Impaired erythropoietin responsiveness in anaemic rheumatoid arthritis patients: potential relation to immune mechanisms.

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-alpha, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-gamma were measured in patients with rheumatoid arthritis. 2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P < 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P < 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P < 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P < 0.0001) and a positive correlation with erythropoietin (r = 0.70, P < 0.0001). 3. Elevated serum tumour necrosis factor-alpha levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-alpha in serum showed an inverse correlation with haemoglobin (r = 0.57, P < 0.001) and a positive correlation with erythropoietin (r = 0.46, P < 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-gamma was not detected in any of the patients investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Value of serum soluble tumour necrosis factor concentrations in the diagnosis and prognosis of renal graft rejection.

Up to the present the histological diagnosis of rejection through biopsy is still the only possibility for a definite rejection diagnosis. We searched for a reliable non-invasive marker of renal graft rejection. By means of a highly sensitive enzyme-linked immunosorbent assay we investigated the changes in the concentration of serum soluble TNF receptor in kidney graft recipients with different clinical courses according to their graft tolerance. sTNF-R in 19 patients with stable graft function (5.3 +/- 3.2 ng/ml) did not differ significantly from those detected in 22 healty volunteers (4.1 +/- 2.2 ng/ml). In contrast 17 patients suffering from acute graft rejection showed highly significantly increases (23 +/- 8.3 ng/ml, P < 0.0001). These elevated concentrations returned to prerejection rejection values after a 3-day anti-rejection therapy with high-dose methylprednisolone. In 18 patients with an irreversible, chronic kidney graft rejection we could demonstrate significantly increased sTNF-R values (20 +/- 7.9 ng/ml); eight of those patients did not reflect on the anti-rejection therapy, so that the elevated concentrations remained even after the administration of high-dose corticosteroids and ATG. Additionally we found soluble TNF receptor concentrations to be increased earlier than other commonly used biochemical parameters such as creatinine. Soluble TNF-R also proved to be useful for the differentiation of cyclosporin nephrotoxicity. Therefore we believe that the soluble TNF-R and its concentration course may be of diagnostic and prognostic value in kidney graft rejection, as it supports the diagnosis of transplant rejection, indicates the rejection event very early, and reflects the response to anti-rejection therapy.

Upregulation of a lymphoid serine protease in kidney allograft recipients.

The presence of a putative, cytotoxicity-linked lymphoid serine esterase (SE) has been studied in 79 kidney graft recipients. Peripheral blood lymphocytes (PBL) bearing an N-alpha-benzyloxy carbonyl-L-lysine thiobenzyl ester (BLT)-specific SE were evaluated by a novel cytochemical staining method. A characteristic of post-allograft patients was an increased presence of SE containing granules in PBL. In 46 patients with stable graft function SE + PBL were 33.41 +/- 10.34% (controls: 26.30 +/- 5.22%, P less than 0.0025), SE + CD4+ 4.32 +/- 3.85% (controls 2.13 +/- 1.52%, P less than 0.0025) and SE + CD8+ T cells 47.68 +/- 18.64% (controls: 28.50 +/- 6.50%, P less than 0.0005). In those graft recipients undergoing a rejection episode a marked upregulation of SE activity could be observed when compared to the stable graft group: SE + PBL were 59.91 +/- 10.89% (P less than 0.0005), SE + CD8+ 74.30 +/- 10.79% (P less than 0.0005) and SE + CD4+ T cells 28.56 +/- 13.50% (P less than 0.0005). In 10 cases this increase of SE activity was observed with a time lag of up to 37 days prior to the onset of clinical or biopsy proven rejections, promptly decreasing in response to methylprednisolone antirejection therapy. In patients with recurrent rejection episodes and subsequent graft loss, a repeating increase of SE activity indicated a failure of therapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human erythropoietin activates a broad spectrum of progenitor cells.

Twenty uremic patients on regular hemodialysis received recombinant human Erythropoietin (rhEPO) in a dosage of 50 U/kg body wt (N = 9) and 80 U/kg body wt (N = 11), respectively, three times weekly. The number of circulating hemopoietic progenitor cells colony-forming unit-granulocyte-erythrocyte-macrophage (CFU-mix), burst-forming unit-erythroid (BFU-E) and colony-forming-granulocyte-macrophage (CFU-GM) in peripheral blood were assayed weekly by means of a commonly applied in vitro clonal assay. A significant increase of peripheral CFU-mix, BFU-E and CFU-GM could be observed within one week of supplementation therapy in both groups. The increase of BFU-E was followed by a rise of hematocrit within four and three weeks, respectively. These results suggest that the stimulatory in vivo effect of rhEPO administered in therapeutical doses is not restricted to the erythroid lineage but also includes progenitor cells committed to the myeloid lineage (CFU-GM) as well as the multipotent progenitors CFU-mix. The increment of circulating progenitor cells was seen with a dosage of 80 U/kg body wt and 50 U/kg body wt as well.

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.

Excessive myocardial calcinosis in a chronic hemodialyzed patient.

Secondary oxalosis in chronic hemodialyzed patients is caused by impaired renal excretion and inadequate removal of oxalic acid during hemodialysis. Ascorbic acid is a precursor of oxalic acid. We report a parathyroidectomized patient with chronic renal failure, on hemodialysis, who received over a period of several months a total dose of 91.0 g ascorbic acid i.v. The plasma oxalic acid level in this patient was 14-fold higher than in healthy persons. Increased oxalic acid synthesis from its precursor ascorbic acid may be responsible for hyperoxalemia, high content of oxalic acid in myocardium, aorta and lung, and calcium oxalate deposition in soft tissues. Application of high doses of ascorbic acid should be avoided in hemodialysed patients with chronic renal failure.

[Cystic renal changes in chronic hemodialysed patients]. / Zystische Nierenveränderungen bei chronisch hämodialysierten Patienten.

In this study we investigated the appearance of renal cysts in 43 chronic hemodialyzed patients using ultrasound (3.5 MHz-sector scanner). The mean age of the patients was 45 years, and the mean duration of dialysis was 26.3 months. In 21 patients (= 49%) cysts could be found. In 10 of these patients a former investigation at beginning of dialysis did not demonstrate any cystic lesions. The diameter of the cysts varied between 5 and 30 mm. Considering the duration of dialysis, in 9 (= 39%) out of 23 patients with a maximum duration of dialysis of 2 years cysts could be demonstrated by ultrasound, and in 12 (= 60%) of 20 patients, who had been dialysed for more than 2 years. The clinical impact of the demonstration of such cysts was recently reported in cases which developed complications like tumour formation or severe bleeding.

[Recurrence of spontaneous kidney rupture in a dialysis patient]. / Zweimalige spontane Nierenruptur bei einem Dialysepatienten.

The case is reported of a 35-year-old man who had been treated with hemodialysis for five years because of renal insufficiency due to chronic glomerulonephritis. Renal cystic disease acquired during maintenance dialysis was complicated by bilateral kidney rupture within an interval of two months. Development of cystic changes of kidneys during long-term hemodialysis was first reported in 1977. The main complications of this cystic transformation are, according to the literature, development of neoplasms and hemorrhage into the cysts. In the present case the clinical symptomatology consisted of episodes of severe pain in the flank, hematuria, hypotension and lowering of hematocrit. An ultrasound study demonstrated enlargement of some cysts compared to another study some months ago, and internal echoes due to hemorrhage could be seen in some of the cysts. Because of the danger of spontaneous kidney rupture with consecutive life-threatening hemorrhage, surgery is indicated in such cases.

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.

[Alpha 1-antitrypsin level in serum of dialyzed and renal transplant patients (author's transl)]. / Konzentration von alpha 1-Antitrypsin im Serum dialysierter und nierentransplantierter Patienten.

alpha 1-Antitrypsin in serum was determined by radial immunodiffusion in 30 healthy persons, 18 dialyzed patients and 11 renal transplant recipients with an observation time up to 24 months after surgery. There was no significant difference in serum alpha 1-antitrypsin concentrations in dialyzed patients when compared to the controls (2570 +/- 570 and 2280 +/- 450 mg/l respectively). alpha 1-Antitrypsin concentration increased significantly from the first day after successful renal transplantation, then decreased again 10 days thereafter. Long term follow up controls 3, 6, 12, 18 and 24 months respectively after surgery--with a good renal transplant function--revealed values within the normal range. An acute rejection episode of the transplant was connected with a significant increase of alpha 1-antitrypsin concentration in the serum. Determination of alpha 1-antitrypsin level in serum can be useful in the diagnosis and prognosis of acute renal transplant rejection.