BACKGROUND:Shiga toxin-producing, enteroaggregative Escherichia coli was responsible for the 2011 outbreak of haemolytic uraemic syndrome (HUS). The present single-centre, observational study describes the 1-year course of the disease with an emphasis on kidney function. Outcome data after 1 year are associated with treatment and patient characteristics at onset of HUS.METHODS:Patients were treated according to a standardized approach of supportive care, including a limited number of plasmapheresis. On top of this treatment, patients with severe HUS (n = 35) received eculizumab, a humanized anti-C5 monoclonal antibody inhibiting terminal complement activation. The per-protocol decision--to start or omit an extended therapy with eculizumab accompanied by azithromycin--separated the patients into two groups and marked Day 0 of the prospective study. Standardized visits assessed the patients' well-being, kidney function, neurological symptoms, haematological changes and blood pressure.RESULTS:Fifty-six patients were regularly seen during the follow-up. All patients had survived without end-stage renal disease. Young(er) age alleviated restoring kidney function after acute kidney injury even in severe HUS. After 1 year, kidney function was affected with proteinuria [26.7%; 95% confidence interval (CI) 13.8-39.6], increased serum creatinine (4.4%, CI 0.0-10.4), increased cystatin C (46.7%, CI 32.1-61.3) and reduced (<90 mL/min) estimated glomerular filtration rate (46.7%, CI 32.1-61.3). Nine of the 36 patients without previous hypertension developed de novo hypertension (25%, CI 10.9-39.1). All these patients had severe HUS.CONCLUSIONS:Although shiga toxin-producing Escherichia coli (STEC)-HUS induced by O104:H4 was a life-threatening acute disease, follow-up showed a good recovery of organ function in all patients. Whereas kidney function recovered even after longer duration of dialysis, chronic hypertension developed after severe HUS with neurological symptoms and could not be prevented by the extended therapy.

BACKGROUND:More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents.PATIENTS AND METHODS:The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group.RESULTS:We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group.CONCLUSION:Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.

Acute kidney injury (AKI), fever, hepatosplenomegaly, and thrombocytopenia are characteristics of Hantavirus infections and leptospirosis, both worldwide zoonoses. Although AKI is usually the result of tubulointerstitial nephritis, glomerular damage with significant albuminuria and hematuria may be noted in both entities. Although Hantavirus infections are endemic in Western Europe and the United States, leptospirosis is predominantly seen in parts of South America and Asia. We here report 3 cases of thrombocytopenic fever and AKI presenting within several months in Northern Germany with initially suspected Hantavirus infection. Serologic testing finally unraveled the diagnosis of leptospiral infection.

BACKGROUND:May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases.METHODS:To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May).RESULTS:Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups.CONCLUSIONS:Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

CONTEXT:An outbreak of Shiga toxin-producing enteroaggregative Escherichia coli (STEC O104:H4) infection with a high incidence of hemolytic uremic syndrome (HUS) occurred in Germany in May 2011. Antibiotic treatment of STEC infection is discouraged because it might increase the risk of HUS development. However, antibiotic therapy is widely used to treat enteroaggregative E coli infection. In the German outbreak, a substantial number of patients received prophylactic azithromycin treatment as part of a therapeutic regimen with the C5 antibody eculizumab.OBJECTIVE:To analyze the duration of bacterial shedding in patients with STEC infection who did and did not receive oral azithromycin therapy.DESIGN, SETTING, AND PATIENTS:At a single center in Lübeck, Germany, 65 patients with STEC infection, including patients with HUS as well as STEC-infected outpatients without manifestation of HUS, were investigated between May 15 and July 26, 2011, and were monitored for a mean of 39.3 days after onset of clinical symptoms.MAIN OUTCOME MEASURE:Carriage of STEC after azithromycin therapy.RESULTS:Twenty-two patients received oral azithromycin and 43 patients did not receive antibiotic treatment. Among antibiotic-treated patients, long-term STEC carriage (>28 days) was observed in 1 of 22 patients (4.5%; 95% CI, 0%-13.3%) compared with 35 of 43 patients (81.4%; 95% CI, 69.8%-93.0%) who were not treated with antibiotics (P < .001). All 22 patients receiving azithromycin treatment had at least 3 STEC-negative stool specimens after the completion of treatment, and no recurrence of STEC was observed in these patients. As proof of principle, 15 patients who initially were not treated with antibiotics and were long-term STEC carriers were treated with oral azithromycin given for 3 days and subsequently had negative stool specimens.CONCLUSION:Treatment with azithromycin was associated with a lower frequency of long-term STEC O104:H4 carriage.

Background: C-reactive protein (CRP) is a key molecule in inflammation and tissue homeostasis and is produced locally by renal tubular epithelial cells. Its significance of expression in contrast to expression of cytotoxic T cell (CTL) markers remains to be elucidated. Methods: By means of real-time PCR, we determined mRNA levels of CRP in 66 renal allograft biopsies with acute allograft failure and in 34 biopsies with chronic dysfunction. Results were compared to expression of CTL components (perforin, granzyme B) and were correlated with histologic diagnoses and outcome. Results: CTL markers were found in most biopsies, and thus were not specific for particular histologies, although expression levels increased significantly with Banff rejection grades. Expression of CRP was highly specific for rejection episodes in acute failure (p < 0.0001) as well as for transplant glomerulopathy or de novo/recurrent glomerulonephritis in chronic failure (p < 0.005). Finally, the presence of CRP expression in renal allografts was associated with a deteriorating 1-year graft function in acute (p < 0.01) as well as chronic allograft dysfunction (p = 0.077). Conclusions: Our data suggest local CRP expression of kidney transplants as an indicator for pathologic entities associated with unfavorable outcomes in the early and late course of kidney transplants.

Potential kidney transplant recipients (KTRs) are screened intensively for the prevalence of coronary artery disease and left ventricular hypertrophy [1], but less attention is given to the prevalence of right heart failure (RHF) or pulmonary hypertension (PH) in patients with end-stage renal disease (ESRD). As PH with consecutive chronic RHF is associated with tricuspid regurgitation [2], inferior cavous vein congestion and subsequent iliac congestion [2, 3], accompanied by deleterious effects on kidney allograft perfusion may arise from reduced venous efflux [3]. Arteriovenous fistulas (AVFs) have been shown to contribute to cardiac abnormalities in KTRs [4, 5], but their impact on RHF, right ventricular dilatation or kidney allograft function has thus far not been evaluated. To emphasize the importance of RHF in ESRD patients and to demonstrate the impact of iliac congestion on the kidney allograft, we retrospectively analysed four patients who presented with an echocardiographic finding of a dilated right ventricle after kidney transplantation. All four patients included in this study were identified in our transplant center in 2008 (8% of all deceased donor kidney transplantations) and did not differ in their usual transplant conditions. None of these patients complained about reduced physical condition or pulmonary distress. They were on hemodialysis prior to kidney transplantation (6 ± 2.2 years) and were among the 23% of KTRs in our center that had at least one dialysis treatment within the first week post-transplant (delayed graft function, DGF). All four patients were biopsied showing acute tubular necrosis and absence of rejection. These KTRs received triple immunosuppression regimen consisting of methylprednisolone, mycophenolate mofetil and one of the calcineurin inhibitors. Duplex ultrasound measurements and echocardiographic studies were performed according to current guidelines [6, 7]. Right heart catheterization (RHC) was performed after 30 min of rest. After measuring the cardiac index (CI), the AVF was compressed with a blood pressure cuff until fistula flow was barely audible with a stethoscope. Mean pulmonary artery pressure (MPAP), CI and pulmonary capillary wedge pressure (PCWP) were re-evaluated under compression of the AVF. PH was diagnosed, wherever the MPAP was equal or >25 mmHg [8]. As RHC confirmed RHF resulting from high-flow AVF in the KTRs, closure of AVF was performed about 17 ± 3 days post-transplant in our center to improve kidney allograft function. Duplex ultrasound detected high-flow AVF (>2.5 l/min fistula flow) as well as a pathologic biphasic flow pattern in the kidney allograft vein of all four KTRs. This was indicative for tricuspid regurgitation and iliac congestion (Fig. 1a). After AVF closure, normal linear flow patterns in the allograft and iliac vein were detected in these patients (Fig. 1b). Duplex ultrasound of kidney allograft vein (a, b) and echocardiography (c, d) prior to (a, c) and after arteriovenous fistula (AVF) closure (b, d). The arrow indicates the septum. RV, Right ventricle; LV, Left ventricle. Echocardiographic investigation revealed a moderately to severely dilated right ventricle with a flattened septum, paradoxical septal movements and severe tricuspid regurgitation associated with elevated pulmonary artery pressure (PAP) (Table 1, Fig. 1c). The measured ejection fraction was above 65% prior to and after AVF closure, demonstrating that left ventricular function was not impaired in any of the patients. RHC demonstrated a significant elevated MPAP and CI but normal PCWP, which confirmed the echocardiographic findings. After AVF obliteration, PAP and MPAP decreased significantly (P < 0.05, paired t-test, Table 1) and CI decreased about 25% to 3.2 ± 0.8 l/min/m2 (P = 0.055). Subsequently, right ventricle dilatation resolved (Fig. 1d). Impressively, urine output significantly improved within 24 h after AVF closure from 630 ± 120 ml/day to 2360 ± 830 ml/day (P < 0.01, paired t-test). This was associated with significant improvement of kidney allograft function in the patients (Table 1). Interestingly, the improvement of allograft function after AVF closure in the KTRs was associated with a significant reduction of total proteinuria, albuminuria and alpha1-microglobulinuria by 55%, 60% and 70% respectively within 24 h after intervention (Table 1). The results of our study show that KTRs with RHF, consecutive tricuspid regurgitation [2] and iliac congestion are at risk for the development of delayed and marginal graft function. We hypothesized, that reduction of venous efflux of the kidney allograft resulting from PH [2, 3] represents the underlying mechanism for DGF in our patients. This is supported by our finding that successful treatment of PH significantly improved allograft function in KTRs within 24 h after intervention. This improvement of allograft function was associated with a decrease of 'congestion albuminuria', and a reduction of alpha1-microglobulinuria reflecting the recovery of renal tubular function after AVF closure. Even if the natural course of DGF is favorable in most KTRs, the immediate response to intervention (24 h) and absence of other adverse factors such as volume depletion or rejection further strengthens our hypothesis. Several investigations revealed that high renal venous pressure is associated with higher creatinine levels or kidney injury in patients with decompensated heart failure [3, 9]. These studies indicate that our observed effect of PH on renal function is not only restricted to transplanted kidneys, as similar effects might play a role in native kidneys as well [3, 9]. The incidence of PH varies between 10% and 40% of KTRs and is related to patient survival [10, 11]. Thus treatment of PH and RHF in ESRD patients seems to be essential to reduce the risk of DGF and poor long-term outcome after kidney transplantation [3]. High volume AVF have been proven to elevate left ventricular end-diastolic diameter (LVEDD), cardiac index and right atrial area [12, 13] as observed in our study. Thus, increasing right ventricular cardiac output [14] and LVEDD produced by high-volume AVF can contribute to an elevated PAP. This pathological mechanism is supported by recent studies demonstrating that AVF flow is the most significant variable correlating with PH in ESRD patients [11] and AVF closure may reverse elevated LVEDD [5, 15]. To optimize post-transplant outcomes, we recommend routine echocardiographic and duplex ultrasound investigations prior to kidney transplantation with a focus on right ventricular dilatation and iliac congestion to detect hemodynamic-relevant high-flow AVF. To clarify the impact of PH on allograft survival, larger studies are needed to address this problem.

Apoptotic mechanisms in proximal renal tubular epithelial cells (PTEC) are crucial in the pathogenesis of acute kidney injury. We investigated whether insulin alters anti-apoptotic signalling in human PTEC. Cells were deprived of insulin for 0, 24 or 48 h and then stimulated with insulin for 0 or 5 min. Apoptosis was induced by camptothecin incubation. Insulin receptor kinase (IR-kinase) activity, phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated PI3-kinase (p85), Ser273-phosphorylation of Akt and caspase-3 activity (C3-activity) were determined. Insulin stimulation increased the activity of IR-kinase, IRS-1 phosphorylation, p85 association with IRS-1 and Ser273-phosphorylation of Akt by at least 250%, respectively and decreased the C3-activity by 45% (p < 0.01, respectively). Deprivation of insulin for 24 and 48 h reduced basal and insulin-stimulated IR-kinase activity, IRS-1 phosphorylation, p85 association with IRS-1 and Ser273-phosphorylation of Akt by 30-40% and increased C3-activity by 15-20% (p < 0.01, respectively). Incubation with camptothecin increased C3-activity by 250-300% (p < 0.001). Subsequent insulin stimulation reversed the camptothecin induced increase of C3-activity. Our data indicate that apoptosis in PTEC is regulated by the insulin dependent PI3-kinase/Akt pathway. The enhancement of tubular-specific cell survival signals might represent a potential therapeutic tool for the protection of renal function in acute kidney injury.