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BACKGROUND Fatigue is an important symptom for many patients, including patients with kidney disease. Cognitive biases, such as attentional bias and self-identity bias, are thought to influence fatigue. Cognitive bias modification (CBM) training is a promising technique to counter fatigue. OBJECTIVE We aimed to evaluate a CBM training among patients with kidney disease and health care professionals (HCPs) and assess acceptability and applicability in the clinical setting using an iterative design process to evaluate expectations and experiences with the training. METHODS This was a longitudinal, qualitative, and multiple stakeholder–perspective usability study in which we interviewed end users and HCPs during the prototyping phase and after the end of training. We conducted semistructured interviews with 29 patients and 16 HCPs. The interviews were transcribed and analyzed thematically. Next to a general evaluation of the training, the acceptability of the training was evaluated using the Theoretical Framework of Acceptability, and applicability was assessed by evaluating obstacles and solutions for implementation in the kidney care setting. RESULTS Generally, participants were positive about the training and its applicability. The biggest negatives were doubts about effectiveness and annoyance about the repetitive character of CBM. Acceptability was judged with a mixed evaluation, with a negative evaluation of perceived effectiveness; mixed results for burden, intervention coherence, and self-efficacy; and positive results for affective attitude, ethicality, and opportunity costs. Barriers for applicability were patients’ varying computer skills, subjectivity of fatigue, and integration with regular treatment (eg, the role of HCPs). Possible solutions included assigning representatives among nurses, offering training on an app, and providing assistance via a help desk. The iterative design process, including repeated waves of testing user expectations and experiences, yielded complementary data. CONCLUSIONS To the best of our knowledge, this study is the first to introduce a CBM training targeting fatigue. Furthermore, this study provides one of the first user evaluations of a CBM training, both among patients with kidney disease and their care providers. Overall, the training was evaluated positively, although acceptability showed mixed results. Applicability was positive although barriers were identified. The proposed solutions require further testing, preferably following the same frameworks, as the iteration in this study contributed positively to the quality of the training. Therefore, future research should follow the same frameworks and consider stakeholders and end users in eHealth intervention design.

Supplemental Digital Content is available in the text., RAASi (renin-angiotensin-aldosterone system inhibitors) are suggested as possible treatment option in the early phase of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. A meta-analysis investigating the possible detrimental effects of RAASi on the severity of (SARS-CoV-2) infection showed that ambulatory use of RAASi, by hospitalized patients, has a neutral effect. It is, however, conceivable that this observation is biased by the fact that antihypertensive medications, are often discontinued at or during admission in hospitalized patients with SARS-CoV-2. We, therefore, investigated the effect of discontinuation of antihypertensive medications, in hospitalized patients with SARS-CoV-2. We performed a retrospective observational study on 1584 hospitalized patients with SARS-CoV-2 from 10 participating hospitals in the Netherlands. Differences in the outcome (severity of disease or death) between the groups in which medications were either continued or discontinued during the course of hospitalization were assessed using logistic regression models. Discontinuation of angiotensin receptor blockers, ACE (angiotensin-converting enzyme) inhibitors and β-blockers, even when corrected for sex, age, and severity of symptoms during admission, resulted in a 2 to 4× higher risk of dying from SARS-CoV-2 infection (odds ratio [95% CI]); angiotensin receptor blockers 2.65 [1.17–6.04], ACE inhibitor (2.28 [1.15–4.54]), and β-blocker (3.60 [1.10–10.27]). In conclusion, discontinuation of at-home ACE inhibitor, angiotensin receptor blockers, or β-blocker in patients hospitalized for a SARS-CoV-2 infection was associated with an increased risk of dying, whereas discontinuation of calcium channel blockers and diuretics was not.

Background Angiotensin II type 1 receptor blockers (ARBs) lower blood pressure (BP) and proteinuria and reduce renal disease progression in many—but not all—patients. Reduction of dietary sodium intake improves these effects of ARBs. Dietary potassium intake affects BP and proteinuria. We set out to address the effect of potassium intake on BP and proteinuria response to losartan in non-diabetic proteinuric chronic kidney disease (CKD) patients. Methods We performed a post hoc analysis of a placebo-controlled interventional cross-over study in 33 non-diabetic proteinuric patients (baseline mean arterial pressure and proteinuria: 105 mmHg and 3.8 g/day, respectively). Patients were treated for 6 weeks with placebo, losartan and losartan/hydrochlorothiazide (HCT), combined with a habitual (∼200 mmol/day) and low-sodium (LS) diet ( Results Mean potassium intake was stable during all six treatment periods. Losartan and losartan/HCT lowered BP and proteinuria in all treatment groups. Patients with high potassium intake showed no difference in the BP effects compared with patients with low potassium intake. The antiproteinuric response to losartan monotherapy and losartan combined with HCT during the habitual sodium diet was significantly diminished in patients with high potassium intake (20% versus 41%, P = 0.011; and 48% versus 64%, P = 0.036). These differences in antiproteinuric response abolished when shifting to the LS diet. Conclusions In proteinuric CKD patients, the proteinuria, but not BP-lowering response to losartan during a habitual high-sodium diet was hampered during high potassium intake. Differences disappeared after sodium status change by LS diet.

Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes, and examines associations between patient characteristics and employment status.We performed a cross-sectional survey study in nine nephrology outpatient clinics in the Netherlands among working age (18-67 years) CKD Stage G3b-G5, dialysis and transplant patients (n = 634; mean age 53.4 years (SD 10); 53% male; 47% Stage G3b-G5, 9% dialysis, 44% transplantation). We assessed employment status, work disability, work-related characteristics (i.e., work situation, working hours, job demands), work functioning (i.e., perceived ability to work, productivity loss, limitations in work), work environment (i.e., work accommodations, psychosocial work environment), as well as health status and fatigue.Sixty-five percent were employed reporting moderate work ability. Of those, 21% received supplementary work disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Work accommodations included reduced working hours, working at a slower pace, adjustment of work tasks or work schedule, and working from home. Multivariable analysis of sustained employment showed associations with younger age, male gender, higher level of education, better general and physical health and pre-emptive transplantation. Transplant patients had the highest work ability and highest expectation to maintain work. Dialysis patients had the highest productivity loss and perceived the most limitations regarding functioning in work. Stage G3b-G5 patients reported the lowest social support from colleagues and highest conflict in work and private life.Employed CKD patients experience difficulties regarding functioning in work requiring adjustment of work or partial work disability. In addition to dialysis patients, stage G3b-G5 patients are vulnerable concerning sustained employment and work functioning.

Introduction Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes, and examines associations between patient characteristics and employment status. Methods We performed a cross-sectional survey study in nine nephrology outpatient clinics in the Netherlands among working age (18–67 years) CKD Stage G3b-G5, dialysis and transplant patients (n = 634; mean age 53.4 years (SD 10); 53% male; 47% Stage G3b-G5, 9% dialysis, 44% transplantation). We assessed employment status, work disability, work-related characteristics (i.e., work situation, working hours, job demands), work functioning (i.e., perceived ability to work, productivity loss, limitations in work), work environment (i.e., work accommodations, psychosocial work environment), as well as health status and fatigue. Results Sixty-five percent were employed reporting moderate work ability. Of those, 21% received supplementary work disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Work accommodations included reduced working hours, working at a slower pace, adjustment of work tasks or work schedule, and working from home. Multivariable analysis of sustained employment showed associations with younger age, male gender, higher level of education, better general and physical health and pre-emptive transplantation. Transplant patients had the highest work ability and highest expectation to maintain work. Dialysis patients had the highest productivity loss and perceived the most limitations regarding functioning in work. Stage G3b-G5 patients reported the lowest social support from colleagues and highest conflict in work and private life. Conclusions Employed CKD patients experience difficulties regarding functioning in work requiring adjustment of work or partial work disability. In addition to dialysis patients, stage G3b-G5 patients are vulnerable concerning sustained employment and work functioning.

Background: Among persons with type 1 diabetes mellitus (T1DM) low concentrations of magnesium have been reported. Previous (small) studies also suggested a relation of hypomagnesemia with (poor) glycaemic control and complications. We aimed to investigate the magnitude of hypomagnesemia and the associations between magnesium with parameters of routine T1DM care in a population of unselected outpatients. Methods: As part of a prospective cohort study, initially designed to measure quality of life and oxidative stress, data from 207 patients with a mean age of 45 [standard deviation (SD) 12] years, 58% male, diabetes duration 22 [interquartile range (IQR) 16, 31] years and glycated haemoglobin (HbA1c) of 60 (SD 11) mmol/mol [7.6 (SD 1.0)%] were examined. Hypomagnesemia was defined as a concentration below Results: Mean magnesium concentration was 0.78 (SD 0.05) mmol/l. A deficiency was present in 4.3% of participants. Among these persons, mean concentration was 0.66 (SD 0.03) mmol/l. There was no correlation between magnesium and HbA1c at baseline ( r = –0.014, p = 0.843). In multivariable analysis, free thiols (reflecting the degree of oxidative stress) were significantly and negatively associated with magnesium concentrations. Conclusion: In this cohort of T1DM outpatients, the presence of hypomagnesemia was infrequent and, if present, relative mild. Magnesium was not associated with glycaemic control nor with presence of micro- and macrovascular complications. Although these results need confirmation, in particular the negative association of magnesium with free thiols, this suggests that hypomagnesemia is not a relevant topic in routine care for people with T1DM.

IntroductionDiabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM) characterized by hyperglycemia and metabolic acidosis. Hypophosphatemia in DKA often occurs during hospital admittance for DKA. Literature on the magnitude, determinants and consequences of hypophosphatemia in DKA is scarce. Primary aim of this study was to investigate the incidence and consequences of hypophosphatemia during hospitalisation for DKA.Research design and methodsCohort study among individuals with T1DM who were admitted for DKA between 2005 and 2020 in an academic and a non-academic hospital. Multivariate regression models were performed to investigate determinants of the lowest phosphate during the treatment of DKA.ResultsA total of 127 episodes of DKA among 80 individuals were identified. Age at DKA presentation was 28 (22–46) years, 45% of the cases was female, diabetes duration was 13.2 (8.9–25.5) years with glycosylated hemoglobin levels of 91.9±26.2 mmol/mol. In 9% of all cases, DKA was the first presentation of T1DM. Lowest phosphate levelss reported during the treatment phase were 0.54 (0.32–0.83) mmol/L and hypophosphatemia was present in 74% (62/84). The time to lowest phosphate was 16 (8–23) hours. In multivariate analysis, baseline bicarbonate and hemoglobin at admission were significantly associated with the lowest phosphate level reported. No adverse effects of hypophosphatemia on hospital stay duration, morbidity or mortality were found, even if left untreated.ConclusionsHypophosphatemia during DKA is common and increases with severe acidosis. However, in this study it was not related to adverse outcomes. Although limitations of this retrospective study should be taken into account, the routine and repeated measurement of phosphate levels in DKA could be reconsidered, provided that possible symptoms related to hypophosphatemia are monitored.

Background: Serum calcification propensity can be monitored using the maturation time of calciprotein particles in serum (T50 test). A shorter T50 indicates greater propensity to calcify; this is an independent determinant of cardiovascular disease. As the intraperitoneal (IP) route of insulin administration mimics the physiology more than the subcutaneous (SC) route in persons with type 1 diabetes (T1DM), we hypothesized that IP insulin influences determinants of calcium propensity and therefore result in a longer T50 than SC insulin administration. Methods: Prospective, observational case-control study. Measurements were performed at baseline and at 26 weeks in age and gender matched persons with T1DM. Results: A total of 181 persons, 39 (21.5%) of which used IP and 142 (78.5%) SC insulin were analysed. Baseline T50 was 356 (45) minutes. The geometric mean T50 significantly differed between both treatment groups: 367 [95% confidence interval (CI) 357, 376] for the IP group and 352 (95% CI 347, 357) for the SC group with a difference of –15 (95% CI –25, –4) minutes, in favour of IP treatment. In multivariable analyses, the IP route of insulin administration had a positive relation on T50 concentrations while higher age, triglycerides and phosphate concentrations had an inverse relation. Conclusion: Among persons with T1DM, IP insulin administration results in a more favourable calcification propensity time then SC insulin. It has yet to be shown if this observation translates into improved cardiovascular outcomes.

Aims: Increased vascular calcification could be an underlying mechanism of cardiovascular complications in type 1 diabetes mellitus (T1DM). Calcification propensity can be monitored by the maturation time of calciprotein particles in serum (T-50 test). A high calcification propensity (i.e. low T-50-value) is an independent determinant of mortality in various populations. Aim was to investigate T-50 levels with indices of calcium metabolism and disease status in T1DM patients.Methods: As part of a prospective cohort study, T1DM patients were examined annually. At baseline T-50 was determined in 216 (77%) patients (57% male) with a mean age of 45 (12) years, diabetes duration 22 [15.8, 30.4] years and HbA1c of 60 (12) mmol/mol (7.6 (1.0) %). Baseline data were collected in 2002 and follow-up data were collected in 2018.Results: The T-50 time was normally distributed with a mean of 339 (60) minutes. Patients in the highest tertile of T-50 (range 369-466) were older, had lower phosphate and PTH and higher magnesium and vitamin D concentrations as compared to the middle (range 317-368) and lowest (range 129-316) tertiles, while eGFR was comparable between groups. During follow-up of 15 years, 43 patients developed a macrovascular complication and 26 patients died. In regression analysis, T-50 was not a prognostic factor for the development of complications or mortality.Conclusions: The T-50 time was associated with indices of increased mineral stress, but not with the development of long-term macrovascular complications. (C) 2019 Elsevier B.V. All rights reserved.

ObjectivesInsight in the prescribing quality for patients with chronic kidney disease (CKD) in secondary care is limited. The aim of this study is to assess the prescribing quality in secondary care patients with CKD stages 3–5 and possible differences in quality between CKD stages.DesignThis was a retrospective cohort study.SettingData were collected at two university (n=569 and n=845) and one non-university nephrology outpatient clinic (n=1718) in the Netherlands.ParticipantsBetween March 2015 and August 2016, data were collected from patients with stages 3a–5 CKD seen at the clinics. Blood pressure measurements, laboratory measurements and prescription data were extracted from medical records. For each prescribing quality indicator, patients with incomplete data required for calculation were excluded.Outcome measuresPotentially appropriate prescribing of antihypertensives, renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, phosphate binders and potentially inappropriate prescribing according to prevailing guidelines was assessed using prescribing quality indicators. Χ2or Fisher’s exact tests were used to test for differences in prescribing quality.ResultsRAAS inhibitors alone or in combination with diuretics (57% or 52%, respectively) and statins (42%) were prescribed less often than phosphate binders (72%) or antihypertensives (94%) when indicated. Active vitamin D was relatively often prescribed when potentially not indicated (19%). Patients with high CKD stages were less likely to receive RAAS inhibitors but more likely to receive statins when indicated than stage 3 CKD patients. They also received more active vitamin D and erythropoietin-stimulating agents when potentially not indicated.ConclusionsPriority areas for improvement of prescribing in CKD outpatients include potential underprescribing of RAAS inhibitors and statins, and potential overprescribing of active vitamin D. CKD stage should be taken into account when assessing prescribing quality.

Highlights • Serum thiols are a marker of oxidative stress. • High serum thiols are associated with better glycemic control and less complications in T2DM. • Free thiols have limited capability for the prediction of long-term complications., Aims Oxidative stress is a driver in the development of type 2 diabetes (T2DM) complications. As thiols (R-SH) are oxidized by reactive oxygen and sulfur species, circulating concentrations may directly reflect systemic redox status. We hypothesized that high serum R-SH concentrations are a reflection of a favourable redox status and may therefore positively associate with disease status. Methods R-SH were measured in serum of 943 T2DM outpatients (55% males, 65 years and HbA1c of 6.7% (50 mmol/mol)) with a follow-up period of 1.2 years. Results In the highest R-SH tertile patients were younger, more often men, had less microvascular complications, lower HbA1c and were more often treated nutritionally or with oral glucose-lowering drugs. Age- and sex adjusted hazard ratios for developing micro-, macro- or any complication plus death were 0.994, 0.992 and 0.993: even after adjustment for potential confounders. The Harrell’s C statistic to predict microvascular complications or any complication plus death was higher in the models with R-SH than in those without R-SH. Conclusions Although R-SH concentrations were associated with a favourable disease status, it did not add to the predictive capacity for long-term complications. Based on the current data R-SH seems unsuitable as a prognostic marker in T2DM.

IntroductionSerum calcification propensity is emerging as an independent predictor for cardiovascular outcomes in high-risk populations. Calcification propensity can be monitored by the maturation time of calciprotein particles in serum (T50 test). A low T50 value is an independent determinant of cardiovascular morbidity and mortality in various populations. Aim was to investigate the T50 and its relationship to type 2 diabetes mellitus.Research design and methodsUsing nephelometry, serum T50 was cross-sectionally measured in 932 stable patients with type 2 diabetes mellitus (55% male) with a median age of 66 (62–75) years, diabetes duration of 6.5 (3.0–10.2) years and hemoglobin A1c (HbA1c) of 49 (44–54) mmol/mol.ResultsSerum T50 was normally distributed with a mean value of 261±66 min. In linear regression, serum T50 was lower in women and current smokers. A lower T50 value was found in patients with a higher HbA1c or higher systolic blood pressure, insulin users and patients with a longer history of diabetes. The association with HbA1c was independent of other determinants in multivariable analysis. There was no association between T50 and previous macrovascular events or the presence of microvascular disease.ConclusionsSerum calcification propensity is independently associated with glycemic control, suggesting that a lower HbA1c may be associated with better cardiovascular outcomes. Retrospective analysis could not establish an association between a history of macrovascular events and T50, and prospective studies will have to be performed to address this hypothesis.Trial registration numberNCT01570140.

BackgroundUrinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy.MethodsWe measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of ≥135 µmol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria 50% reduction from baseline.ResultsSixty-nine patients were included. Median follow-up was 35 months (interquartile range 18–63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62–0.87) for kidney injury molecule-1 and 0.74 (0.62–0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome.ConclusionKidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic membranous nephropathy. They did not add prognostic value compared to measurement of either alpha-1-microglobulin or beta-2-microglobulin.

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin-angiotensin-aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF.

Objective:Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction.Methods:To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 5013 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (19449mmol Na(+/)day) or low sodium diet (102 +/- 52mmol Na+/day) on top of either lisinopril (40mg/day; single RAAS-blockade) or lisinopril plus valsartan (320mg/day; dual RAAS-blockade).Results:Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P=0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P=0.020).Conclusion:In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.

Summary. Background: Overt proteinuria is a strong risk factor for thromboembolism, owing to changes in the levels of various coagulation proteins and urinary antithrombin loss. The described coagulation disturbances in these patients are based on outdated studies conducted primarily in the 1970s and 1980s. Whether these coagulation disturbances resolve with antiproteinuric therapy has yet to be studied. Methods: At otal of 32 patients with overt proteinuria (median, 3.7 g day )1 ; interquartile range, 1.5–5.6) were enrolled in this intervention crossover trial designed to assess optimal antiproteinuric therapy with sodium restriction, losartan, and diuretics. Levels of various procoagulant and anticoagulant proteins, and parameters of two thrombin generation assays (calibrated automated thrombogram [CAT] and prothrombin fragment 1 + 2) were compared between the placebo period and the maximum antiproteinuric treatment period. As a secondary analysis, coagulation measurements of the placebo period in these patients were compared with those of 32 age-matched and sex-matched healthy controls. Results: Median proteinuria was significantly lower during the maximum treatment period (median, 0.9 g day )1 ; interquartile range, 0.6–1.4; P < 0.001) than during the placebo period. Similarly, levels of various liver-synthesized procoagulant and anticoagulant proteins, activated protein C resistance and prothrombin fragment 1 + 2 levels were significantly lower during the maximum treatment period than during the placebo period. However, von Willebrand factor and factor VIII levels were similar. On the basis of the higher levels of procoagulant proteins (fibrinogen, FV, FVIII, and von Willebrand factor) and both thrombin generation assays, patients were substantially more prothrombotic than healthy controls (P < 0.004). Conclusions: Antiproteinuric therapy ameliorates the prothrombotic state. Proteinuric patients are in a more prothrombotic state than healthy controls.

Background and objectives Connective Tissue Growth Factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra- and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD.Design, setting, participants, & measurements In a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 +/- 62 versus 93 +/- 52 mmol Na+/d).Results CTGF was elevated in plasma (464 [387 to 556] pmol/L) and urine (205 [135 to 311] pmol/24 h) of patients compared with healthy controls (n = 21; 96 [86 to 108] pmol/L and 73 [55 to 98] pmol/24 h). Urinary CTGF was lowered by antiproteinuric intervention, in proportion to the reduction of proteinuria, with normalization during triple therapy (CTGF 99 [67 to 146] in CKD versus 73 [55 to 98] pmol/24 h in controls). In contrast, plasma CTGF was not affected.Conclusions Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD. Clin J Am Soc Nephrol 6: 1845-1850, 2011. doi: 10.2215/CJN.08190910

Background. Chronic kidney disease (CKD) typically extends over decades. Longitudinal monitoring of kidney function in CKD is thus of great importance. Here, we retrospectively evaluate use of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to monitor long-term course of kidney function and to identify individuals with progressive kidney function loss.Methods. Patients were selected from our outpatient clinic for having four glomerular filtration rate measurements (mGFR, I-125-iothalamate) and at least >= 4 years of follow-up. Renal function slopes were obtained by within-individual linear regression.Results. Sixty-five nondiabetic CKD patients (40 male, mean baseline age 44 +/- 12 years) with a median (range) of 9 (4-16) mGFR measurements and a median follow-up of 11 (4-33) years were included. Both equations significantly underestimated mGFR/(BSA) at baseline and at the end of follow-up. mGFR slope was significantly underestimated by the MDRD study but not by CKD-EPI equation (slopes -1.41 +/- 2.06, -1.07 +/- 1.72 and -1.39 +/- 1.77 mL/min/1.73m(2)/year, respectively). Sensitivity and specificity to identify progressive kidney function loss (mGFR/(BSA) slope > 1.5 mL/min/1.73m(2)/ year, n = 23) were 78 and 88% for the MDRD study and 91 and 80% for CKD-EPI equation. In the subgroup of progressors, both MDRD study and CKD-EPI equation underestimated the rate of mGFR loss (P Conclusions. Long-term course of mGFR is reasonably well estimated by CKD-EPI and slightly underestimated by MDRD study equation. Patients with progressive kidney function loss may, however, not be reliably identified, so caution is warranted when using these equations in clinical practice.

Kidney injury molecule-1 (KIM-1) is a marker for renal proximal tubular damage, the hallmark of virtually all proteinuric, toxic and ischaemic kidney diseases. KIM-1 has gained increasing interest because of its possible pathophysiological role in modulating tubular damage and repair. In this respect, it is interesting that the best biomarkers often turn out to be important in modulation of damage and some even become therapeutic targets. The emphasis of this review is on structural and biochemical aspects of KIM-1, its expression pattern and its pathophysiological role in renal disease. We also discuss the prognostic impact of KIM-1 in relation to urinary protein excretion. Glomerular (proteinuria) and interstitial markers (KIM-1) might have independent prognostic impact and so may provide independent treatment targets. Finally, the potential of KIM-1 as biomarker of renal damage, as a predictor of renal function decline and its perspectives for monitoring therapy response, are discussed.

Contains fulltext : 81723.pdf (Publisher’s version ) (Closed access) BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression. METHODS: Six weeks after the induction of AN, rats were treated with vehicle (n = 8), lisinopril (75 mg/L, n = 10), spironolactone (3.3 mg/day, n = 12) or the combination of lisinopril and spironolactone (n = 14) for 12 weeks. Age-matched healthy rats served as controls (n = 6). After 18 weeks, renal heparanase and heparan sulfate (HS) expression were examined by immunofluorescence staining. In addition, the effect of aldosterone, AngII and ROS on heparanase expression in cultured podocytes was determined. RESULTS: Treatment with lisinopril, spironolactone or their combination significantly blunted the increased glomerular heparanase expression and restored the decreased HS expression in the GBM. Addition of aldosterone to cultured podocytes resulted in a significantly increased heparanase mRNA and protein expression, which could be inhibited by spironolactone. Heparanase mRNA and protein expression in podocytes were also significantly increased after stimulation with AngII or ROS. CONCLUSIONS: Our in vivo and in vitro results show that not only AngII and ROS, but also aldosterone is involved in the regulation of glomerular heparanase expression.

Objective: Dyslipidemia contributes to increased cardiovascular risk in nephrotic syndrome. We questioned whether reduction in proteinuria not only lowers low-density lipoprotein cholesterol (LDL-C), but also high-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) mass and whether changes in HDL-C were related to changes in plasma adiponectin. Methods: Thirty-two non-diabetic proteinuric patients (12 on statin therapy), were followed during two double blind 6-week periods of placebo and treatment (low sodium + 100mg losartan + 25 mg hydrochlorothiazide). Results: With placebo HDL-C was lower but LDL-C and CETP were not different in proteinuric patients compared with matched controls. LDL-C, HDL-C and CETP decreased upon proteinuria reduction. The decrease in LDL-C correlated with the drop in CETP and the degree of proteinuria reduction. HDL-C also decreased in proportion to proteinuria lowering. Individual changes in HDL-C were correlated with changes in adiponectin. Conclusion: LDL-C lowering upon robust reduction of proteinuria may be affected by changes in plasma CETP mass, but this treatment also decreases HDL-C in relation to the degree of proteinuria reduction. This adverse effect on HDL-C may in part be attributable to changes in adiponectin.

Background: Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels.Study Design: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial.Setting & Participants: 34 proteinuric patients without diabetes from our outpatient renal clinic.Intervention: Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet.Outcomes & Measurements: Urinary excretion of KIM-1, total protein, and N-acetyl-beta-D-glucosaminidase (NAG) as a positive control for tubular injury.Results: Mean baseline urine protein level was 3.8 +/- 0.4 (SE) g/d, and KIM-1 level was 1,706 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 388 ng/d; P = 0.04), losartan/high sodium (1,184 +/- 296 ng/d; P = 0.09), losartan/LS (921 +/- 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 +/- 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 +/- 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P Limitations: Post hoc analysis.Conclusions: Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria. Am J Kidney Dis 53:16-25. (C) 2008 by the National Kidney Foundation, Inc.

Background. Advanced glycation end products (AGEs) are involved in diabetic nephropathy (DN). The AGE formation inhibitor pyridoxamine (PM) is renoprotective in DN and in normoglycaemic obese Zucker rats. In chronic allograft nephropathy (CAN), renal AGE accumulation occurs as well.Methods. To investigate whether inhibition of AGE formation is renoprotective in CAN, we studied the Fisher 344 to Lewis (F-L) allograft rat model of experimental CAN. Fisher to Fisher (F-F) isografts served as controls. Proteinuria, renal function and renal histology of untreated transplanted rats (F-L n = 8, F-F n = 8) were compared to rats receiving PM 2 g/l in drinking water for 20 weeks starting at transplantation (F-L n = 5, F-F n = 10). All rats received cyclosporin A (1.5 mg/kg/day) for 10 days after transplantation to prevent early acute rejection.Results. Compared to untreated allografts, PM significantly decreased proteinuria (76 +/- 18 vs 29 +/- 3 mg/ day), serum creatinine (130 +/- 12 vs 98 +/- 5 mu mol/l), focal glomerulosclerosis (116 +/- 27 vs 16 +/- 5 AU), glomerular macrophage influx (5.6 +/- 0.6 vs 3.3 +/- 1.0), interstitial fibrosis (132 +/- 24 vs 76 +/- 2 AU) and interstitial macrophage influx (47.0 +/- 8.7 vs 15.4 +/- 5.0. Moreover, PM significantly ameliorated tubular accumulation of pentosidine, compared to untreated allografts (2.5 +/- 0.6 vs 0.3 +/- 0.3, all p Conclusion. PM exerts renoprotective effects and decreases renal pentosidine accumulation in experimental CAN, suggesting a detrimental role for renal AGE accumulation in the pathogenesis of renal damage in this non-diabetic model. These results indicate that inhibition of AGE formation might be a useful adjunct therapy to attenuate CAN.

Background— No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients. Methods and Results— A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42±18 years) were enrolled. Mean follow-up was 10±9 years. Nephrotic syndrome was defined by proteinuria ≥3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P =0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE ( P ≤0.02). Conclusions— This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE.

Background/Aims: Advanced glycation end products (AGEs) are involved in diabetic nephropathy. The AGE inhibitor pyridoxamine (PM) is renoprotective in experimental chronic allograft nephropathy supporting its potential in non-diabetic renal damage. Methods: We studied the effects of PM in adriamycin nephropathy (AN; 1.5 mg/kg i.v.). Six weeks after disease induction, treatment started with vehicle (VEH), lisinopril (ACEi; 75 mg/l drinking water), PM (2 g/l) and PM + lisinopril (PM/ACEi) (n = 12 per group) for 18 weeks. Age-matched healthy rats (n = 6) served as controls (CON). Results: ACEi reduced proteinuria, blood pressure, and renal damage. PM gradually increased blood pressure and not affected proteinuria. In PM/ACEi the antiproteinuric and blood pressure-lowering effects of ACEi were abrogated during long-term treatment. Remarkably, creatinine, focal glomerulosclerosis and interstitial fibrosis were considerably increased under PM/ACEi. Pronounced hypercholesterolemia, which occurred in both PM-treated groups, was accompanied by marked glomerular lipid deposition. Conclusion: PM was not renoprotective in AN. By contrast, renal damage was aggravated when PM was combined with ACEi. Despite the fact that there is no current evidence that these findings apply to the drug as used in human diabetic nephropathy, we emphasize the importance of close monitoring of blood pressure, lipids and possible direct toxic effects in future studies with PM in renal patients, especially when combining PM with ACEi.

Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p

Background. Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking.Methods. Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry.Results. Renal pentosidine was elevated in untreated AN (0.14 +/- 0.04 mu mol/mol valine) vs healthy controls (0.04 +/- 0.01 mu mol/mol valine, P Conclusion. Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease.

Mesangial accumulation of GA-pyridine, a novel glycolaldehyde-derived AGE, in human renal disease. Background Advanced glycation end products (AGEs) contribute to diabetic and atherosclerotic end-organ damage, but the mechanisms of AGE-formation and AGE-induced damage are unclear. Glycolaldehyde (GA) is a Maillard-reaction intermediate and can be formed by reaction of L-serine with the myeloperoxidase-system. GA reacts with proteins to form AGEs, such as GA-pyridine, which is specific for protein modification by GA. GA-pyridine accumulates in human atherosclerotic lesions. As atherosclerosis and progressive glomerulosclerosis share many similarities, we hypothesized that GA-pyridine accumulates in renal diseases, especially those with prominent mesangial involvement. Methods Paraffin-embedded renal biopsies from 55 patients with various renal diseases, as well as control tissue, obtained from the unaffected part of kidneys from 10 patients with renal cell carcinoma were immunohistochemically stained with a monoclonal antibody directed against GA-pyridine and were scored semiquantitatively. Additional sections were scored for mesangial matrix expansion (MME) and focal glomerular sclerosis (FGS). Results In normal human kidneys, GA-pyridine was mainly localized in tubular epithelial cells, but not in the glomerular mesangium. Significant mesangial GA-pyridine accumulation was found in disorders with mesangial involvement as a common denominator. In contrast, mesangial GA-pyridine accumulation was less prominent in renal diseases without prominent mesangial involvement. Moreover, mesangial GA-pyridine accumulation was more pronounced in kidneys with higher MME and FGS scores across the different diagnoses. Conclusion GA-pyridine accumulates in the mesangium in human renal disease, in particular in disorders with mesangial involvement. Further studies should elucidate whether mesangial GA-pyridine plays a role in the progression of glomerular damage.

Objective LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin–kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. Methods Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m 2 , proteinuria 1.9 [0.9–3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na + /day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3–1.1] g/day ( P Results Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161–314] vs. 143 [113–190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline ( R = 0.399, P = 0.018) and at maximal antiproteinuric treatment ( R = 0.525, P = 0.001), but did not decrease during proteinuria reduction ( P = 0.84). Individual changes in total cholesterol ( R = 0.365, P = 0.024), non-HDL cholesterol ( R = 0.333, P = 0.041), and LDL cholesterol ( R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment ( P = 0.04). Conclusion Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects.

Background. Renin angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both under- and overtitration of sodium targeting can easily occur. We evaluated whether N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of volume expansion, predicts the benefits of sodium targeting in CKD patients.Methods. In a cross-over randomized controlled trial, 33 non-diabetic CKD patients (proteinuria 3.8 +/- 0.4 g/24 h, blood pressure 143/86 +/- 3/2 mmHg, creatinine clearance 89 +/- 5 mL/min) were treated during 6-week periods with placebo, angiotensin receptor blockade (ARB; losartan 100 mg/day) and ARB plus diuretics (losartan 100 mg/day plus hydrochlorothiazide 25 mg/day), combined with LS (93 +/- 52 mmol Na+/24 h) and regular sodium diet (RS; 193 +/- 62 mmol Na+/24 h, P Results. NT-proBNP was elevated in patients during placebo + RS [90 (60-137) versus 35 (27-45) pg/mL in healthy controls, P = 0.001]. NT-proBNP was lowered by LS, ARB and diuretics and was normalized by ARB + diuretic + LS [39 (26-59) pg/mL, P = 0.65 versus controls]. NT-proBNP levels above the upper limit of normal (>125 pg/mL) predicted a larger reduction of blood pressure and proteinuria by LS and diuretics but not by ARB, during all steps of the titration regimen.Conclusions. Elevated NT-proBNP levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of sodium targeting, but not RAAS blockade, in proteinuric CKD patients. Importantly, this applies to the untreated condition, as well as to the subsequent treatment steps, consisting of RAAS blockade and even RAAS blockade combined with diuretics. NT-proBNP can be a useful tool to identify CKD patients in whom sodium targeting can improve blood pressure and proteinuria.

Item does not contain fulltext BACKGROUND: The variable course of immunoglobulin A nephropathy (IgAN) warrants accurate tools for the prediction of progression. Urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are markers for the detection of early tubular damage caused by various renal conditions. We evaluated the prognostic value of these markers in patients with IgAN. METHODS: We included patients (n = 65, 72% male, age 43 +/- 13 years) with biopsy-proven IgAN, who were evaluated for proteinuria. Urinary KIM-1 and NGAL were measured by enzyme-linked immunosorbent assay. We analysed data using Cox regression for the outcome end-stage renal disease (ESRD). RESULTS: Median serum creatinine was 142 mumol/L and proteinuria 2.2 g/day. During follow-up (median 75 months), 23 patients (35%) developed ESRD. In patients with IgAN median urinary KIM-1 excretion was 1.7 ng/min and NGAL excretion was 47 ng/min, both significantly higher than in healthy controls. KIM-1 and NGAL were correlated with proteinuria (r = 0.40 and 0.34, respectively, P < 0.01) and each other (r = 0.53, P < 0.01) but not with estimated glomerular filtration rate (eGFR). Interestingly, KIM-1 was not significantly correlated with the excretion of alpha(1)-microglobulin (alpha(1)m) and beta(2)-microglobulin (beta(2)m), known markers of tubular injury. Univariate analysis showed that baseline serum creatinine and urinary excretion of total protein, alpha(1)m, beta(2)m, immunoglobulin G, KIM-1 and NGAL were significantly associated with ESRD. By multivariate analysis, serum creatinine and KIM-1 excretion proved to be significant independent predictors of ESRD. CONCLUSION: KIM-1 and NGAL excretion are increased in patients with IgAN and correlate with proteinuria but not with eGFR. Baseline serum creatinine and urinary KIM-1, but not proteinuria, are independent predictors of ESRD.

Aldosterone, a steroid hormone with mineralocorticoid activity, is far more than merely a salt-and-water hormone. Aldosterone has a number of non-classical, mineralocorticoid receptor (MR)-mediated actions, including tissue remodeling, modulation of vascular tone and stimulating inflammation and fibrosis, which may fuel progression of end organ damage. Aldosterone breakthrough during blockade of the renin-angiotensin aldosterone system (RAAS) may explain why this treatment regimen only confers partial cardiovascular and renal protection. Of major interest, aldosterone is deleterious only if inappropriately high for its sodium status i.e. high aldosterone and high sodium. The mechanism of sodium dependence of aldosterone-induced renal and cardiovascular damage continues to fascinate. Aldosterone excess increases sodium and fluid retention and consequently increases blood pressure, which, in turn, mediates target organ damage. Moreover, blood pressure independent effects play a role with dissociation of low circulating and high tissue aldosterone levels during high sodium intake and possibly enhanced MR signaling. MR blockade is a valuable strategy, which has potency to halt the progressive end organ damage as observed during current treatments. In heart failure, MR blockade on top of RAAS blockade reduces hard clinical endpoints. Despite encouraging results on the intermediate endpoint proteinuria, long-term data on the efficacy and safety of MR blockade in preventing dialysis and/or cardiovascular endpoints in chronic kidney disease are still lacking. It is obligatory that future clinical studies on the effects of MR blockade on end-organ damage take into account the sodium status.

Renin-angiotensin-aldosterone system (RAAS) blockade improves prognosis in renal patients, but usually requires diuretic co-treatment. RAAS blockade can decrease erythropoietin (EPO) and/or haemoglobin (Hb) levels. Diuretics decrease EPO in rodents, but their effect on EPO and Hb in humans is unknown. Proteinuric renal patients with preserved renal function were treated during 6-week periods with placebo, losartan 100 mg/day (LOS) and LOS plus hydrochlorothiazide 25 mg/day (LOS/HCT), in random order. Hb was inversely related to proteinuria, and EPO levels were inappropriately low in relation to Hb. Hb was lowered by LOS with and without HCT. EPO was decreased by LOS/HCT, but not by LOS. EPO and Hb are reduced by HCT added to LOS in proteinuric renal patients with preserved renal function. We hypothesize that EPO reduction by HCT is caused by a decrease in renal oxygen requirement, which is the main stimulus for EPO production, due to the inhibition of active tubular sodium reabsorption. Further studies should explore the exact mechanism of this phenomenon and its clinical impact

Kidney injury molecule-1 (KIM-1) is a marker for renal proximal tubular damage, the hallmark of virtually all proteinuric, toxic and ischaemic kidney diseases. KIM-1 has gained increasing interest because of its possible pathophysiological role in modulating tubular damage and repair. In this respect, it is interesting that the best biomarkers often turn out to be important in modulation of damage and some even become therapeutic targets. The emphasis of this review is on structural and biochemical aspects of KIM-1, its expression pattern and its pathophysiological role in renal disease. We also discuss the prognostic impact of KIM-1 in relation to urinary protein excretion. Glomerular (proteinuria) and interstitial markers (KIM-1) might have independent prognostic impact and so may provide independent treatment targets. Finally, the potential of KIM-1 as biomarker of renal damage, as a predictor of renal function decline and its perspectives for monitoring therapy response, are discussed.

Waanders F, Rienstra H, Walther Boer M, Zandvoort A, Rozing J, Navis G, van Goor H, Hillebrands JL. Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats. Am J Physiol Renal Physiol 296: F1072-F1079, 2009. First published February 25, 2009; doi:10.1152/ajprenal.90643.2008.-Chronic transplant dysfunction (CTD) is the leading cause of long-term renal allograft loss and is characterized by specific histological lesions including transplant vasculopathy, interstitial fibrosis, and focal glomerulosclerosis. Increasing evidence indicates that aldosterone is a direct mediator of renal damage via the mineralocorticoid receptor (MR). The MR antagonist spironolactone is renoprotective in native chronic kidney disease, but its effects on CTD are unknown. We studied the effects of spironolactone treatment on CTD development in the Dark Agouti-to-Wistar-Furth renal allograft transplant model, by treatment with 20 mg/kg spironolactone or vehicle daily by oral gavage from 2 days before transplantation (donors and recipients) throughout the experiment (12 wk, recipients). Dark Agouti-to-Dark Agouti isografts served as negative controls. Spironolactone significantly ameliorated the development of transplant vasculopathy in allografts by reducing the number of affected intrarenal arteries. In addition, spironolactone treatment showed a trend toward reduced proteinuria and focal glomerulosclerosis, and significantly reduced glomerular macrophage influx. However, spironolactone treatment did not affect interstitial fibrosis, interstitial macrophage influx, creatinine clearance, and systolic blood pressure. We conclude that spironolactone selectively ameliorates transplant vasculopathy and glomerular lesions in renal CTD in rats. These results suggest that spironolactone may have renoprotective potential as an adjunct treatment in renal transplantation to ameliorate CTD.

Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol 296: F1314-F1322, 2009. First published April 1, 2009; doi: 10.1152/ajprenal.90755.2008.-Endothelial progenitor cells (EPC) contribute to repair and maintenance of the vascular system, but in patients with chronic kidney disease (CKD), the number and function of EPC may be affected by kidney dysfunction. We assessed numbers and the angiogenic function of EPC from patients with CKD in relation to disease progression. In a cross-sectional, prospective study, 50 patients with varying degrees of CKD, including 20 patients undergoing dialysis and 10 healthy controls, were included. Mononuclear cells were isolated, and circulating EPC were quantified by flow cytometry based on expression of CD14 and CD34. EPC were cultured on fibronectin-coated supramolecular films of oligocaprolactone under angiogenic conditions to determine their angiogenic capacity and future use in regenerative medicine. CKD patients had normal numbers of circulating CD14(+) EPC but reduced numbers of circulating CD34(+) EPC. Furthermore, EPC from patients with CKD displayed functional impairments, i.e., hampered adherence, reduced endothelial outgrowth potential, and reduced antithrombogenic function. These impairments were already observed at stage 1 CKD and became more apparent when CKD progressed. Dialysis treatment only partially ameliorated EPC impairments in patients with CKD. In conclusion, EPC number and function decrease with advancing CKD, which may hamper physiological vascular repair and can add to the increased risk for cardiovascular diseases observed in CKD patients.

There is large interindividual variability in the antiproteinuric response to blockade of the renin-angiotensin-aldosterone system (RAAS). A low-sodium diet or addition of diuretics enhances the effects of RAAS blockade on proteinuria and BP, but the efficacy of the combination of these interventions is unknown. Therefore, this randomized, double-blind, placebo-controlled trial to determine the separate and combined effects of a low-sodium diet and hydrochlorothiazide (HCT) on proteinuria and BP was performed. In 34 proteinuric patients without diabetes, mean baseline proteinuria was 3.8 g/d, and this was reduced by 22% by a low-sodium diet alone. Losartan monotherapy reduced proteinuria by 30%, and the addition of a low-sodium diet led to a total reduction by 55% and the addition of HCT to 56%. The combined addition of HCT and a low-sodium diet reduced proteinuria by 70% from baseline (all P

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.