Efficacy of CytoSorb®: a systematic review and meta-analysis.

INTRODUCTION: Cytokine adsorption using the CytoSorb® adsorber has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® adsorber with regard to mortality in various settings. METHODS: We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010-29.5.2022). We considered randomized controlled trials and observational studies with control groups. The longest reported mortality was defined as the primary endpoint. We computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analysed all studies combined and divided them into the subgroups: sepsis, cardiopulmonary bypass surgery (CPB), other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334). RESULTS: Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® intervention did not lower mortality (RR [95%-CI]: all studies 1.07 [0.88; 1.31], sepsis 0.98 [0.74; 1.31], CPB surgery 0.91 [0.64; 1.29], severe illness 0.95 [0.59; 1.55], SARS-CoV-2 1.58 [0.50; 4.94]). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (1.22 [1.02; 1.46]). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Of the eligible 34 studies only 12 were randomized controlled trials. All observational studies showed moderate to serious risk of bias. INTERPRETATION: To date, there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of diagnoses that justifies its widespread use in intensive care medicine.

Renal events in patients receiving neprilysin inhibitors: a systematic review and meta-analysis.

BACKGROUND: While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. METHODS: We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. RESULTS: Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)]. CONCLUSION: NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.

[Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia]. / Insulinautoimmunsyndrom : Eine seltene, aber wichtige Differentialdiagnose der Hypoglykämie.

A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.

Long-term B cell depletion associates with regeneration of kidney function.

BACKGROUND: Chronic kidney disease (CKD) is a common condition that increases mortality and the risk of cardiovascular and other morbidities regardless of underlying renal condition. Chronic inflammation promotes renal fibrosis. Recently, renal B cell infiltrates were described in chronic kidney disease of various etiologies beyond autoimmunity. METHODS: We here investigated B cells and indicators of tertiary lymphoid structure formation in human renal biopsies. Renal function was studied during long-term B cell depletion in human patients with membranous nephropathy and with CKD of unknown origin. RESULTS: Cytokine profiles of tertiary lymphoid structure formation were detected in human renal interstitium in a range of kidney diseases. Complex B cell structures consistent with tertiary lymphoid organ formation were evident in human membranous nephropathy. Here, B cell density did not significantly associate with proteinuria severity, but with worse excretory renal function. Proteinuria responses mostly occurred within the first 6 months of B cell depletion. In contrast, recovery of excretory kidney function was observed only after 18 months of continuous therapy, consistent with a structural process. Renal tertiary lymphatic structures were also detected in the absence of autoimmune kidney disease. To start to address whether B cell depletion may affect CKD in a broader population, we assessed kidney function in neurologic patients with CKD of unknown origin. In this cohort, eGFR significantly increased within 24 months of B cell depletion. CONCLUSION: Long-term B cell depletion associated with significant improvement of excretory kidney function in human CKD. Kinetics and mechanisms of renal B cell aggregation should be investigated further to stratify the impact of B cells and their aggregates as therapeutic targets.

Extracorporeal cytokine removal in severe CAR-T cell associated cytokine release syndrome.

PURPOSE: Life-threatening complications of CD-19 Chimeric antigen receptor - T (CAR-T) cells such as the cytokine release syndrome (CRS)) have been reported. Treatment is limited to IL-6 blockade and steroids although global removal of elevated soluble inflammatory factors might be more effective. METHODS: Clinical course of a CRS patient treated with extracorporeal cytokine adsorption (Cytosorb®). A panel of 48 cytokines, chemokines and endothelial markers has been analyzed longitudinally. Ex vivo stimulation of endothelial cells to visualize (immunocytochemistry) and quantify (ECIS, TER) endothelial barrier effects. RESULTS: Following CAR-T cell application a 65 years old male developed grade 4 CRS with refractory shock (3 vasopressors) and severe capillary leakage (+37 L/24 h resuscitation). Treatment included IL-6 blockade, methylprednisolone and additionally Cytosorb hemoperfusion. While multiple soluble inflammatory factors were elevated and most of them decreased by more than 50% following Cytosorb, markers of endothelial injury increased steadily (e.g. Angpt-2/Angpt-1) leading to profound endothelial activation and leakage in ex vivo assays. CONCLUSION: This is the first reported use of cytokine adsorption for CRS showing efficacy in absorption of various cytokines but not endothelial growth factors. A randomized controlled trial to evaluate additional Cytosorb treatment in CRS is currently recruiting at our institution (NCT04048434).

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

Greater Susceptibility for Metabolic Syndrome in Pediatric Solid Organ and Stem Cell Transplant Recipients.

BACKGROUND: Cardiovascular comorbidity is of increasing importance after transplantation. Metabolic syndrome (MS) contributes to the risk for cardiovascular sequelae. Our aim was to assess the risk for MS in pediatric solid organ and stem cell transplant recipients by comparing them with matched untransplanted peers in a multicenter study. METHODS: We prospectively assessed MS in 295 pediatric transplant recipients and compared them with 1475 age- and sex-matched controls. RESULTS: Posttransplant metabolic syndrome (PTMS) was most frequent in lung (43%) and kidney (39%), followed by liver (16%) and stem cell (13%) recipients, compared with nontransplanted peers (4%; P < 0.01). The risk of displaying PTMS was almost 22-fold higher after lung (95% confidence interval, CI, 8.2-57.4), 16-fold higher after kidney (95% CI, 9.1-28.9), 5-fold higher after liver (95% CI, 2.1-10.1), and 4-fold higher after stem cell (95% CI, 1.4-9.5) transplantation. The contribution of individual components leading to MS differed depending on transplant type. In the combined analysis of all transplant groups, older age, less physical activity, calcineurin or mammalian target of rapamycin inhibitor-based immunosuppression, and hypovitaminosis D were associated with PTMS. CONCLUSIONS: By investigating a large group of patients, our study not only shows a high prevalence of PTMS but also identifies kidney and lung transplant patients as being at a particularly high risk. Moreover, knowledge on the factors associated with PTMS allows for individualized treatment approaches as well as potential preventive measures.

Renal transplant recipients receiving loop diuretic therapy have increased urinary tract infection rate and altered medullary macrophage polarization marker expression.

Loop diuretics deplete the renal cortico-medullary salt gradient that has recently been established as a major modulator of immune responses. Renal transplant recipients suffer from a markedly increased rate of urinary tract infections (UTIs). Whether diuretic therapy affects renal macrophage polarization in the human kidney graft and the incidence of UTI have not been reported. In a cohort of 112 adult renal allograft recipients, loop diuretic therapy significantly correlated with the rate of UTI during five years after transplantation in uni- and multivariable regression analysis. The M1 macrophage marker human leukocyte antigen-DR (HLA-DR) and the M2 macrophage marker CD206 co-localized with the pan-macrophage marker CD68 in the kidney graft. Both were more common in renal medulla than cortex. With increasing loop diuretic dose, the renal medullary M1/M2 macrophage marker ratio decreased in early surveillance biopsies of this cohort. In vitro, the sodium chloride concentration dose-dependently increased monocyte chemotactic cytokine CCL2 production in human myeloid and renal tubular epithelial cells. More CCL2 was detected in the renal medulla than cortex of the kidney grafts. However, in patients receiving loop diuretic therapy, the renal cortico-medullary CCL2 gradient was diminished and CCL2 serum levels decreased significantly. Thus, diuretic therapy associated with increased bacteriuria and leukocyturia after kidney transplantation and a decreased M1/M2 macrophage marker ratio in the renal medulla. Hence, adjustment of diuretic therapy should be investigated further as a possible approach in patients with frequent UTIs.

Cardiovascular risk factors and subclinical organ damage after hematopoietic stem cell transplantation in pediatric age.

Advances in allogeneic hematopoietic stem cell transplantation (HSCT) in malignant and non-malignant diseases result in more long-term survivors, in whom cardiovascular (CV) disease is one leading non-cancer cause of death. This study aimed to evaluate risk factors and subclinical CV organ damage in survivors after HSCT in pediatric age. We enrolled 64 children in a cross-sectional approach 3.3 ± 3.1 years after HSCT. Anthropometric data, laboratory values, office and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated, showing a high prevalence of obesity, hypertension and dyslipidemia. CV organ damage was determined by non-invasive measurements of aortic pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima media thickness (IMT). Increased IMT and elevated PWV reflecting subclinical vascular damage were detected in 48% (IMT) and 6% (PWV) of our population. For IMT, physical activity had a positive impact and was worsened by time after HSCT. Our results show a surprisingly high rate of subclinical CV organ damage and classical risk factors. Therefore, diagnosis and management of well-known CV risk factors belong to clinical care after HSCT.

Macrophage density in early surveillance biopsies predicts future renal transplant function.

Inflammation impairs renal allograft survival but is difficult to quantify by eye at low densities. Here we measured leukocyte abundance in early surveillance biopsies by digital image analysis to test for a role of chemokine receptor genotypes and analyze the predictive value of leukocyte subsets to allograft function. In six-week surveillance biopsies, T-cell (CD3), B-cell (CD20), macrophage (CD68), and dendritic cell (CD209) densities were assessed in whole slide scans. Renal cortical CD3, CD20, and CD68 were significantly higher in histologic rejection. The CCR2 V64I genotype was associated with lower CD3 and CD209 densities. Above-median CD68 density was significantly associated with lower combined patient and graft survival with a hazard ratio of 3.5 (95% confidence interval 1.1-11.0). Both CD20 and CD68 densities inversely correlated with estimated glomerular filtration rate (eGFR) four years after transplantation. Additionally, CD68 correlated with eGFR loss. Among histological measurements including a complete Banff classification, only CD68 density was a significant predictor of an eGFR under 30ml/min after four years (odds ratio 7.4, 1.8-31.0) and part of the best eGFR prediction set in a multivariable linear regression analysis of multiple clinical and pathologic parameters. In a second independent cohort, the original CD68 median maintained its discriminative power for survival and eGFR. Thus, digital high-resolution assessment of CD68+ leukocyte infiltration significantly improves prognostic value of early renal transplant biopsies.

Aortic Pulse Wave Velocity in Healthy Children and Adolescents: Reference Values for the Vicorder Device and Modifying Factors.

BACKGROUND: Aortic pulse wave velocity (PWV), an indicator of arterial stiffness, independently predicts cardiovascular mortality risk in adults. Arterial stiffening advances with age and seems accelerated in children with certain disease conditions such as chronic kidney disease or diabetes. The Vicorder, an oscillometric device to measure PWV, has been validated in children, but reference values in a large pediatric cohort, association to carotid stiffness and influence of individual and family risk factors have not been determined. METHODS: Pulse waves were captured in 1,003 healthy children (aged 6-18 years) in 6 centers and gender-specific reference data normalized to age/height were constructed. In 589 children carotid distensibility and intima media thickness were measured. Gestational and family history was reported. RESULTS: PWV correlated with age (r = 0.57, P < 0.0001) with significant gender-related differences starting at age 9. Further significant correlations were seen for height, weight, body mass index, blood pressure, pulse pressure, and heart rate. Independent predictors for PWV in a multivariate regression analysis were gender, age, height, weight, mean arterial pressure, and heart rate. Risk factors for higher PWV included small for gestational age at birth, secondhand smoking, parental hypertension, and obesity. PWV showed weak correlations with 2 of the carotid distensibility measures, but not with intima media thickness. CONCLUSION: This study defines reference values for PWV captured by the Vicorder device in children and adolescents and reveals associations with potential cardiovascular risk factors in a healthy population. Gender-specific percentiles for age/height will allow for the assessment of pediatric cohorts using this oscillometric method.

Serum neutrophil gelatinase-associated lipocalin (NGAL) in patients with Shiga toxin mediated haemolytic uraemic syndrome (STEC-HUS).

Neutrophil gelatinase-associated lipocalin (NGAL) is an increasingly used biomarker for acute kidney injury (AKI). Its utility in adult patients with AKI caused by Shiga toxin producing Escherichia coli infection (STEC)-associated haemolytic-uraemic syndrome (HUS), remains unknown. We aimed to evaluate the prognostic value of serum NGAL admission levels for the need of renal replacement therapy (RRT) in STEC-HUS patients. Baseline serum NGAL was determined by ELISA in 39 patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May-July 2011. Patients with HUS had significant higher NGAL levels than healthy controls (379 [248 - 540] vs 39.0 [37.5-45] ng/ml, p < 0.0001). During clinical course, 24 patients required RRT at a median of five days after admission. NGAL admission levels were higher in patients requiring RRT (476 (344-639) ng/ml) compared to patients not requiring RRT (257 (196-426) ng/ml; p < 0.001). Unadjusted and adjusted logistic regression analyses identified NGAL as an independent predictor for need of RRT. In a combined model, a joint NGAL/AKIN classification approach improved the predictive accuracy for need of RRT over either marker alone. The combined categorical cut-off point defined by NGAL ≥ 330 ng/ml and presence of AKI (AKIN ≥ I) on admission correctly identified 20 of 24 patients requiring RRT (odds ratio 20, sensitivity 83%, specificity 80%, negative predictive value 75%, positive predictive value 87%). NGAL may serve as an adjunctive tool to improve risk prediction in patients with STEC-HUS.

Clinical and health care use characteristics of patients newly starting allopurinol, febuxostat, and colchicine for the treatment of gout.

OBJECTIVE: Gout is a common form of inflammatory arthritis with an increasing prevalence in developed countries. It is well known that many patients with gout have significant comorbidities and high health care utilization. We aimed to describe the clinical characteristics and health care utilization patterns in patients with gout who were newly prescribed allopurinol, febuxostat, or colchicine. METHODS: We used US insurance claims data (2009-2011) to conduct a population-based cohort study. RESULTS: There were 25,051 allopurinol, 4,288 febuxostat, and 6,238 colchicine initiators. The mean age was 53 years and 83-87% were men. More than one-half of the patients had hypertension and hyperlipidemia, 20% had diabetes mellitus, and 10% had cardiovascular disease. The mean uric acid level was similar across the groups at baseline, ranging from 8.1-8.5 mg/dl. Compared with allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care utilization, including outpatient, inpatient, or emergency room visits, both at baseline and during followup. Use of gout-related drugs such as opioids, steroids, and nonsteroidal antiinflammatory drugs was most common in febuxostat initiators and least common in colchicine initiators. The median daily doses at both the start and end of treatment were 300 mg for allopurinol, 40 mg for febuxostat, and 1.2 mg for colchicine. The doses of allopurinol and febuxostat were rarely increased during followup. CONCLUSION: Patients who started allopurinol, febuxostat, or colchicine for gout generally had hyperuricemia and multiple comorbidities. Febuxostat initiators had more comorbidities and greater use of health care resources and gout-related drugs than the other groups. Overall, the doses of allopurinol or febuxostat remained unchanged over time.

Zinc-alpha2-glycoprotein in patients with acute and chronic kidney disease.

BACKGROUND: Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein which is synthesized in a variety of cell types. AZGP1 has functionally been implicated in lipid metabolism, the regulation of cell cycling and cancer progression. Previous studies have shown increased circulating AZGP1 levels in patients with chronic kidney disease but AZGP1 has not been investigated in acute kidney injury (AKI). In this study, serum AZGP1 levels were measured in acute and chronic kidney disease to test for a correlation to renal function and other clinical parameters. METHODS: We performed ELISA based measurements of AZGP1 serum levels in 21 patients suffering from grade 3 AKI and in 20 chronic hemodialysis patients. In AKI patients, AZGP1 was first measured before initiation of acute renal replacement therapy and a second measurement was done during renal functional recovery. Sera of healthy blood donors served as controls. The association of AZGP1 with acute and chronic renal dysfunction was analysed, as well as the correlation with clinical parameters, body composition and biochemical variables. RESULTS: Levels of circulating AZGP1 were significantly elevated in AKI patients. High initial levels of AZGP1 correlated with extra-renal complications but not with parameters of renal function. At follow-up, AZGP1 levels were still increased but now correlated significantly with creatinine, eGFR and urea. Circulating AZGP1 in chronic hemodialysis patients was higher than in AKI patients. An association to parameters of lipid metabolism was not found. CONCLUSIONS: This study illustrates that circulating AZGP1 is not only elevated in chronic hemodialysis patients but also sharply increases during the early phase of AKI. The unexpected association with extra-renal complications during AKI needs further exploration as it might point to unknown biological effects of AZGP1.

New high-cutoff dialyzer allows improved middle molecule clearance without an increase in albumin loss: a clinical crossover comparison in extended dialysis.

BACKGROUND: Accumulation of middle molecules is thought to have adverse effects in patients with acute kidney injury (AKI). Elimination of middle molecules by non-convective means, i.e. hemodialysis, remains difficult. The aim of the study was to investigate the removal characteristics of a new high permeability membrane in AKI patients undergoing extended dialysis (ED). PATIENTS AND METHODS: We performed a prospective, crossover study comparing the EMiC2 dialyzer (1.8 m(2), FMC, Germany) and AV 1000S (1.8 m(2), FMC) in 11 critically ill patients with AKI. ß2-Microglobulin, cystatin c, creatinine, and urea were measured before and after 0.5, 5.0 and 10 h of ED. Serum reduction ratios, dialyzer clearances, and mass in the total collected dialysate were determined. RESULTS: Dialyzer clearance of ß2-microglobulin (EMiC2: 52 ± 1.7 ml/min, AV 1000S: 41.7 ± 1.5 ml/min, p = 0.0002) and cystatin c (EMiC2: 47.2 ± 1.2 ml/min, AV 1000S: 34.2 ± 2.3 ml/min, p < 0.0001) was markedly different, as was the reduction of serum levels of ß2-microglobulin (EMiC2: 54.3 ± 3.6%, AV 1000S: 39.1 ± 4.5%, p = 0.025) and cystatin c (EMiC2: 38.9 ± 2.6%, AV 1000S: 28.0 ± 3.9%, p = 0.043). Additionally, we observed a higher total amount of these substances in the collected dialysate. There was no significant difference in the total amount of albumin eliminated per treatment. CONCLUSION: The new EMiC2 dialyzer enhances removal of middle molecules without an increase in albumin loss. The clinical relevance of this finding needs to be determined.

Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study.

OBJECTIVE: To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. DESIGN: Multicentre retrospective case-control study. SETTING: 23 hospitals in northern Germany. PARTICIPANTS: 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. MAIN OUTCOME MEASURES: Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. RESULTS: 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P = 0.03), fewer deaths (0% v 5%, p = 0.029), required no abdominal surgery, and excreted E coli for a shorter duration. CONCLUSIONS: Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

Cellular senescence limits regenerative capacity and allograft survival.

Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16(INK4a) expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16(INK4a)-dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a(-/-) mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF(-/-) donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.

Renal resistive index in addition to low-grade albuminuria complements screening for target organ damage in therapy-resistant hypertension.

OBJECTIVE: We examined the value of renal resistive index (RRI) for prevalence of cardiovascular target organ damage in therapy-resistant hypertension in comparison to low-grade albuminuria. METHODS: Eighty-four patients with therapy-resistant hypertension (age 59.7 +/- 8.1 years) were screened for cardiovascular target organ damage with coronary computed tomography, cardiac magnetic resonance imaging (MRI), Doppler sonography for the assessment of carotid intima media thickness and, RRI, pulse wave velocity and for low-grade albuminuria of at least 10 mg/day in men and 15 mg/day in women, respectively. RESULTS: In patients with RRI greater than 0.7 pulse wave velocity (11.6 +/- 3.7 vs. 9.8 +/- 2.2 m/s; P = 0.02) intima media thickness (0.85 +/- 0.09 vs. 0.76 +/- 0.1 mm; P = 0.007) and Agatston score of coronary calcification (640 +/- 915 vs. 129 +/- 256; P = 0.05) were increased, whereas left ventricular mass (127 +/- 24.5 vs. 125 +/- 15.0 g; P = 0.70) was similar between the two groups. When patients were categorized according to low-grade albuminuria left ventricular mass was significantly higher in those with low-grade albuminuria (123 +/- 25.8 vs. 135 +/- 15.7 g; P = 0.01), whereas vascular parameters (intima media thickness, Agatston score, pulse wave velocity) did not differ between the two groups. CONCLUSION: In patients with therapy-resistant hypertension RRI reflects functional and structural vascular parameters, whereas low-grade albuminuria is related to cardiac structural changes. Thus, measurement of RRI in addition to low-grade albuminuria complements screening for target organ damage in therapy-resistant hypertension.