Intrarenal Doppler ultrasonography in patients with HFrEF and acute decompensated heart failure undergoing recompensation.

OBJECTIVES: Renal venous congestion due to backward heart failure leads to disturbance of renal function in acute decompensated heart failure (ADHF). Whether decongestion strategies have an impact on renal venous congestion is unknown. Objective was to evaluate changes in intrarenal hemodynamics using intrarenal Doppler ultrasonography (IRD) in patients with heart failure with reduced ejection fraction (HFrEF) and ADHF undergoing recompensation. METHODS: Prospective observational study in patients with left ventricular ejection fraction (LV-EF) ≤ 35% hospitalized due to ADHF. IRD measurement was performed within the first 48 h of hospitalisation and before discharge. Decongestion strategies were based on clinical judgement according to heart failure guidelines. IRD was used to assess intrarenal venous flow (IRVF) pattern, venous impedance index (VII) and resistance index (RI). Laboratory analyses included plasma creatinine, eGFR and albuminuria. RESULTS: A number of 35 patients with ADHF and LV-EF ≤ 35% were included into the study. IRD could be performed in 30 patients at inclusion and discharge. At discharge, there was a significant reduction of VII from a median of 1.0 (0.86-1.0) to 0.59 (0.26-1.0) (p < 0.01) as well as improvement of IRVF pattern categories (p < 0.05) compared to inclusion. Albuminuria was significantly reduced from a median of 78 mg/g creatinine (39-238) to 29 mg/g creatinine (16-127) (p = 0.02) and proportion of patients with normoalbuminuria increased (p = 0.01). Plasma creatinine and RI remained unchanged (p = 0.73; p = 0.43). DISCUSSION: This is the first study showing an effect of standard ADHF therapy on parameters of renal venous congestion in patients with HFrEF and ADHF. Doppler sonographic evaluation of renal venous congestion might provide additional information to guide decongestion strategies in patients with ADHF.

[Acute kidney injury: from creatinine to KIM­1?] / Akute Nierenschädigung: von Kreatinin zu KIM­1?

In addition to the early detection of an acute kidney injury (AKI), several problems or questions have to be addressed. These include the identification of the etiology, the severity (functional or structural), the prognosis (recovery or transition to chronic renal failure), the course of the disease (dialysis or not), and the identification of specific treatment options for AKI. The following article provides an overview of established and new AKI biomarkers as well as an outlook on the potential of future biomarker-associated models of AKI.

[Baroreflex activation therapy : Indication and evidence in resistant hypertension and heart failure]. / Barorezeptoraktivierungstherapie : Indikation und Evidenz bei therapieresistenter Hypertonie und Herzinsuffizienz.

Baroreflex activation therapy (BAT) is a sympathoinhibitory procedure for treatment of therapy-resistant hypertension (rsHTN) and severe heart failure with reduced ejection fraction (HFrEF) that been available for several years. The double-blind, randomized Rheos Pivotal Trial demonstrated a blood pressure lowering effect in patients with rsHTN for the first-generation BAT device. A smaller randomized study in heart failure showed that the Barostim Neo system is safe and can improve heart failure symptoms and decrease neuroendocrine activation. However, for this unilateral system, which is currently in clinical use, no data from large randomized trials exist. Despite existing data for BAT in rsHTN and HFrEF, large randomized trials, showing reduction of blood pressure and cardiovascular events are still lacking. Therefore, BAT's efficacy and safety cannot be conclusively assessed.

[Therapy-resistant and therapy-refractory arterial hypertension]. / Therapieresistente und -refraktäre arterielle Hypertonie.

Therapy-resistant and therapy-refractory arterial hypertension differ in prevalence, pathogenesis, prognosis and therapy. In both cases, a structured approach is required, with the exclusion of pseudoresistance and, subsequently, secondary hypertension. Resistant hypertension has been reported to be more responsive to intensified diuretic therapy, whereas refractory hypertension is presumed to require sympathoinhibitory therapy. Once the general measures and the drug-based step-up therapy have been exhausted, interventional procedures are available.

[Cardio-renal axis : Relationship of heart failure and renal insufficiency as comorbidities]. / Herz-Nieren-Achse : Beziehung von Herz- und Niereninsuffizienz als Komorbiditäten.

Heart failure and kidney dysfunction are common comorbidities with overlapping and synergizing mechanisms. Coincidence of both pathologies aggravates disease progression rates, symptoms, and outcomes. The treatment of patients with advanced renal insufficiency is faced with limited evidence for therapies that are standard of care in patients with normal and moderate kidney failure, frequent deterioration of kidney function during therapy, and onset of hyperkalemia, which pose challenges for clinical care, requiring intensified physician-patient contacts. A special challenge is the so-called diuretic resistance, which may require extracorporeal drainage.

Successful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with Belimumab in a 19-year-old woman.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

Improvement of renal graft function after conversion from a calcineurin inhibitor including immunosuppression to a mycophenolate sodium including regimen: a 4-year follow-up.

BACKGROUND: The most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs. METHODS: In the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test. RESULTS: The mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects. CONCLUSION: These data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.

The CX(3)C-chemokine fractalkine in kidney diseases.

The chemokine CX(3)C-L/FKN is expressed in both soluble and transmembrane/mucin hybrid forms, thus combining chemoattractant functions together with receptor/adhesion molecule properties. In contrast to other chemokine receptors, CX(3)C-R is expressed not only on lymphoid cell populations, but also on several intrinsic cells including tubular epithelial cells and renal fibroblasts where it regulates various aspects of cell viability, matrix synthesis and degradation, migration, inflammation as well as oxidative stress. In the kidney, the chemokines/receptor pair has been shown to play a role in nephrogenesis as well as in the pathogenesis primary and secondary nephropathies. In several animal models and human specimens with acute and chronic renal failure including allograft nephropathy, CX(3)C-L/CX(3)C-R has been shown to exert immune and non-immune mediated renal damages. A blockade of this chemokine system ameliorated acute and chronic renal damages, though the latter to a more robust extent. There seems to a role of the CX(3)C-L/CX(3)C-R pair in mediating acute renal inflammation as well as in progressive chronic renal failure. However, functional studies are lacking for many aspects and further studies are necessary to better define the functional properties of CX(3)C-L/FKN and its receptor.

[Microalbuminuria and albuminuria: differential diagnosis and consequences for treatment]. / Mikroalbuminurie und Albuminurie: Differenzialdiagnose und therapeutische Konsequenzen.

The occurrence of microalbuminuria or albuminuria indicates a disturbance of the barrier function of endothelial cells, basement membrane or of a structural-renal disease (including diseased podocytes). The prevalence of microalbuminuria in the general population is about 8 %, however, in high risk groups, prevalence rates of 50 % and more have been observed. Its incidence is strongly associated with increased cardiovascular morbidity and mortality. Blood pressure control and the blockade of the renin-angiotensin-aldosteron-system (RAAS), respectively, is the central mechanism to reduce cardio-vascular-renal end points as well as mortality.

Decrease in serum tacrolimus level and rise in serum creatinine under late addition of cinacalcet in a renal transplant recipient with hyperparathyroidism: a case report.

Cinacalcet is a calcimimetic drug that has been approved for treatment of secondary and tertiary hyperparathyroidism in patients with renal failure requiring renal replacement therapy. A few cases of successful treatment in renal transplant patients immunosuppressed with cyclosporine have been reported. Herein we have reported the case of a 48-year-old renal transplant recipient presenting with secondary hypercalcemic hyperparathyroidism (parathyroid hormone [PTH] 896 pg/mL; total calcium, up to 3.3 mmol/L) under immunosuppressive therapy with tacrolimus. Owing to substantial comorbidity and a high operative risk, we decided to initiate a therapeutic trial with cinacalcet. Using a daily dose of 30 mg of Cinacalcet, normal calcium levels and a mild fall in PTH levels (decline of 62 pg/mL) were achieved within the first week of treatment. At this point, we also observed a marked decrease in tacrolimus levels (from 6.3 to 2.6 mg/dL) without any change in concomitant medications. Thus, we adapted the tacrolimus dosage. Concurrent with cinacalcet therapy, there was a rise in serum creatinine levels (from 3.9 to 4.9 mg/dL before discontinuation of cinacalcet), which was not reversible after termination of 3 weeks of treatment with cinacalcet, but continued. Cinacalcet and tacrolimus are both metabolized via cytochrome P 450. The documented decrease in tacrolimus serum levels, suggested a drug-drug interaction between tacrolimus and cinacalcet. The irreversible deterioration in renal function may be attributed to nephrotoxic properties of cinacalcet, but may also indicate an acceleration of the natural course of chronic allograft nephropathy.

Potential role of fractalkine receptor expression in human renal fibrogenesis.

The inhibition of several chemokine/chemokine receptors has been shown to reduce progressive renal interstitial fibrosis. In this study, we examined the expression of the CX(3)C receptor in human renal biopsies with interstitial fibrosis and from normal kidneys by real-time polymerase chain reaction (PCR) and immunohistochemistry. The CX(3)C receptor was not only detected in mononuclear, tubular epithelial, and dendritic cells but also in alpha-smooth muscle actin and vimentin-positive interstitial myofibroblasts in fibrotic kidneys. Real-time PCR indicated a significant upregulation of CX(3)C receptor mRNA in fibrotic kidneys compared with non-fibrotic nephropathies or donor biopsies. In renal fibroblasts in vitro, hydrogen peroxide increased the expression of the CX(3)C receptor, an increase that was inhibited by N-acetylcysteine and catalase. However, neither proinflammatory nor profibrotic cytokines resulted in this upregulation. Stimulation of fibroblasts by CX(3)C ligand led to a significant enhancement of migration, which was abrogated by pre-incubation with a blocking anti-CX(3)C receptor antibody. Our studies indicate that renal fibrosis is associated with the expression of CX(3)C receptors on human renal fibroblasts. The expression is induced by reactive oxygen species suggesting a role of oxidative stress.

Effective treatment of hepatitis C-associated immune-complex nephritis with cryoprecipitate apheresis and antiviral therapy.

A 38-year-old pregnant woman (19th week of pregnancy) complained of fatigue, cold inducible paresthesias, generalized edema and mild arterial hypertension. Her past medical history was notable for frequent episodes of polyarthralgia and positivity for rheumatoid factor. On admission, acanthocyturia and unselective glomerular-tubular proteinuria with 19 g/d were detected with a slight decrease in creatinine clearance. Rheumatoid factor was robustly elevated and a cryocrit of 1.5 vol%, caused by a so far unknown replicative hepatitis C, was detected. Renal biopsy yielded membrano-proliferative glomerulonephritis. During pregnancy, high-dose corticosteroid therapy was administered. Edema disappeared and blood pressure normalized under albumin substitution and low-dose furosemide application. However, Cesarian section became necessary due to placental insufficiency at 27 weeks of gestation. Thereafter, neither virus load, cryocrit nor proteinuria decreased significantly under a combined therapy with pegylated interferon-a and ribavirin. Thus, cryoprecipitate apheresis was initiated resulting in robust decreases of clinical complaints, viral load, cryocrit and proteinuria. Cryoglobulinemia with renal involvement caused by hepatitis C is difficult to treat due to limitations of immunosuppressive and anti-viral therapy. In our patient, cryoprecipitate apheresis was a safe and effective therapeutic addition to standard therapy.

Bioimpedance analysis and intradialytic hypotension in intermittent hemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is one of the most severe complications during hemodialysis. Its appearance is caused in part by rapid fluid removal with concomitant failure in blood pressure regulation but also by other dialytic-dependent and independent factors. PATIENTS AND METHODS: We investigated total (TBW), extracellular (ECW) and intracellular water (ICW) in chronic intermittent hemodialysis dialysis hypotension-prone (CRF-HP, n = 11) and nonhypotension-prone (CRF-NHP, n = 10) patients with end-stage renal disease before, every 30 minutes during, as well as after dialysis and within onset of intradialytic hypotension by multifrequent bioimpedance analysis (BIA). Additionally, intradialytic time course of BIA in patients with acute renal failure (ARF) and septic shock (n = 10) was observed. RESULTS: IDH occurred in 72.1% of CRF-HP and in 80% of ARF patients. In CRF-HP and CRF-NHP, ECW significantly decreased by -12.44 +/- 4.22% in CRF-HP and -9.0 +/- 6.2% in CRF-NHP comparing pre- and post-dialysis values (each p < 0.01). Conversely, ICW increased by +11.5 +/- 11.3% in CRF-HP and +18.4 +/- 25.2% in CRF-NHP (each p < 0.05). In patients with ARF no significant changes could be detected. Calculated ECW/ICW and ECW/TBW ratio significantly decreased in CRF patients with a higher rate in CRF-HP patients (p < 0.05). Neither ECW/ICW nor ECW/TBW ratio correlated with mean arterial pressure. The onset of intradialytic hypotension (n = 35) did not differ intraindividually compared to normotensive periods (n = 411). Fluid removal in CRF patients seems to be mainly from the extracellular space. The reduced decreases in ECW/ICW and ECW/TBW ratios in CRF-HP compared to CRF-NHP may indicate an insufficient refilling from intra- to extracellular compartment in CRF-HP. CONCLUSION: In conclusion, multifrequent BIA is not capable to predict hypotension in the individual patient during a particular dialysis session.

[Erdheim-Chester disease]. / Erdheim-Chester-Krankheit.

HISTORY AND CLINICAL FINDINGS: A 55-year-old female was admitted complaining of musculoskeletal pain and weakness of both lower extremities for a number of years. Due to a hypothalamic mass of unknown aetiology a diabetes insipidus, a gonadotrophic, somatotrophic and a partially corticotrophic insufficiency had developed. INVESTIGATIONS: Laboratory investigations yielded elevated levels of several inflammatory parameters (C-reactive protein, blood sedimentation rate, fibrinogen and thrombocytes). Serological parameters indicating a systemic rheumatic disorder were absent. X-ray examination revealed combined osteolytic and osteoblastic lesions within the distal parts of both femora and within the proximal portions of both tibiae. MRI showed signal alterations and (99m)Technetium bone scan exhibited a considerably increased uptake. Histopathologically, a biopsy of the left tibia showed multifocal small infiltrates of foamy histiocytes indicating Erdheim-Chester disease (ECD). TREATMENT AND COURSE: Under treatment with glucocorticosteroids musculoskeletal complaints improved, but re-appeared following dose reduction. A therapeutic trial using methotrexat did not affect the complaints. CONCLUSION: The Erdheim-Chester syndrome is considered to belong to diseases with a proliferation of the monocytic-histiocytic and dendritic cellular system. In the presence of symmetric musculoskeletal symptoms associated with osteosclerotic and osteolytic lesions particularly occurring in the long bones of the lower extremities and concomitant with elevated serum markers of inflammation, the Erdheim-Chester disease should be taken into account. To date, no validated therapy exists.

Benign prostatic hyperplasia (BPH) requiring transurethral resection in freshly transplanted renal allograft recipients.

With recent progress in surgery and immunosuppression, more and more older men receive a kidney transplant. Thus, it is likely that the incidence of BPH in male transplant recipients is growing in parallel with age. Nonetheless, no data exist about diagnostic parameters for BPH in freshly transplanted male kidney allograft recipients. We evaluated whether established diagnostic and therapeutic criteria for BPH are valid for the evaluation of renal transplant recipients. BPH was diagnosed in 8 of 11 recipients older than 55 years. In all freshly transplanted renal allograft recipients, lower urinary tract symptoms (LUTS) were detected using an international prostate symptoms score (IPSS). This score was 9.6 +/- 7.1 in patients without BPH, and significantly higher with 21.1 +/- 4.3 in patients with BPH. In receiver-operating characteristics (ROC) curve analysis a cut-off of 15.5 was calculated to distinguish best between BPH and non-BPH giving an accuracy of 90.2%. Acute urinary retention (AUR) was the predominant sign, which occurred in all BPH patients but only in 6.9% in non-BPH patients. Bladder outlet obstruction (BOO) was also common with a reduced uroflow with 9.5 +/- 2.2 ml/sec in non-BPH and 3.0 +/- 1.8 ml/sec in BPH (8/11 BPH-patients developed AUR prior to measurement). By digital rectal examinations, benign prostate enlargement was estimated as minimal in 10 of 11 cases of BPH. In urethrocystoscopy kissing lobes were detected in all cases of BPH. Since medical treatment with alpha-receptor antagonists was not successful, a surgical procedure using a transurethral resection was performed without any complications in all cases. Symptoms did not recur after resection, and BOO improved with increased uroflow measurements with 12.3 +/- 4.8 ml/sec 8 days after resection. We conclude that LUTS and BOO are common in freshly transplanted renal allograft recipients. The sudden onset of outlet obstruction without the potentiality of adaptation of urinary bladder may effect lower urinary tract symptoms and bladder outlet obstruction. We conclude that an elevated IPSS over 15.5 in combination with AUR and typical urethrocystoscopy results are the best methods to diagnose BPH. Conversely, our results indicate that uroflowmetry and digital rectal examination are neither sensitive nor specific. In addition, once BPH has been diagnosed and treatment with receptor antagonists does not relieve urinary tract symptoms, surgical resection should be considered.

Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients.

BACKGROUND: The multidrug resistance (MDR) gene product P-glycoprotein (P-gp) is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including the immunosuppressant cyclosporine A (CsA). We have previously shown that CsA increases P-gp expression in proximal tubule and endothelial cells in vitro. The aim of the present study was to investigate the in vivo relevance of these observations in renal allograft biopsies from CsA-treated patients. METHODS: P-gp expression was determined by immunohistochemistry of paraffin sections using two different monoclonal antibodies (UIC2 and MRK16). Biopsies were taken from CsA-treated renal transplant patients with different histopathological diagnoses (N = 79) and were compared with biopsies from normal human kidneys (N = 13) or with allograft biopsies from patients under a CsA-free immunosuppression (N = 15). Moreover, biopsies from 10 donor kidneys before implantation and during rejection episodes ("zero biopsies") were investigated. RESULTS: P-gp expression in biopsies with acute tubular necrosis (ATN; N = 10) after CsA treatment was significantly higher in arterial endothelia, proximal tubules, and epithelial cells of Bowman's capsule (BC), whereas P-gp was sparsely induced in CsA nephrotoxicity (N = 19) compared with controls. Acute cellular (N = 30) and vascular rejection (N = 10) or chronic allograft nephropathy (N = 10) after CsA was associated with strong P-gp expression in infiltrating leukocytes and increased P-gp expression in arterial endothelia, proximal tubules, and BC. In contrast, biopsies of patients treated with a CsA-free immunosuppression regimen did not show increases in P-gp expression compared with controls. Zero biopsies showed a weak, homogeneous, nonpolarized expression of P-gp in tubules and an increased expression of P-gp after CsA therapy in the brush border, arterial endothelia, and BC. CONCLUSIONS: CsA treatment was associated with increased P-gp expression in parenchymal cells of kidney transplants with ATN, acute or chronic transplant rejection, but P-gp was not increased in patients with CsA nephrotoxicity. This indicates that CsA induces its own detoxification by P-gp and that inadequate up-regulation of P-gp in renal parenchymal cells contributes to CsA nephrotoxicity. Increased expression of P-gp in infiltrating leukocytes correlated with the severity of allograft rejection, suggesting that P-gp may decrease the immunosuppressive efficacy of CsA. Thus, individual differences in the P-gp induction response of CsA-exposed renal parenchymal cells and/or infiltrating leukocytes may predispose to either CsA nephrotoxicity or rejection, respectively.