[Acute renal failure associated with malignant hypertension]. / Akutes Nierenversagen bei maligner Hypertonie.

HISTORY AND CLINICAL FINDINGS: A 37-year-old woman was referred to the interdisciplinary emergency room with a high blood pressure and headaches. She complained about nausea and vomiting. She has been treated for hypertension for approximately 9 years in an outpatient clinic. INVESTIGATIONS: The patient's blood pressure was elevated up to 248/132 mm Hg. Emergency laboratory test revealed high blood creatinine (19,29 mg/dl) and blood urea nitrogen (365 mg/dl) along with the decreased haemoglobin concentration and normal thrombocytes. Urinalysis showed a mild hematuria and proteinuria. The CT-scan and sonography of the abdomen showed no relevant renal artery stenosis or any relevant intestinal organ damages. TREATMENT AND COURSE: An immediate antihypertensive medication was started in the emergency room, which resulted in a gradual decrease of blood pressure. Due to hypertension-induced acute renal failure, a hemodialytic treatment was initiated. After several sessions of hemodialysis, the levels of blood urea nitrogen and creatinine gradually decreased but remained elevated. The patient was included into the renal transplantation program due to the anuric renal failure. CONCLUSIONS: Acute renal failure associated with very high blood pressure and retinal bleedings is characteristics of malignant hypertension resulting frequently from pre-existing essential hypertension. In addition, uremia is a major cause of mortality in malignant hypertension. Excessive arterial pressure leads to endothelial damage of arterioles and capillaries. The ischemic collapse of glomerula promotes further irreversible renal injury, and eventually leads to a long-term hemodialysis or renal transplantation.

High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener's granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide.

The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegener's granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200-1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2-6 courses of HAP. Remission was maintained for 16-24 months. The remaining two patients with WG were withdrawn after 2-3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6-9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.

Enalapril and losartan augment endogenous nitric oxide release in Takayasu's arteritis--a case report.

Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis who had been unilaterally nephrectomized and presented with malignant hypertension due to renal artery stenosis. Hypertension was refractory to conventional antihypertensive treatment, and stenosis was not accessible by interventional angioplasty. Initiation of enalapril and losartan therapy was successful in improving blood pressure without deterioration of renal function due to ischemic failure. Antihypertensive treatment resulted in dramatically stimulated endogenous nitric oxide (NO) synthesis, while elevated plasma endothelin-1 levels were unchanged. Renovascular hypertension in Takayasu's arteritis is associated with an imbalance of vasoconstrictor peptide endothelin-1 and vasodilator peptide NO. Successful treatment of hypertension by enalapril or losartan results in improved endogenous NO synthesis, which putatively counterbalances excessive vasoconstrictor actions and may retard the progression of renal failure.

Highly sensitive DNA typing for detecting tumors transmitted by transplantation.

DNA typing of a variable number of tandem repeats (VNTRs) and of short tandem repeats (STRs) is a modern forensic method for the identification of biological material. In many cases, amplification by the polymerase chain reaction (PCR), especially of STRs, allows DNA typing of minute amounts of or degraded DNA. Here we describe the successful use of forensic DNA typing to clarify the origin of a malignant tumor. We report two cases of metastatic malignant melanoma of unknown origin that developed a few months after transplantation in two recipients of kidneys from the same donor. Fresh metastatic tissue and blood from the first recipient, reference DNA of the donor, and only paraffin-embedded tissue from the second recipient were available for analysis. To investigate whether the melanoma originated in the donor, DNA analysis of nine polymorphic loci was performed. The results of the analysis showed that, in both cases, the tumors were genetically different from the recipient DNA but matched the donor DNA. One incident of allele loss was attributed to a mutation event. We conclude that the metastatic melanoma in both recipients originated in the donor and was transmitted by renal transplantation.

Limited T-cell repertoire in renal allograft and allogeneic melanoma transmitted by the graft.

In a patient with metastatic melanoma transmitted by the renal allograft, HLA serves as an alloantigen per se and is associated with tumor antigens at the same time. The influence of this antigeneic pattern on the Vbeta T-cell repertoire in an allogeneic melanoma, allograft, and peripheral blood mononuclear cells (PBMC) was assessed by polymerase chain reaction. Vbeta13.1 and 19 were found in both the melanoma and the graft. Vbeta14 was detected only in the melanoma and Vbeta6 was detected only in the kidney. PBMC revealed an unrestricted Vbeta pattern. Markers for cytotoxic activity of T cells--granzyme B and perforin--were not expressed during immunosuppressive therapy as clinically reflected in a nonrejecting allograft and in a progressing melanoma. In vitro PBMC proliferated to recombinant interleukin-2, whereas recombinant interferon-gamma did not augment this response. Initiation of immune therapy, in addition to discontinuation of immunosuppression, might support the rejection of the allogeneic tumor by dominant Vbeta T cells.

Tumors after renal transplantation.

The purpose of this retrospective study was to analyze the development of malignancies after renal transplantation. 633 renal graft recipients with an organ function longer than 1 year were followed up over a mean period of 67.6 +/- 48.7 months. Only 12 recipients received grafts from living-related donors. 38 recipients (6.0%) exhibited cancer of either the skin, the genitourinary system, the bronchial system, the female breast, or the colon. All tumors were de novo malignancies. The number of patients developing a tumor was significantly higher in the cyclosporine-treated group than in patients with conventional immunosuppression. 15 patients died within a mean survival time of 7.7 +/- 12.1 months. The frequency of disorders makes it necessary for organ transplant recipients to have routine examinations both before and at regular intervals after transplantation. This includes examination of the patient's skin, native kidneys and cervical smears for females.

Malignancies of the genito-urinary system following renal transplantation.

OBJECTIVE: To analyse the development of malignancies of the genito-urinary system after renal transplantation. PATIENTS AND METHODS: A total of 868 renal graft recipients were followed up over a mean period of 41.8 +/- 45 months. Fifteen patients received grafts from living related donors and 853 were transplanted with kidneys from cadavers. RESULTS: Twelve patients (1.4%) exhibited cancer of the genito-urinary system: 11 tumours were de novo malignancies. One small renal carcinoma was transplanted from a living related donor. The incidence of tumours of the genito-urinary system was 34 in 100,000 patient years in the patients treated with cyclosporin and 32 in 100,000 patient years in the conventional therapy group. Four patients died within a mean survival time of 14.4 months. Comparison of our results with sex- and age-specific incidence rates in a reference population showed an increase in malignant tumours of the genitourinary system by a factor of 7.3 in males and 11.2 in females. CONCLUSIONS: The frequency of disorders after transplantation necessitates routine examinations in organ transplanted recipients both before and at regular intervals after transplantation, including the patient's native kidneys and cervical smears in females.

Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/Ia molecules.

This study was undertaken to evaluate the monocyte function of uraemic non-responders to hepatitis B vaccination. Therefore, some parameters concerning antigen processing by monocytes (Mo) as antigen presenting cells (APC) were analysed. It was found that in uraemic non-responders, (1) the internalization of HBsAg by monocytes was significantly decreasjed-HBsAg complexed with specific IgG or as immune complex isolated from patients is better internalized compared with free HBsAg; (2) during antigen presentation the expression of adhesion (ICAM-1) and accessory (HLA-DR/Ia) molecules was significantly decreased in uraemic patients, especially in non-responders; and (3) impaired internalization of HBsAg as well as a decrease in ICAM-1 and HLA-DR/Ia expression, correlated well with the blunted proliferation of CD4(+) T cells stimulated by autologous monocytes induced by HBsAg.

Non-responsiveness to hepatitis B vaccination in haemodialysis patients: association with impaired TCR/CD3 antigen receptor expression regulating co-stimulatory processes in antigen presentation and recognition.

The study was undertaken to evaluate the relationship between non-responsiveness to hepatitis B (HBV) vaccination in haemodialysed patients and HBs antigen (Ag) presentation and recognition depending on TCR/CD3 receptors expression. We have found that the cause of the blunted response to HBV vaccination is multifactorial and seems to be associated with the following: (1) A reduced number of TCR/CD3 antigen receptor complexes on freshly isolated uraemic CD4 T cells, especially in non-responders. (2) The blunted proliferative response of uraemic CD4 T cells isolated from non-responders and stimulated for 6 days by autologous monocytes presenting HBsAg was associated with the decreased density of the TCR/CD3 receptors. (3) Moreover, in uraemic non-responders the expression of adhesion and accessory molecules on monocytes (intercellular adhesion molecule-1/ICAM-1, HLA-DR/Ia/) was significantly decreased following the culture with autologous monocytes serving as HBsAg-presenting cells. CD4 molecules and lymphocyte function antigen-1 beta/LFA-1 beta/ on helper-inducer T cells were increased before and after the culture. (4) These findings were also associated with a diminished binding capacity of IL-1 beta and IL-6 to their receptors on helper-inducer T cells. (5) IL-2, IFN-gamma and IL-4 production was decreased in uraemic non-responders, especially after 72 h of the culture. (6) Inhibited proliferation of helper-inducer T cells in uraemic non-responders was only partially reversible in the presence of exogenous IL-1 beta, IL-6, IL-2 and IFN-gamma. (7) HLA typing of uraemic non-responders was associated with extended haplotype: HLA A1,B8,DR3,DR7,DQ2.

Signalling via the TCR/CD3 antigen receptor complex in uremia is limited by the receptors number.

The TCR/CD3 receptor complex plays a key role in antigen recognition and T-cell activation. Therefore, the present study investigates TCR alpha/beta (TCR1) and CD3 receptor density (RD, number of receptors per cell) on uremic helper-inducer (CD4) T lymphocytes in relation to T-cell proliferative response induced by anti-CD3 monoclonal antibodies (mAb). We found, that: (1) the number of TCR/CD3 receptors on uremic helper-inducer (CD4) T lymphocytes is decreased and correlated well with the blunted lymphocyte proliferation induced by anti-CD3 mAb; (2) these findings were associated with diminished binding capacity of IL-1 beta and IL-6 to their receptors (IL-1R, IL-6R) on helper-inducer T cells, whereas (3) the IL-2 receptor (IL-2R) and molecule expression of CD4 and lymphocyte function antigen-1 (LFA-1) were increased, and (4) uremic monocytes displayed a decreased density of intercellular adhesion molecule-1 (ICAM-1) expression, which interacts as receptor-ligand pair with LFA-1. The incubation of uremic and control peripheral blood mononuclear cells with uremic serum enhanced these above-mentioned changes in the expression of examined receptors and molecules. These data might also support the hypothesis that the blunted T-cell response to antigen in uremia is due to downregulation of the TCR/CD3 receptor complex by uremic milieu.

Pharmacokinetics of omega-3-fatty acids during ingestion of fish oil preparations.

An in vivo comparison of three dosages (3 g, 6 g, 12 g) of two different fish oil preparations in terms of plasma concentrations of their major active components eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was performed. The plasma accumulation was measured during 28 days of ingestion and an equally long wash out period. Data were scrutinized for bioavailability in order to distinguish between the efficiency of the two preparations. Rapid increases in EPA and DHA plasma concentrations can be demonstrated at all dosages during a 28-day ingestion period. EPA accumulated more during ingestion of high than of low dosages of fish oil. DHA revealed almost identical increases and peak values in plasma concentrations in all subgroups. The present data demonstrate dose dependent increases of EPA concentrations whereas DHA plasma concentrations are comparable in all dosages investigated. Measurable EPA and DHA plasma concentration levels are inappropriate means to explain clinical effectiveness. These results were found in both commercially available fish oil preparations. Direct comparison of both preparations revealed no differences in bioavailability.

The risk of infection following OKT3 and antilymphocyte globulin treatment for renal transplant rejection: results of a single center prospectively randomized trial.

Some 43 of 60 (72%) renal allograft recipients who were prospectively randomized to receive either OKT3 monoclonal antibody (n = 30) or ALG (antilymphocyte globulin) polyclonal antibody (n = 30) for steroid-resistant rejection suffered from infection, 25 (83%) following OKT3 and 18 (60%) following ALG treatment (P < 0.05). Clinically evident herpes infection was most frequently seen (9 and 7, respectively), followed by pneumonia (6 and 1, respectively P < 0.05), urinary tract infection and wound infection (2 of each in both groups) fungal (Candida) and multibacterial infections. One patient died in each group due to cytomegalovirus (CMV) pneumonia, giving a mortality of 4.3% in each group. Actuarial 1-year graft and patient survival rates were 80% and 97% in both groups, respectively. It is concluded that ALG and OKT3 are equally effective in renal allograft rejection resistant to steroid treatment, however, the risk of infection appears to be higher with OKT3.

Changes in the alpha adrenergic system and increase in blood pressure with recombinant human erythropoietin (rHuEpo) therapy for renal anemia.

Recombinant human erythropoietin (rHuEpo) is effective in correcting renal anemia with the development of hypertension as the most frequent side-effect. Compared to hemodialysis patients with normal hemoglobin concentration, nine examined patients with transfusion-dependent renal anemia had low blood pressure in the context of high alpha 2-receptor densities and high plasma levels of catecholamines. This constellation can be explained by a defective receptor-ligand-interaction. During treatment with rHuEpo all patients showed an increase in blood pressure due to increased peripheral resistance, accompanied by a significant fall in plasma noradrenaline and alpha 2-receptor-density. There was a significant negative correlation between hemoglobin concentration and alpha 2-receptor density. We conclude that correction of renal anemia abolishes anemia-mediated disturbance of alpha 2-receptor function with the consequence of receptor down-regulation and increased vasoconstriction, which contributes to the rise in arterial blood pressure.