Jan A. Krikken

Benefits of dietary sodium restriction in the management of chronic kidney disease

Purpose of reviewTo evaluate the role of restricting dietary sodium intake in chronic kidney disease (CKD) and its complications. Recent findingsA consistent line of evidence shows that high dietary sodium intake is a determinant of therapy resistance to blockade of the renin–angiotensin–aldosterone system (RAAS). Addition of sodium restriction to RAAS blockade or to RAAS blockade combined with a diuretic permits a further reduction in urinary protein excretion of approximately 30%, which could be expected to reduce long-term renal risk by 25%. SummaryHigh sodium intake increases blood pressure and proteinuria, induces glomerular hyperfiltration and blunts the response to RAAS blockade. Although recommended in international guidelines, sodium restriction is not a spearhead in treating renal patients. Sodium status is only rarely mentioned in recent large intervention studies in CKD. Sodium intake in CKD is similar to that in the general population. Reduction of sodium intake to the target of 50–85 mmol/24 h in patients with CKD reduces blood pressure and proteinuria, the latter by approximately 30%, and should be actively pursued to improve outcome in CKD.

Obesity and Renal Hemodynamics

Obesity is a risk factor for renal damage in native kidney disease and in renal transplant recipients. Obesity is associated with several renal risk factors such as hypertension and diabetes that may convey renal risk, but obesity is also associated with an unfavorable renal hemodynamic profile independent of these factors, and that may exert effects on renal damage as well. In animal models of obesity-associated renal damage, micro-puncture studies showed glomerular hypertension and hyperfiltration. In humans an elevated glomerular filtration rate has been demonstrated in several studies, sometimes associated with hyperperfusion as well, independent of blood pressure or the presence of diabetes. An elevated filtration fraction was found in several studies, consistent with glomerular hypertension. This renal hemodynamic profile resembles the hyperfiltration pattern in diabetes and is therefore assumed to be a pathogenetic factor in renal damage. Of note, the association between body mass index and renal hemodynamics is not limited to overt obesity or overweight, but is also present across the normal range, without a particular threshold. Multiple factors are assumed to contribute to these renal hemodynamic alterations, such as insulin resistance, the renin-angiotensin system and the tubulo-glomerular responses to increased proximal sodium reabsorption, and possibly also inappropriate activity of the sympathetic nervous system and increased leptin levels. Obesity has a high world-wide prevalence. On a population-basis, therefore, its contribution to long-term renal risk may be considerable, especially as it is usually clustered with risk factors like hypertension and insulin resistance. In short-term studies the renal hemodynamic alterations in obesity and the associated proteinuria were reversible by weight loss, and renin-angiotensin system-blockade, respectively. These interventions are therefore likely to have the potential to limit the renal risks of obesity.

Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial

BACKGROUND Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. METHODS In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. FINDINGS Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. INTERPRETATION We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. FUNDING None.

Higher body mass index is associated with higher fractional creatinine excretion in healthy subjects

BACKGROUND Accurate glomerular filtration rate (GFR) measurement in normal to high range is important for epidemiological studies and workup for kidney donation. Creatinine-based equations perform poorly in this GFR range. Creatinine clearance (CrCl) provides a substitute, provided urine is collected accurately and tubular creatinine handling can be accounted for. The latter is poorly characterized in the normal GFR range. METHODS Therefore, we studied performance of CrCl, fractional creatinine excretion (FE(creat)) and its determinants in 226 potential kidney donors (47% males, mean 53 ± 10 years). GFR was assessed as (125)I-iothalamate clearance, simultaneously with 2-h CrCl and 24-h CrCl. RESULTS Mean GFR was 101 ± 18, 2-h CrCl 110 ± 20 and 24-h CrCl 106 ± 29 mL/min/1.73 m(2). Mean bias of 24 h CrCl was 7.4 [inter-quartile range -6.7 to 20.0] mL/min/1.73 m(2), precision (R(2)) 0.39 and 30% accuracy 82%. Mean FE(creat) was 110 ± 11%. FE(creat) correlated with body mass index (BMI) (r = 0.34, P < 0.001). Consequently, bias of 24-h CrCl increased from 2.7 (inter-quartile range -6.5 to 16.7) to 8.6 (inter-quartile range -5.8 to 20.5) and 12.6 (inter-quartile range 7.0 to 25.4) mL/min in subjects with BMI <25, 25-30 and >30 kg/m(2), respectively (P < 0.05). On multivariate analysis, BMI and gender were predictors of FE(creat). CONCLUSIONS CrCl systematically overestimates GFR in healthy subjects. The overestimation significantly correlates with BMI, with higher FE(creat) in subjects with higher BMI. The impact of BMI on tubular creatinine secretion can be accounted for, when using CrCl for GFR assessment in the normal to high range, by the following formula: GFR = 24-h CrCl - (22.75 + 0.76 × BMI - 0.29 × mean arterial pressure (-6.11 if female).

Lower HDL-C and apolipoprotein A-I are related to higher glomerular filtration rate in subjects without kidney disease

Animal experiments show that the kidney contributes to apolipoprotein (apo)A-I catabolism. We tested relationships of HDL cholesterol (HDL-C) and apo-I with kidney function in subjects without severe chronic kidney disease. Included was a random sample of the general population (part of the PREVEND cohort). Kidney function [estimated glomerular filtration rate (e-GFR) by two well-established equations and creatinine clearance], HDL-C, triglycerides, apoA-I and insulin resistance (HOMAir) were measured in 2,484 fasting subjects (e-GFR≥45 ml/min/1.73m2) without macroalbuminuria, cardiovascular disease, diabetes, or the use of anti-hypertensives and/or lipid-lowering agents. HDL-C (r = −0.056 to −0.102, P < 0.01 to < 0.001) and apo A-I (r = −0.096 to −0.126, P < 0.001) were correlated inversely with both GFR estimates and creatinine clearance in univariate analyses. Multiple linear regression analyses also demonstrated inverse relationships of HDL-C and apoA-I with all measures of kidney function even after adjustment for age, sex, waist circumference, HOMAir, triglycerides, and urinary albumin excretion (P = 0.053 to 0.004). In conclusion, HDL-C and apoA-I are inversely related to e-GFR and creatinine clearance in subjects without severely compromised kidney function, which fits the concept that the kidney contributes to apoA-I regulation in humans. High glomerular filtration rate may be an independent determinant of a pro-atherogenic lipoprotein profile.

Performance of MDRD study and CKD-EPI equations for long-term follow-up of nondiabetic patients with chronic kidney disease

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, (125)I-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/1.73 m(2)/year, respectively). Sensitivity and specificity to identify progressive kidney function loss (mGFR/(BSA) slope > 1.5 mL/min/1.73 m(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 < 0.05) 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.

Hemopexin activity is associated with angiotensin II responsiveness in humans.

Background: Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro. Whether hemopexin is involved in the responsiveness to ang II in vivo is unknown. Therefore, we tested whether variations in endogenous hemopexin activity are associated with the responsiveness of blood pressure to ang II in healthy volunteers. Method: Healthy men (n = 33, age 26 ± 9) were studied in balance on low sodium (50 mmol Na+ per 24 h) and high sodium (200 mmol Na+ per 24 h) diet, respectively. After baseline measurements of blood pressure, ang II was infused at 0.3, 1 and 3 ng/kg per min for 1 h per dose. Hemopexin activity was measured at baseline in EDTA–plasma samples by an amidolytic assay with a chromogenic substrate suitable for hemopexin activity evaluation. Results: During high sodium the hemopexin activity was lower; 1.6 × 105 (0.6 × 105 − 4.7 × 105) versus 2.8 × 105 (1.1 × 105 − 5.1 × 105) arbitrary units (P < 0.01) and the pressor response to 3 ng ang II/kg per minute larger than during low sodium (17.6 ± 6.5 versus 14.6 ± 6.9 mmHg, P < 0.01). Hemopexin activity negatively correlated with the pressor response to ang II during either type of sodium intake (high sodium: r = 0.42, P < 0.05; low sodium: r = 0.35, P < 0.05). Conclusion: These in-vivo data obtained in healthy individuals support recent in-vitro data showing that active hemopexin downregulates the availability of the AT1-R. Therefore, activated hemopexin might be considered as a factor mediating ang II effects upon blood pressure by modulating AT1-R availability.

Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects.

Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin–angiotensin–aldosterone system (RAAS) may be related to variation in the plasma CETP level. We questioned whether the plasma CETP level would affect RAAS responsiveness to low sodium diet and the blood pressure response to angiotensin-II infusion in healthy subjects. Methods: RAAS parameters and blood pressure were determined during liberal sodium diet (200 mmol/24 h) and low sodium diet (50 mmol/24 h) in 67 healthy men. Blood pressure response to incremental angiotensin-II infusion was assessed in 34 subjects during liberal sodium diet. Correlation analysis was performed to test whether RAAS responsiveness and blood pressure were related to plasma CETP mass, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I measured during liberal sodium diet. Results: CETP mass ranged from 1.29 to 2.95 mg/l. No significant differences in (changes) in mean arterial pressure, aldosterone and active plasma renin concentration in response to low sodium were observed between the lowest and highest tertiles of CETP mass, HDL-C and apolipoprotein A-I. These outcome variables were also not significantly correlated with CETP, HDL-C and apolipoprotein A-I, except for a modest relation of aldosterone measured during low sodium with apolipoprotein A-I (r = 0.28, p = 0.022). Blood pressure response to angiotensin-II was similar between CETP tertiles. Conclusions: Mineralocorticoid and blood pressure responsiveness to dietary salt intake are not significantly related to physiological interindividual differences in plasma CETP. We suggest that a lower CETP mass does not exert adverse effects on blood pressure regulation.

High plasma hemopexin activity is an independent risk factor for late graft failure in renal transplant recipients

Chronic low‐grade inflammation is involved in late renal transplant dysfunction. Recent studies suggest a role for hemopexin, an acute phase protein, in kidney damage. We investigated whether hemopexin activity (Hx) predicts graft failure in renal transplant recipients (RTRs). In 557 RTRs with functioning grafts for ≥1 year, Hx was measured in citrate‐plasma. RTRs were divided according to Hx into two groups; A: sextile 1–5 (464 RTRs, 83%) and B: sextile 6 (92 RTRs, 17%). Hx [median (IQR) 11.1 (3.3–19.1) arbitrary units] was measured at 6.0 (2.6–11.5) years post‐transplant. RTRs with high Hx (group B) had significantly higher urinary protein excretion (UP) and diastolic blood pressure than group A, despite significantly more prevalent use of renin‐angiotensin‐aldosterone system inhibitors. After follow‐up [4.6 (3.8–5.2) years], incidence of graft failure in group A was 25 (5%) and in group B 14 (15%,P = 0.0009)  After adjustment for high‐sensitivity C‐reactive protein (hsCRP), UP and other potential confounders, Hx remained an independent predictor of graft failure [HR = 2.5 (95% CI 1.2–5.3), P = 0.01]. In conclusion, elevated Hx predicts late graft failure in RTRs, independent of hsCRP and UP. This suggests that Hx measurement, next to measurement of creatinine clearance and UP, could be of value for the identification of RTRs at risk for graft failure.

Renal hemodynamics in overweight and obesity: pathogenetic factors and targets for intervention

Weight excess is a risk factor for progressive renal function loss, not only in subjects with renal disease or renal transplant recipients, but also in the general population. Considering the increasing prevalence of obesity worldwide, weight excess may become the main renal risk factor on a population basis, all the more so because the risk is not limited to morbid obesity, but is already apparent in the overweight range. The mechanism of the renal risk is multifactorial. In addition to the role of comorbid conditions such as hypertension and diabetes, current evidence supports a pathogenetic role for renal hemodynamics, specifically glomerular hyperfiltration, and also glomerular hypertension. Weight excess is associated with an elevated glomerular filtration rate and a less pronounced rise in renal plasma flow, resulting in an elevated filtration fraction. This suggests glomerular hypertension due to afferent–efferent dysbalance, which impairs glomerular protection from systemic hypertension. Data in renal transplant recipients support the pathogenetic role of elevated glomerular pressure for long-term renal prognosis. Blockade of the renin–angiotensin–aldosterone system can reverse the renal hemodynamic abnormalities. The obesity-associated renal risk is unfavourably affected by high sodium intake. This may be due to the effects of sodium on blood pressure, which is often sodium-sensitive in obesity, but direct renal effects are also present. Interestingly, sodium restriction ameliorates overweight-associated hyperfiltration in overweight subjects. More focus on weight excess as a renal risk factor is warranted. Preventive measures should focus on weight excess as well as on specific protection against renal damage, by renin–angiotensin–aldosterone system-blockade and moderate sodium restriction.