Phenylalanine and tyrosine metabolism in renal failure: dipeptides as tyrosine source.

Several lines of evidence suggest that tyrosine formation is impaired in renal failure. The concentration of tyrosine is decreased and the phenylalanine/tyrosine ratio is increased in plasma and in skeletal muscle cells. After an oral or intravenous load, the rise of plasma phenylalanine is augmented, the clearance is decreased, oxidation is diminished and the corresponding rise of plasma tyrosine level is blunted. Tyrosine elimination and oxidation are not altered in uremia. The defect in tyrosine formation may be especially important in uremic patients on a low protein diet supplemented with tyrosine-free essential amino acid preparations and in subjects on artificial nutritional support. Thus, tyrosine should be regarded as a conditionally essential amino acid in renal failure and should be supplied exogenously, at least in these patient groups. Oral tyrosine supplementation was shown to replete plasma and intracellular pools and improve nitrogen balance in chronic renal failure patients on a low protein diet. However, because of poor solubility in aqueous solutions, tyrosine cannot be included in the free form in amino acid solutions for parenteral nutrition. To circumvent stability or solubility problems, tyrosine containing dipeptides and/or N-acetyl-tyrosine may serve as tyrosine sources for parenteral supply. Renal failure does not affect alanyl-tyrosine hydrolysis, and there is an immediate increase of plasma tyrosine concentration after peptide infusion. Elimination and hydrolysis of glycine-tyrosine is retarded in renal failure, but the clearance exceeds clinically relevant infusion rates. After infusion of N-acetyl-tyrosine, no increase in plasma tyrosine is seen, and the half-life N-acetyl-tyrosine is grossly prolonged in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Clotting activities and antigen concentrations of contact factors in kidney disease.

Factor XII, prekallikrein (PK) and high molecular weight kininogen (HMWK) clotting activities and antigen concentrations in kidney disease patients were studied. Chronic hemodialysis led to a reduction of F XII, PK and HMWK clotting activities. F XII and PK antigen levels were also low. In contrast, the HMWK antigen was normal with respect to concentration as well as electrophoretic migration behaviour on 2 D-immunelectrophoresis. In kidney transplant recipients more than three month after the transplantation, we found an increased of F XII and PK clotting activities, which appeared to depend on the time elapsed since the operation. However, the antigen levels remained normal. The group of chronic kidney disease patients not requiring hemodialysis exhibited normal mean values of all three clotting activities as well as normal F XII and HMWK antigen levels. The PK antigen was reduced. However, a separate evaluation of F XII clotting activities (F XII:C) in patients with glomerular nephritis showed elevated F XII:C which correlated with the BUN values. During acute processes of the kidney disease we observed very high PK clotting activities, which normalized with stabilization of the patients. Our results show that the contact phase coagulation factors behave abnormally in certain kidney disease patients.

Prekallikrein, HMW-kininogen and factor XII in various disease states.

The behaviour of prekallikrein (PKK), factor XII, high molecular weight kininogen (HMWK) and kallikrein-inhibitor (KK-I) in 367 patients with various diseases is described. Malignancies lead to elevation of factor XII and KK-I, and reduction of PKK. The effect is more pronounced in patients with metastases. In renal diseases also one or more of the above mentioned parameters are abnormal. Defects requiring dialysis treatment significantly impair the contact factors. In this group low levels of PKK, Factor XII and HMWK and increased KK-I are common. In chronic renal disease patients, only F XII and KK-I are elevated, whereas PKK and HMWK are normal. Kidney transplantation leads to a rise in KK-I and reduction of PKK and HMWK. The values almost normalize few days after the operation. Factor XII, slightly increased immediately after transplantation, remains high in long term transplant recipients, whereas HMWK falls below normal. In liver disease patients, acute and chronic hepatitis, cirrhosis of the liver and coma, PKK is reduced. In cases with acute hepatitis PKK raises with recovery. Cirrhosis and coma lead to low HMWK and factor XII concentrations. KK-I is mostly affected during acute hepatitis, and is then highly increased. Our results clearly demonstrate that the biologic activity of one or more of contact factors is affected in many diseases.

Persistent pituitary-thyroid dysfunction patients following renal transplantation.

Pituitary-thyroid function, which is known to be altered in patients with chronic renal insufficiency, has been evaluated after successful kidney transplantation in 36 patients and compared with that in 15 healthy subjects. Thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was in the low range of normal in 24, and markedly decreased in 12 patients (< 0.0005). In the former group serum thyroxine was normal, whereas triiodothyronine was lowered; in the latter group thyroxine, although within the normal range, and triiodothyronine levels were reduced when compared with that of healthy controls. This differential TSH response to TRH was unrelated to kidney transplant function, duration of renal insufficiency or duration of the preceding hemodialysis, or to the dose and dosing schedule of prednisolone therapy. However, a slight negative correlation between the dose of prednisolone administered and TSh responsiveness to TRH as well as serum triiodothyronine was established (P < 0.05). Thus, corticoid treatment may in part be responsible for the alteration in TSH secretion and in the peripheral conversion of thyroxine to triiodothyronine. Other, as yet undefined factors, such as patients' variability in pituitary susceptibility to the polypragmatic therapy administered, have to be suspected as the major causes of the persistent pathological pituitary-thyroid function tests observed after renal transplantation.

Diminished serum folic acid levels in renal transplant recipients.

Serum folic acid levels were determined by radioimmunoassay in 26 chronic hemodialysis patients, in 52 renal transplant recipients and in 20 healthy controls. In the dialyzed patients, the mean serum folic acid level was 3.37 +/- 1.25 ng/ml and was significantly lower than that of the controls (6.1 +/- 1.38 ng/ml, P less than 0.001). In renal transplant recipients the mean folic acid concentration was 4.09 +/- 1.58 ng/ml and was also significantly decreased (P less than 0.001). 15 (29 per cent) out of 52 renal transplant patients showed serum folic acid concentrations lower than 3.0 ng/ml. Diminished serum folic acid levels were found not only in patients shortly after surgery but also in cases with excellent graft function up to 6 years after transplantation. The highest serum folic acid level was observed in one transplant patient who had taken no azathioprine for 24 months. Macrocytosis was found in 52 per cent of our renal transplant patients. There was no significant difference between the serum folic acid levels of renal transplant recipients with (n = 27) and without (n = 25) macrocytosis; however, serum creatinine levels were significantly lower in cases revealing macrocytosis. Relative folic acid deficiency does not seem to be responsible for macrocytosis after renal transplantation. Macrocytosis was observed only in patients with good graft function treated with azathioprine. Serum vitamin B12 levels were within the normal range in both dialyzed and renal transplant patients.

Successful outcome of a complicated pregnancy in a renal transplant recipient taking cyclosporine A.

The successful outcome of a pregnancy complicated by reversible renal failure secondary to total ureteral obstruction caused by a pregnant uterus and treated temporarily with nephrostomy is reported. The cyclosporine A (CsA) and prednisone treated female recipient of a cadaveric renal allograft gave birth to a male child, which at 2080 grams was small for gestational age (35 weeks of pregnancy). The child presented neither signs of congenital anomalies or chromosome aberrations nor nephrotoxicity, hepatotoxicity or anemia. Simultaneous measurement of trough CsA blood levels (CsA RIA, Sandoz) displayed reduced values in the child's blood (mother 864 ng/ml-4 hours after oral CsA intake; son 312 ng/ml). Beside postrenal failure the patient's pregnancy was complicated by 7 rejection episodes treated with high doses of methylprednisone (total dose 5 g) with reversible damage of the transplant function, two episodes of a urinary tract infection and increasing anemia necessitating blood transfusions. The HIV negative patient had developed a Kaposi's sarcoma 6 weeks after grafting. The progression of infiltrating skin lesions during pregnancy was not seen.

[Problems of infections following renal transplantation (author's transl)]. / Infektionsprobleme nach Nierentransplantation

Infections arising as a complication of immunosuppressive therapy were analyzed in more than 40 renal transplant patients. Bacterial infections were observed in 78.0%, viral in 68.3% and mycotic infections in 56.3% of cases seen during a 3-year investigation. Infection was the cause of death in 5 out of 8 cases with fatal complications. Bacterial infections of the lungs were amongst the gravest post-transplant complications. Hepatitis B, herpes simplex and cytomegalovirus were the most common viral infections. Simultaneous bacterial, viral and Candida albicans infections--so-called "triple infections"--with a very poor prognosis were diagnosed in 25% of the investigated cases. The data show that after cadaveric kidney transplantation special emphasis should be laid on careful prophylaxis of infections and diagnostic measures for the early recognition of possible infections arising as a complication of immunosuppressive therapy.

[An evaluation of candida serology following renal transplantation and its connexion with other postoperative complications (author's transl)]. / Vergleichende Untersuchungen über den Aussagewert der Candidaserologie nach Nierentransplantation.

53 renal transplant recipients aged 13 to 58 years were followed up regularly clinically, microbiologically and serologically over observation periods ranging from 6 to 82 months following transplantation with a view to diagnosing mycetic complications. The only (facultative) pathogenic species found was Candida albicans. This species was isolated in every single patient, but far-reaching differences were observed with regard to the degree of form of infection in the individual person. Mainly, cases showed only a transient growth of Candida to a greater or lesser extent on the mucous membranes of the orointestinal tract, but in few cases serious systemic forms like fungaemia and urinary tract infections were manifest. Comparing the mycological and clinical findings it was apparent that the degree of mycetic infection and attendant complications was closely correlated to the incidence and severity of several--at least primarily--non-mycetic complications postoperatively, such as disorders of transplant function, rejection reactions, diabetes and bacterial infections. A causal connexion, thus, probably exists between postoperative mycetic and non-mycetic complications and the presumable underlying pathological mechanism is discussed.

[Frequency of cardiovascular risk factors in renal transplant patients (author's transl)]. / Häufigkeit potentieller Risikofaktoren kardiovaskulärer Erkrankungen bei nierentransplantierten Patienten.

The incidence of cardiovascular risk factors was studied in 83 renal transplant recipients: 84.3% showed at least one cardiovascular risk factor, hyperuricaemia was found in 42.2%, hypertension in 39.7%, hypercholesterolaemia in 31.3%, hypertriglyceridaemia in 27.7%, diabetes mellitus in 19.3%, obesity in 14% and nicotine abuse in 13.2% of the patients. Patients aged from 30 to 39 and 40 to 49 showed a mean incidence of 2.7 and 2.9, respectively out of the 7 investigated cardiovascular risk factors. The results demonstrate that renal transplant patients are a high-risk group for the development of degenerative cardiovascular diseases.

[Oto-rhino-laryngological complications in patients receiving intermittent haemodialysis and in renal transplant recipients (author's transl)]. / Oto-rhino-laryngologische Komplikationen chronisch dialysierter und nierentransplantierter Patienten

Patients with chronic uraemia and renal transplant recipients were examined for oto-rhino-laryngological diseases over the course of a five-year period. During dialysis treatment, 58 out of 77 chronic uraemic patients developed complications, mainly affecting the nose and the ear, on a degenerative or toxic uraemic basis. In the period under review, renal transplantations were carried out in 63 patients, in whom infectious processes had occurred mainly in the upper respiratory and digestive tracts; postoperative immuno-suppressive therapy is responsible for the morbidity in these cases. Particular reference is made to the necessity of eradicating any possible sources of infection already during the period of dialysis treatment and to the importance of cooperation between physicians and oto-rhino-laryngologists.

[Fungal infections -- always dangerous for immunosuppressed patients (author's transl)]. / Pilzinfektionen -- weiterhin gefährlich für den immunsuppressiv behandelten Patienten.

Four renal transplant recipients, treated with the immunosuppressive combination of azathioprine-prednisolone, developed organ or systemic mycoses caused by Candida albicans and, in one case, additionally by Trichophyton rubrum. Ketoconazole, a new wide-spectrum antimycotic drug, was successfully used in the treatment of the fungal infections in these patients. The oral route of administration, good tolerance and excellent results are good recommendations for this drug.

[Plasma glycolate concentrations under conditions of dialysis]. / Plasma-Glykolatkonzentration unter Dialysebedingungen.

Plasma glycollate and oxalate concentrations were measured in 20 patients undergoing chronic haemodialysis treatment. The mean plasma glycollate level was 173.7 +/- 52.9 mumol/l, which was not significantly different from the normal value (means = 145.8 +/- 37.8 mumol/l). The mean plasma oxalate concentration (means = 128.7 +/- 25.6 mumol/l) was about 8 times higher than the value found in normal volunteers (means = 16.8 +/- 6.0 mumol/l). During haemodialysis lasting for 6 hours the plasma oxalate concentration decreased by 53.5%. However, no decline in plasma glycollate levels was noted. Since glycollate was not found in ultrafiltrates obtained in vivo, it is concluded that glycollate is not eliminated during haemodialysis treatment.

[Mixed infection after renal transplantation (author's transl)]. / Mehrfachinfektionen nach Nierrentransplantation.

Severe mixed infection was observed in 9 out of 101 renal transplant recipients over a period of 6 years and was characterized by the simultaneous incidence of bacterial, fungal and viral infections. Severe septicaemia was clinically evident in all cases. The critical clinical situation called for a rapid assessment of the differential diagnosis and relevant bacterial, fungal and viral investigations. Antibacterial and antimycotic therapy must be instituted as soon as possible on account of the high mortality from mixed infection in renal transplant recipients. The reduction or discontinuation of immunosuppressive therapy during infection did not impair renal transplant function.

[Morbidity during regular dialysis treatment and after renal transplantation (author's transl)]. / Morbidität während chronischer Hämodialyse und nach Nierentransplantation.

Renal transplantation was associated with a lesser degree of morbidity than chronic dialysis treatment in a group of 48 patients with end-stage renal failure. Morbidity was defined as total days of in-patient hospitalization divided by total days of risk. The morbidity during chronic intermittent dialysis, with a mean observation time of 296.1 (20 to 2255) days, was 11.8%, whereas after renal transplantation, with a mean observation time of 1004.0 (131 to 2400) days, only 7.6% of all days at risk were spent in hospital. Morbidity rises to 38.1% during chronic dialysis if all dialysis days on an out-patient basis are considered as hospitalization days. Morbidity was lowest (3.8%) in patients sent home for the first time with a functioning graft. Cardiac complications and fluid lung were the most common causes for morbidity during haemodialysis treatment; morbidity after renal transplantation was mainly due to renal rejection and infections under non-specific immunosuppression. Social and occupational rehabilitation was better after renal transplantation than during haemodialysis treatment. It can be concluded from these data that with regard to the quality of life renal transplantation is the preferable alternative in the management of end-stage renal failure.

[Osteopathy and serum parathormone and 25-hydroxycholecalciferol levels in patients on long-term haemodialysis (author's transl)]. / Osteopathie, Parathormon- und 25-Hydroxycholekalziferol-Konzentrationen im Serum bei chronisch dialysierten Patienten.

Skeletal radiological changes were analyzed in 22 patients treated by chronic haemodialysis. Furthermore, the serum parathormone and 25-hydroxycholecalciferol concentrations were determined. X-ray evidence of renal osteopathy was found in 13 patients (59%). Extraskeletal calcification, subperiostal erosions and cystoids were the predominant lesions. Serum iPTH concentrations were increased in 21 out of 22 haemodialyzed patients. The serum 25-hydroxycholecalciferol concentration was normal. The results of this study seem to indicate that other factors apart from secondary hyperparathyroidism have a share in the development of renal osteopathy in patients on chronic haemodialysis.

[Cyclosporin therapy in minimal change nephritis]. / Cyclosporintherapie bei Minimal-change-Nephritis.

In 5 cases with minimal change nephritis Cyclosporine A has been added to the conventional steroid therapy, when relapse of nephrotic syndrome occurred while reducing the daily prednisolone dose. The intended cyclosporine trough level ranged from 250 ng/ml to 450 ng/ml whole blood, estimated by the RIA method. Proteinuria disappeared in 4 out of the 5 cases, in the other one urinary protein excretion was strikingly reduced. In the 4 cases with complete remission of proteinuria prednisolone was tapered. These patients have cyclosporine A as the sole immunosuppressive drug since 56 weeks and do not show proteinuria. Side effects of cyclosporine therapy have been slight deterioration of kidney function in 2 out of the 5 cases and the occurrence of hypertension in 4 patients.

[Macrocytosis in renal transplant patients (author's transl)]. / Makrozytose bei Patienten nach Nierentransplantation

Since macrocytosis was observed in a high percentage of our renal transplant patients, a follow-up study was carried out on 36 patients with determination of the mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and haemoglobin concentration (MCHC). These parameters were determined monthly for periods of up to two years (16 cases) following transplantation. There was a rise in both MCV and MCH within one month. Macrooperative MCHC, however, remained normal. Anaemia was absent or mild. The bone marrow showed striking megaloblastic changes with nuclear-cytoplasmatic dissociation in both red and white cell precursors. Vitamin B 12 absorption tests were normal in all 8 patients investigated. Macrocytosis was not detectable in two patients with a low serum iron concentration. Macrocytosis disappeared in 4 patients with chronic rejection when progressive renal failure developed. It is concluded that azathioprine therapy induces macrocytosis in renal transplant patients provided renal function is satisfactory.

[Disturbances of lipid metabolism following renal transplantation (author's transl)]. / Fettstoffwechstörungen nach Nierentransplantation

The serum cholesterol and triglyceride levels and the lipoprotein electrophoretic pattern were investigated in 33 kidney transplant recipients. These patients showed elevated serum cholesterol and triglyceride levels in comparison with a group of healthy control subjects. Lipoprotein electrophoresis showed a predomination of types II a, II b and IV, according to Frederickson. The causes of the disturbances in lipid metabolism are discussed. There is a definite risk of cardiovascular disease in kidney transplant patients as a consequence of the altered lipid metabolism.

[Behaviour of serum and urinary lysozyme after renal transplantation (author's transl)]. / Verhalten des Lysozyms in Serum und Harn nach Nierentrasplantation

The behaviour of serum and urinary lysozyme was investigated before and after renal transplantation in 20 patients. The mean postoperative observation time was 67.8 (10 to 212) days. In 11 patients with reversible olig-anuria due to prolonged preoperative ischaemia, lysozymuria lasted for a period of 17 days after surgery, whereas in 8 patients with immediate transplant function lysozymuria disappeared 7 days after transplantation. Serum lysozyme concentrations were markedly elevated before transplantation in all patients. In patients with transplant failure due to ischaemia, normalization of serum lysozyme levels was achieved 28 days after surgery; patients with immediate function showed normal serum lysozyme levels already 7 days after transplantation. Prolonged lysozymuria was also noticed in 2 cases with irreversible ischaemic transplant failure, in 1 case with recurrence of glomerulonephritis and in 1 further case with acute pyelonephritis in the transplant. In 7 cases with an acute renal rejection crisis, lysozymuria was evident 0.7 days before clinical diagnosis of rejection. Serum lysozyme levels showed a strong correlation with serum correlation with serum creatinine concentrations. Therefore, lysozymuria in renal transplant patients indicates tubular transplant damage of varied aetiology. Elevated serum lysozyme levels, on the other hand, seem to reflect a reduced glomerular filtration rate.

[Hepatitis b infection in renal transplant recipients (author's transl)]. / Nierentransplantation und Hepatitis-B-Infektion.

During a period of 4 1/2 years the incidence and clinical course of endemic hepatitis B infection was studied in 43 renal transplant recipients with an observation time of 3 to 47 (average: 26.3) months after surgery. During the investigation period 27 out of 43 patients (62.8 per cent) had hepatitis B infection. In 8 patients HBs antigenaemia persisted after chronic dialysis treatment. After surgery HBs antigenaemia was detected for the first time in 7 patients. Recurrence of HBs antigenaemia was noted in one patient. In 7 further cases with HBs antigenaemia after transplantation regular controls of HBsAg and HBsAb were not available before transplantation. In 2 patients HBs antibodies were detectable at the time of transplantation; 2 further patients developed HBs antibodies postoperatively. Hepatitis B infection showed a mild and persistent clinical course. 6 out of 7 icteric patients simultaneously had other severe mycotic and viral infections. Therefore, the conclusion was drawn that in patients with coexisting multiple infections liver damage is not necessarily attributable to HBs antigenaemia.