Measuring Albuminuria in Individuals With Obesity: Pitfalls of the Urinary Albumin-Creatinine Ratio.

An increased urinary albumin excretion rate is an important early risk factor for chronic kidney disease and other major outcomes and is usually measured using the urinary albumin-creatinine ratio (ACR). Obesity is highly prevalent in the general and chronic kidney disease populations and is an independent risk factor for moderately increased albuminuria (henceforth, moderate albuminuria). In this review, we describe how the ACR was developed and used to define moderate albuminuria. We then investigate how biases related to urinary creatinine excretion are introduced into the ACR measurement and how the use of the 30-mg/g threshold decreases the performance of the test in populations with higher muscle mass, with a primary focus on why and how this occurs in the obese population. The discussion then raises several strategies that can be used to mitigate such bias. This review provides a comprehensive overview of the medical literature on the uses and limitations of ACR in individuals with obesity and critically assesses related issues. It also raises into question the widely accepted 30-mg/g threshold as universally adequate for the diagnosis of moderate albuminuria. The implications of our review are relevant for clinicians, epidemiologists, and clinical trialists.

Obesity-Related Glomerulopathy: Clinical Management.

Obesity-related glomerulopathy (ORG) and other obesity-associated kidney diseases pose a major challenge to the treating nephrologist. We review the benefits of weight loss and optimal management of ORG and kidney disease in the setting of obesity. Therapeutic strategies in ORG were limited mainly in the past to weight loss through lifestyle interventions and bariatric surgery, antihypertensive treatment, and renin-angiotensin-aldosterone system blockade. Current approaches to obtain the desired weight loss include novel pharmacologic therapies that have been approved for the treatment of diabetes while offering kidney protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1-receptor agonists. This review focuses on the nephroprotective role of the renin-angiotensin-aldosterone system blockade and of these new pharmacologic agents, and on the renal effects of bariatric surgery in chronic kidney disease.

Microalbuminuria After Kidney Transplantation Predicts Cardiovascular Morbidity.

Background: Microalbuminuria is a well-characterized marker of kidney malfunction, both in diabetic and non-diabetic populations, and is used as a prognostic marker for cardiovascular morbidity and mortality. A few studies implied that it has the same value in kidney transplanted patients, but the information relies on spot or dipstick urine protein evaluations, rather than the gold standard of timed urine collection. Methods: We revisited a cohort of 286 kidney transplanted patients, several years after completing a meticulously timed urine collection and assessed the prevalence of major cardiovascular adverse events (MACE) in relation to albuminuria. Results: During a median follow up of 8.3 years (IQR 6.4-9.1) 144 outcome events occurred in 101 patients. By Kaplan-Meier analysis microalbuminuria was associated with increased rate of CV outcome or death (p = 0.03), and this was still significant after stratification according to propensity score quartiles (p = 0.048). Time dependent Cox proportional hazard analysis showed independent association between microalbuminuria and CV outcomes 2 years following microalbuminuria detection (HR 1.83, 95% CI 1.07-2.96). Conclusions: Two years after documenting microalbuminuria in kidney transplanted patients, their CVD risk was increased. There is need for primary prevention strategies in this population and future studies should address the topic.

Association of obesity and muscle mass with risk of albuminuria in renal transplant recipients.

BACKGROUND: Increased albuminuria is a predictor of graft loss in kidney graft recipients. It is unknown whether obesity is an independent risk factor for the development of increased albuminuria in this population. The aim of this study was to elucidate the association between obesity and albuminuria in renal transplant recipients. METHODS: We enrolled 330 renal transplant recipients and prospectively collected demographic, anthropomorphic, clinical and laboratory variables susceptible to influence albumin excretion. The outcome was albuminuria, measured using accurately timed urine collections. Data from 201 patients were analyzed after exclusion of participants with missing data and patients enrolled less than 6 months since renal transplantation. Analysis was carried out for an early and a late period, defined according to the 2.4-year median follow-up time. RESULTS: Body mass index (BMI), waist circumference and urinary creatinine excretion rate were independent predictors of albuminuria in the late post-transplant period, indicating that the predictive value of body mass index for albuminuria is related to both increased abdominal fat mass and increased muscle mass. BMI was an independent predictor of microalbuminuria. Waist circumference and urinary creatinine were independent predictors of microalbuminuria for values above certain cutoffs: 110% of the accepted thresholds defining abdominal obesity and 1500 mg/day, respectively. CONCLUSIONS: These associations, which have not previously been reported, suggest, but do not prove, that an imbalance between metabolic demand and nephron mass may be responsible for increased albuminuria in the renal transplant population.

Consequences of Glomerular Hyperfiltration: The Role of Physical Forces in the Pathogenesis of Chronic Kidney Disease in Diabetes and Obesity.

BACKGROUND: Glomerular hyperfiltration (GH) is a hallmark of renal dysfunction in diabetes and obesity. Recent clinical trials demonstrated that SGLT2 inhibitors are renoprotective, possibly by abating hyperfiltration. The present review considers the current evidence for a cause-to-effect relationship between hyperfiltration-related physical forces and the development of chronic kidney disease (CKD). SUMMARY: Glomerular hyperfiltration is associated with glomerular and tubular hypertrophy. Hyperfiltration is mainly due to an increase in glomerular capillary pressure, which increases tensile stress applied to the capillary wall structures. In addition, the increased ultrafiltrate flow into Bowman's space heightens shear stress on the podocyte foot processes and body surface. These mechanical stresses lead to an increase in glomerular basement membrane (GBM) length and to podocyte hypertrophy. The ability of the podocyte to grow being limited, a mismatch develops between the GBM area and the GBM area covered by foot processes, leading to podocyte injury, detachment of viable podocytes, adherence of capillaries to parietal epithelium, synechia formation and segmental sclerosis. Mechanical stress is also applied to post-filtration structures, resulting in dilation of glomerular and tubular urinary spaces, increased proximal tubular sodium reabsorption by hypertrophied epithelial cells and activation of mediators leading to tubulointerstitial inflammation, hypoxia and fibrosis Key Messages: GH-related mechanical stress leads to both adaptive and maladaptive glomerular and tubular changes. These flow-related effects play a central role in the pathogenesis of glomerular disease. Attenuation of hyperfiltration is thus an important therapeutic target in diabetes and obesity-induced CKD.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation.

PURPOSE: High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. METHODS: All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. RESULTS: A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3-5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71-4.62, p = 0.218 and HR 1.08, 95% CI 0.39-2.99, p = 0.780) in univariate and multivariate analyses, respectively. CONCLUSIONS: Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

Post renal transplant anemia: severity, causes and their association with graft and patient survival.

BACKGROUND: Post transplantation anemia (PTA) is common among kidney transplant patients. PTA is associated with increased graft loss and in most studies with increased mortality. However, the effect of the severity of anemia on this associations was not thoroughly evaluated. METHODS: Patients who underwent kidney transplantation in Rabin Medical Center (RMC) were included in the study. Data were collected during the years 2002-2016. Anemia was defined as hemoglobin (Hb) level less than 12 g/dL in women and less than 13 g/dL in men, in accordance with World Health Organization (WHO) criteria. Severe anemia was defined as hemoglobin lower than 11 g/dL. Primary outcome was a composite of patient and graft survival. We used univariate and multivariate models to evaluate association between severity and specific causes of anemia with the outcomes. As the risk associated with anemia changed over time we analyzed the risk separately for the early and the late period (before and after 1251 days). RESULTS: Our cohort included 1139 patients, 412 (36.2%) of which had PTA and 134 (11.7%) had severe anemia. On multivariable analysis, severe anemia was highly associated with the primary outcome at the early period (HR 6.26, 95% CI 3.74-10.5, p < 0.001). Anemia due to either AKI & acute rejection (11.9% of patients) or infection (16.7%), were associated with primary outcome at the early period (HR 9.32, 95% CI 5.3-26.41, p < 0.001 and HR 3.99, 95% CI 2.01-7.95, p < 0.001, respectively). There was non-significant trend for association between anemia due to Nutritional deficiencies (29.1%) and this outcome (HR 3.07, 95% CI 0.93-10.17, p = 0.067). CONCLUSION: PTA is associated with graft loss and mortality especially during the first three years. Anemia severity affects this association. An anemia workup is recommended for PTA.

The effect of cause, timing, kidney function recovery, and recurrent events on the prognosis of acute kidney injury in kidney transplant recipients.

AIM: To assess the incidence of acute kidney injury (AKI) and its common etiologies in kidney transplant recipients and the effect of AKI's characteristics on graft survival. METHODS: In a retrospective longitudinal cohort study, all serum creatinine (SCr) values of patients that had kidney transplantation between 01/2002-12/2010 were retrieved. AKI was defined as a 50% increase in SCr. Etiologies, recurrence, timing, and kidney function dynamics during the event were evaluated. The primary endpoint was defined as graft loss. Time-varying Cox model was used for the analysis. RESULTS: Of 659 patients, 208 (31.6%) patients had 321 documented AKI events. Of these, 138 (66.4%) patients had one event, and 70 (33.6%) patients had recurrent events. The leading etiologies of the first AKI event were as follows: infection (33.4%), hypovolemia (14.3%), and unknown etiology (16.8%). Both first and recurrent AKI events were associated with an increased risk of graft loss (HR: 2.76, 95% CI: 1.95-3.89) and (HR: 4.54, 95% CI: 2.59-7.93), respectively. This deleterious association was lower within three months after transplantation, compared to later events. Patients in whom kidney function returned to baseline were less prone to graft loss. CONCLUSIONS: Late-onset, incomplete recovery, and recurrent AKI events are associated with increased graft loss.

Transcatheter aortic valve implantation versus conservative treatment in chronic kidney disease patients.

AIMS: There are no studies comparing transcatheter aortic valve implantation (TAVI) to conservative management in patients with chronic kidney disease stage 3-5 and severe aortic stenosis. We sought to compare the mortality rate and change in renal function in this patient population. METHODS AND RESULTS: This was a single-centre retrospective cohort study that included all patients with chronic kidney disease stage 3-5 and severe aortic stenosis who underwent TAVI or were treated conservatively between 2010 and 2015. Three hundred and sixty patients were included (162 TAVI and 198 conservatively treated patients). Several statistical methods were used, including propensity score matching and inverse probability weighting. Mean follow-up was 1.9 years. Conservative management was associated with a hazard ratio of 3.95 (95% CI: 2.59-6.02) for mortality compared with TAVI. After one year there was a significant decrease in renal function in the control group (39.6±13.9 ml/min to 34.4±15.3 ml/min), but not in the TAVI group (41.7±13 ml/min to 42.9±14.5 ml/min) (p-value=0.001). CONCLUSIONS: TAVI is associated with improved survival in patients with aortic stenosis and chronic kidney disease stage 3-5 compared to conservative management and protects from further decline in renal function up to one-year follow-up.

Familial Mediterranean Fever Is Associated With Increased Mortality After Kidney Transplantation-A 19 Years' Single Center Experience.

BACKGROUND: Current data regarding the outcome of kidney transplantation in patients with familial Mediterranean fever (FMF) who reach end-stage renal disease (ESRD) due to reactive amyloidosis A (AA) are scarce and inconclusive. METHODS: The outcomes of 20 patients with FMF and biopsy-proven AA amyloidosis that were transplanted between 1995 and 2014 were compared with 82 control patients (32 with diabetes mellitus and 50 with nondiabetic kidney disease). Major outcome data included overall patient and graft survivals. RESULTS: During a mean overall follow-up of 116.6 ± 67.5 months 11 patients (55%) with FMF died versus 26 patients (31%) in the control group. Median time of death for patients with FMF was 61 months (range, 16-81) after transplantation. Estimated 5-year, 10-year, and actuarial 15-year overall patients survival rates were 73%, 45%, and 39%, respectively, for patients with FMF, versus 84%, 68% and 63%, respectively, for the control group (P = 0.028). FMF was associated with more than twofold increased risk for death after transplantation, and with a threefold increased risk for hospitalization because of infections during the first year. Infections and cardiovascular disease were the cause of death in the majority of patients with FMF. Overall graft survival was similar between the groups. Recurrence of AA amyloidosis was diagnosed in 2 patients during the first year after transplantation. CONCLUSIONS: FMF is associated with increased risk of mortality after kidney transplantation.

The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation.

PURPOSE: Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. METHODS: We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. RESULTS: Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation. CONCLUSION: Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.

Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation.

Background: The variability of tacrolimus blood levels has been shown to be associated with inferior graft survival. However, the effect of variability during the early post-transplantation period has not been evaluated. We sought to evaluate the association between time-weighted variability in the early post-transplantation period and graft survival. We also explored the interaction between drug level variability and exposure to inadequate drug levels. Methods: This retrospective cohort study included all patients who underwent kidney transplantation in the Rabin Medical Center and were treated with tacrolimus. Time-weighted coefficient of variability (TWCV) was defined as time-weighted standard deviation divided by the mean drug level. Univariate and multivariate Cox proportional hazard model was used with the primary outcome of patients and graft survival. Results: The study population included 803 patients who underwent kidney transplantation between 1 January 2000 and 29 September 2013. The high tertile of TWCV of tacrolimus blood levels was associated with reduced graft survival by univariate and multivariate analyses [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.14-2.53, P = 0.01 and HR 1.74, 95% CI 1.14-2.63, P = 0.01, respectively]. The interaction between high TWCV and exposure to inadequately low drug levels was significantly associated with reduced survival (P = 0.004), while the interaction between TWCV and high drug blood levels was not. One hundred and thirty patients (16.2%) had the combination of high TWCV and exposure to low drug values (<5 ng/mL). These patients had reduced graft survival by univariate and multivariate analyses (HR 2.42, 95% CI 1.57-3.74, P < 0.001 and HR 2.6, 95% CI 1.65-4.11, P < 0.001, respectively). Conclusions: The combination of high TWCV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period.

Angiotensin converting-enzyme inhibition restores glomerular glycosaminoglycans in rat puromycin nephrosis.

BACKGROUND: Aberrant glomerular polyanionic charge of glycosaminoglycans (GAGs) and sialic acid expression has been observed in proteinuric human and experimental glomerular diseases. Angiotensin-converting enzyme inhibitors (ACEI) lower proteinuria and amend renal function deterioration via hemodynamic mechanisms. We tested the hypothesis that ACEI modulate proteinuria additionally by modifying glomerular GAGs. METHODS: In this study, we explored the effects of the ACEI enalapril on proteinuria and GAG synthesis in puromycin aminonucleoside (PAN)-treated rats. We employed cationic colloidal gold (CCG) localization in glomerular basement membranes (GBM) to identify GAGs by electron microscopy and determined sialic acid residues by immunohistochemical staining with lectins. To clarify ACEI effects on GAG production in vitro, we studied de novo GAG synthesis into newly synthesized proteoglycans in podocytes and mesangial cells using 35S incorporation. Cells were incubated with or without PAN, and with increasing doses of the ACEI enalaprilat. RESULTS: PAN rats developed severe proteinuria that was significantly improved by enalapril treatment. In non-treated PAN rats GBM GAGs were reduced, whereas in the enalapril-treated group GBM GAGs were significantly increased to control levels. Enalapril did not affect glomerular sialic acid. Furthermore, in cultured podocytes and mesangial cells PAN decreased de novo GAG synthesis, an effect which was significantly ameliorated by enalaprilat treatment. CONCLUSION: Treatment with ACEI improves permselectivity properties of the glomerular capillary wall by maintaining its GAG content. This finding provides an additional new mechanism, whereby ACEI exert anti-proteinuric effects.

Cytomegalovirus-negative kidney transplant recipients are at an increased risk for malignancy after kidney transplantation.

BACKGROUND: The effect of cytomegalovirus (CMV) serology status on malignancy risk in kidney transplanted patients is not clear yet. METHODS: In a nested case-control study, CMV serology status was compared between patients with a malignancy and 2:1 matched control patients without a malignancy. In a cohort study, the hazard of malignancy was compared between patients that were CMV-negative but had a CMV-positive donor and other patients, using Cox analysis. RESULTS: Fifty-two of 599 patients transplanted in our center between 2001 and 2014 developed a malignancy. Nine (17.3%) of the 52 patients that developed cancer were CMV-negative but had a-CMV-positive donor compared with 6 (5.8%) of the 104 matched control patients (odd ratio 3.42, 95% confidence interval [CI] 1.15-10.2, P=.021). By univariate Cox model, there was a trend toward increased cancer risk in CMV-negative patients with a positive donor (hazard ratio [HR] 1.95, 95% CI 0.95-4.0, P=.07), but after adjusting for multiple covariates, CMV-negative status was significantly associated with increased risk of cancer (HR 2.55, 95% CI 1.23-5.26; P=.012). CONCLUSIONS: CMV-negative patients that had a CMV-positive donor were found to have a higher risk of malignancy after kidney transplantation.

Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.

Effect of Acetazolamide on Obesity-Induced Glomerular Hyperfiltration: A Randomized Controlled Trial.

AIMS: Obesity is an important risk factor for the development of chronic kidney disease. One of the major factors involved in the pathogenesis of obesity-associated kidney disease is glomerular hyperfiltration. Increasing salt-delivery to the macula densa is expected to decrease glomerular filtration rate (GFR) by activating tubuloglomerular feedback. Acetazolamide, a carbonic anhydrase inhibitor which inhibits salt reabsorption in the proximal tubule, increases distal salt delivery. Its effects on obesity-related glomerular hyperfiltration have not previously been studied. The aim of this investigation was to evaluate whether administration of acetazolamide to obese non diabetic subjects reduces glomerular hyperfiltration. MATERIALS AND METHODS: The study was performed using a randomized double-blind crossover design. Obese non-diabetic men with glomerular hyperfiltration were randomized to receive intravenously either acetazolamide or furosemide at equipotent doses. Twelve subjects received the allocated medications. Two weeks later, the same subjects received the drug which they had not received during the first study. Inulin clearance, p-aminohippuric acid clearance and fractional lithium excretion were measured before and after medications administration. The primary end point was a decrease in GFR, measured as inulin clearance. RESULTS: GFR decreased by 21% following acetazolamide and did not decrease following furosemide. Renal vascular resistance increased by 12% following acetazolamide, while it remained unchanged following furosemide administration. Natriuresis increased similarly following acetazolamide and furosemide administration. Sodium balance was similar in both groups. CONCLUSIONS: Intravenous acetazolamide decreased GFR in obese non-diabetic men with glomerular hyperfiltration. Furosemide, administered at equipotent dose, did not affect GFR, suggesting that acetazolamide reduced glomerular hyperfiltration by activating tubuloglomerular feedback. TRIAL REGISTRATION: ClinicalTrials.gov NCT01146288.

The very old on hemodialysis: 8 years' experience in a single unit.

BACKGROUND: Elderly patients constitute a significant proportion of chronically dialyzed patients. This study evaluated mortality rates and predictors of mortality among very old patients receiving chronic hemodialysis (HDx). METHODS: A single-center retrospective analysis was carried out on patients >84 years of age who started chronic dialysis between 2004 and 2012. Univariate and multivariate analyses determined which parameters predicted survival. RESULTS: Twenty-nine hemodialyzed patients (19 males) were studied. Mean age was 88 ± 3 years. Median survival time was 38 months (range 4-96). One-year and 2-year survival probability was 80 and 65%, respectively. The most common cause of death was complicated peripheral vascular disease. Multivariate analysis revealed the following: for each 1 g/dl decrease in serum albumin level, the hazard ratio for patient death was 2.63 (p = 0.017), and for each weekly HDx treatment time decrease of 1 h, the hazard ratio for patient death was 1.40 (p = 0.006). CONCLUSION: Very elderly patients can be hemodialyzed with cautious optimism.

Proximal tubular hypertrophy and enlarged glomerular and proximal tubular urinary space in obese subjects with proteinuria.

BACKGROUND: Obesity is associated with glomerular hyperfiltration, increased proximal tubular sodium reabsorption, glomerular enlargement and renal hypertrophy. A single experimental study reported an increased glomerular urinary space in obese dogs. Whether proximal tubular volume is increased in obese subjects and whether their glomerular and tubular urinary spaces are enlarged is unknown. OBJECTIVE: To determine whether proximal tubules and glomerular and tubular urinary space are enlarged in obese subjects with proteinuria and glomerular hyperfiltration. METHODS: Kidney biopsies from 11 non-diabetic obese with proteinuria and 14 non-diabetic lean patients with a creatinine clearance above 50 ml/min and with mild or no interstitial fibrosis were retrospectively analyzed using morphometric methods. The cross-sectional area of the proximal tubular epithelium and lumen, the volume of the glomerular tuft and of Bowman's space and the nuclei number per tubular profile were estimated. RESULTS: Creatinine clearance was higher in the obese than in the lean group (P=0.03). Proteinuria was similarly increased in both groups. Compared to the lean group, the obese group displayed a 104% higher glomerular tuft volume (P=0.001), a 94% higher Bowman's space volume (P=0.003), a 33% higher cross-sectional area of the proximal tubular epithelium (P=0.02) and a 54% higher cross-sectional area of the proximal tubular lumen (P=0.01). The nuclei number per proximal tubular profile was similar in both groups, suggesting that the increase in tubular volume is due to hypertrophy and not to hyperplasia. CONCLUSIONS: Obesity-related glomerular hyperfiltration is associated with proximal tubular epithelial hypertrophy and increased glomerular and tubular urinary space volume in subjects with proteinuria. The expanded glomerular and urinary space is probably a direct consequence of glomerular hyperfiltration. These effects may be involved in the pathogenesis of obesity-related renal disease.

Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone.

BACKGROUND: The incidence of left ventricular hypertrophy (LVH) in primary aldosteronism (PA) is higher than in essential hypertension. LVH is an independent cardiovascular risk factor. Treatment of PA with mineralocorticoid receptor blockers (MRBs) improves LVH. Previous studies included relatively small groups, low incidence of LVH and used high MRB dose. We tested the hypothesis that long-term regression of LVH in PA/low-renin hypertension may be achieved with low-dose MRB. METHODS: Forty-eight patients (male/female 28/20, age 61.4 years, range 47-84) had PA (low renin, high aldosterone and high aldosterone/renin ratio, n=24) or low-renin hypertension (low renin, normal aldosterone and high aldosterone/renin ratio, n=24). All had either LVH or concentric remodelling. All had an echocardiogram both at baseline and at 1 year after the initiation of spironolactone. A subgroup of 29 patients had an echocardiogram at baseline, 1 year (range 0.5-1.5) and 3 years (range 1.8-7). RESULTS: At baseline, spironolactone was commenced in all patients. The dose was 33.3±13.7 and 29.0±11.7 mg/day at 1 year and 3 years, respectively. A total of 73% of the patients received ≤37.5 mg/day. Introduction of spironolactone enabled the reduction of other antihypertensive medications (from 2.6±1.2 to 1.5±1.0 at 1 year). At 1 year, systolic and diastolic blood pressure decreased (149.3±14.1 to 126.2±12.0 mmHg, P<0.001, and 88.2±9.8 to 78.3±7.1 mmHg, P<0.001, respectively). At baseline, LVH was present in 39 of the 48 (81%) patients, and concentric remodelling, i.e. increased relative wall thickness (RWT) with a normal left ventricular mass index (LVMI), in 36 (75%). At 1 year, LVMI decreased in 44 of the 48 (92%) patients (142.9±25.4 versus 117.7±20.4 g/m2, P<0.001). LVH normalized in 16 of the 39 (41%) patients. RWT normalized in 36% of the patients. The changes in blood pressure and LVMI did not correlate. At 3 years, LVH decreased further and normalized in 57% of the patients. CONCLUSIONS: In patients with PA/low-renin hypertension, long-term regression of LVH may be achieved with low-dose MRB.

Changes in inflammatory markers during a hemodialysis session and their relation to vascular access type.

PURPOSE: In an attempt to better understand the relationship between vascular access and inflammation we assessed the effect of vascular access on inflammatory markers changes during hemodialysis (HD) session. METHODS: Fifty HD patients were included: 23 patients with central venous catheters (CVC) and 27 patients with arteriovenous fistulas (AVF). Blood samples for high sensitivity C-reactive protein (hsCRP), Interleukin 6 (IL-6), and Tumor Necrosis Factor α (TNF α) were collected before and after HD session. The outcome was the change in the inflammatory markers during the dialysis. RESULTS: Predialysis hsCRP levels were high in 70% of patients, without differences between the groups. Predialysis values were also similar in the two groups for IL-6 and TNF α. There was no increase in hsCRP values following HD and no difference between the change from baseline values in the CVC and AVF groups (-0.01±0.09 mg/dL and -0.01±0.13 mg/dL, respectively [P=.95]). IL-6 values increased during the HD session in the AVF group and non-significantly decreased in the CVC group. The change from baseline values was statistically significantly greater in the AVF group compared to the CVC group (0.76±1.44 ng/mL and -0.52±1.66 ng/mL, respectively, P=.006). TNF α values were significantly decreased in the CVC group and were not changed in the AVF group. The decrease from baseline values was not different between the groups. CONCLUSIONS: Chronic inflammation is present in most HD patients. No increase in pro-inflammatory parameters was seen after a HD session in patients treated via CVC or AVF.