[Diagnosis and treatment of chronic kidney disease]. / Diagnostik und Therapie der chronischen Nierenerkrankung.

Chronic kidney disease is defined by decreased glomerular filtration rate or proteinuria. Diabetic nephropathy and hypertensive renal damage are responsible for the majority of cases. The initiation of therapy has to consider if causal treatment of the underlying disease is possible and indicated. In all patients, even if specific treatment is not possible, therapy should aim at reducing progression of kidney failure. Chronic kidney diseases tend to intrinsic deterioration that persists after cessation of the causative damaging pathomechanism. Progression of disease can be delayed; the most important measures include strict blood pressure control, reduction of proteinuria, and avoidance of further renal harm. Kidney disease induces typical sequelae such as left ventricular hypertrophy, vascular calcification, anemia, and renal osteodystrophy. While these are well understood nowadays therapeutic options are limited. The uremic syndrome is to be avoided by renal replacement therapy.

[Multicenter trial for sudden hearing loss therapy - planning and concept]. / Multizentrische Studie zur Hörsturztherapie - Planung und Konzeption.

Systemic steroids are widely used worldwide as a standard of care for primary therapy of idiopathic sudden sensorineural hearing loss (ISSHL). The German ISSHL guideline recommends high-dose steroids for primary therapy of ISSHL, without evidence from randomized controlled trials (RCTs). The rationale for the treatment of ISSHL using high dose steroids is only based on retrospective cohort studies.This article describes the planning and initiation of a multicenter, national, randomized, controlled clinical trial entitled Efficacy and safety of high dose glucocorticosteroid treatment for idiopathic sudden sensorineural hearing loss - a three-armed, randomized, triple-blind, multicenter trial (HODOKORT). This clinical trial aims to compare standard dose with two types of high-dose steroids for primary systemic therapy with respect to their efficacy in improving hearing, and thus communication ability, in patients with idiopathic sudden sensorineural hearing loss.This study is funded by the "Clinical Trials with High Patient Relevance" research program in the health research framework of the German Federal Ministry of Education and Research. It is one of two studies by the German Study Center of Clinical Trials of the German Society of Otorhinolaryngology, Head and Neck Surgery (DSZ-HNO). Planning and initiation was done in cooperation with the DSZ-HNO, the Coordination Center of Clinical Trials of the Martin-Luther-University Halle-Wittenberg, and the Study Center of the University Hospital Freiburg.

[Clinical issues with uremia]. / Klinische Probleme der Urämie.

Uremia describes the consequences of intoxication in chronic renal failure with substances that are renally cleared in healthy individuals. Acute uremia is a syndrome of gastrointestinal symptoms, pericarditis, pleuritis, and central nervous system alterations ending with coma. These symptoms can be resolved by renal replacement therapy. In addition, chronic uremia can result in damage of multiple organ systems, which continues to advance despite dialysis therapy. This is caused by retention of toxins that cannot be adequately removed due to insufficient treatment time or a molecular weight range hampering elimination. Uremic toxins can be generated by the energy or nucleic acid metabolism, they can be proteins or large molecules that are altered chemically by the uremic milieu. Chronic uremia can influence the majority of long-term complications of chronic renal failure: systemic microinflammation, cardiovascular disease, immunodeficiency, malnutrition, anemia, bone metabolism, and polyneuropathy. There are few therapeutic options other than kidney transplantation.

[Electrolyte disorders]. / Störungen des Elektrolytstoffwechsels.

Disorders of electrolyte balance are frequent and pathophysiologically complex. Sodium is responsible for a large part of the osmolarity of extracellular fluids. Therefore, pathological concentrations of serum sodium reflect the relation between sodium and water in the extracellular compartment rather than the total body sodium content. The causes of hypo- or hypernatremia can only be deduced if total body volume status is considered. Patients with hyponatremia and volume deficit should receive sodium chloride solution while patients with this disorder in the presence of volume overload need strict water restriction. In certain cases additional specific pharmacotherapy directed at the effects of antidiuretic hormone may be considered. Potassium and calcium are extracellular regulatory ions; their concentrations do not relevantly contribute to osmolarity and water distribution but to electrophysiologically relevant transmembrane potentials. These ions are influenced by active membrane transporters and regulated by several hormones. The rather small extracellular pools are overfilled or depleted by alterations of intake and excretion. In addition, several inborn or acquired defects of transmembrane transporters may severely alter their extracellular concentrations. Therapy needs to consider the specific mechanisms that led to the electrolyte disorder including modification of intake, excretion or extra-intracellular distribution.

[Hygiene in nephrology]. / Hygiene in der Nephrologie.

Patients with chronic kidney diseases are particularly at risk of infections and must therefore be protected against the risks of infection in dialysis treatment. Viral hepatitis no longer plays a very prominent role in dialysis facilities because nosocomial transmission can be reliably avoided. Nowadays, patients colonized with multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria or vancomycin-resistant enterococci, are more common. Bloodstream infections, which particularly occur in dialysis via central venous catheters, are potentially very dangerous for patients. Regular surveillance and targeted interventions in the event of excessive infection numbers are necessary. The hygienic handling of dialysis fluids has now become established through decades of experience and is ensured through the use of quality management systems. The coronavirus crisis poses special challenges for dialysis centers.

[Waiting list management]. / Wartelistenpflege.

Listing a patient on the Eurotransplant waiting list for a kidney transplantation obliges transplant centers to ensure that an allocated organ can also be transplanted, as long as there are no acute recipient-specific medical or personal contraindications. Assessing the ability for transplantation over a period of up to 10 years between initiation of dialysis and an organ offer represents a major challenge in manpower and logistic efforts. The present article reviews specific aspects regarding waiting list management on the basis of current guideline recommendations and literature data.

CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients.

Migration of monocytes into the vessel wall contributes to the onset and progression of atherosclerosis. Because monocytes are a heterogeneous population, we determined potential associations between monocyte subsets and cardiovascular events in a prospective cohort of 94 dialysis patients followed for 35 months. The incidence of cardiovascular events and death measured by Kaplan-Meier plots and flow cytometric analysis of monocyte subsets showed that total leukocyte and monocyte numbers failed to predict event-free survival. Among monocyte subsets, a high CD14(++)CD16(+) monocyte number was associated with higher rates of cardiovascular events and death. In a multivariate proportional hazards model adjusted for classical cardiovascular risk factors, patients with CD14(++)CD16(+) monocyte numbers in the top quartile were at higher risk of cardiovascular events and death compared to patients in the lowest quartile. Our study suggests that the number of CD14(++)CD16(+) monocytes was independently associated with cardiovascular events and death in a high-risk population of dialysis patients.

Proinflammatory CD14+CD16+ monocytes are associated with subclinical atherosclerosis in renal transplant patients.

Atherosclerotic cardiovascular disease is a major cause of death in renal transplant (TX) recipients. Atherosclerotic lesions are characterized by monocytic infiltration. Circulating monocytes can be divided into functionally distinct subpopulations, among which CD14++CD16+ and CD14+CD16+ monocytes (summarized as CD16+ monocytes) are proinflammatory cells. We hypothesized that the frequency of circulating CD16+ monocytes is associated with subclinical atherosclerosis in TX patients. Monocyte subpopulations were quantified in 95 TX and 31 hemodialysis patients (HD). In TX patients, subclinical atherosclerosis was determined by carotid intima media thickness (IMT) measurement. TX patients had lower frequencies of CD16+ monocytes than HD patients. When stratifying by immunosuppressive treatment, patients on methylprednisolone (MP) therapy had fewer CD14+CD16+ monocytes than patients not receiving MP. CD14+CD16+ monocytes decrease very shortly after transplantation. CD14+CD16+ monocyte frequency correlated with IMT in TX recipients (r = 0.34, p < 0.001). This correlation was most pronounced among patients without MP treatment (r = 0.55, p = 0.02). In a multivariate regression analysis, the association of CD14+CD16+ monocytes with IMT was independent from traditional cardiovascular risk factors. The frequency of proinflammatory CD14+CD16+ monocytes is independently associated with subclinical atherosclerosis in transplant recipients. Further studies on the association between circulating leukocytes and atherosclerosis should take monocyte heterogeneity into account.

T cells involved in psoriasis vulgaris belong to the Th1 subset.

Although the pathogenesis of psoriasis vulgaris is still unknown, several characteristics point to an immunologically mediated process. Epidermal psoriatic lesions are characterized by a hyperproliferation of keratinocytes and an infiltration of T lymphocytes and granulocytes. Because the former may be mediated in part by lymphokines secreted by T cells, we have focused our interest on the in vivo and in vitro cytokine secretion patterns of T lymphocytes from psoriatic lesions. In five patients T lymphocytes were obtained from epidermal specimens. The cells were propagated with lectin and irradiated feeder cells and subsequently cloned by limiting dilution. The resulting T-cell clones were phenotypically and functionally characterized. Our data show that the majority of T-cell clones were CD4+ (74%), whereas only 25% were CD8+ and 1% were CD4-/CD8-. Also, we have further investigated the cytokine secretion pattern of T-cell lines or CD4+ T-cell clones, respectively. All cells tested produced interferon-gamma whereas only a minority secreted interleukin (IL)-4. Moreover, these cells produced high amounts of IL-2 but only little or no IL-10 or tumor necrosis factor-alpha. To correlate these data with the in vivo situation, biopsies from psoriatic lesions of five patients were investigated for the presence of the mRNA of IL-4, IL-10, and interferon-gamma using the polymerase chain reaction. In these biopsies only the mRNA for the Th1 cytokine interferon-gamma but not for the Th2 cytokines IL-4 and IL-10 could be detected. Identical experiments were performed to test the in vivo cytokine production of synovial fluid mononuclear cells of two patients with arthropathia psoriatica. Again, only the mRNA for interferon-gamma but not IL-4 could be detected. This indicates that T cells involved in psoriasis exhibit a Th1-like cytokine secretion profile.

Glucocorticoids inhibit activation-dependent expression of costimulatory molecule B7-1 in human monocytes.

BACKGROUND: Glucocorticoids act as immunosuppressive drugs mainly via their effects on antigen-presenting cells. They are known to influence production of cytokines as well as expression of cell surface molecules. B7 molecules belong to the most important costimulatory signals for T-cell activation during transplant rejection. They are expressed on antigen-presenting cells and up-regulated during the immune response. We studied the influence of glucocorticoids on the regulation of these accessory signals. METHODS: Human monocytes were purified from peripheral blood of healthy volunteers by centrifugal counterflow elutriation. Activation-dependent transcription and expression of B7-1 (CD80) and B7-2 (CD86) were detected by reverse transcription-polymerase chain reaction and flow cytometry in the absence or presence of glucocorticoids. RESULTS: The expression pattern of B7-1 and B7-2 on monocytes depends on the type of stimulation. Activation by interferon-gamma induces both B7-1 and B7-2, whereas cAMP exclusively up-regulates B7-2. Glucocorticoids selectively inhibit the expression of B7-1 while leaving B7-2 unaffected. The effect occurs at concentrations that are reached during therapeutical application of the substances in humans. It is mediated via the cytoplasmic glucocorticoid receptor, as it can be abrogated by the glucocorticoid receptor antagonist RU38486. Inhibition of B7-1 occurs at the transcriptional level. Up-regulation of the molecule can similarly be inhibited by hydrocortisone, prednisolone, and dexamethasone at equipotent doses. CONCLUSIONS: Inhibition of the up-regulation of B7-1 by glucocorticoids is a previously unknown mechanism of action of these substances and may relevantly contribute to their effects as immunosuppressive drugs.

Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation.

BACKGROUND: Immunosuppressive treatment in transplant patients frequently causes infectious complications with cytomegalovirus (CMV). The extent of CMV replication can be followed by a number of diagnostic methods. There is, however, no simple diagnostic tool to assess the quality of the cellular antiviral immune response of an individual patient. This would be of particular importance for therapy decisions, as patients with detectable virus load do not necessarily develop CMV-related disease. Using a rapid whole blood assay, the frequencies of CMV-reactive CD4 and CD8 T cells were followed after renal transplantation to characterize their relative contribution in the containment of CMV infection. METHODS: T cells from transplant patients ands healthy control persons were stimulated with CMV antigen in vitro. Based on specific cellular activation and induction of intracellular cytokines, the frequency of CMV-reactive CD4 and CD8 T cells was determined using flow cytometry. Viral load quantified using the "hybrid-capture" assay. RESULTS: The absence of CMV complications in long-term transplant recipients is reflected by stable virus-specific T-cell frequencies, which do not differ from healthy CMV-positive controls. In contrast, during the first months after transplantation, clinical symptoms are preceded by a decrease in CMV-reactive CD4 T-cell frequencies and an increase in CMV load. CONCLUSIONS: The individual immune response and CMV replication are critically balanced and can be characterized by assesing both viral load and antiviral T cells. Our experimental design allows the identification of patients with sufficient, insufficient, or absent T-cell activity and can serve as diagnostic tool to facilitate decisions on antiviral therapy.

Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease.

Patients with chronic renal failure show an immunodeficiency characterized by frequent infectious complications and a low response to vaccinations. This is paralleled in vitro by a low T-cell proliferation on mitogenic stimuli because of an impaired costimulation by accessory cells. Furthermore, alterations of the cytokine profile are correlated with impaired immune function. The immune system is influenced by both uremia and renal replacement therapy. To evaluate the influence of hemodialysis on immune parameters, we studied patients before and after the initiation of chronic hemodialysis therapy. Fourteen patients with end-stage renal failure were tested before dialysis initiation and during the first 6 weeks of hemodialysis treatment. We determined the in vitro T-cell proliferation, as well as plasma levels of interleukin-6 (IL-6) and the release of IL-6 and IL-10 into culture supernatant poststimulation with lipopolysaccharide. After 6 weeks of intermittent hemodialysis, in vitro T-cell proliferation on stimulation improved significantly (stimulation index, 21.6 +/- 18.5 versus 58.1 +/- 45.5; P < 0.01). This improvement occurred regardless of whether synthetic dialyzers or cellulosic membranes were used for the initiation of dialysis. Plasma IL-6 levels, as well as IL-6 and IL-10 secretion, did not change during the study period. In patients with end-stage renal disease, the initiation of hemodialysis led to a significant improvement of in vitro T-cell proliferation. This effect may have a role for an improvement of immune function in vivo. The expected normalization of IL-6 and IL-10 production may be masked by cytokine induction through hemodialysis membranes.

Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction.

Cytokine induction by dialyzer membranes has been related to several acute and chronic side effects of hemodialysis treatment, among them being immune dysfunction and progressive atherosclerosis. Surface modification of cuprophane dialyzers with the antioxidant vitamin E is a new approach to enhance biocompatibility and improve cytokine levels, as well as immune function. Twenty-one patients undergoing treatment with hemophane (HE) dialyzers were enrolled onto a crossover study with a vitamin E-coated (VE) dialyzer or a synthetic polyamide (PA) dialyzer. In vitro assays of lymphocyte activation and measurements of cytokine induction were performed to evaluate biocompatibility. Four weeks of treatment with either VE or PA dialyzers enhanced in vitro proliferation of peripheral blood leukocytes in comparison to treatment with HE membranes used before study entry. Enhancement of lymphocyte function was independent of dialysis efficiency, which was kept constant during the study. In the interdialytic interval, preactivation of monocytes for the production of interleukin-6 (IL-6) did not differ between VE or PA dialysis. In contrast, the VE membrane reduced acute production of IL-6 during a dialysis treatment, whereas the PA membrane did not. Unlike IL-6, the regulatory cytokine IL-10 is not inhibited by either membrane. This is important because IL-10 is believed to have a beneficial effect on immune function in dialysis patients. The VE membrane, despite being based on a cuprophane backbone, is similar to the highly biocompatible PA dialyzer in terms of its effect on lymphocyte function, whereas it exerts an additional suppressive effect on the overproduction of proinflammatory cytokines.

Selective sequestration of cytokine-producing monocytes during hemodialysis treatment.

Hemodialysis treatment leads to leukocyte activation and cytokine production. Studying this effect has been complicated because cell activation by blood membrane contact also induces adherence factors on leukocytes, leading to margination of cells to the endothelium of the lung. Using single-cell cytokine determination, we studied the relation between cytokine production and cell sequestration during dialysis therapy. Blood was sampled in 11 chronic hemodialysis patients using hemophane dialyzers before hemodialysis and at 20 and 120 minutes of treatment. Lipopolysaccharide (LPS)-induced cytokine production in monocytes was studied by intracellular staining for interleukin-6 (IL-6) and IL-10 and flow cytometry. Results obtained in dialysis patients were compared with samples from an ex vivo dialysis system. Monocyte maturation stage was evaluated by detection of several surface markers through flow cytometry. Within 20 minutes of hemodialysis, the numbers of circulating monocytes decreased to one third of initial values. Before dialysis, 56.7% +/- 15.7% of circulating monocytes responded to LPS by the production of IL-6. This fraction decreased to 21.1% +/- 17.3% (P < 0.001 versus before hemodialysis) at 20 minutes and 32.3% +/- 13.8% (P < 0.001 versus before hemodialysis) at 120 minutes of treatment. A similar decrease occurred for IL-10. Cytokine-positive cells did not decrease during ex vivo dialysis. Surface marker studies showed that mature monocytes expressing HLA-DR or CD86 were predominantly removed. We provide the first evidence for a subtype-specific sequestration of monocytes caused by dialysis treatment. Fully differentiated cells capable of cytokine production and antigen presentation are removed and relatively immature cells remain in circulation.

Molecular aspects of T- and B-cell function in uremia.

Chronic renal failure is associated with severe alterations of the immune system. Infections are responsible for a large part of the mortality in hemodialysis patients, and vaccination is mostly ineffective. Global tests of the immune function show greatly diminished activation of T cells. However, the intrinsic function of T and B cells is normal when they are provided with normal signaling from antigen-presenting cells (APCs). Patients with chronic renal failure show a defective function of costimulation derived from APCs leading to impaired activation of effector lymphocytes. Two major components of immune deviation are relevant: reduced signaling caused by impaired expression of the costimulatory molecule B7-2 (CD86) on monocytes leads to low activation of helper T cells. This dysfunction is associated with uremia and may be improved by high-efficiency renal replacement therapy. The other component is inflammatory activation of APCs mainly due to the hemodialysis procedure. Inflammation, characterized by overproduction of cytokines such as interleukin-1beta (IL-1beta) or IL-6, correlates with low effector activation. Furthermore, inflammatory cytokines such as IL-12 deviate the functional pattern of T-cell activation toward Th1 differentiation, thus leading to an additional reduction of Th2- and B-cell function. The individual severity of inflammatory alterations is partially controlled by the negatively regulating cytokine IL-10, which, on a genetic basis, can be up-regulated to a different extent in individual patients. Therapeutic interventions to improve immune dysfunction include the enhancement of dialysis efficiency and the reduction of inflammatory alterations by the use of highly biocompatible dialyzers.

[Differential diagnosis of urinary findings]. / Was hinter dem pathologischen Urinbefund steckt.

Classical urinalysis is extremely useful in the differential diagnosis of diseases of the kidneys and lower urinary tract. Although dipsticks are suitable for orientational purposes, when pathology is indicated, and when renal disease presents, they must be supplemented by urine microscopy or quantitative and qualitative protein electrophoresis to establish the diagnosis. Phase-contrast microscopy can distinguish glomerular from nonglomerular hematuria and thus guide the further diagnosis, and the detection of leukocytes and bacteria confirms the diagnosis of urinary tract infection. In asymptomatic patients microhematuria or proteinuria is detected more frequently with increasing age. A differentiated diagnostic strategy must be adapted to the individual risk of the patient, and must avoid overdiagnosis while not missing potentially serious pathology.

[Indocyanine green elimination for the evaluation of liver function: prognostic value in patients with community-acquired sepsis]. / Indocyaningrün-Elimination als Maß der Leberfunktion : Prognostische Bedeutung bei Patienten mit ambulant erworbener Sepsis.

BACKGROUND: The aim of our clinical study was to correlate liver function measured by indocyanine green (ICG) elimination and clinical outcomes in patients with an early stage of community-acquired sepsis (CAS). MATERIALS AND METHODS: A total of 341 patients (≥ 18 years) presenting with suspicion of CAS or evidence of an infection and fulfillment of ≥ 2 systemic inflammatory response syndrome (SIRS) criteria were included in the observational study"Prognosis of early sepsis 2" (Prognose der frühen Sepsis 2, ProFS 2). Patients who had been hospitalized within the last 7 days were excluded. In a subgroup of these patients (n = 72) who were transferred to an intensive or intermediate care unit according to the clinical judgment of the treating physicians, ICG elimination (plasma disappearance rate, ICG-PDR; 15 min retention rate, ICG-R15) was assessed by using a noninvasive monitoring system (LiMON, PULSION Medical Systems, Germany). ICG-PDR and -R15 were determined on the day of admission (n = 72) and after 96 h (n = 34). The primary end point of the study was defined as death within 30 days. Secondary endpoints were need for renal replacement therapy, requirement for invasive mechanical ventilation, and length of stay in an intermediate or intensive care unit. RESULTS AND CONCLUSION: In contrast to patients with sepsis or severe sepsis, ICG elimination was found to be significantly impaired in patients with septic shock. Furthermore, a significant predictive value of ICG-PDR and -R15 on the day of admission for the need for subsequent renal replacement therapy (n = 12) was observed. In addition, reduced ICG elimination was associated with a longer stay in an intermediate or intensive care unit. However, ICG elimination on admission could not predict 30-day mortality (n = 14) or requirement of mechanical ventilation (n = 20).

Laparoscopic versus open bilateral nephrectomy in transplant recipients with medication-resistant hypertension: final results of a multicenter study with 15 years of follow-up.

BACKGROUND: The objective of this study was to evaluate the outcomes of laparoscopic bilateral nephrectomy (LBN) compared with open bilateral nephrectomy (OBN) in transplant recipients with medication-resistant hypertension. MATERIAL AND METHODS: Between 1994 and 2009, 66 renal transplant recipients underwent LBN due to poorly controlled hypertension. We compared them with 44 previous patients who underwent OBN. RESULTS: The mean operative times for LBN and OBN were 195.4 ± 60.1 minutes and 145.7 ± 30.2 minutes, respectively (P = .013). The mean hospital stays were 4.2 ± 2.1 in the LBN versus 10.3 ± 3.9 days in the OBN groups; the mean complication rates were 9.1% versus 18.2%, respectively. At follow-up, the blood pressure (mean value 130/90 mm Hg) in 45 patients (68.2%) among the LBN group was well controlled without the need for antihypertensive medications. In 19 patients (28.8%) significantly fewer antihypertensive drugs (1 or 2) were needed compared with the preoperative status. The remaining 2 patients (3%), both of whom had returned to hemodialysis due to chronic transplant rejection, remained on a combination of 3 or more antihypertensive drugs. Among the open surgery group, 23 subjects (52.3%) showed significantly decreased arterial blood pressure without needing medical therapy; 18 patients (40.9%) required 1 or 2 drugs and the remaining 3 (6.8%) were on a combination of 3 or more antihypertensives. The last cohort had returned to hemodialysis due to chronic transplant rejection. CONCLUSIONS: LBN showed a higher efficacy than open surgery to treat medication-resistant hypertension after renal transplantation, reducing the postoperative trauma and the morbidity rate in high-risk transplant recipients.