[Life threatening hypercalcemia in a young man with ALL]. / Lebensbedrohliche Hyperkalzämie bei einem jungen Mann mit ALL.

HISTORY AND ADMISSION FINDINGS: A 16-year-old man experienced fatigue, vomiting and diffuse abdominal pain. Since 4 days he had myalgia in both arms and legs. On examination only a tachycardia of 110/min was noticed. INVESTIGATIONS: Laboratory tests revealed hemoglobin 12.7 g/dl, leucocytes 10,300/microliter, platelets 89,000/microliter, LDH 191 U/l, sodium 134 mmol/l, potassium 2.76 mmol/l, calcium 4.52 mmol/l (I), creatinine 1.13 mg/dl, urea 72 mg/dl, uric acid 11.2 mg/dl. The levels of PTH (0 pg/ml), PTH-related peptide, vitamin D, vitamin A, IGF-1, STH, 5-HIES and interleukin 6 were within normal limits. TNF-alpha 25.9 pg/ml (< 8.1). The electrocardiography revealed a sinus rythm with a QT-time of 0.28 s (= 100%). Multiple osteolytic bone leasions were seen in thoracic CT-scan. Abdominal sonography showed normal liver structure, multiple subhepatic lymph nodes without splenomegaly. The cytologic examination of the bone marrow demonstrated a diffuse infiltration by a common acute leukemia. TREATMENT AND COURSE: The rehydration with physiologic saline (3500 ml/d) was initiated in the ICU. Furosemide was added for further renal excretion. Additionally prednisone (100 mg/d) and calcitonin (300 I.E./d) were given. The calcium level fell within two days. No cardiac arrhythmia nor acute renal failure were seen. After definitive diagnosing the patient was treated corresponding to a specific protocol. One year later the relapsing ALL was diagnosed also by hypercalcemia (5.9 mmol/l). The level of TNF-alpha before and after correction of hypercalcemia was 20 pg/ml. CONCLUSION: The acute treatment of hypercalcemia is independent of the underlying cause (rehydration with physiologic saline, renal excretion with furosemide, inhibition of osteoclastic activity). The main causes are hyperparathyreoidism or malignancys (90%). We describe TNF-alpha as a possible marker of tumoral load of a common ALL but we are not able to reveal a correlation between TNF-alpha and the calcium level.

Continuous haemofiltration with r-hirudin (lepirudin) as anticoagulant in a patient with heparin induced thrombocytopenia (HIT II).

A 60-year-old man was admitted to the hospital with aortic dissection. An operative excision and replacement with a Y-graft was performed. Postoperatively he developed multiple organ dysfunction and required intermittent haemofiltration (anticoagulation with heparin). An ischemia of the left leg occurred at the third postoperative day. The initial platelet count was 99,000/microliter. Continuous haemofiltration (CVVH) was started three days later. Thrombotic obstructions of haemodialysis filters and catheters occurred frequently and heparin-induced thrombocytopenia (HIT II) was suspected. Antibodies against heparin were found in the HIPA test. Despite heparin free citrate dialysis and anticoagulation with danaparoid thrombotic obstructions of filters and catheters continued. Therefore the anticoagulation therapy during CVVH was changed to recombinant hirudin (lepirudin). Starting dose was a bolus of 0.01 mg/kg bw followed by the same amount as maintenance dose per hour. Anticoagulation was adjusted to an increase of aPTT (activated partial thromboplastin time) to 1.5-2 times its normal value. A dose of 0.005 mg/kg bw/h lepirudin was sufficient to maintain adequate anticoagulation. After changing to lepirudin no further catheter obstructions were observed and the platelets recovered slowly. Renal function improved and five weeks after admission endogenous creatinine clearance showed a value of 25 ml/min. We conclude that lepirudin is an effective anticoagulant during CVVH in patients with HIT II. In partly permeable polysulfon filters a dose of 0.005 mg/kg bw/h lepirudin is sufficient to maintain adequate anticoagulation. Monitoring anticoagulation by measuring the increase of aPTT (factor 1.5-2.0) seems to be safe. However, optimally the r-hirudin concentration should be measured directly using the Ecarin clotting time.

High-dose torasemide, given once daily intravenously for one week, in patients with advanced chronic renal failure.

Effects, both acute and after repeated dosing of 200 mg of intravenous torasemide in comparison to baseline values on placebo, were investigated with respect to 24 h fractional volume excretion and electrolyte excretion, signs of peripheral edema and changes in body weight in the present open uncontrolled multicenter study. Fourty-four patients with advanced chronic renal failure (mean creatinine clearance 8.9 +/- 9.6 ml/min, range 1.1-63.7 ml/min) were enrolled after they had given their informed consent. The increase vs placebo in the primary efficacy variable 24 h fractional volume excretion was statistically significant both acutely (p = 0.0001) and after repeated daily injections (p = 0.0012). The acute changes of the means of fractional volume excretion (from 14.32% to 21.07%) and of absolute 24 h urinary volume (from 1303 ml to 2124 ml) were as expected from earlier data. In addition to the acute results our study showed that after seven days of daily injections there was still a considerable diuretic effect (mean fractional volume excretion: 18.10%, absolute 24 h urinary volume: 1664 ml). Our data support earlier results in that the change in fractional potassium excretion was considerably smaller than that of sodium of chloride excretion. However, this effect which was more pronounced after acute administration of torasemide seems to vanish after repeated dosing. After repeated dosing there was only a minor change in calcium excretion and there was no alteration in phosphate excretion, neither acutely nor with repeated dosing. Along with the enhanced diuresis there was a relevant reduction in body weight and a clinical significant improvement preexisting signs of peripheral edema. Torasemide was found to be also efficacious in patients on hemodialysis (with residual diuresis of > or = 300 ml): after the first i.v. dose of 200 mg torasemide the mean fractional volume excretion was increased from 16.22% at baseline by 3.42% to 18.99% (in absolute 24 h urinary volume from 1044 ml at baseline by 563 ml to 1607 ml). In parallel, the mean fractional sodium excretion was increased from 8.67% at baseline by 2.99% to 11.14% (in absolute 24 h urinary sodium excretion from 83.3 mmol at baseline by 51.2 mmol to 128.0 mmol). There was no serious adverse events related to the administration of torasemide. Torasemide appears to be a good choice for the treatment of patients with renal failure.

Observations on renal replacement services in Russia, Belarus and Lithuania.

This report describes the current financial, technical and medical status of nephrology, dialysis and renal transplant services in these countries with the hope of helping our colleagues there to upgrade their standards of care. The general impression is that physicians as well as administrators in these countries are eager to improve conditions of patient care despite a disastrous economical climate. Our view is that we can help by providing literature, textbooks, journals, travel funds, by offering visiting fellowships to individual physicians, and by forming partnerships between nephrology centres.

Cyclosporine pharmacokinetics and variability from a microemulsion formulation--a multicenter investigation in kidney transplant patients.

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.

Improved classification of proteinuria by semiautomated ultrathin SDS polyacrylamide gel electrophoresis.

The quantitative and qualitative analysis of proteinuria by electrophoretic means proved to be a potent diagnostic tool for differentiation of functional renal impairment. The purpose of this study was to compare the macro scale SDS-PAGE technique, which has been used for the last two decades, with semiautomated electrophoresis using an ultrathin SDS-PAA gel with silver staining (Phast system). The new system proved to be quick and easy to handle. Separation of proteins in the range of 70-320 kD were of comparable quality to the macro scale system (unselective and selective glomerular proteinurias with 68 to 150 and 68 to 350 kD components, respectively, as well as total serum proteins), but there was considerable improvement regarding the quality and visibility of protein bands in the range of 11-70 kD. This improvement led to a new classification of micromolecular protein bands into three groups: the smallest microproteins (11-22 kD), the larger microproteins (23-40 kD) and the largest microproteins (41-68 kD). Thereby it was possible to obtain an improved definition of electrophoretic patterns of urinary proteins, which is described in detail.

[Fractional clearance of beta-2-microglobulin in the diagnostic and prognostic assessment of kidney diseases]. / Fraktionelle Clearance des beta-2-Mikroglobulins in der Diagnose und Prognosestellung bei Nierenkrankheiten.

The micromolecular proteinuria (67-11 Kd), originating from tubulo-interstitial disorders, might be determined by SDS- or gradient-PAGE or by individual marker proteins. The latter procedure in addition to PAGE is necessary in case of heavy proteinurias. The tubular resorptive capacity for microproteins, analysed by fractional beta-2-M-clearances, decreases with deteriorating GFR. Values for FrCl beta 2M above the expected level were associated with tubulo-interstitial, but also with diabetic and rapidly progressing glomerular nephropathies. In the latter group these findings might be of prognostic importance. In contrast, the U-beta-2-M-determination in long term observation of kidney transplants had no diagnostic nor prognostic value.

Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: a controlled, multi-center study.

In a randomized study of 26 patients with histologically confirmed rapidly progressive crescentic glomerulonephritis, 12 patients were treated with immunosuppressants alone (corticosteroids, cyclophosphamide and azathioprine) while the other 14 patients received not only the identical immunosuppressive treatment but also plasma exchange therapy for four weeks. No statistically significant difference was found between the two groups. After 8 weeks, 73% and 69% of the patients in each respective group showed recompensation of renal function; serum creatinine fell from initially 7.0 and 6.2 mg/dl mean to 2.7 and 2.3 mg/dl mean, and under continued immunosuppression did not rise in the following months. Thus, in non-autoantibody induced rapidly progressive glomerulonephritis, kidney function could be improved substantially by immunosuppressive therapy, but an advantage of supplementary plasma exchange could not be shown.

Mild proteinuria in patients with unilateral kidney.

Arterial blood pressure, 24 h urinary excretion, and glomerular filtration rate (GFR) in 24 patients with unilateral kidney were compared with an age and sex matched control group of healthy persons. Of the patients with unilateral kidney, 13 were uninephrectomized and 11 patients had a congenital unilateral kidney. The 24 h urinary protein excretion in patients with one kidney was significantly higher (630 +/- 51 mg/24 h) compared to the control group (206 +/- 36 mg/24 h). The arterial systolic and diastolic blood pressures and GFR did not differ in both groups. Furthermore, no differences were found between patients with unilateral kidneys following nephrectomy or renal agenesis. This study shows that mild proteinuria occurs in patients with unilateral kidney. An increased risk for deterioration in renal function or severe arterial hypertension was not detected in this investigation.

[Does febrile proteinuria exist?]. / Gibt es die "Febrile Proteinurie"?

The significance of proteinuria during febrile infectious diseases is widely underestimated, although the more marked proteinuria probably signalizes a parainfectious nephropathy rather than a functional disorder. This study shows that mild proteinuria of less than 0.65 g/24 h (normal range less than 0.3 g/24 h using the sensitive tannine-FeCl3-technique) might be caused by the elevated body temperature alone. 9 out of 18 volunteers without renal disease undergoing experimental hyperthermia of 40-41 degrees C for 1-2 h did not develop a proteinuria according to quantitative and qualitative (SDS-PAGE) measurements. In 6/18 the amount and composition of urinary proteins changed giving a glomerular type of proteinuria, possibly caused by temperature related transient glomerular alterations. In 3/18 a mild glomerulopathy existed before hyperthermia, as deduced from a glomerular pattern despite a quantitatively physiological proteinuria, leading in all 3 to pathological proteinuria during hyperthermia. In all 18 volunteers alterations reversed to normal within 12 h. Therefore, the degree of proteinuria during febrile diseases should be considered. Proteinuria of less than 0.5-1 g/24 h in adults might be explained by an altered glomerular function alone. Proteinurias exceeding this value, with a slow regressing tendency will indicate glomerular or tubulo-interstitial diseases, caused possibly by immunologic or toxic products resulting from underlying infectious disease.

Urinary protein patterns and preeclampsia.

A retrospective study of urinary protein patterns, as determined by SDS-PAA-disc-electrophoresis was performed in 107 patients in third trimester of pregnancy because of preeclampsia. The aim was to determine whether the protein patterns allow a differentiation between nephropathies associated with genuine toxaemia of pregnancy and those in which toxaemia was superimposed on preexisting renal glomerular or tubular disease. The magnitude and type of proteinuria was related to the mean arterial pressure (MAP). 47% of all patients showed a mixed protein pattern independent of the MAP-severity. This form of proteinuria is probably associated with a genuine toxaemia of pregnancy. It was not possible to determine if pure glomerulopathies whose frequency rose with MAP, had already been present before pregnancy. In a third of the 22 patients followed-up post-partum pathological protein patterns or increased protein excretion was detected. This implies that 35% of the nephropathies were present before pregnancy. However, differentiation between preexisting and toxaemia associated nephropathy was not always possible. SDS-PAA-analysis of urinary protein should be carried out in earlier stages of pregnancy in cases of increasing MAP and proteinuria.

[Results of continuous permanent irrigation in diffuse purulent peritonitis]. / Ergebnisse der kontinuierlichen Dauerspülung bei diffus-eitriger Peritonitis.

In a prospective study continuous peritoneal lavage was carried out in 30 patients with diffuse purulent or fecal peritonitis using a volume of 20-50 1/24 h during 5-7 days. Bacteria were recognised in the effusate until day 5. Protein losses per 24 hours amounted to 4,1-46 g. A mean value of 14,5 +/- 14 g was determined. The fractional protein clearance of IgG had increased compared to other proteins. A mortality of 26,7% was obtained. Death causes were the consequences of septic shock. In none of the investigated cases remaining empyemas in the peritoneal cavity could be shown. There was no support for the establishment of lavage tracks.

Diagnostic significance of SDS-PAA-electrophoresis of urinary proteins: different forms of proteinuria and their correlation to renal diseases.

Different types of urinary protein excretion may be recognized by determination of the proteins molecular weight. Beside chromatography different electrophoretic procedures have been applied to urinary proteins to study the underlying renal disease. The various zone electrophoreses separate merely by surface charge, proteins however covered by sodium dodecyl sulfate (SDS) migrate according to their molecular radius. So by SDS-polyacrylamide electrophoresis (SDS-PAe) macromolecular proteinurias (Mr 60,000- greater than 300,000 daltons) due to glomerular damage may be distinguished from micromolecular forms (Mr 10,000-70,000 d) due to tubular dysfunction. By densitometric quantitation of the separated Ig and transferrin an index of the glomerular selectivity is obtained, i.e. the capacity of the glomerular system, to retain serum proteins of a Mr above 150,000 d. By this procedure proliferative and degenerative glomerulopathies may be distinguished from minimal change disease, focal glomerular sclerosis and early membranous nephropathy; serial determinations of this selectivity index in the latter two disease entities show a gradual deterioration of glomerular protein handling with time. A glomerular proteinuria of even "physiological" quantity has been proved as early sign of renal involvment in systemic diseases; it may be detected earlier as for example the retinopathy in juvenile diabetics. Micromolecular proteinurias also occur at least in two forms: the typical tubular proteinuria (MW 10,000-70,000 d) is associated with acute or chronic severe tubular dysfunction as in interstitial nephritis and acute kidney failure; rejection episodes of kidney transplants lead to transient tubular proteinurias, too. The second form of micromolecular proteinuria (Mr 40,000-70,000 d) has been found frequently in association with a glomerular in diabetic and hypertensive glomerulosclerosis. By measuring clearances of the microproteins, the proteinuria with this pattern could be established as form independant from glomerular and tubular proteinurias. The constancy of the two micromolecular proteinurias led to the hypothesis of at least two selective mechanism of tubular protein resorption. SDS-PAe additionally allows the differentiation of extrarenal proteinurias, as caused by overflow, paraproteins, postrenal Ig-secretion or bleeding etc. In comparing clinical and in part histological data of about 2,000 patients suffering from kidney diseases the analysis of urinary proteins by this method has been proved as valuable non-invasive tool for diagnosis and follow-up.

Studies on excretion of renal antigens in normal and pathological urine.

The report deals with attempts to identify and quantitate renal antigens excreted into the urine of normal subjects and patients with renal disease. Although no useful information was obtained on the possible excretion of glomerular basement membrane antigens, renal tubular epithelial antigen (RTE) proved to be interesting. Curiously, massive excretion of RTE occurred most prominently in cases of 'minimal change' disease. In addition, a correlation between the selectivity of the proteinuria and excretion of RTE was noted. In general there did not seem to be any relation between RTE excretion and tubular/interstitial lesions.

Polymeric albumin in the urine of patients with nephrotic syndrome.

Dimer and polymer albumin was detected in the urine of a proportion of pantients with a nephrotic syndrome. Most of it was present as S-S bonded dimer and polymer; co-polymers, however, with IgG and alpha (1) anti-trypsin could be demonstrated. It is suggested that albumin polymerizes after it has passed the glomerular membrane. Albumin dimer was associated mainly with minimal change disease and early membranous glomerulopathy in patients, who in general responded well to therapy.