Avry Chagnac

The effects of weight loss on renal function in patients with severe obesity.

Severe obesity is associated with increased renal plasma flow (RPF) and glomerular filtration rate (GFR). The aim of the present study was to examine whether weight loss may reverse glomerular dysfunction in obese subjects without overt renal disease. Renal glomerular function was studied in eight subjects with severe obesity (body mass index [BMI] 48.0 +/- 2.4) before and after weight loss. Nine healthy subjects served as controls. GFR and RPF were determined by measuring inulin and PAH clearance. In the obese group, GFR (145 +/- 14 ml/min) and RPF (803 +/- 39 ml/min) exceeded the control value by 61% (90 +/- 5 ml/min, P = 0.001) and 32% (610 +/- 41 ml/min, P < 0.005), respectively. Consequently, filtration fraction was increased. Mean arterial pressure, although normal, was higher than in the control group (101 +/- 4 versus 86 +/- 2 mmHg, P < 0.01). After weight loss, BMI decreased by 32 +/- 4%, to 32.1 +/- 1.5 (P = 0.001). GFR and RPF decreased to 110 +/- 7 ml/min (P = 0.01) and 698 +/- 42 ml/min (P < 0.02), respectively. Albumin excretion rate decreased from 16 microg/min (range, 4 to 152 microg/min) to 5 microg/min (range, 3 to 37 microg/min) (P < 0.01). Fractional clearance of albumin decreased from 3.2 x 10(-6) (range, 1.1 to 23 x 10(-6)) to 1.2 x 10(-6) (range, 0.5 to 6.8 x 10(-6)) (P < 0.02). This study shows that obesity-related glomerular hyperfiltration ameliorates after weight loss. The improvement in hyperfiltration may prevent the development of overt obesity-related glomerulopathy.

Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption

BACKGROUND Obesity is associated with hypertension and glomerular hyperfiltration. A major mechanism responsible for the obesity-associated hypertension is renal salt retention. An increased glomerular filtration fraction (FF) is expected to raise postglomerular oncotic pressure and to increase proximal tubular sodium reabsorption. The aim of the present study was to verify whether obesity-associated hyperfiltration leads to increased postglomerular oncotic pressure and increased proximal sodium reabsorption. METHODS Twelve obese subjects (BMI >36) and 19 lean subjects participated in the study. They underwent measurement of glomerular filtration rate (GFR), renal plasma flow (RPF) and fractional excretion of lithium (FE Li). RESULTS GFR, RPF and FF were 61%, 28% and 29% higher, respectively, in the obese than in the control group (P < 0.00001 for GFR, P < 0.005 for RPF and P < 0.00005 for FF). Half of the obese group had increased FF with increased GFR, while the other half had normal FF with high-normal or increased GFR. Postglomerular oncotic pressure was 13% higher (P < 0.03) and FE Li was 33% lower (P < 0.005) in the obese group with high FF than in the lean group. Postglomerular oncotic pressure and FE Li were normal in the obese group with normal FF. CONCLUSIONS These results suggest that glomerular hyperfiltration may lead to increased proximal tubular sodium reabsorption in the obese.

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.

Lean body mass normalizes the effect of obesity on renal function

Descriptors of body size and renal function are the most important covariates in pharmacokinetic studies. Several methods can be used to estimate glomerular filtration rate (GFR) [1], the most common being Cockcroft and Gault [2]. Studies of GFR in the obese population have shown both increases in GFR [3] and no change [4]. Methods based on creatinine (see for an overview [5]) may overestimate GFR due to its active secretion. In contrast, inulin is considered an accurate measure of GFR [6]. We hypothesize that GFR, when scaled by lean body weight, will not be different between obese and non-obese subjects. GFR data were obtained from a previous study [7] undertaken at Tel Aviv University Medical School, Israel by one of the co-authors (A.C.). The dataset comprised 17 patients (seven male and 10 female), ranging in age from 23 to 46 years, of whom nine (three male and six female) were normal weight [body mass index (BMI) 30 kg m−2). All patients had normal serum creatinine concentration. GFR was determined by inulin clearance, which was 145 ± 38.5 ml min−1 (mean ± SD) and 89.8 ± 15.3 ml min−1 in the obese and lean population, respectively. The obese patients underwent gastroplasty after the initial renal function tests. Measurements of GFR were repeated at least 12 months after surgery and were 109.9 ± 20.6 ml min−1. Only two individuals in the postsurgery obesity group achieved a BMI of <30 kg m−2; the remaining six individuals, although achieving significant reductions in body mass, remained above the BMI cut-off. This provided 11 observations in the lean group (nine originally lean and two obese who became lean) and 14 observations in the obese group (eight originally obese and repeated measures on six who remained obese). The non-normalized values of GFR were compared between obese and non-obese individuals, as were GFR values when normalized by total body weight and lean body mass (see Figure 1). Lean body mass was calculated using the method of Janmahasatian [8], which is a function of total body weight, height and sex. Statistical comparisons were performed using repeated measures analysis of variance. Figure 1 Box plots of glomerular filtration rate (GFR) for lean and obese subjects. In all figures there were 11 observations of GFR from lean subjects (nine from the original lean patients and two from patients who were obese and became lean after surgery) and ... The (non-normalized) GFR values were higher by 42% in the obese compared with non-obese patients (P = 0.003) (Figure 1a) and 36% lower (P = 0.002) in obese than normal weight individuals when normalized by total body weight. In contrast, when normalizing GFR by lean body mass, there was no apparent difference in the GFR between obese and control individuals (P = 0.27) (Figure 1c). Renal function, as defined by GFR, is increased in the obese population. Normalizing GFR to total body weight (to produce ml min−1 kg−1) results in overcompensation of the effects and the conclusion that obese patients have a lower GFR (per kg) than non-obese patients. This suggests that the increase in excess adipose tissue does not contribute entirely to an increase in renal function. In contrast, normalizing GFR by lean body mass appears to explain ‘apparent’ differences between obese and non-obese individuals. Indeed, further support for the benefit of normalizing by lean mass was gained when the index variable, BMI, was randomly reassigned (thereby eliminating the true influence of obesity) in the data and the analysis re-performed many times. If lean body mass was seen as an appropriate descriptor then no dataset generated under this method should show a statistically significant difference between the reclassified ‘lean’ and ‘obese’ patients. No statistical differences in GFR when normalised by lean body mass were evident in any of the randomised datasets. In conclusion, it appears that renal function is closely related to lean body mass, which should be used in preference to total body weight for estimating creatinine clearance.

Non-Occlusive Mesenteric Ischemia in Chronically Dialyzed Patients: A Disease with Multiple Risk Factors

Background: Non-occlusive mesenteric ischemia (NOMI) can be a fatal complication in dialysis patients. Intradialytic hypotension is usually the precipitating factor. The occurrence of 16 cases in 5 years (1998–2002), compared with only 4 in previous years, led us to investigate other risk factors contributing to NOMI. A control group of stable hemodialysis patients was used for comparison. Results: 20 patients were studied: 17 diagnosed surgically, and 3 clinically. The mean age was 70.8 ± 1.8 years, and the male:female ratio 7:13. Nineteen patients were on hemodialysis. Clinically overt atherosclerosis was present in 17 patients. Preceding dialysis-associated hypotension was identified in all patients studied and access thrombosis in 6 patients. In all patients, abdominal pain was the presenting symptom. Initial abdominal examination was unimpressive in 16 patients. The hemoconcentration, leukocytosis and metabolic acidosis were the most prominent laboratory findings. 5/11 abdominal sonograms showed intestinal pathology. 2/3 angiographies were diagnostic. Three patients responded to early fluid challenge and did not require surgery. Pathology was related to the area of the superior mesenteric artery in all 15 patients operated. Twelve (60%) patients died from the event. The 1-year mortality rate was 17/20 patients (85%). Possible contributing factors, other than dialysis-associated hypotension, included: high-dose recombinant human erythropoietin (rhEPO) therapy (179 ± 35 vs. 116 ± 10 U/kg/week in the control group, p < 0.05); metastatic calcifications (abdominal aorta 14/14, aortic valve 11/18; medial calcification of mesenteric arteries in 2/11 pathology specimens); digoxin, and hypoalbuminemia. Conclusions: The increased incidence of NOMI in dialysis patients may be related to overly aggressive rhEPO therapy and the unsuspected presence of mesenteric arterial medial calcifications. Identification of patients at risk, prevention of intradialytic hypotension and a controlled increase in dry weight may help to reduce the incidence of NOMI in chronically dialyzed patients.

Improved Immunogenicity of a Novel Third-Generation Recombinant Hepatitis B Vaccine in Patients with End-Stage Renal Disease

Hepatitis B (HBV) infection remains a significant epidemiological problem in the end-stage renal disease (ESRD) population. Vaccination programs using second-generation vaccines lead to effective seroprotection in only 50–60% of these patients. The purpose of this case series was to describe our experience with a novel third-generation vaccine, Bio-Hep-B®, in ESRD patients who had not developed protective anti-HBs titers following a second-generation HBV vaccination protocol. Twenty-nine ESRD patients who had not responded in the past to a standard second-generation HBV vaccination protocol were included in this series. Each patient received 10 µg of Bio-Hep-B® intramuscularly at 0, 1 and 6 months. A month after completion of the vaccination protocol, anti-HBs antibody levels were measured. Following immunization, 25 of 29 patients (86%) developed seroprotective anti-HBs levels ≧10 mIU/ml. There was a significant difference in the titers of anti-HBs antibodies prior to and following vaccination (p < 0.0001). Statistical analysis of the variables age, gender, diagnosis, dialysis mode, weight, hemoglobin, albumin, and KT/V failed to detect predictors of antibody response. A retrospective analysis of the results of a second-generation vaccination program for the years 1999–2001 in our department showed that 19 of 36 (56.4%) ESRD patients developed seroprotection. In conclusion, the results of this study show that the third-generation HBV vaccine Bio-Hep-B® is highly immunogenic in the population of ESRD patients who did not respond in the past to a second-generation vaccine. This enhanced seroprotection offers hope that the new vaccine will reduce the rate of non-responders and help to eliminate HBV infection from dialysis centers.

Subclavian Vein Stenosis, Permanent Cardiac Pacemakers and the Haemodialysed Patient

Two cases of subclavian vein stenosis secondary to permanent cardiac pacemakers are presented. Both stenoses were asymptomatic until arteriovenous fistulae/grafts were constructed in order to initiate haemodialysis. One patient experienced severe oedema of the arm which necessitated surgical closure of the graft. A literature review into major venous stenosis and cardiac pacemakers reveals an asymptomatic, but evidently underestimated, problem. As more elderly patients will be accepted onto haemodialysis programmes, this above-mentioned problem may become more common. Therapeutic answers as to haemodialysis access are discussed in these patients with permanent pacemakers who need haemodialysis.

Effect of Increased Dialysate Volume on Peritoneal Surface Area among Peritoneal Dialysis Patients

Large dialysate volumes are often required to increase solute clearance for peritoneal dialysis patients. The resulting increase in solute clearance might be attributable to an increased plasma-to-dialysate concentration gradient and/or to an increased effective peritoneal surface area. One of the factors affecting the latter is the peritoneal surface area in contact with dialysate (PSA-CD). The aim of this study was to estimate the change in PSA-CD after a 50% increase in the instilled dialysate volume for patients undergoing peritoneal dialysis. PSA-CD was estimated by using a method applying stereologic techniques to computed tomographic (CT) scans of the peritoneal space. The peritoneal cavity of 10 peritoneal dialysis patients was filled with a solution containing dialysate, half-isotonic saline solution, and contrast medium. Peritoneal function tests and CT scanning of the abdomen were performed twice for each patient (with an interval of 1 wk), after instillation of a 2- or 3-L solution. Scanning of thin helical CT sections was performed, and 36 random sections of the abdomen were obtained after reconstruction. A grid was superimposed on the sections. The surface area was estimated by using stereologic methods. After instillation of the 2-L solution, the volume of the peritoneal solution at the time of CT scanning was 2.32 +/- 0.05 L. The PSA-CD was 0.57 +/- 0.03 m(2), ranging from 0.41 to 0.76 m(2). The use of the 3-L solution increased the peritoneal volume by 46 +/- 2%. PSA-CD increased by 18 +/- 2.3% to 0.67 +/- 0.04 m(2) (range, 0.49 to 0.84 m(2); P < 0.01). Creatinine mass transfer increased from 112 +/- 10 mg to 142 +/- 11 mg (P < 0.0001). The slope of the change of the plasma-to-dialysate creatinine concentration gradient with time decreased from -2.26 +/- 0.23 x 10(-2) to -1.97 +/- 0.16 x 10(-2) (P = 0.01). K(BD-0) (permeability-surface area product or mass area transfer coefficient at time 0 of the dwell) increased from 10.6 +/- 0.7 to 13.6 +/- 1.2 ml/min (P < 0.02). These data demonstrate that increasing the instilled dialysate volume by 50% for peritoneal dialysis patients results in significant increases in the PSA-CD and K(BD).

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.