemofiltration (p < .001; 7.39 +/- 0.02 vs. 7.31 +/- 0.02). The pH values in group 1 did not normalize until after 4 days. The filtration volume of 1.5 L/hr led to a quicker increase in bicarbonate concentrations after 24 hrs of therapy (group 1, 2.8 +/- 3.2 mmol/L; group 2, 6.5 +/- 3.1 mmol/L, p <.001)., Conclusions: The standardized urea clearance Kt/V is a valuable tool in the treatment of acute renal failure. Higher Kt/V levels were associated with a better control of uremia and acid-base balance. However, there were no differences in the clinical course, patient survival, percentage of patients with or without renal failure who were transferred from the intensive care unit, or Acute Physiology and Chronic Health Evaluation III scores.

Background: Cyclooxygenase-2 (COX-2), the inducible isoform of the cyclooxygenases, is upregulated in various inflammatory renal diseases and responsible for prostaglandin formation. As prostaglandins are known to influence cell adhesion processes, we investigated the effect of COX-2 inhibition on the expression of alpha(v) integrins, which are also enhanced in renal diseases and control the adherence between the endothelium and the extracellular matrix (ECM) in the glomerulus., Methods: Healthy female Wistar rats and animals with previously induced passive Heymann nephritis (PHN) received either 5 mg/kg body weight/day celecoxib or a placebo. After 28 days, renal cortical mRNA expression of COX-2 and alpha(v) integrin subunits was determined., Results: Rats with PHN showed a significant 1.7-fold increase in renal cortical mRNA expression of alpha(v) integrin subunits. Treatment with celecoxib increased cortical alpha(v) integrin mRNA expression 2.2-fold (p < 0.05) in healthy animals and 4.0-fold (p < 0.05) in rats with PHN, but lowered COX-2 mRNA expression in rats with PHN to 0.8-fold (p < 0.05). An inverse correlation between the expression of COX-2 and alpha(v) integrins in rats with PHN was demonstrated., Conclusions: It is suggested that COX-2-derived prostaglandins suppress the expression of alpha(v) integrins. This implies a previously unknown role for COX-2 in chronic inflammation in the kidney., (Copyright 2003 S. Karger AG, Basel)

History and Admission Findings: A 39-year-old man was referred for assessment of a nephrotic syndrome. He reported deteriorating health with bouts of fever and microhaematuria and proteinuria in the past year. At the age of 24 years a ventriculoatrial shunt had been inserted for an internal hydrocephalus. At another hospital he was given steroids for a nephrotic syndrome suspected of being associated with membranoproliferative glomerulitis, but the disease progressed. On admission he had severe generalised oedema with a temperature of 38,5;C. His general condition was poor. He had no neck stiffness., Investigations: Parameters of inflammation were raised. Serum creatinine and creatinine clearance were normal. Levels of complements C3 and C4 were reduced. The proteinuria was 9g/24h. Renal biopsy revealed type 1 membranoproliferative glomerulonephritis. Micrococcus roseus/varians was demonstrated several times by aerobic blood cultures., Treatment and Course: The findings suggested chronically infected ventriculoatrial shunt as cause of the glomerulonephritis. The shunt was, therefore, removed. The same pathogens were grown from it on aerobic culture medium. Six months after removal and replacement of the shunt and treatment of the infection the proteinuria had fallen to 0.45 mg/h; serum creatinine was 1.0 mg/dl., Conclusion: When membranoproliferative glomerulonephritis has been demonstrated, secondary forms should be considered in the differential diagnosis. In most cases specific treatment can prevent progression of the renal disease.

Background and Objective: Cyclosporin A ( CsA) plays a confounding part in the treatment of nephrotic syndrome. Renal hemodynamics and glomerular permselectivity were investigated in patients with glomerulonephritis to analyse the antiproteinuric action of CsA and to differentiate between nephrotoxic and immunosuppressive effects., Methods: We studied 19 patients with nephrotic syndrome after 6 months of treatment with CsA (membranous glomerulonephritis-MGN, n = 10; focal segmental sclerosing glomerulonephritis - FSGN, n = 5; minimal changes glomerulonephritis - MCGN, n = 4). Patients were studied three times within 3 weeks with (A) and without (B) CsA treatment (A-B-A'). Blood pressure, creatinine, proteinuria, C(In), C(PAH), C(Dex) were measured (analysis according to the model of Deen et al., Am J Physiol. 1985; 249 : 374)., Results: GFR (C (In)) increased significantly after withdrawal of CsA from 54 +/- 7.3 to 64 +/- 8.5 ml/min (p < 0.01). Proteinuria increased after withdrawal of cyclosporin (B) between 21 % (MGN) and 45 % (FSGN). After withdrawal of CsA (B) there was no change of FC(dex) in patients with MGN and FSGN. Withdrawal of CsA in patients with MCGN induced a significant decrease in glomerular selectivity in the high molecular range., Conclusion: These data demonstrate that CsA is able to induce even in the short term a significant increase in glomerular permselectivity in MCGN. The acute effects on GFR predominantly determined the acute antiproteinuric effects in patients with MGN and FSGN.

Amiodarone is an antiarrhythmic drug that can cause interstitial pneumonitis leading to pulmonary fibrosis. A 62-year-old man suffering from atrial fibrillation and recurrent dyspnea was treated with amiodarone. After 15 months of treatment, HRCT revealed bilateral interstitial and alveolar opacifications with high-attenuating pleural-parenchymal consolidations, suggesting amiodarone induced pneumonitis. Three months after cessation of amiodarone treatment, HRCT shows complete regression of pneumonitis. Amiodarone pneumonitis can be misinterpreted and mistreated in patients with further underlying diseases. The present case report demonstrates the diagnostic value of HRCT in the diagnosis of interstitial pneumonitis.

Background: With the use of systemic cyclosporin A (CsA), graft prognosis after high-risk penetrating keratoplasty has improved considerably. However, the application of CsA is limited owing to a variety of severe side effects. In this prospectively randomized study mycophenolate mofetil (MMF), a safe and efficient immunosuppressive medication after renal transplantation, was compared with CsA after high-risk penetrating keratoplasty., Methods: Twenty-nine high-risk keratoplasty patients were treated with MMF 2x 1 g daily; another 27 patients received CsA, aiming at blood trough levels of 120-150 ng/ml. Systemic immunosuppression was scheduled for 6 months. In both groups oral corticosteroids (fluocortolone 1 mg/kg) were administered for 3 weeks postoperatively., Results: During the first year after operation, no graft failure was recorded. Two years postoperatively 92%/82% and 3 years postoperatively 74%/69% of grafts were clear in the MMF and CsA group, respectively (Kaplan Meier P=0.33, logrank test). In total, two graft failures were recorded in the MMF group and four in the CsA group. Three years postoperatively 53% of the grafts were rejection-free in the MMF group and 73% in the CsA group (Kaplan Meier P=0.46, log-rank test). Eight endothelial immune reactions were observed in the MMF group (three under systemic immunosuppression/five thereafter; six mild/two severe) and five in the CsA group (three under systemic immunosuppression/two thereafter; three mild/two severe). Side effects occurred in six patients under MMF and 11 under CsA., Conclusions: Concerning efficacy, no statistically significant difference between systemic MMF and systemic CsA administered for 6 months after high-risk penetrating keratoplasty could be shown. Systemic MMF was proven to be at least as safe as CsA. The main mechanism in improving graft survival is a shift from severe to milder endothelial immune reactions, as already demonstrated for CsA. Thus, MMF may become an alternative to CsA for immunosuppression after penetrating high-risk keratoplasty. About 2 years postoperatively, pharmacologically induced relative immunological tolerance slowly decreases. Therefore, long-term administration of systemic MMF should be evaluated in further studies.

Background: Hyperkalemia and metabolic acidosis are common manifestations in patients receiving the immunosuppressive agent cyclosporine A (CsA) and the recently introduced FK506. We compared the acute toxic and antiproliferative effects as well as the effects on the transport activity of Na(+)/K(+)-ATPase and Na(+)/K(+)/2Cl(-) cotransporter of CsA and FK506 in an established cell line of distal/collecting tubule origin (MDCK cells)., Methods: MDCK cells were exposed to various concentrations of CsA or FK506 and the effects on cell viability (MTT test and neutral red uptake), plasma membrane integrity (lactate dehydrogenase (LDH) release) and cell proliferation (bromodeoxyuridine (BrdU) incorporation) were compared. For transport studies, after confluence, MDCK cells were exposed to CsA or FK506 for 48 h in the presence and absence of aldosterone. Ouabain- and bumetanide-sensitive (86)Rubidium uptake measurements were used to study the activity of the Na(+)/K(+)-ATPase and Na(+)/K(+)/2Cl(-) cotransporter at the surface of intact cells., Results: After 24 h of exposure CsA reduced the number of viable cells to 50% at 30 microM, whereas for FK506 2-3 times higher concentrations had to be employed. Similarly, LDH release was stimulated tenfold by 30 microM CsA but only fourfold by 70 microM FK506. In contrast, DNA synthesis was affected at lower concentrations of FK506 than of CsA. In cells treated for 24 h BrdU incorporation was significantly inhibited by 3 microM FK506, whereas a similar inhibition required 10 microM CsA. The transport activity of Na(+)/K(+)-ATPase and of Na(+)/K(+)/2Cl(-) cotransporter were significantly decreased (37 and 63%, respectively) on CsA administration (8 microM). In CsA-treated cells the K(+) channel blockers barium (1 mM), TEA (10 mM) and quinine (1 mM) did not further inhibit the transport activities suggesting that CsA might also act via inhibition of K(+) channels. FK506 at 8 microM had no effect on Na(+)/K(+)-ATPase transport activity but stimulated Na(+)/K(+)/2Cl(-) cotransporter activity by 59%. The stimulatory effect was abolished by K(+) channel blockers indicating that recycling of K(+) might increase by FK506. The simultaneous presence of aldosterone (5 microM) protected the cells from the inhibitory effect of CsA on Na(+)/K(+)-ATPase and Na(+)/K(+)/2Cl(-) cotransporter activity. The stimulatory effect of FK506 on the Na(+)/K(+)/2Cl(-)cotransporter activity was completely abolished in the presence of aldosterone., Conclusions: Both CsA and FK506 showed acute toxicity in MDCK cells in vitro with the effects of FK506 being less pronounced. CsA and FK506 had different effects on the in vivo transport rates of the Na(+)/K(+)-ATPase and the Na(+)/K(+)/2Cl(-) cotransporter; CsA inhibited the activity of the Na(+)/K(+)-ATPase and the Na(+)/K(+)/2Cl(-) cotransporter whereas FK506 stimulated the activity of Na(+)/K(+)/2Cl(-) cotransporter. These effects were abolished by the application of aldosterone., (Copyright 2001 S. Karger AG, Basel)

Background: Ischemic heart disease is the major cause of death in patients with end-stage renal disease. The high prevalence of coronary artery disease results in a rising number of dialysis patients requiring myocardial revascularisation., Objective: The objective of this study was to compare the outcomes of recurrent angina, myocardial infarction, rate of reinterventions and cardiovascular death following percutaneous coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) in patients with end-stage renal disease., Patients and Methods: In a retrospective investigation 40 patients with chronic renal failure undergoing primarily PTCA and 65 patients undergoing CABG were included. Both groups were comparable for gender, duration on dialysis and the number of cardiovascular risk factors per patient. Patients undergoing PTCA were younger (53 +/- 12 years vs. 57 + 8 years; p < 0.05) and more often diabetics (30% vs. 14%; p < 0.05)., Results: Most patients in both groups had a multi-vessel disease (95% in the CABG group vs. 74% in the PTCA group), in the CABG group there were significantly more patients with a triple-vessel disease (62% with vs. 40% in the PTCA group; p < 0.01), PTCA was primarily successful in 95% of the patients while complete revascularization was achieved in 88% of patients undergoing CABG. The perioperative mortality after CABG was 4.8% as compared to none after interventional revascularisation. The cumulative freedom of angina after 6, 12 and 24 months after intervention was significantly lower after PTCA (54%, 40%, 29%) than after bypass grafting (97%, 94%, 90%, p < 0.001). The frequency of reinterventions following PTCA was significantly higher compared to patients following CABG (p < 0.001). After PTCA 15 patients needed further revascularisations, 8 of them underwent CABG, whereas after CABG only two patients required additional myocardial revascularisation. There was no significant difference in the overall mortality between both groups; the survival rate after 12 and 24 months was 95% and 82% after PTCA and 93% and 86% after CABG, respectively., Condition: Although patients receiving CABG had a more severe coronary artery disease the overall mortality was comparable and clinical and functional outcome was improved compared to patients after coronary angioplasty.

Background and Objective: Despite significant efficacy of melphalan and prednisone in the therapy of systemic AL(light chain amyloid)amyloidosis the prognosis of the disease is poor. In patients with severe renal manifestation the reported results of low-dose melphalan therapy are inconclusive with respect to relief of clinical symptoms and overall prognosis., Patients and Methods: We report our results of therapy in a group of 22 patients (8 women, 14 men, mean age 60 years) with renal involvement as the main manifestation of systemic AL-amyloidosis without overt myeloma., Results: Ten patients were treated with low doses of melphalan and prednisone. No significant clinical improvement was observed in any case: the patients died an average of 12 months after diagnosis of the disease. Three patients were treated with high doses of melphalan followed by autologous stem cell transplantation. One patient died due to septicaemia after high-dose chemotherapy. Two of the patients experienced significant remission and live virtually free of clinical symptoms 12 and 18 months after therapy. Nine patients were treated only symptomatically: four of them were alive an average of 30 months after diagnosis of systemic AL-amyloidosis., Conclusions: Only high-dose melphalan therapy offered a realistic chance of amelioration of clinical symptoms in our group of patients, although therapy-associated risks seem to be high. In patients with severe renal amyloidosis, who are not considered for high-dose therapy, particularly careful consideration of potential benefits and possible risks of conventional melphalan therapy is necessary, because the results of this approach are in doubt.

Background: The acute renal failure remains a diagnostic challenge for the clinician., Case Reports: Between 1991 and 1996, acute renal failure caused by hantavirus infection was diagnosed in 4 previously healthy male patients. Main symptoms consisted of fever, headache, arthralgia, lumbar and abdominal pain as well as a decline in diuresis. The ultrasonography showed a slight splenomegaly in 2 patients. The clinical chemistry showed elevated serum creatinine from 2.2 mg/dl to 6.7 mg/dl and thrombocytopenia from 4000 to 150,000/microliter. The examination of the urine showed slight proteinuria and microhematuria. The kidney biopsy of 1 patient showed a reversible damage of the tubuli. The pathologic findings normalized within 3 weeks in 3 patients without need for dialysis. One patient developed a severe clinical course with acute renal failure and pulmonary edema requiring dialysis. In all patients, the renal function improved.

Background: Cardiovascular disease is a major cause of mortality in chronic uremic patients. We studied whether homocysteine is an independent cardiovascular risk factor for patients with end-stage renal disease (ESRD)., Patients and Methods: The study included 163 patients and controls (Group 1: healthy controls, n = 20; Group 2: patients with chronic renal failure, serum creatinine < or = 4 mg/dl, n = 23; Group 3: patients with ESRD, n = 91; Group 4: renal transplant recipients, serum creatinine < or = 2.5 mg/dl, n = 29). We registered patients for the following factors: age, diabetes, smoking, lipids, vitamin B12, folic acid and homocysteine. The coronary heart disease was diagnosed by coronary angiography., Results: The cardiovascular risk profile (hypertension, diabetes, smoking, hyperlipidemia) among uremic patients was significantly increased compared to the healthy controls. There was a significant correlation between the impairment of renal function and the increase of the homocysteine concentration (Group 1: 12 +/- 4.3 mumol/l vs Group 3: 27.8 +/- 15.8 mumol/l; p < 0.001). There was no significant difference of homocysteine between the patients with coronary heart disease and those without (29.9 +/- 18.1 mumol/l vs 26.6 +/- 14.4 mumol/l, not significant)., Conclusion: In this study a significant correlation between the number of cardiovascular risk factors and the incidence of cardiovascular disease was proven. Although homocysteine was increased among patients with impaired renal function, hyperhomocysteinemia could not be identified as a significant risk factor for coronary heart disease in patients with ESRD. It is assumable that the pathogenesis of coronary heart disease in patients with ESRD is of multifactorial origin.

Objective: To determine the impact of different hemofiltration (HF) replacement fluids on the acid-base status and cardiovascular hemodynamics in patients with acute renal failure (ARF) and continuous veno-venous hemofiltration (CVVH)., Design: Prospective, cohort study., Setting: Intensive Care Unit of the Heinrich Heine University Hospital, Düsseldorf, Germany., Subject and Methods: One hundred and thirty-two critically ill patients with acute renal failure and continuous veno-venous HF were studied. Fifty-two patients were subjected to lactate-based (group 1), and 32 to acetate-based hemofiltration (group 2) while 48 (group 3) were treated with bicarbonate-based buffer hemofiltration fluid. Fifty-seven had a septic, and 75 a cardiovascular, origin of the ARF. Creatinine, blood urea nitrogen (BUN), serum bicarbonate, arterial pH, lactate and Apache II scores were noted daily., Main Results: The mean CVVH duration was 9.8 +/- 8.1 days, mortality was 65%. No difference was present between the groups under investigation with regard to the main clinical parameters. Lactate- and bicarbonate-based hemofiltration led to significantly higher serum bicarbonate and arterial pH values as compared to the acetate-based hemofiltration. Serum bicarbonate values at 48 h after the initiation of CVVH treatment were 25.7 +/- 3.8 mmol/l (p < 0.001) in group 1, 20.6 +/- 3.1 mmol/l in group 2 and 23.3 +/- 3.9 mmol/l (p < 0.001) in group 3. While a lack of increase in serum bicarbonate and arterial pH was correlated to poor prognosis in lactate- and bicarbonate-based hemofiltration, no such observation was made in acetate-based hemofiltration. Cardiovascular hemodynamics were superior in patients treated with lactate- and bicarbonate-based buffer solution as compared to those treated with acetate-based buffer solution., Conclusions: The degree of correction of acidosis during hemofiltration was determined by patient outcome in patients treated with lactate- and bicarbonate-based buffer solutions, but not in patients receiving acetate-buffered solution. Bicarbonate and lactate-based buffer solutions were found to be superior to acetate-based replacement fluid.

Continuous venovenous hemofiltration (CVVH) is the most widely used renal replacement therapy for the treatment of critically ill patients with acute renal failure on the intensive care unit. Whether or not congestive heart failure is an indication for CVVH is controversial and needs to be discussed. Therefore, we present a patient with congestive heart failure who was treated successfully with CVVH.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce an inhibition of cyclooxygenase (COX), an enzyme that makes prostaglandins. Two isoforms of COX exist: COX-1 represents the constitutively expressed enzyme, whereas COX-2 is the inducible isoform. This study investigated the role of COX-2 in the inflammatory processes of the kidneys of rats with passive Heymann nephritis (PHN), and focused of the effect of a selective COX-2 inhibitor, flosulide. COX-2-selective inhibitors are thought to represent potent anti-inflammatory agents without major renal side effects., Methods: PHN was induced by injecting heterologous Fx1A antiserum into female Wistar rats. Two treatment groups, each consisting of 12 rats with PHN, received either 3 or 9 mg of flosulide/kg body wt/day and were compared with untreated controls. After four weeks, the generation of thromboxane B2 (TxB2) and 6-keto-PGF1alpha were determined in renal tissue and in urine. COX-2 protein expression was investigated by Western blotting using a selective antibody., Results: Rats with PHN exhibited a marked proteinuria of 71 +/- 8 mg/24 hr as compared with 2.0 +/- 0.3 mg/24 hr in healthy controls (P < 0.01). Treatment with flosulide reduced the proteinuria to 26.1 +/- 9 mg/24 hr at 3 mg flosulide/kg body wt/day and 35.5 +/- 6 mg/24 hr at 9 mg/kg body wt/day, which was equivalent to a reduction of proteinuria by a maximum of 65% (P < 0.05). This was accompanied by an increase in glomerular TxB2 from 3073 +/- 355 to 5255 +/- 1041 pg/mg glomerular protein and 6-keto-PGF1alpha from 1702 +/- 161 to 2724 +/- 770 pg/mg glomerular protein in rats with PHN. COX-2 protein expression was also highly elevated in comparison to healthy controls. Low-dose flosulide treatment had no effect on COX protein expression and renal prostaglandin formation. High-dose flosulide treatment reduced renal prostaglandin production and caused a marked decline in COX-1 and COX-2 protein expression. Urine prostanoid excretion remained unchanged in all therapeutic groups. There was a small though significant reduction in renal creatinine clearance from 0.86 ml +/- 0.2/min in untreated controls to 0.6 ml +/- 0.1/min in flosulide-treated rats with PHN (P < 0.01) after four weeks., Conclusions: Under the influence of flosulide, a highly COX-2-selective inhibitor, we observed an antiproteinuric drug effect. The inflammation in PHN induced COX-2 protein expression that was not affected by low-dose flosulide. COX-1 and COX-2 protein expression was affected by high-dose flosulide, which therefore might lose its selectivity. High-dose flosulide induced a decrease in glomerular prostanoid production possibly because of COX-1 inhibition. Our results suggest that the therapeutic use of flosulide in proteinuria seems advantageous and deserves further studies because the basal prostaglandin levels remain unchanged in the low-dose-treated group, indicating that the compensatory capacity of prostaglandin production, which is essential for the regulation of renal hemodynamics, is maintained.

Critically ill patients with acute renal failure usually present with an unstable acid-base balance, often leading to cardiovascular complications and multi-organ failure. Therefore, to prevent metabolic acidosis, acid-base balance must be normalized and maintained; these patients are primarily treated with continuous hemofiltration techniques using different replacement fluids to influence the acid-base values. Dialysate solutions can be an acetate-based, lactate-based, citrate-based or bicarbonate-based buffer. This article discusses the strengths and weaknesses of each type of hemofiltration replacement fluid.

Background: Based on the observation of 7 patients with chronic IgA nephritis and on a course to end-stage renal failure after several years, D'Amico et al. [1993] reported on a "point of no return" at 2.5 to 3 mg/dl serum creatinine. After exceeding this limit all 7 patients exhibited an irreversible progressive renal failure., Patients and Methods: Therefore, 115 patients with IgA nephritis from the "German Glomerulonephritis Therapy Study" were examined in order to look for the existence of such a "point of no return"., Results: Three different courses could be distinguished: a stable chronic course with constantly normal or only minor elevated serum creatinine lasting for years (91 patients), a progressive course with continuously increasing serum creatinine (22 patients), and a rare (only 2 patients) early acute course with a short-term increase of serum creatinine followed by a rapid return to the normal range. After exceeding 3 mg/dl serum creatinine no remissions were observed in the progressive cases. Sixteen patients showed a rapid, continuously progressive course until end-stage renal failure with exactly the same progression as the 7 patients of D'Amico et al. Six patients of the 22 progressors were not observed long enough. The serum creatinine level doubled on average from 3 to 6 mg/dl within 10 months., Conclusion: Our study confirmed the existence of a "point of no return" at 3 mg/dl (265 micromol/l) during the natural course of chronic IgA nephritis.

Background: Despite significant effects of melphalan and prednisone in the therapy of systemic AL-amyloidosis, overall prognosis is poor and remission of clinical symptoms cannot generally be expected. The course of the disease and results of therapy are possibly influenced by the degree and distribution of organ manifestation at the time of diagnosis. We report a group of patients with renal involvement as the main manifestation of disease., Patients: Fifteen patients with systemic Al-amyloidosis without symptomatic myeloma (4 women, 11 men, median age 61 [34 to 71] years) have been attended to at our department and were treated throughout the course of the disease., Results: Since primary symptoms were frequently unspecific, the maximum time to diagnosis came to 28 months. Renal involvement was primarily evident at the time of diagnosis when all patients manifested proteinuria or renal insufficiency. Ten patients were treated with a melphalan and prednisone containing chemotherapeutic protocol. A significant clinical improvement was observed in no case. One patient in an advanced stage of disease died after the administration of a high-dose regimen of melphalan with blood stem-cell support subsequent to sepsis., Conclusion: We do not see an absolute indication for chemotherapy. The unfavorable prognosis--14 patients died an average of 13 months after diagnosis--requires a particularly careful consideration of potential benefits and possible risks accompanying cytostatic therapy.

Background: Cardiovascular disease is a leading cause of death after renal transplantation (RTx), and the incidence is considerably higher than in the general population. Aim of this study was to evaluate the incidence of atherosclerotic cardiovascular complications after RTx, the prevalence of cardiovascular risk factors, prior to and following RTx, and the association between the risk factors and complications., Patients and Methods: Analysis of atherosclerotic cardiovascular diseases (coronary artery disease, cerebral and peripheral vascular disease) and cardiovascular risk factors before and after transplantation in 427 renal transplant recipients between 1987 and 1992 (mean age at transplantation 45 +/- 12 years, 58% male, 7% diabetics) with a mean posttransplant follow-up of 28 +/- 20 months., Results: Following RTx 11.7% developed atherosclerotic cardiovascular diseases, the majority coronary artery disease (9.8%). The comparison of risk factors 12 months before and 24 months following transplantation showed: The prevalence of systemic hypertension (from 67% to 86%), diabetes mellitus (from 7% to 16%) and obesity with a body mass index > 25 kg/m2 (from 26% to 48%) had increased significantly whereas the number of smokers halved to 20%. The triglycerides decreased significantly (from 235 +/- 144 mg/dl to 217 +/- 122 mg/dl). The total and HDL cholesterol rose significantly (from 232 +/- 65 mg/dl to 273 +/- 62 mg/dl and from 47 +/- 29 mg/dl to 56 +/- 21 mg/dl, respectively). The LDL cholesterol increase was insignificant (from 180 +/- 62 mg/dl to 189 +/- 53 mg/dl). In the univariate analysis, cardiovascular diseases were significantly associated with male gender, age over 50 years, diabetes mellitus (DM), smoking, total cholesterol > 200 mg/dl, LDL cholesterol > 180 mg/dl, HDL cholesterol < 55 mg/dl, fibrinogen > 350 mg/dl, body mass index > 25 kg/m2, and more than 2 antihypertensive agents per day. The Cox proportional hazards model revealed DM with a relative risk (RR) of 4.3, age > 50 years (RR = 2.7), body mass index > 25 kg/m2 (RR = 2.6), smoking (RR = 2.5), and LDL cholesterol > 180 mg/dl (RR = 2.3) as independent risk factors., Conclusions: The high incidence of cardiovascular disease following renal transplantation is mainly due to a high prevalence and accumulation of classical risk factors before and following transplantation. The treatment of the risk factors must be effective and introduced early in the course of renal failure, further, they must be continued following transplantation. Future prospective studies should evaluate the success of treatment regarding reduction of cardiovascular morbidity and mortality in this high risk population.

History and Clinical Findings: A 49-year-old patient, a hobby hunter, fell ill acutely with joint and limb pain, abdominal pain, nausea and subfebrile temperatures. At hospitalization, the patient was in bad general condition, showing ascites and lid edema, and acute renal failure was diagnosed., Investigations: Laboratory tests revealed marked thrombocytopenia (15,000/ml), leucocytosis, elevated levels of creatinine, blood urea nitrogen and liver enzymes, respectively. Blood gas analysis showed metabolic acidosis. Chest X-ray showed an interstitial fluid accumulation, abdominal ultrasound disclosed ascites and enlarged kidneys as in acute renal failure. Immunologic tests verified the diagnosis of an acute hantavirus infection, by use of specific molecular biology techniques a previously unknown virus strain was identified., Treatment and Course: Hantavirus infections in western Europe usually show a benign course. However, in the present case, acute progressive pulmonary failure developed despite effective dialysis so that mechanical ventilation was necessary for several weeks. Dialysis had to be carried out for 17 days. As a complication a severe ulcero-destructive tracheobronchitis developed, caused by Aspergillus fumigatus. After several weeks, both renal and pulmonary function had returned to normal., Conclusion: Hantavirus infections may lead to severe and complicated courses also in western Europe. By use of new immunologic and molecular biology techniques a specific diagnosis is possible.

Unlabelled: Cardiovascular disease is a leading cause of death after renal transplantation (tpx), and the incidence is considerably higher than in the general population., Objective: To evaluate the incidence of atherosclerotic cardiovascular complications after tpx, the prevalence of cardiovascular risk factors, prior to and following tpx, and the association between the risk factors and complications., Patients and Methods: Analysis of atherosclerotic cardiovascular diseases (coronary artery disease, cerebral and peripheral vascular disease) and cardiovascular risk factors before and after transplantation in 427 renal transplant recipients between 1987 and 1992 (mean age at transplantation 45+/-12 years, 58% male, 7% diabetics) with a mean post-transplant follow-up of 29+/-20 months., Results: Following tpx 11.7% developed atherosclerotic cardiovascular diseases, the majority coronary artery disease (9.8%). The comparison of risk factors 12 months before and 24 months following transplantation showed: prevalence of systemic hypertension (from 73% to 85%), diabetes mellitus (from 7% to 16%) and obesity with a body mass index >25 kg/m2 (from 26% to 48%) had increased significantly whereas the number of smokers halved to 20%. Triglycerides decreased significantly (from 235 mg/dl to 217 mg/dl). Total and HDL cholesterol rose significantly (from 232 mg/dl to 273 mg/dl and from 47 mg/dl to 56 mg/dl, respectively). LDL cholesterol increase was significant (from 180 mg/dl to 189 mg/dl). In the univariate analysis, cardiovascular diseases were significantly associated with male gender, age over 50 years, diabetes mellitus (DM), smoking, total cholesterol > or=200 mg/dl, LDL cholesterol >180 mg/dl, HDL cholesterol < or =55 mg/dl, fibrinogen > or =350 mg/dl, body mass index >25 kg/m2, serum uric acid >6.5 mg/dl and with more than two antihypertensive agents per day. The Cox proportional hazards model revealed DM with a relative risk (RR) of 4.3, age >50 years (RR=2.7), body mass index >25 kg/m2 (RR=2.6), smoking (RR=2.5), LDL cholesterol >180 mg/dl (RR=2.3) and uric acid >6.5 mg/dl as independent risk factors., Conclusions: The high incidence of cardiovascular disease following renal transplantation is mainly due to a high prevalence and accumulation of classical risk factors before and following transplantation. Future prospective studies should evaluate the success of treatment regarding reduction of cardiovascular morbidity and mortality in this high risk population.

Background: In this retrospective study our aim was to evaluate the effectiveness of systemic cyclosporin A (CsA) after keratoplasties with an elevated risk for immune reactions as the only elevated risk factor., Patients and Methods: Between November 1986 and June 1994, 1121 penetrating keratoplasties, 646 normal-risk and 475 high-risk keratoplasties were performed. In 130 out of the 475 high-risk keratoplasties an elevated risk for immune reactions was the only elevated risk factor. Twenty-six of these 130 high-risk keratoplasties were treated with systemic CsA., Results: In the high-risk group keratoplasties with an elevated risk for immune reactions as the only elevated risk factor no permanent graft failure occurred with CsA (100% clear grafts). Without CsA the percentage of clear grafts in this high risk group was only 71.7% according to Kaplan Meier 3 years postoperatively in contrast to 86.0% in normal-risk keratoplasties. The differences between these three groups were statistically significant. In the high-risk group keratoplasties with on elevated risk for immune reactions as the only elevated risk factor more immune reactions occurred than without CsA or than in normal-risk keratoplasties. However, these immune reactions were mostly of the benign chronic types., Conclusions: Systemic CsA considerably improves graft prognosis after high-risk keratoplasties with an elevated risk for immune reactions as the only elevated risk factor. With CsA application we observed a significant shift from acute to chronic immune reactions, which respond much better to topical steroids.

Patients with end-stage renal disease (ESRD) have a high incidence of coronary artery disease. In 30-60% of these patients coronary artery disease can be demonstrated by coronary angiography often prompting myocardial revascularization. Previous studies on PTCA in patients with ESRD have suggested a high rate of procedural complications and restenosis. We studied the rate of restenosis after PTCA in 23 patients with chronic renal failure (17 males, 6 females, age: 52.5 +/- 18.3 years). After primarily successful PTCA all patients were restudied angiographically within 6-12 months. Using quantitative coronary angiography 13 patients (56%) demonstrated restenosis (stenosis > 50% luminal diameter). In 11 of these patients further revascularization therapy was indicated (6 x PTCA, 5 x CABG). Before follow-up angiography 12 patients demonstrated recurrence of angina pectoris, the sensitivity of clinical symptoms for angiographic restenosis was 69%. High concentrations of triglycerides (265 +/- 160 mg/dl), total cholesterol (258 +/- 53 mg/dl) with low HDL-levels (34 +/- 14 mg/dl) as well as elevated plasma levels of fibrinogen (481 +/- 114 mg/dl) were measured before PTCA. The mechanisms contributing to the high rate of coronary restenosis in patients with ESRD remain unclear, influence of lipid abnormalities, hemostatic factors and fibrinolytic state as well as primarily uremic factors have to be discussed. Prospective interventional studies are needed to address the relevance of PTCA for myocardial revascularization in this patient group.

Erythropoietin (Epo) is a glycoprotein hormone produced in the kidney in response to hypoxia or anaemia. In acute renal failure (ARF) anaemia also occurs and current opinion is that Epo production is depressed with inappropriately low plasma levels throughout the uraemic phase. Our study was designed to determine the excretion of Epo in patients with ARF. Fifty-nine ventilated patients were studied, 39 with ARF and continuous veno-venous haemofiltration therapy (group 1) and 13 patients with normal renal function who served as a control group (group 2). All patients with ARF were anaemic and needed a mean transfusion of 0.6 units/day. Values for vitamin B12, folic acid, serum iron and ferritin were normal. While patients with normal renal function had Epo values within the normal range, patients with ARF had significantly higher values at the onset of haemofiltration therapy. Mean Epo (mean +/- SEM) values on days 0-2 were 92.6 +/- 11.7 mU/ml in group 1 and 16.5 +/- 6.4 mU/ml in group 2 (p < 0.0002). Epo levels declined in group 1 to 49 +/- 10.5 mU/ml on days 9 and 10 compared to 23 +/- 9.1 mU/ml in group 2 (ns). These values were maintained until the end of the observation period. No differences were seen between oliguric and non-oliguric patients. Our data show that patients with ARF have increased Epo levels at the beginning of the disease with a strong tendency to decrease, suggesting that there might be inadequate Epo levels during the course of acute renal failure.

Background: It was the purpose of this study to compile the results of all high-risk keratoplasties (kp) performed in our hospital under systemic ciclosporin A (Ci A) cover from 1987 through 1994., Methods: One hundred and thirty-one keratoplasties were performed. Ci A was administered for an average period of 9.4 months. We aimed at trough levels of 100-150 ng/ml (monoclonal RIA/TDx). The 29 kp in group A were second or third repeat kp and/or the recipient cornea had severe deep vascularization in all quadrants and/or a transplant position at the limbus was inevitable (expected risk: only immune reactions). The 40 kp in group B were threatened by severe ocular surface disorders (without severe limbal stem cell insufficiency) and by immune reactions (atopic keratopathy, keratoconus with severe endogenous eczema or chronic blepharokeratoconjunctivitis). In the 45 kp of group C resurfacing problems from severe limbal stem cell insufficiency and immune reactions were anticipated (severe burns, pseudopemphigoid or Lyell syndrome). Group D comprised 17 kp with various diagnoses (e.g. kp in newborns, rheumatic and Acanthamoeba keratitis)., Results: In group A 91% of the grafts were clear 2 years postoperatively, in group B 76%, in group C 38% and in group D 18%. In 32 of 41 failed grafts (78%), resurfacing problems were the only reason for or participated in final graft failure. Immune reactions and other causes of graft failure were of minor importance., Conclusions: (1) Systemic Ci A cover can efficiently suppress immune reactions. (2) With the suppression of immune reactions, resurfacing disorders become the most important single cause for functional graft failure. (3) For eyes with a considerable loss of limbal stem cells, limbal stem cell transplantation should be combined with systemic Ci A cover in order to improve the long-term prognosis for penetrating keratoplasty.

Objective: To determine retrospectively the complications and long-term results of aortocoronary bypass grafting in patients with end-stage renal disease., Patients and Methods: 65 patients with coronary heart disease (CHD) and on dialysis (54 men, 11 women; average age 56.9 +/- 8.1 years) underwent aortocoronary bypass grafting between 1982 and 1992. Mean duration of dialysis (haemo- or peritoneal) was 41.1 +/- 45.0 (1-215) months. All patients had had haemofiltration treatment in conjunction with the bypass operation., Results: Coronary angiography demonstrated triple-vessel disease in 40 patients (62%). Average number of bypasses was 2.8 per patient. Perioperative death rate was 4.6%. 95% of survivors were free of symptoms 6 months postoperatively. Long-term survival rate was 71% after 3 years and 55% after 5 years., Conclusion: Aortocoronary bypass grafting for CHD in patients with end-stage renal disease can be performed with a low perioperative mortality rate and significantly improves symptoms.

The German Collaborative Glomerulonephritis Therapy Study, which celebrated its 10th anniversary in 1996, has collected data on more than 1,000 patients with biopsy-proven glomerulonephritis. 929 patients could be evaluated and 500 were treated according to at least one of various protocols developed for a randomized controlled trial. Current results show that prednisolone is effective in minimal-change nephropathy, and in combination with other immunosuppressants it can reduce proteinuria in individual cases of focal and segmental glomerulosclerosis, membranous glomerulonephritis and nephrotic IgA nephropathy. The majority of tested treatment protocols did not prove to be superior to symptomatic therapy for long-term outcome.

Idiopathic membranoproliferative glomerulonephritis (MPGN) has a poor prognosis, with 90% of patients requiring dialysis treatment after 20 years regardless of therapy. Up to 34% of patients may die due to thrombotic complications or sepsis. This study investigates the influence of aspirin plus dipyridamole on proteinuria and renal function in nephrotic MPGN patients with moderately reduced glomerular filtration rate. Eighteen patients with biopsy-proven MPGN (15 type I, 3 type II) and nephrotic syndrome were randomly assigned to receive protein restriction, antihypertensive therapy (control group) or in addition aspirin and dipyridamole (treatment group). Patients were prospectively followed for a mean of 36 months. Serum creatinine remained unchanged after 36 months compared to baseline in both groups. In the treatment group proteinuria was reduced from 8.3 +/- 1.4 to 1.6 +/- 0.7 g/day (P < 0.05). In control patients proteinuria decreased from 7.1 +/- 1.6 to 4.3 +/- 1.1 g/day. After 36 months proteinuria was significantly lower in the treatment group compared to control (P < 0.02 Mann-Whitney rank sum test). In conclusion, aspirin plus dipyridamole may be of value in reversing nephrotic syndrome and associated risks in patients with MPGN and moderately reduced renal function.

Basal renin secretion and the diagnostic value of a captopril stimulation (captopril test) in identifying renovascular hypertension secondary to transplant renal artery stenosis was assessed in 69 patients with hypertension after renal transplantation. An increase of plasma renin activity of 260% 1 h after captopril was considered as a positive result, assuming renovascular hypertension. Six of 69 patients had a positive captopril test, of these patients 5 had transplant renal artery stenosis. These patients were treated with percutaneous transluminal angioplasty (PTA) or surgery. Based on angiographic results and blood pressure response after PTA or surgery the captopril test showed a sensitivity of 100% and a specificity of 92% in the identification of hemodynamically significant stenosis of the transplant artery. Therefore, the captopril test provides a suitable screening instrument for the differential diagnosis of hypertension following renal transplantation.

We studied the renin-angiotensin system (RAS) and atrial natriuretic peptide (ANP) after amino acid loading in order to elucidate whether or not glomerular hyperfiltration is mediated by these hormones. Eight healthy controls without kidney disease (group 1), 8 renal graft recipients (group 2) and 8 patients after nephrectomy (group 3) were studied. Furthermore, we investigated the influence of amino acid loading on RAS and ANP and glomerular filtration during acute application of captopril in healthy controls. Clearances in insulin (CIn) and para-aminohippuric acid (CPAH) were determined during an infusion of 0.9% saline and during amino acid loading. CIn increased in healthy controls from 96.5 +/- 3.3 to 111.9 +/- 4.4 ml/min (p < 0.01), CPAH rose from 577 +/- 28.7 to 618.9 +/- 38 ml/min (p = NS). During the combined application of amino acid infusion and 25 mg captopril, CIN increased to 125.0 +/- 16.4 ml/min/1.73 m2 (p < 0.01) and there was no significant increase in CPAH which was 595 +/- 77 ml/min/1.73 m2. There was no significant change in renal vascular resistance, but filtration fraction increased from 17 +/- 1 to 19 +/- 1% under amino acid infusion and increased further under the application of captopril to 21 +/- 2% (p < 0.05). In renal graft recipients, CIn had a tendency to increase during amino acid infusion from 78.4 +/- 5.8 to 84.7 +/- 6.5 ml/min (p = NS). In patients after nephrectomy, CIn did not increase (84.5 +/- 6 ml/min) but CPAH did from 345.7 +/- 26.3 to 409 +/- 24.1 ml/min (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The chronic nephrotoxic effects of cyclosporine (CsA) include proximal tubular atrophy and vacuolization. This study investigated the effect of CsA on renal hemodynamics and segmental electrolyte transport in CsA-treated patients. The clearance of inulin (CIn) and PAH para-amino-hippuric acid (CPAH) was determined; proximal tubular function was studied using a lithium clearance method and calculating tubular phosphate reabsorption per milliliter of glomerular filtrate (TP/CIn). Twenty patients without renal disease were investigated: ten treated with CsA because of nonrenal grafting (group 1) and ten healthy volunteers (group 2). The results obtained were compared with those from 20 renal allograft recipients, of whom ten were treated with CsA and methylprednisolone (group 3) and ten with azathioprine and methylprednisolone (group 4). CIn and CPAH were significantly impaired in patients treated with CsA. No significant impairment of lithium clearance as induced by CsA was observed. The fractional excretion of lithium was slightly increased in patients treated with CsA compared to their respective controls. TP/CIn was lower in graft recipients compared to controls; no impairment of phosphate reabsorption as induced by CsA was found. The fractional tubular excretion of lithium was slightly increased compared to controls, rising evidence that proximal tubular reabsorption of lithium was decreased. Tubular reabsorption of phosphate was not impaired. The decrease in glomerular filtration and renal perfusion during chronic treatment with CsA was accompanied by a reduced proximal reabsorptive capacity, as was shown by lithium clearance. Our data do not support the hypothesis that functional parameters of the proximal tubular system can be used as indicators of CsA-induced nephrotoxicity.

The aim of the study was to determine the influence of ciclosporin (Cs) on prostacyclin and thromboxane generation. Four groups of patients were studied. Group 1: Controls, n = 10. Group 2: Patients without kidney disease treated with Cs, n = 10. Group 3: Patients after transplantation treated with azathioprine, n = 10. Group 4: Renal transplant recipients receiving Cs, n = 10. Parameters investigated: CIn, CPAH, TxB2 in plasma, serum and urine; 6-oxo-PGF1 alpha in plasma and urine, urinary 2,3-dinor-TxB2 excretion. CPAH and CIn were significantly decreased during Cs treatment. Plasma TxB2 levels were enhanced in patients without kidney disease receiving Cs (group 2) amounting to 189 +/- 106 pg/ml as compared to 12 +/- 4 pg/ml in controls (group 1). In patients without kidney disease (group 2), plasma 6-oxo-PGF1 alpha was increased (20 +/- 9 pg/ml) as compared to controls in group 1. Plasma TxB2 and plasma 6-oxo-PGF1 alpha were increased in renal graft recipients without any difference due to different immunosuppressive drugs. Treatment with Cs was associated with impaired renal function and resulted, in patients without kidney disease, in elevated plasma TxB2 and plasma 6-oxo-PGF1 alpha. This effect could not be proven in renal graft recipients. We suggest that the deleterious effect of Cs on kidney function is presumably not paralleled by corresponding changes in prostaglandin and thromboxane formation.

Starting with single cases in 1985, we have routinely applied systemic cyclosporin A since 1987 in high-risk keratoplasty patients for a period of up to 37 months postoperatively. In all, 69 eyes undergoing 74 perforating keratoplasties have thus far been treated. A considerable percentage of them initially suffered from chemical burns or from endogenous eczema associated with chronic atopic inflammation. All patients were followed closely and their courses were reevaluated retrospectively. Our current conclusions are that (1) immune reactions are efficiently inhibited with constantly effective blood levels of cyclosporin A, which has enormously increased the rate of keratoplasty successful in these patients; (2) if drug blood levels fall too low due to noncompliance of the patient or to metabolic disturbances, immune reactions may occur, especially during the early postoperative months; (3) serious chronic surface problems, which are especially associated with chemical burns, atopic inflammation, and other chronic kerato-conjunctival diseases, are partly ameliorated but not completely eliminated (surface disorders are presently ranked as the number one cause of transplant failure, whereas immune reactions can be effectively suppressed by cyclosporin A); and (4) close medical follow-up has revealed no serious systemic complication of cyclosporin A prophylaxis over periods of up to 37 months. The present study was not conducted in a prospective, double-blind, controlled fashion.

Long-term administration of ciclosporin has been complicated by side-effects, the predominant being nephrotoxicity. We performed renal function studies on 20 patients treated with ciclosporin (group 1) and on 12 patients serving as controls (group 2). Only patients with serum creatinine less than 1.3 mg/dl entered the study. The renal function studies consisted of: Inulin clearance, PAH clearance, sodium sulphate loading, sodium bicarbonate loading. Plasma renin activity (PRA), inactive renin (IR) and aldosterone (ALDO) were measured basally and after stimulation with 40 mg furosemide i.v. Serum creatinine was not significantly impaired under ciclosporin with 1.1 +/- 0.1 mg/dl vs 0.9 +/- 0.1 mg/dl in the control group (ns). Glomerular filtration rates as measured by creatinine and inulin clearance were significantly impaired in group 1 as compared to group 2. Inulin clearance was impaired by ciclosporin with 93.5 +/- 4.4 ml/min/1.73 m2 as compared to 121 +/- 6.6 ml/min/1.73 m2 (p less than 0.05) in patients of group 2. The PAH clearance in ciclosporin treated patients was impaired, with 379 +/- 22.1 ml/min/1.73 m2 in group 1 as compared to 605 +/- 39 ml/min/1.73 m2 (p less than 0.001) in group 2. Mean arterial pressure and renovascular resistance were significantly increased in ciclosporin treated patients. We demonstrated, by means of sodium sulphate and bicarbonate loading, incomplete distal tubular acidosis in 3 patients from group 1 but in none of group 2. There was no difference in basal plasma renin activity (PRA), but during volume contraction induced by furosemide there was only blunted response by PRA in patients receiving ciclosporin with 2.7 +/- 0.3 ng/ml/h as compared to 7.7 +/- 0.5 ng/ml/h in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

A severe, spontaneously acquired, bilateral, sight threatening Ulcus rodens Mooren of a 31 years old type I diabetic will be demonstrated in its clinical course. An improvement was achieved by a systemic immunomodulating therapy with Ciclosporin A that had to be tapered after 3 weeks due to severe side effects. The exclusive local therapy showed no effect at all. Later, the patient underwent a penetrating keratoplasty and extracapsular cataract extraction of both eyes under systemic Ciclosporin A therapy. The graft of the left eye failed due to a foudroyant bacterial infection whereas the keratoplasty of the right eye was successful up to this day despite of various complications.

There are typical morphological indicators of tubular defects during the administration of ciclosporin A (CSA). Distal tubular function remains unclear although hyperkalemia is a common clinical feature in these patients. We performed renal function studies 3 months after renal transplantation on 35 patients (group 1) treated with CSA. The results were compared to those of a control group consisting of 15 patients transplanted earlier and treated with azathioprine (group 2). Only patients with stable renal function (creatinine less than or equal to 2.0 mg/dl) entered the investigation consisting of: inulin (In) clearance; p-aminohippuric acid (PAH) clearance; ammonium chloride loading; sodium sulfate loading, and sodium bicarbonate loading. Plasma renin activity and aldosterone were measured basally and after stimulation with 40 mg i.v. furosemide. Clearances of In and PAH were significantly impaired during the administration of CSA. Group 1: CIn 73.3 +/- 8.7 ml/min/1.73 m2 (p less than 0.01), CPAH 263 +/- 58.3 ml/min/1.73 m2 (p less than 0.01); group 2: CIn 89.6 +/- 19.1 ml/min/1.73 m2, CPAH 338.7 +/- 63.5 ml/min/1.73 m2. Incomplete distal tubular acidosis could be demonstrated in 8 patients from group 1 but none of group 2. Hyporeninemic hypoaldosteronism could be demonstrated in 4 patients during the administration of CSA. CSA in therapeutic doses significantly impairs renal perfusion, glomerular filtration, distal acidification and the renin-aldosterone axis.