Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline.

BACKGROUND: Zinc deficiency is commonly encountered in chronic kidney disease (CKD). The aims of this study were to assess whether zinc deficiency was related to increased renal excretion of zinc and to the progression of CKD. METHODS: Plasma and 24-h urinary zinc levels, urinary electrolytes and uromodulin were measured in 108 CKD patients and 81 individuals without CKD. Serum creatinine values were collected for 3 years to calculate the yearly change in estimated glomerular filtration rate (eGFR). Multivariable regression analysis was performed to assess the association between baseline zinc levels and yearly change in eGFR. RESULTS: CKD patients had lower circulating zinc levels and higher 24-h urinary zinc excretion than non-CKD participants (612.4 ± 425.9 versus 479.2 ± 293.0 µg/day; P = 0.02). Fractional excretion (FE) of zinc was higher and it significantly increased at more advanced CKD stages. Zinc FE was correlated negatively with 24-h urinary uromodulin excretion (r=-0.29; P < 0.01). Lower baseline plasma zinc levels were associated with a faster yearly decline of renal function in age, gender, diabetes and hypertension adjusted models, but this relationship was no longer significant when baseline eGFR or proteinuria were included. CONCLUSIONS: Zinc levels are lower in CKD, and not compensated by reduced renal zinc excretion. The inverse association between urinary zinc excretion and uromodulin possibly points to an impaired tubular activity, which could partly account for zinc imbalance in CKD. These data suggest that zinc status is associated with renal function decline, but further studies elucidating the underlying mechanisms and the potential role of zinc supplements in CKD are needed.

[The skin as « third kidney ¼]. / La peau comme « troisième rein ¼.

The skin is the largest human organ playing an important role in protection, thermoregulation and sensation. Recent studies suggest that a new function has to be added: the storage of sodium. There is increasing evidence that sodium can accumulate in the skin, which suggests that the skin contributes to the regulation of sodium balance in humans, and possibly to the control of extracellular volume and blood pressure homeostasis. The main product of the skin is sweat. Body sweat contains electrolytes and urea. Their concentration can increase considerably when sweat production is stimulated by saunas or hot baths. This finding has motivated studies investigating the effect of stimulated sweating on volume control in patients suffering from kidney disease or heart failure. The physiological concept that sees the skin as third kidney and its possible clinical applications are discussed in this article.

La peau est le plus grand organe humain qui a des fonctions de protection, de thermorégulation et de sensation. Des études récentes suggèrent qu'il faut lui rajouter une fonction supplémentaire: le stockage du sodium. La peau participe ainsi au bilan hydrosodé, et possiblement à la régulation du volume extra-cellulaire et de la pression artérielle. Le produit principal de la peau est la sueur. La quantité d'électrolytes et d'urée sécrétée par la sueur n'est pas négligeable, et peut considérablement augmenter en cas de stimulation par des saunas ou bains chauds. Cette découverte a motivé des études utilisant la transpiration stimulée comme traitement chez des patients souffrant d'insuffisance rénale ou cardiaque. Dans cet article, nous ferons le point sur ces nouveaux concepts physiologiques et leurs possibles applications dans notre pratique clinique.

Hyponatremia is a marker of disease severity in HIV-infected patients: a retrospective cohort study.

BACKGROUND: Hyponatremia is a frequent electrolyte disorder in HIV-infected patients with a prevalence of up to 56% in the pre-cART era. Several studies have demonstrated that patients with hyponatremia are at an increased risk of death. We aimed to investigate the prevalence of hyponatremia in the recent cART-era and evaluate its association with mortality. METHODS: Single-center retrospective cohort study. A total of 1196 newly diagnosed and cART-naïve HIV patients followed at the AIDS Reference Center, St Pierre University Hospital in Brussels, Belgium, between 1 January 1998 and 31 December 2013 were included. Hyponatremia was defined as a baseline natremia lower than 135 mmol/l. The outcome of interest was the occurrence of death. RESULTS: In this study 177 (14.8%) patients had hyponatremia at baseline with a median natremia of 132.0 mmol/l [interquartile range (IQR) 130.0-134.0 mmol/l]. Hyponatremic patients had a lower CD4 cell count (207.5 ± 197.7/µl vs 400.4 ± 277.0/µl; P < 0.0001) and a higher prevalence of AIDS (50.3% vs 12.4%; P < 0.0001) compared to normonatremic patients. A significantly higher proportion of patients with hyponatremia were hospitalized at first contact (72.3% vs 20.0%; P < 0.0001). During the follow-up hyponatremic patients had a shorter median time to a first hospitalization (2.0 IQR [0.0-12.0] months vs 13.0 IQR [2.0-29.0] months; P = 0.001) and an increased incident hospitalization rate (785/1000 patient-years, 95% CI 725-845 vs 370/1000 patient-years, 95% CI 352-388; P < 0.0001]. The incident mortality rate was 28.3/1000 patient-years (95% CI 18.15-42.16) in patients with hyponatremia compared to 9.33/1000 patient-years (95% CI 6.63-12.75) in normonatremic patients (P < 0.0001). Three-year cumulative survival rates were 85.8% ± 3.0% in hyponatremic patients and 96.3% ± 0.7% in normonatremic patients (log-rank P < 0.0001). However, in a multivariate Cox model adjusting for other risk factors such as AIDS, CD4 count < 350/µl and hepatitis C, hyponatremia was no longer a predictor for patient death (hazard ratio: 1.03, 95% CI 0.54-1.97; P = 0.935). CONCLUSIONS: Hyponatremia is a marker of severity of HIV-disease but not an independent risk factor for mortality. HIV-patients with a low serum sodium at baseline might benefit from a close follow-up to improve outcomes.

[How to start an antihypertensive treatment: from evidence to personalized choice]. / Comment initier un traitementantihypertenseur ? De l'évidenceà la personnalisation.

Considering the high prevalence of hypertension among general population, the general practitioner is frequently challenged to start an antihypertensive therapy, which aims to lower blood pressure and to reduce the cardiovascular risk. At the initial stage, several critical questions must be asked : « Is a pharmacological treatment necessary ? ¼, « Which are the target blood pressures ? ¼ and « Which antihypertensive drug should be chosen to start therapy ? ¼The aim of this article is to give general practicioners some practical tools to guide them in the initial management of hypertensive patients.

En raison de la forte prévalence de l'hypertension artérielle dans la population générale, le praticien est fréquemment amené à proposer un traitement antihypertenseur dont l'objectif est de normaliser la pression artérielle et réduire le risque cardiovasculaire. Au stade initial, plusieurs questions doivent être posées : « Un traitement pharmacologique est-il nécessaire ? ¼, « Quelles sont les pressions cibles ? ¼ et « Avec quel médicament antihypertenseur faut-il commencer ? ¼Le but de cet article est de donner aux praticiens quelques outils pour les guider dans la prise en charge initiale des patients hypertendus.

Subacute cognitive deterioration with high serum anti-thyroid peroxidase antibodies: two cases and a plea for pragmatism.

Autoimmune encephalopathy is a rare but potentially reversible cause of cognitive deterioration and neuropsychiatric disturbances. We describe two older female patients with subacute cognitive decline and marked neuropsychiatric disturbances in the presence of high serum anti-thyroid peroxidase antibodies and with normal dosage of free thyroxine 4. One patient recovered almost completely after oral corticotherapy. Differential diagnosis and the role of biomarkers, in particular, are discussed. We support a pragmatic approach involving a short empirical therapeutic trial with intravenous or oral corticoids; this should be considered in all patients with subacute encephalopathy and with laboratory arguments for an underlying autoimmune aetiology.

Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study.

BACKGROUND: Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. METHODS: A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). RESULTS: In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). CONCLUSION: Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Short-term changes in dietary sodium intake influence sweat sodium concentration and muscle sodium content in healthy individuals.

OBJECTIVE: There is increasing evidence that sodium can be stored in the skin and muscles without being osmotically active, yet whether acute changes in dietary sodium intake alter sweat and muscle sodium content has not been investigated previously. METHODS: In a cross-over design, we assessed muscle sodium content by Na-MRI in 38 healthy normotensive volunteers (aged 33.5 ±â€Š11.1 years, 76.3% women) after 5 days of high-sodium diet (6 g of salt added to their normal diet) and 5 days of a low-sodium diet. In a subgroup of 18 participants (72.2% women) we conducted quantitative pilocarpine iontophoretic sweat collections and measured the sodium concentration in sweat. Plasma aldosterone and plasma renin activity levels were measured in all participants. RESULTS: Under high-sodium diet conditions urinary sodium excretion, muscle sodium content and sweat sodium concentration all increased significantly. Muscle sodium content (rm = 0.47, P = 0.03) and sodium sweat concentration (rm = 0.72, P < 0.001) correlated positively with salt intake as estimated by 24-h urine sodium excretion. Age, sex or the phase of the menstrual cycle did not influence muscle or sweat sodium concentrations or their changes. In contrast, plasma aldosterone levels were negatively associated with both muscle sodium (rs = -0.42, P = 0.0001) and sweat sodium content (rs = -0.52, P = 0.002). Plasma renin activity correlated negatively with sweat sodium (rs = -0.43, P = 0.012) and muscle sodium levels (rs = -0.42, P < 0.001). CONCLUSION: Muscle and sweat sodium concentrations are significantly higher on a high-salt intake in healthy male and female individuals, suggesting that muscle and sweat play a role in regulating sodium balance in humans.

New Insights on the Role of Sodium in the Physiological Regulation of Blood Pressure and Development of Hypertension.

A precise maintenance of sodium and fluid balance is an essential step in the regulation of blood pressure and alterations of this balance may lead to the development of hypertension. In recent years, several new advances were made in our understanding of the interaction between sodium and blood pressure regulation. The first is the discovery made possible with by new technology, such as 23Na-MRI, that sodium can be stored non-osmotically in tissues including the skin and muscles particularly when subjects are on a high sodium diet or have a reduced renal capacity to excrete sodium. These observations prompted the refinement of the original model of regulation of sodium balance from a two-compartment model comprising the extracellular fluid within the intravascular and interstitial spaces to a three-compartment model that includes the intracellular space of some tissues, most prominently the skin. In this new model, the immune system plays a role, thereby supporting many previous studies indicating that the immune system is a crucial co-contributor to the maintenance of hypertension through pro-hypertensive effects in the kidney, vasculature, and brain. Lastly, there is now evidence that sodium can affect the gut microbiome, and induce pro-inflammatory and immune responses, which might contribute to the development of salt-sensitive hypertension.

Acute hyperglycemia increases renal tissue oxygenation as measured by BOLD-MRI in healthy overweight volunteers.

AIM: Animal studies have suggested that acute hyperglycemia induces transient renal hypoxia and kidney damage, yet this has not been tested in humans. Therefore, we assessed in human subjects the effect of acute hyperglycemia on renal tissue oxygenation as measured with blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI). METHODS: In this single center prospective interventional study, healthy overweight subjects were recruited. BOLD-MRI was performed before and immediately after the intravenous administration of 0.15 g/kg of glucose in a 20% solution under standard hydration and fasting conditions. R2* maps were analyzed using the twelve layer concentric objects (TLCO) technique, a semi-automatic procedure which divides the kidney parenchyma in 12 equal layers at increasing depth. R2* is a measure of local desoxyhemoglobin concentrations, with high R2* values corresponding to low oxygenation. RESULTS: Nineteen overweight subjects were enrolled (age 37 ±â€¯10 years, BMI 28.9 ±â€¯3 kg/m2, HbA1c 5.4 ±â€¯0.3%, 57.9% women): 5 were glucose intolerant, none had diabetes. The mean glycemia rose from 4.5 ±â€¯0.3 mmol/l to 9.0 ±â€¯0.9, 8.9 ±â€¯0.7, 7.7 ±â€¯0.6 and 6.8 ±â€¯0.8 mmol/l at respectively 1, 10, 20 and 30 min after IV glucose. Circulating insulin levels quadrupled. The mean R2* values decreased significantly in all kidney layers, irrespective of glucose intolerance. The lower BMI, the larger the decrease in R2*(spearman's r = 0.41, p = 0.035). CONCLUSION: These data show that acute hyperglycemia decreases the R2* signal in humans, suggesting an acute increase in renal tissue oxygenation. The precise mechanism of this observation remains unknown, and whether this phenomenon also occurs in patients with diabetes needs additional studies.

Impact of salt reduction in meals consumed during hemodialysis sessions on interdialytic weight gain and hemodynamic stability.

INTRODUCTION: Patients on hemodialysis (HD) are advised to limit daily water- and salt intake to reduce interdialytic weight gain (IDWG). To counterbalance protein-losses, protein-rich meals are sometimes provided during HD sessions, but their salt content is not always taken into account. The aim of this study was to assess the influence of a lower salt content of meals provided during HD sessions on IDWG, blood pressure (BP), and hemodynamic stability during dialysis. METHODS: This monocentric, interventional study was proposed to all the patients treated with three weekly HD sessions. The first two months of the study (high salt period), the patients continued to receive one sandwich containing 2.4 g of salt per session. Then, we reduced its salt content from 2.4 to 1.4 g, and patients received this "low-salt sandwich" at each dialysis session for four months. The mean values of IDWG, BP, and dry weight of the first two months were compared with those collected during the low salt periods (2-6 months). FINDINGS: Forty out of 76 patients who initially agreed to participate were free of hospitalization, transplantation, and transfer to another center or death during the study period and were included in the final analysis (35% women). Median age was 63 years (range 28-90), 22.5% had a residual diuresis > 0.5 L/day. IDWG baseline decreased from 2.17 ± 0.98 to 2.03 ± 1 kg (P = 0.001) two months and to 2.09 ± 1.01 kg (P = 0.009) four months after we had lowered the salt content of the sandwich. The number of symptomatic intradialytic hypotension was also reduced (6.1% vs., respectively, 3.2% and 3.3% of HD sessions; P = 0.004). DISCUSSION: IDWG was reduced and hemodynamic stability improved after the reduction of the salt content of perdialytic meals. This suggests that salt consumed during HD matters and might influence salt and water intake outside the dialysis unit.