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Introduction: The prevalence of hypertension among patients with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) ranges from 72 to 88% depending on applied diagnostic criteria and the chosen method of blood pressure measurement. Despite the guidelines recommending the widespread use of renin-angiotensin system blockers (RASBs) in patients with kidney disease, their utilization in patients on HD may be suboptimal, especially in patients with preserved diuresis. This hesitance that often steams from concern is often due to fear of a decrease in eGFR and a subsequent decrease in diuresis. The aim of this study was to compare clinical characteristics, blood pressure, safety, and HD adequacy indices in hypertensive HD patients on multiple antihypertensive drug regimens, including diuretic treated with RASB (RASB group) or without RASB (no-RASB) with preserved residual diuresis. We sought to examine the real-life use of RASB in HD patients in relation to their clinical characteristics, blood pressure, safety, and HD adequacy., Methods: From a database of 5,879 patients receiving HD (mean age 65.2 ± 14.2 years, 60% of males) of the largest provider of HD in the country, we selected the subgroup treated with at least three antihypertensive medications including diuretics. We compared patients treated with RASB to counterparts without RASB (no-RASB)., Results: The RASB group has similar age and gender proportions as well as BMI and bioimpedance compared to counterparts. However, dry body mass was significantly lower in the RASB group (78.1 ± 18.3 kg vs. 80.0 ± 18.2 kg, p < 0.017). Prevalence of diabetes mellitus was similar in both groups, but RASB-treated patients have cardiovascular diseases more frequently (70.1 vs. 60.8%; p < 0.001). Systolic blood pressure and the number of antihypertensive drugs used were significantly higher in RASB patients than in counterparts (146 ± 16 mm Hg vs. 144 ± 15 mm Hg; p < 0.001 and 4.1 ± 0.9 vs. 3.5 ± 0.5; p < 0001, respectively). RASB-treated patients have significantly longer dialysis vintage (52.7 ± 44.4 months vs. 40.2 ± 40.9 months; p < 0.001) and dialysis time (722 ± 87.1 min/week vs. 713 ± 93.4 min/week; p < 0.017) than counterparts. Serum potassium was slightly but significantly higher in RASB (5.3 ± 0.8 mmol/L vs. 5.1 ± 0.7 mmol/L; p < 0.01)., Conclusions: In the real world setting, RASB can be safely used in HD patients treated with diuretics with preserved residual diuresis. Given that many HD patients present numerous multimorbidities, RASB should not only be considered as an additional hypotensive drug in poorly controlled hypertension but also in other compelling indications in HD patients. The tendency toward hyperkalemia in HD patients could be effectively managed with appropriate diet and HD prescription adjustments., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome., Summary: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure., Key Messages: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics., Summary: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms., Key Message: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: This study aimed to evaluate the association between the NephroCheck® test AKIRisk® score, diuretic efficiency (DE), and the odds of worsening kidney function (WKF) within the first 72 h of admission in patients hospitalized for acute heart failure (AHF)., Methods: The study prospectively enrolled 125 patients admitted with AHF. NephroCheck® test was obtained within the first 24 h of admission. DE was defined as net fluid urine output per 40 mg of furosemide equivalents., Results: The median AKIRisk® score was 0.11 (IQR 0.06-0.34), and 38 (30.4%) patients had an AKIRisk® score >0.3. The median cumulative DE at 72 h was 1,963 mL (IQR 1317-3,239 mL). At 72 h, a total of 10 (8%) patients developed an absolute increase in sCr ≥0.5 mg/dL (WKF). In a multivariable setting, there was an inverse association between the AKIRisk® score and DE within the first 72 h. In fact, the highest the AKIRisk® score (centered at 0.3), the higher the likelihood of poor DE (below the median) and WKF at 72 h (odds ratio [OR] 2.04; 95%; CI: 1.02-4.07; p = 0.043, and OR 3.31, 95% CI: 1.30-8.43; p = 0.012, respectively)., Conclusion: In patients with AHF, a higher NephroCheck® AKIRisk® score is associated with poorer DE and a higher risk of WKF at 72 h. Further research is needed to confirm the role of urinary cell cycle arrest biomarkers in the AHF scenario., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Some patients with cardiorenal syndrome 1 and congestion exhibit resistance to diuretics. This scenario complicates management and is associated with a worse prognosis. In some cases, rescue treatment may be considered by starting kidney replacement therapies or ultrafiltration. This decision is complex and necessitates a profound understanding of these techniques and the pathophysiology of this syndrome. These modalities are classified into continuous, intermittent, and ultrafiltration therapies, each with its own advantages and disadvantages that are pertinent in selecting the optimal treatment., Summary: In patients with diuretic-resistant cardiorenal syndrome, extracorporeal ultrafiltration and kidney replacement therapies have the potential to relieve congestion, restore the neurohormonal system, and improve quality of life., Key Messages: (i) In cardiorenal syndrome, the resistance to diuretics is common. (ii) Extracorporeal ultrafiltration and renal replacement therapies are rescue options that may improve the management of these patients. (iii) Better understanding of these modalities will help the development of new devices which are friendlier, safer, and more affordable for patients in these clinical settings., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Fluid overload is a risk factor for increased morbidity and mortality, especially in patients with heart disease. The treatment options are limited to diuretics and mechanical fluid removal using ultrafiltration or renal replacement therapy. This paper provides an overview of the challenges of managing fluid overload, outlines the risks and benefits of different pharmacological options and extracorporeal techniques, and provides guidance for clinical practice., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Acute decompensated heart failure (ADHF) has the highest rate of hospital readmission among all medical conditions and portends a significant financial burden on healthcare systems worldwide. Hospitalization for ADHF is primarily driven by congestion, with intravenous loop diuretics representing the cornerstone of therapy. However, it is well described that a significant subset of patients is discharged with residual fluid overload. While the cause of the incomplete decongestion is multifactorial, the development of diuretic resistance is a well-characterized contributing factor with consequent poor outcomes. Moreover, the therapeutic response to diuretics is known to lack predictability. Extracorporeal ultrafiltration (a mechanical pump-driven therapy) has emerged as an option to overcome shortcomings of the diuretics. It allows clinicians to customize the volume and the rate of fluid removal to the needs and clinical characteristics of the patients. The results of the currently available studies indicate that this therapy is associated with more efficient fluid and sodium removal compared to medical therapy, hence leading to reduction in the rate of readmissions and a potential salutary impact on the financial burden associated with the care of these patients. While isolated ultrafiltration can be performed by conventional machines used for renal replacement therapy, the advent of simplified, portable, and user-friendly devices that are specifically designed for extracorporeal ultrafiltration therapy has further enhanced the interest in this therapeutic modality and increased the potential for its more widespread use. Further, development in this direction through device miniaturization may extend the horizons of indications and the applicability of this therapy even in the ambulatory settings., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration., Summary: Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice., (© 2021 S. Karger AG, Basel.)

Background: The renin-angiotensin-aldosterone axis plays a pivotal role in the pathophysiology of acute and chronic heart failure (HF) and represents an important target for guideline-directed medical therapy., Summary: The use of appropriate directed medical therapies for inhibition of the renin-angiotensin-aldosterone axis in chronic HF has been the subject of several landmark clinical trials, with high levels of adherence exhibited in the outpatient setting. However, less clarity exists with respect to the initiation, continuation, and cessation of renin-angiotensin-aldosterone system inhibitors (RAASi) in the setting of acute HF and exacerbation of HF necessitating hospitalization. In this review, we summarize relevant aspects of the physiology of the renin-angiotensin-aldosterone axis in acute HF and during decongestion. We also summarize the available evidence for the risks and benefits of initiating and continuing RAASi in acute HF. Key Message: We offer a decision-making pathway for the use of RAASi in the setting of acute HF that would help guide the cardiologist and nephrologist caring for patients with acute HF and cardiorenal syndrome., (© 2020 S. Karger AG, Basel.)

Aim: This study aimed to explore the role of peritoneal ultrafiltration (UF) in cardiorenal syndrome (CRS) patients for fluid and metabolic control., Background: Peritoneal UF is safely and efficiently used for the management of CRS. It has been shown to provide efficient UF in hypervolemic patients., Methods: Thirty (20 males and 10 females) CRS patients were treated by peritoneal dialysis (PD) and UF. The baseline data of the patients (demographics, causes of heart failure, the presence of pacemaker or implantable cardioverter-defibrillator, the need for extracorporeal UF or paracentesis or thoracentesis, comorbidity, drugs, left ventricular ejection fraction [LVEF] and pulmonary artery systolic pressure [PAPs], pericardial effusion, physical examination, body weight, NYHA class, dialysis regime, urine output, N-terminal pro-B-type natriuretic peptide [NT-proBNP] level, hemoglobin, estimated glomerular filtration rate [eGFR], and other routine biochemical determinations) were recorded at the onset, every 6 months, and then annually. Echocardiograms were performed at baseline and after 6 and 12 months. The time points of complications associated with PD, the need for hemodialysis, the day of death, and causes of death were documented., Results: Mean age was 69 ± 8 years (range 49-84 years). The average PD duration was 18.25 ± 14.87 months. According to the CKD-EPI, initial mean GFR was 34.34 ± 11.9 mL/min/1.73 m2 (range 16.57-59.0), and this increased to 45.48 ± 26.04, 45.10 ± 28.58, and 41.10 ± 25.68 mL/min/1.73 m2 in the third, sixth, and twelfth months, respectively. There was a significant increase in the first 3 months and a significant decrease between the third and twelfth months (respectively, p = 0.018 and p = 0.043). There was no difference in eGFR levels between baseline and the end of the first year (p = 0.217). In the first 3 months, there was a significant decline in urea levels to 79.38 ± 36.65 from 109.92 ± 42.44 mg/dL and this was maintained until the end of the first year of PD therapy (after 3 months, p = 0.002; after 1 year, p = 0.024). However, there was no significant change in creatinine levels within the first year (p = 0.312). There was a significant increase in hemoglobin level up to the end of the first year of PD (after 3 months, p = 0.000; after 12 months, p = 0.013). There was a marked decrease in NT-proBNP levels in the first 6 months (p = 0.011). Functional capacity (according to NYHA classification) improved in all patients by the third month of PD treatment (p < 0.001). This early improvement was maintained in many patients during the following 12 months (p < 0.001). There was a marked decrease in NT-proBNP levels in the first 6 months (p = 0.011). At the end of the first year, there was an approximate 15% reduction in NT-proBNP levels (p = 0.647). Hospitalizations decreased to 6 ± 15 days/patient-year (range 18-122 days) from 62 ± 24 days/patient-year (p = 0.000)., Conclusion: Peritoneal UF is a treatment method that maintains renal function and electrolyte balance, improves cardiac function, and reduces hospitalizations in CRS patients. We observed that this treatment significantly increased functional capacity and quality of life and significantly reduced hospital admissions., (© 2020 S. Karger AG, Basel.)

Objective: In acute heart failure (AHF), early assessment of spot urinary sodium (UNa) has emerged as a useful biomarker for risk stratification and monitoring. The objective of this study was to investigate (a) whether early spot UNa predicts 24-h diuretic efficiency and (b) the clinical factors associated with early spot UNa in patients with AHF and concomitant renal dysfunction (RD)., Methods: This is a post hoc analysis of the IMPROVE-HF trial, in which 160 patients with AHF and RD (estimated glomerular filtrate rate [eGFR] <60 mL/min/1.73 m2) were included. Diuretic efficiency was calculated as the net fluid output produced per 40 mg of furosemide equivalents in 24 h. The association between early spot UNa and diuretic efficiency and clinical variables associated with UNa were evaluated using multivariate linear regression analysis. The contribution of the exposures in the predictability of the models was assessed with the coefficient of determination (R2)., Results: The mean age of the study population was 78 ± 8 years. The median (interquartile range) diuretic efficiency, early spot UNa, aminoterminal pro-brain natriuretic peptide, and eGFR were 747 (490-1,167) mL, 90 mmol/L (65-111), 7,765 pg/mL (3,526-15,369), and 33.7 ± 11.3 mL/min/1.73 m2, respectively. In a multivariate setting, lower UNa was significantly and nonlinearly associated with lower diuretic efficiency (p = 0.001), explaining the 44.4% of the model predictability. Natremia and surrogates of congestion emerged as the main factors related to UNa., Conclusions: In patients with AHF and RD at presentation, early spot UNa was inversely related to 24-h diuretic efficiency., (© 2020 S. Karger AG, Basel.)

Background: Renal function tends to deteriorate in a hyperchloremic acidifying environment, which is reflected by a decrease in the difference between sodium and chloride., Objectives: To examine the effect of furosemide administered under hyperchloremic acidosis on intraoperative oliguria and acute kidney injury in patients with preoperatively normal renal function., Methods: In patients undergoing abdominal or orthopedic surgeries (April 2010-November 2018), we retrospectively identified patients who preoperatively had a normal renal function but experienced intraoperative oliguria under hyperchloremic acidosis (a sodium-chloride difference < 30 mEq/L) without dehydration. We compared the perioperative urine output and the incidence of postoperative acute kidney injury between patients who intraoperatively received an initial dose of 5 mg of furosemide (the furosemide group) and patients who did not intraoperatively receive furosemide (the control group)., Results: We identified 62 patients in the furosemide group and 48 patients in the control group. The furosemide group intraoperatively received 0.11 ± 0.06 mg/kg of furosemide (range 0.06-0.39 mg/kg). Compared to the control group, the furosemide group had greater urine output (mL/kg/h) in the operating room (1.1 ± 0.7 vs. 0.3 ± 0.1, p < 0.01) and on postoperative day 1 (1.2 ± 0.5 vs. 1.1 ± 0.4, p = 0.02). The incidence of postoperative acute kidney injury was lesser in the furosemide group than that in the control group (8.0 vs. 27.0%, p < 0.01; multivariate OR 0.18; 95% CI 0.05-0.61; p < 0.01)., Conclusions: In surgery patients under hyperchloremic acidosis, furosemide (0.1 mg/kg) resolved intraoperative oliguria and reduced the incidence of postoperative acute kidney injury., (© 2019 S. Karger AG, Basel.)

Background: Loop diuretics (LD) are widely used in emergency and intensive care medicine., Summary: The substances increase the clearance of electrolytes and water; thus, they allow us to control hypervolemia and to prevent patients from pulmonary edema. LD are also frequently applied to patients with an acute decrease in glomerular filtration rate, namely, acute kidney injury (AKI). Nevertheless, volume depletion may be associated with reduced renal perfusion and possibly slower restitution or even aggravation of kidney dysfunction. Several trials on the preventive or therapeutic efficacy of LD have been published since the early 1970s. Our review article is intended to summarize the most important references related to this topic. In addition, we discuss the diagnostic value of the so-called furosemide stress test. The currently available data indicate that LD may act in a beneficial manner as long as euvolemia is maintained (matched hydration). Key Massages: LD are not beneficial for AKI treatment if kidney-related endpoints are considered. In certain situations, AKI prevention with LD can be associated with favorable outcomes as long as euvolemia is maintained. LD can help to identify AKI subjects at a higher risk of AKI progression, but the exact clinical consequences need to be determined., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches., Summary: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Objective: The aim of this study was to examine the effect of volume status on the progressions of renal disease in normovolemic and hypervolemic patients with advanced non-dialysis-dependent chronic kidney disease (CKD) who were apparently normovolemic in conventional physical exam-ination., Materials and Methods: This was a prospective interventional study performed in a group of stage 3-5 CKD patients followed up for 1 year. Three measurements were made for volume and renal status for every patient. The fluid status was assessed by a bioimpedance spectroscopy method. A blood pressure (BP) value > 130/80 mm Hg prompted the initiation or dose increment of diuretic treatment in normovolemic patients., Result: Forty-eight patients (48%) were hypervolemic. At the end of the 1-year follow-up, hypervolemic patients were found to have a significantly lower estimated glomerular filtration rate and higher systolic BP compared to baseline. Hypervolemia was associated with an increased incidence of death., Conclusion: We have shown that maintenance of normovolemia with diuretic therapy in normovolemic patients was able to slow down and even improve the progression of renal disease. Volume overload leads to an increased risk for dialysis initiation and a decrease in renal function in advanced CKD. Volume overload exhibits a stronger association with mortality in CKD patients., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Left ventricular diastolic dysfunction (LVDD) frequently occurs in chronic kidney disease (CKD) and is associated with heart failure and higher mortality. LVDD is observed in patients with early stages of CKD and is associated with cardiovascular events, in patients undergoing incident hemodialysis in the absence of systolic function. The pathogenesis of CKD includes abnormal ventricular filling in diastole and a higher LV filling pressure (LVFP) because of LV hypertrophy (LVH), in addition to myocardial interstitial fibrosis. Therefore, LV dysfunction tends to cause pulmonary congestion. In patients with CKD, the mechanism of LVDD is complicated and mainly involves LVH, which is a physiological response to pressure and volume overload. Other factors related to CKD, including LVH, neurohumoral alterations, inflammation, anemia, and mineral disorders, might cause the development of LVDD. Echocardiography is frequently used for noninvasive evaluation of diastolic function and for estimating LVFP. Echocardiographic quantification of LVFP is based on the E/e' ratio, where E is the early mitral flow velocity on transmitral Doppler and e' is the early mitral annulus velocity obtained from tissue Doppler. An E/e' ratio <8 is considered to be normal, whereas a ratio >15 is considered to mirror the increase in LVFP. The main strategy for treating LVDD is to minimize the large volume shift to control blood pressure and prevent myocardial interstitial fibrosis., (© 2018 S. Karger AG, Basel.)

Optic neuropathy (ON) is commonly complicated by microcystic macular edema (MME), that is, small vertical cystoid spaces in the inner nuclear layer (INL) of the macula. We performed a retrospective consecutive case series of 14 eyes from 11 patients with ON and MME that were treated with oral acetazolamide, acting on cellular water transport. Contralateral eyes without MME were used as controls. Segmentation of images obtained with OCT was used to determine changes of individual retinal layer thickness during treatment. Retinal INL thickness consistently decreased in all eyes after 2-3 weeks of treatment. Recurrence of MME was observed after treatment cessation. No significant change of retinal thickness was found in contralateral unaffected eyes. Visual function did not change with treatment. Acetazolamide significantly improved the MME in eyes with ON. However, visual function did not. Acetazolamide is a treatment option for MME associated with ON but without an impact on the visual function., (© 2018 S. Karger AG, Basel.)

Background: Hyponatremia is the most common electrolyte abnormality found in hospitalized patients with acute heart failure (AHF) and is related to poor prognosis. This study sought to evaluate: (1) the different prognostic impact of dilutional versus depletional hyponatremia, evaluating short- and long-term outcome; (2) the relationship between both types of hyponatremia and intravenous furosemide dose, renal function changes, and persistent congestion at discharge., Methods: This retrospective single-center study included 233 consecutive patients with a primary diagnosis of AHF. Hyponatremia was defined as serum sodium < 135 mEq/L, which could be either dilutional (hematocrit < 35%) or depletional (hematocrit ≥35%). Persistent congestion was defined as a congestion score ≥2 at discharge. Patients were followed 180 days for occurrence of death or rehospitalization for AHF., Results: Hyponatremia was present in 68/233 patients with 27 cases classified as dilutional hyponatremia versus 41 as depletional. The proportion of patients with persistent congestion was higher in the dilutional hyponatremia group, but similar in the depletional hyponatremia group (52 vs. 81 vs. 58%; p = 0.02). After adjustment for important baseline characteristics, dilutional hyponatremia was significantly associated with the risk of death or rehospitalization for AHF at 60 days (HR 2.17 [1.08-4.37]; p = 0.03) and 180 days (HR 1.88 [1.10-3.21]; p = 0.02). In contrast, depletional hyponatremia was only significantly associated with the same endpoint at 180 days (HR 1.64 [1.05-2.57]; p = 0.03)., Conclusions: Low hematocrit levels in AHF patients with hyponatremia characterize a population that is more difficult to decongest and has poor clinical outcome. In contrast, patients with hyponatremia but normal hematocrit are better decongested and have better short-term outcome., (© 2018 S. Karger AG, Basel.)

Background/aims: Immune responses are involved in arterial hypertension. An observational cross-sectional case control study was conducted to estimate the association between Toll-like receptor 4 (TLR4) expression and interleukin (IL)-17A serum levels in patients with controlled and non-controlled hypertension., Methods: We have enrolled 105 non-complicated otherwise healthy hypertensive patients: 53 with well-controlled blood pressure and 52 non-controlled. TLR4 peripheral monocytes expression and serum IL-17A levels were determined by flow cytometry and ELISA, respectively., Results: Non-controlled patients exhibited higher TLR4 expression than well-controlled (25.60 vs. 21.99, P=0.011). TLR4 expression was lower in well-controlled patients who were prescribed beta blockers (18.9 vs. 22.6, P=0.005) and IL-17A concentration was higher in patients using diuretics in either group (1.41 vs. 2.01 pg/ml, P<0.001; well-controlled 1.3 vs. 1.8 pg/ml, P= 0.023; non-controlled 1.6 vs. 2.3 pg/ml, P=0.001). Correlation between IL-17A concentration and hypertension duration was observed in non-controlled patients (Spearman correlation coefficient . ρ=0.566, P<0.001) whereas in well-controlled patients a correlation was found between hypertension duration and TLR4 expression (ρ=0.322, P=0.020)., Conclusions: Arterial hypertension stimulates the immune response regardless of blood pressure regulation status. Prolonged hypertension influences peripheral monocyte TLR4 expression and IL-17A serum levels. Anti-hypertensive drugs have different immunomodulatory effects: diuretics are associated with higher IL-17A concentration and beta-blockers with lower TLR4 expression., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Background: Low serum bicarbonate concentrations are associated with mortality and kidney disease progression. Data regarding associations between bicarbonate and cardiovascular disease (CVD) are scarce., Methods: We performed a cohort study of 6,229 adult participants from the Multi-Ethnic Study of Atherosclerosis, a community-based cohort free of CVD at baseline. Serum bicarbonate was measured at baseline. Cardiovascular outcomes were defined as: (1) subclinical CVD (left ventricular mass [LVM] and aortic pulse pressure [PP] measured at baseline), (2) incident atherosclerotic cardiovascular events (CVE; composite of myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease death, and stroke death), and (3) incident heart failure., Results: During a median (interquartile range) follow-up of 8.5 (7.7-8.6) years, 331 (5.3%) participants had an incident CVE and 174 (2.8%) developed incident heart failure. We stratified analyses by use of diuretics because we observed a significant interaction between diuretic use and bicarbonate with study outcomes. Among diuretic nonusers, with adjustment, bicarbonate ≥25 mEq/L was associated with an estimated 3.0 g greater LVM (95% CI 0.5-5.0) and 1.0 mm Hg higher aortic PP (95% CI 0.4-2.0) compared to bicarbonate 23-24 mEq/L. Each 1 mEq/L of bicarbonate increase was associated with a 13% higher risk of incident heart failure (hazards ratio 1.13, 95% CI 1.01-2.11). Among diuretic users, higher bicarbonate was not associated with CVD. Bicarbonate was not associated with incident atherosclerotic CVE irrespective of diuretic use., Conclusion: Among nonusers of diuretics in a large community-based study, higher serum bicarbonate concentrations are associated with subclinical CVD and new heart failure., Competing Interests: Authors do not have any disclosures., (© 2016 S. Karger AG, Basel.)

Introduction: The objective was to evaluate the effect of hydrochlorothiazide and alendronate on urine calcium and bone mineral density in calcium stone-forming patients., Material and Methods: A prospective, non-randomized, non-observational comparative study was performed; this study included 111 patients with recurrent calcium stones, divided into 3 groups according to the treatment received. Group 1: 36 patients were treated with alendronate, 70 mg/week; Group 2: 34 patients were treated with alendronate, 70 mg/week + hydrochlorothiazide, 50 mg/day; Group 3: 41 patients were treated with hydrochlorothiazide, 50 mg/day. All patients received recommendations on diet and fluid intake. Other variables of bone mineral density were studied and analyzed, including bone remodeling markers and urinary calcium before and after 2 years of treatment. The statistical analysis was performed using the SPSS 17.0 program, with a statistical significance of p < 0.05., Results: After 2 years of treatment, a significant difference was observed in the β-crosslaps and a bone mineral density improvement in Group 1, along with a decrease in urinary calcium. In Group 3, a statistically significant difference was found in urinary calcium and fasting calcium/creatinine ratio, as well as an improvement in bone mineral density after 2 years of medical treatment. In Group 2 patients treated with the combination, there was an improvement in bone mineral density and a decrease in the β-crosslaps marker similar to patients in Group 1, and a decrease in urinary calcium similar to those in Group 3., Conclusion: Combined alendronate + hydrochlorothiazide treatment offers the best results along with the improvement in bone mineral density and decrease in urine calcium in patients with recurrent calcium stones., (© 2016 S. Karger AG, Basel.)

Background: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in SLC12A3. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS., Methods: Sixty-seven patients with GS underwent SLCl2A3 analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored., Results: Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) and 32 patients with abnormal glucose metabolism., Conclusions: We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes., (© 2016 S. Karger AG, Basel.)

The use of angiotensin converting enzyme (ACE) inhibitors in combination with diuretics is a common strategy used for the treatment of patients affected by heart failure. An infant affected by initial congestive cardiac failure, after starting the treatment with enalapril in association with furosemide, developed acute kidney injury (AKI). No underlying renal disease or renal artery stenosis was found. He recovered from kidney injury after the therapy was suspended, thus suggesting that the drug combination is responsible for the onset of the adverse reaction. The present case report, the appraisal of the current knowledge on the onset of AKI and the analysis of available pharmacovigilance databases indicate that particular caution should be exercised when infants affected by heart failure are treated with the enalapril and furosemide combination therapy. Moreover, we strongly suggest an up-to-date revision of the ACE-inhibitor dosing guidelines in pediatric patients to define unambiguously the safe upper limits of this class of drugs., (© 2015 S. Karger AG, Basel.)

Background: Ultrafiltration is an adjunctive treatment for decompensated heart failure patients with cardiorenal syndrome. The efficacy and safety of ultrafiltration in the patient cohort are still unknown., Methods: We systematically reviewed and evaluated randomized controlled trials, comparing diuretics with ultrafiltration in adult patients with decompensated heart failure and cardiorenal syndrome through January 2014. The primary outcomes were body weight loss and total fluid removal., Results: We identified 8 trials including 608 patients. In a random-effects model, the pooled difference of body weight loss was 1.44 kg between patients receiving ultrafiltration and diuretics (95% CI, 0.29-2.59; p = 0.01). The difference of fluid removal was 1.28 l between groups (95% CI, 0.43-2.12; p = 0.003). The RR for mortality was 0.90 for ultrafiltration compared with diuretics (95% CI, 0.61-1.33; p = 0.60) and the RR for renal function deterioration was 1.29 (95% CI, 0.90-1.85; p = 0.17). There is a trend toward reducing readmission rate in ultrafiltration group., Conclusions: Ultrafiltration is a safe and effective strategy in the treatment of cardiorenal syndrome without increasing the risk of renal deterioration.

Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic β cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life., (© 2015 S. Karger AG, Basel.)

The majority of outpatients with heart failure (HF) have chronic kidney disease (CKD) as an important comorbidity. Both glomerular filtration rate and abnormal urinary albumin excretion are major predictors of outcome in HF patients. Despite this, patients with renal dysfunction have been systematically excluded from the large randomized HF trials. There is lack of evidence for optimal treatment in these cardiorenal patients and treatment nihilism may account in part for their bad prognosis. Identifying and monitoring the progression of renal disease and making an effort to preserve renal function should be an important task in the management of all patients with HF. In this review, the current understanding of the pathophysiology of renal dysfunction in outpatients with HF will be summarized. Furthermore, important principles of the identification and management of cardiorenal patients will be described in order to make the physician more capable of managing outpatients with HF and renal dysfunction., (© 2015 S. Karger AG, Basel.)

Calcium and bone disorders in children and adolescents are treated with a wide variety of drugs. Several of these drugs have been used for many years on the basis of accepted practice, without being subjected to rigorous trials. Bisphosphonates are the mainstay treatment for children with osteoporosis, but newer, more potent compounds such as zoledronate and risedronate have begun to replace the older-generation bisphosphonates. Hypocalcaemia is managed with calcium and vitamin D and its metabolites. In difficult cases that are secondary to hypoparathyroidism, subcutaneous injections or infusions of parathyroid hormone have been used. Multiple daily phosphate supplements and calcitriol are the standard treatment for hypophosphataemic rickets, but trials of an anti-fibroblast growth factor 23 antibody appear promising, and the results are eagerly awaited. Many new medications are undergoing clinical trials and are starting to emerge as viable treatment options for children. Some of these drugs target specific diseases, such as recombinant alkaline phosphatase for hypophosphatasia and a C-type natriuretic peptide analogue for achondroplasia. Other drugs, such as denosumab and odanacatib, have been used successfully in the adult population, and the appropriate use of these drugs in children is now being evaluated., (© 2015 S. Karger AG, Basel.)

Background: Use of antihypertensive medications (AHM) after living kidney donation is not well described., Methods: We examined a database wherein national transplant registry data for 4,650 living kidney donors in 1987-2007 were linked to pharmacy claims from a US private health insurer (2000-2007 claims) to identify post-donation AHM fills. Cox regression with left- and right-censoring was used to estimate the frequencies and relative likelihood (adjusted hazards ratios, aHR) of post-donation AHM fills according to donor demographic traits. Medication possession ratio (MPRs), defined as (days of AHM dispensed)/(days observed), were also compared among donors and non-donor general beneficiaries., Results: Overall, 17.8% of the sample filled at least one AHM by 5 years post-donation. As compared with White living donors, African-Americans had 37% higher relative likelihood of any AHM use after donation (aHR 1.37, p < 0.0007), including significantly higher likelihoods of filling diuretics (aHR 2.25, p < 0.0001), ACEi/ARBs (aHR 1.46, p < 0.01), calcium channel blockers (aHR 1.56, p = 0.03), and vasodilators/other agents (aHR 2.17, p = 0.03). MPRs for any AHM and subcategories were lower among donors compared with age- and sex-matched non-donors. However, AHM MPRs rose in donors with multiple hypertension diagnoses, and prescription fill exposure for all AHM classes except diuretics was similar among donors and general non-donors with ≥ 3 hypertension diagnoses., Conclusions: While AHM requirements are lower after kidney donation than among unscreened general persons, racial variation in AHM use occurs in privately insured donors. Demonstration of pharmaceutical care needs of insured donors supports the need for long-term follow-up and healthcare access for all donors., (© 2014 S. Karger AG, Basel.)

Background: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics., Methods: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites)., Results: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and β2-microglobulin performed better compared to Cr in estimating RPF, β-trace protein, β2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index., Conclusion: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

Background: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients., Methods: The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs., Results: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia., Conclusions: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician., (© 2013 S. Karger AG, Basel.)

Background/aims: There are no published studies assessing the safety and efficacy of thiazides as antihypertensives in kidney transplantation (KTX)., Methods: This was a longitudinal retrospective cohort study conducted in adult KTX recipients. Patients were grouped based on receiving thiazides following KTX. Safety and efficacy comparisons were made between thiazide recipients and unexposed patients, as well as change in blood pressure (BP) within thiazide patients., Results: 1,093 patients were included (thiazide group: 108, unexposed group: 985). Mean follow-up was 7.3 ± 4.5 years. Thiazide recipients were older (53 ± 11 vs. 48 ± 13 years, p < 0.001) and more likely to be female (52 vs. 41%, p = 0.023) and have pre-KTX hypertension (97 vs. 88%, p = 0.004) or diabetes (36 vs. 27%, p = 0.035). After controlling for baseline differences, safety analysis revealed thiazide recipients were not more likely to be readmitted to the hospital, but were at higher risk to develop hyperkalemia (56 vs. 38%, p < 0.001) or hypokalemia (28 vs. 18%, p = 0.010), with similar rates of hypotension, decreased estimated glomerular filtration rate, graft loss and death. Efficacy analysis demonstrated systolic (147 ± 17 to 139 ± 18 mm Hg, p < 0.001) and diastolic (79 ± 9 to 77 ± 11 mm Hg, p < 0.001) BPs were significantly reduced after thiazide initiation. Compared to unexposed patients, thiazide recipients had higher mean BPs during the entire follow-up (142/78 vs. 136/77, p < 0.001), with similar BPs while on thiazides and comparable rates of goal BPs (<130/80 mm Hg, 32 vs. 36%, p = 0.219)., Conclusions: In KTX, based on long-term outcomes, thiazides appear to be safe and effective antihypertensives; in the short-term, thiazides may increase the risk of developing potassium disturbances., (Copyright © 2013 S. Karger AG, Basel.)

Interactions between the heart and the kidneys are increasingly acknowledged among both cardiologists and nephrologists. The term cardiorenal syndrome now applies to the bidirectional nature of how disease in one organ system affects the function of the other organ system. Cardiovascular disease is a major threat to patients with chronic kidney disease, while renal dysfunction is prevalent in patients with cardiac disease and is a significant predictor of prognosis in cardiac patients. Still, renal patients with cardiac disease have largely been excluded from the clinical trials that have been the basis of modern cardiologic treatment. In this review, the current understanding of the pathophysiological mechanisms involved in the cardiorenal syndrome and potential therapeutic implications will be summarized from a nephrologist's point of view. Probably, fragile cardiorenal patients will benefit from an enhanced collaboration between cardiologists and nephrologists to secure the best treatment given under safe conditions., (Copyright © 2013 S. Karger AG, Basel.)

Background: While the combination of an angiotensin receptor blocker with thiazide diuretics produces a clinically beneficial reduction in blood pressure in patients who otherwise only partially respond to monotherapy with an angiotensin receptor blocker, blood pressure-lowering therapy with combination antihypertensive drug regimens in patients with cerebral hemodynamic impairment may adversely affect cerebral hemodynamics. The purpose of the present exploratory study was to determine whether blood pressure-lowering therapy with the combination of the angiotensin receptor blocker losartan plus hydrochlorothiazide (LPH) worsens brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease., Methods: Patients with losartan-resistant hypertension and reduced cerebrovascular reactivity (CVR) to acetazolamide due to symptomatic chronic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease were prospectively entered into the present study and received 50 mg/day of losartan plus 12.5 mg/day of hydrochlorothiazideat 14 weeks after the last ischemic event. Cerebral blood flow (CBF) and CVR were measured before and 12 weeks after initiating LPH using N-isopropyl-p-[(123)I]-iodoamphetamine single-photon emission computed tomography (SPECT). A region of interest (ROI) was automatically placed in the MCA territory on each SPECT image using a three-dimensional stereotactic ROI template., Results: None of the 18 patients who participated in the study experienced any new neurological symptoms or adverse effects related to antihypertensive drugs. Systolic (p < 0.001) and diastolic (p < 0.001) blood pressures were significantly reduced after the administration of LPH, with average reductions of 11 mm Hg in systolic blood pressure and 10 mm Hg in diastolic blood pressure. While in the affected hemisphere CBF did not differ between measurements taken before and after the administration of LPH, CVR was significantly higher after the administration of LPH than before (p = 0.007) and was significantly improved in 5 of 18 patients. In the contralateral hemisphere, CBF and CVR did not differ between measurements taken before and after the administration of LPH. There were no patients who experienced a significant deterioration in CBF or CVR in the affected or contralateral hemisphere after the administration of LPH., Conclusions: Although the present study was exploratory and its results were preliminary due to the small sample size, the current data suggest that blood pressure-lowering therapy with LPH apparently does not result in worsening of cerebral hemodynamics in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic ICA or MCA steno-occlusive disease., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: Data on the prevalence, treatment and control of hypertension in patients with advanced chronic kidney disease (CKD) are limited. This study aimed to examine the above factors in a cohort of predialysis patients., Methods: During a period of 4 months, we recorded information on blood pressure (BP), comorbidities, medications and related parameters of patients followed up in the Low-Clearance Clinic of our Department. Control rates of hypertension were calculated at two thresholds: <130/80 and <140/90 mm Hg. Univariate and multiple linear regression analyses were employed to assess factors associated with BP control., Results: In the population studied [n = 238, males 58.4%, age 66.21 ± 4.2 years (mean ± SD), estimated glomerular filtration rate 14.5 ± 4.8 ml/min/1.73 m(2)], the prevalence of hypertension was 95.0%. Treatment rate among hypertensives was at 99.1%. On average, 3.04 ± 1.32 antihypertensive drugs were used, ranging from 1 to 7 agents. BP control rates at the <130/80 and <140/90 mm Hg thresholds were 26.5% and 48.2%, respectively. The systolic goal was achieved in 31.0% and 50.4%, whereas the diastolic goal was achieved in 67.7% and 91.2% of patients, respectively. In multivariate analysis, only black race was independently and inversely related with hypertension control (β = -0.187, p = 0.030). No specific antihypertensive class showed independent associations with control., Conclusions: Hypertension is highly prevalent in predialysis CKD patients. An almost universal treatment, employing a multi-agent regime, can help towards improved rates of control. Systolic BP is the main barrier to successful control and black race is associated with poorer control rates., (Copyright © 2012 S. Karger AG, Basel.)

Background: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia., Aims: To review the long-term treatment of NSIAD., Methods: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports., Results: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient., Conclusions: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion., (Copyright © 2012 S. Karger AG, Basel.)

Background: Blood pressure (BP) reduction in patients with chronic kidney disease (CKD), particularly with a renin-angiotensin system inhibitor (RASI), commonly leads to an initial decrease in glomerular filtration rate. The current clinical guideline, based on studies with single RASIs, is to tolerate an increase in the serum creatinine only up to 30%. This guideline has aptly guided CKD care for over a decade, but should be updated in the contemporary context of more aggressive RASI and diuretic use., Methods: This study is a retrospective review of 48 mostly African-American patients with CKD treated with multiple and/or high-dose renin-angiotensin system (RAS) inhibition and diuretics, targeting both low BP and reduction of urine protein. RASI was not reduced in response to initial increases in serum creatinine greater than 30%., Results: A clinically well-tolerated increase in serum creatinine over 30% during the first year occurred in 41% of the patients. Treatment was unaltered, and target goals for BP and urine protein were typically achieved. After the point of maximal serum creatinine in the first year, these patients had minimal progression of disease over the next 6 years, with a long-term estimated glomerular filtration rate slope of only -0.52 ml/min/year/1.73 m(2). Only 25% progressed to end-stage renal disease or death., Conclusion: The 30% limitation to initial increases in the serum creatinine still pertains for single RASI at usual doses. However, favorable long-term outcomes suggest that initial increases over 30% should be tolerated in the context of dual goal-directed, more aggressive RASI and diuretic use., (Copyright © 2012 S. Karger AG, Basel.)

The aim of this study was to investigate whether continuous hemodiafiltration (CHDF) with a high-performance membrane dialyzer made of polymethylmethacrylate (PMMA-CHDF) in the treatment of septic shock patients with acute renal failure (ARF) is clinically relevant. 30 patients were treated with PMMA-CHDF. 13 patients treated with CHDF used a hemofilter made of polyacrylonitrile membrane (PAN-CHDF). Systolic blood pressure significantly increased in the PMMA-CHDF group following 24 h of treatment (p < 0.01), whereas it did not improve in the PAN-CHDF group. Urine volume significantly increased in the PMMA-CHDF group following 24 h of treatment which was more than in the PAN-CHDF group (p < 0.05). 28-day survival was 83.3% in the PMMA-CHDF group and 30.8% in the PAN-CHDF group, respectively (p < 0.01). We can assume that PMMA-CHDF in the treatment of septic shock patients with ARF is clinically relevant., (Copyright © 2011 S. Karger AG, Basel.)

In the US and Europe, approximately 90% of heart failure (HF) hospitalizations are due to symptoms and signs of sodium and fluid excess. Congestion is associated with HF progression. According to data from large national registries, approximately 40% of hospitalized HF patients are discharged with unresolved congestion, which may contribute to unacceptably high rehospitalization rates. Diuretics reduce the symptoms and signs of fluid overload, but their effectiveness can be reduced by excess salt intake, underlying chronic kidney disease, renal adaptation to their action, and neurohormonal activation. In addition, the production of hypotonic urine limits the ability of loop diuretics to reduce total body sodium. Ultrafiltration is the mechanical removal of fluid from the vasculature. Clinical studies of ultrafiltration have shown that removal of isotonic fluid relieves symptoms of congestion, improves cardiac filling pressures and exercise capacity, and restores diuretic responsiveness in patients with diuretic resistance, concomitantly with favorable effects on pulmonary function, ventilatory efficiency, and neurohormonal activation. Ultrafiltration has been shown to reduce rehospitalizations in a randomized controlled trial of patients with decompensated HF. Future larger controlled clinical trials should evaluate the effect of ultrafiltration on survival., (Copyright © 2011 S. Karger AG, Basel.)

Intravenous fluids are commonly administered to patients with developing septic acute kidney injury (AKI). Conversely, fluids are just as commonly removed with diuretics or renal replacement therapy (RRT) techniques or ultrafiltration in patients with cardiorenal syndromes (CRS). In both groups, there is controversy regarding fluid management. However, in patients with septic AKI, the deleterious consequences of overzealous fluid therapy are increasingly being recognized, while concerns exist both about the possible adverse effects of excessive and/or insufficient fluid removal with diuretics or ultrafiltration in CRS. In this article, we discuss how interstitial edema can further delay renal recovery and why conservative fluid strategies are now being advocated in septic AKI. In patients with septic AKI, this strategy might require RRT to be given earlier to assist with fluid removal. However, in patients with either septic AKI or CRS, hypovolemia and renal hypoperfusion can occur if excessive fluid removal is pursued with diuretics or extracorporeal therapy. Thus, accurate assessment of fluid status and careful definition of targets are needed to improve clinical outcomes. Controlled studies of conservative versus liberal fluid management in patients with AKI or CRS seem justified., (2010 S. Karger AG, Basel.)

Diuretics are the most commonly used drugs to treat clinically diagnosed fluid overload in patients with heart failure. There is no conclusive evidence that they alter major outcomes such as survival to hospital discharge or time in hospital compared to other therapies. However, they demonstrably achieve fluid removal in the majority of patients, restore dry body weight, improve the breathlessness of pulmonary edema and are unlikely to be subjected to a large double-blind randomized controlled trial in this setting because of lack of equipoise. The effective and safe use of diuretics requires physiological understanding of the pharmacokinetics and pharmacodynamics of diuretic therapy, an appreciation of the clinical goals of diuretic therapy, the application of physiological targeting of dose, an understanding of the effects of hemodynamic impairment on their ability to achieve fluid removal, an appreciation of the effects of combinations of different diuretics in patients refractory to single agents and an understanding of the most common side effects of such therapy. The use of continuous infusions of loop diuretics, sometimes combined with carbonic anhydrase inhibitors and/or aldosterone antagonists and/or thiazide diuretics can prove particularly effective in patients with advanced heart failure. Such therapy often requires more intensive monitoring than available in medical wards. If diuretic therapy fails to achieve its clinical goals, ultrafiltration by semipermeable membranes is reliably effective in achieving targeted fluid removal. The combination of diuretic therapy and/or ultrafiltration can achieve volume control in essentially all patients with heart failure., (Copyright (c) 64\C S. Karger AG, Basel.)

Ultrafiltration is the mechanical removal of fluid from the vasculature. Hydrostatic pressure is applied to blood across a semipermeable membrane to separate isotonic plasma water from blood. Because solutes in blood freely cross the semipermeable membrane, large amounts of fluid can be removed at the discretion of the treating physician without affecting any change in the serum concentration of electrolytes and other solutes. Ultrafiltration has been used to relieve congestion in patients with heart failure for almost four decades. In contrast to the adverse physiological consequences of loop diuretics, numerous studies have demonstrated favorable responses to ultrafiltration. Such studies have shown that removal of large amounts of isotonic fluid relieves symptoms of congestion, improves exercise capacity, improves cardiac filling pressures, restores diuretic responsiveness in patients with diuretic resistance, and has a favorable effect on pulmonary function, ventilatory efficiency, and neurohormonal activation. Ultrafiltration is the only fluid removal strategy shown to improve outcomes in randomized controlled trials of patients hospitalized with decompensated heart failure., (2010 S. Karger AG, Basel.)

Fluid balance management in pediatric critically ill patients is a challenging task, since fluid overload (FO) in the pediatric ICU is considered a trigger of multiple organ dysfunction. In particular, the smallest patients with acute kidney injury are at highest risk to develop severe interstitial edema, capillary leak syndrome and FO. Several studies previously showed a statistical difference in the percentage of FO among children with severe renal dysfunction requiring renal replacement therapy. For this reason, in children priority indication is currently given to the correction of water overload. If this concept is so important in the critically ill small children, where capillary leak syndrome is a dramatic manifestation, it has probably been underestimated in critically ill adults and only recently re-evaluated. The present review will shortly describe nutrition strategies in critically ill children, it will discuss dosages, benefits and drawbacks of diuretic therapy, and alternative diuretic/nephroprotective drugs currently proposed in the pediatric setting. Finally, specific modalities of pediatric extracorporeal fluid removal will be presented. Fluid management, furthermore, is not only the discipline of removing water: it should also address the way to optimize fluid infusions and, above all, one of the most important fluids infused to all ICU patients with renal dysfunction: parenteral nutrition., (Copyright 2010 S. Karger AG, Basel.)