Claudia M.B. Helou

Effects of nicotine exposure on renal function of normal and hypercholesterolemic rats.

Background/Aims: Renal risks of nicotine exposure associated with hypercholesterolemia are still unknown. Methods: Thus, hypercholesterolemic rats (HC) and their control (C) were evaluated by inulin clearance (InCl) measured at baseline and during nicotine infusion (100 μg/kg b.w.). Five groups were studied: (i) C; (ii) DEN (C submitted to a renal denervation); (iii) C + L-arginine (0.25% in drinking water); (iv) HC, and (v) HC + L-arginine (0.25% in drinking water). Furthermore, C and HC had their renal blood flow (RBF) measured and they have also been chronically treated with nicotine (12.5 μg/ml in drinking water) to assess InCl on the 8th day. Results: Nicotine increased blood pressure in C, DEN and HC and reduced InCl only in C. L-Arginine treatment blunted nicotine effects on blood pressure and increased InCl only in C. Moreover, nicotine did not change RBF in C but elicited in HC, whereas renal vascular resistance was increased in C and unchanged in HC. Indeed, chronic nicotine exposure has also reduced InCl in C. Conclusion: Nicotine acted on the adrenergic system and nitric oxide counteracted this action in C, but the same may not be applied to HC. An impairment in renal autoregulation may explain why InCl was unchanged in HC.

Effect of Low and High Potassium Diets on H+-K+-ATPase and Na+-K+-ATPase Activities in the Rat Inner Medullary Collecting Duct Cells

This study was designed to measure H-K-ATPase and Na-K-ATPase activities in rat inner medullary collecting duct (IMCD) cells during potassium depletion and loading. Both enzyme activities were similarly distributed from the proximal to the distal portion of this nephron segment. One week K depletion did not stimulate H-K-ATPase activity but reduced Na-K-ATPase activity. Within 2 weeks after the onset of potassium depletion, the rats developed metabolic alkalosis, and H-K-ATPase activity was suppressed while Na-K-ATPase activity had returned to control values. H-K-ATPase activity was suppressed following potassium loading whereas Na-K-ATPase activity was unchanged. The results are consistent with the presence of H-K-ATPase in IMCD and indicate that H-K-ATPase and Na-K-ATPase activities are modulated by potassium intake.

High Cholesterol Feeding May Induce Tubular Dysfunction Resulting in Hypomagnesemia

Background/Aims: Hypomagnesemia may induce hypercholesterolemia, but the contrary has not been described yet. Thus, magnesium homeostasis was evaluated in rats fed a cholesterol-enriched diet for 8 days. This study has a relevant clinical application if hypomagnesemia, due to hypercholesterolemia, is confirmed in patients with long-term hypercholesterolemia. Methods: Both hypercholesterolemic (HC) and normocholesterolemic rats (NC) were divided into sets of experiments to measure hemodynamic parameters, physiological data, maximum capacity to dilute urine (CH2O), variations (Δ) in [Ca2+]i and the expression of transporter proteins. Results: HC developed hypomagnesemia and showed high magnesuria in the absence of hemodynamic abnormalities. However, the urinary sodium excretion and CH2O in HC was similar to NC. On the other hand, the responses to angiotensin II by measuring Δ [Ca2+]i were higher in the thick ascending limb of Henle’s loop (TAL) of HC than NC. Moreover, high expression of the cotransporter NKCC2 was found in renal outer medulla fractions of HC. Taken together, the hypothesis of impairment in TAL was excluded. Actually, the expression of the epithelial Mg2+ channel in renal cortical membrane fractions was reduced in HC. Conclusion: Impairment in distal convoluted tubule induced by hypercholesterolemia explains high magnesuria and hypomagnesemia observed in HC.

Rosiglitazone did not induce acute kidney injury in normocholesterolemic rats despite reduction in glomerular filtration rate.

Background/Aims: Rosiglitazone (RGL) has been used to ameliorate lipids homeostasis and also to treat inflammatory diseases. However, RGL may reduce renal blood flow and glomerular filtration rate (GFR) predisposing to acute kidney injury (AKI). We investigated whether the treatment with RGL induces AKI in normocholesterolemic (NC) and hypercholesterolemic (HC) rats. Methods: We measured GFR by inulin clearance technique and we quantified urinary neutrophil gelatinase-associated lipocalin (uNGAL) in all groups at baseline and during Ang II-stimulated vasoconstriction. Moreover, we evaluated the presence of renal damaged by histologic examination. Results: At baseline, NC and HC had normal and similar GFR. RGL treatment reduced GFR only in NC+RGL. Unexpectedly, HC+RGL showed high levels of uNGAL although GFR was at normal range. During Ang II-stimulated vasoconstriction, all groups showed reduction in GFR to the same range and we found high levels of uNGAL and high score of renal damage in HC and HC+RGL. Conclusion: RGL acts distinctly in normocholesterolemia and in hypercholesterolemia. Reduction in GFR provoked by RGL treatment did not allow the diagnosis of AKI in NC even in the presence of ANG II-stimulated vasoconstriction. However, AKI was diagnosed in HC+RGL at baseline although GFR was within normal range.

Early predictors of acute kidney injury in patients with cirrhosis and bacterial infection: urinary neutrophil gelatinase-associated lipocalin and cardiac output as reliable tools.

Background Hemodynamic abnormalities and acute kidney injury (AKI) are often present in infected cirrhotic patients. Hence, an early diagnosis of AKI is necessary, which might require the validation of new predictors as the determinations of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and cardiac output. Methods We evaluated 18 infected cirrhotic patients subdivided into two groups at admission (0 hours). In Group I, we collected urine samples at 0 hours, 6 hours, 24 hours, and 48 hours for uNGAL and fractional excretion of sodium determinations. In Group II, we measured cardiac output using echocardiography. Results The age of patients was 55.0±1.9 years, and 11 patients were males. The Model for End-Stage Liver Disease score was 21±1, whereas the Child–Pugh score was C in 11 patients and B in 7 patients. Both patients in Group I and Group II showed similar baseline characteristics. In Group I, we diagnosed AKI in 5 of 9 patients, and the mean time to this diagnosis by measuring serum creatinine was 5.4 days. Patients with AKI showed higher uNGAL levels than those without AKI from 6 hours to 48 hours. The best accuracy using the cutoff values of 68 ng uNGAL/mg creatinine was achieved at 48 hours when we distinguished patients with and without AKI in all cases. In Group II, we diagnosed AKI in 4 of 9 patients, and cardiac output was significantly higher in patients who developed AKI at 0 hours. Conclusion Both uNGAL and cardiac output determinations allow the prediction of AKI in infected cirrhotic patients earlier than increments in serum creatinine.

Chronic Nicotine Exposure Reduces Klotho Expression And Triggers Different Renal And Hemodynamic Responses In Klotho-Haploinsufficient Mice

The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury. Here, we investigated renal Klotho protein expression in a mouse model of chronic (28-day) nicotine exposure, in which mice received nicotine or vehicle (saccharine) in drinking water, comparing wild-type (WT) mice, klotho-haploinsufficient ( kl/+) mice, and their respective controls, in terms of the effects of that exposure. Nicotine exposure was associated with a significant decline in renal Klotho expression in WT and kl/+ mice as well as a reduction in the glomerular filtration rate in WT mice. Although plasma electrolytes were similar among the groups, fractional excretion of sodium was reduced in both nicotine-exposed groups. The nicotine-WT mice presented augmented baroreflex sensitivity to nitroprusside and augmented sympathetic cardiac modulation. However, nicotine- kl/+ mice presented higher plasma levels of urea and aldosterone together with a higher α-index (spontaneous baroreflex) and higher peripheral sympathetic modulation, as evaluated by spectral analysis. We can conclude that nicotine downregulates Klotho expression as well as that renal and autonomic responses to nicotine exposure are modified in kl/+ mice.

Maternal Hypercholesterolemia Associated with Nicotine Exposure in Adulthood May Induce Kidney Injury in Male Rats if Hypomagnesemia Occurs

Background/Aims: Maternal hypercholesterolemia is a risk factor to renal injury in rat pups at adulthood, especially if they feed a cholesterol-enriched diet after weaning. However, the renal function of male pups of dams with hypercholesterolemia (PH) that were fed a regular chow from weaning to adulthood needs investigation, particularly those exposed to an adverse risk such as nicotine. Methods: We evaluated the renal function of PH animals and we compared the data with those found in male pups of control dams (PC) at 3- and 6-month-old by inulin clearance. Moreover, we investigated the effect of nicotine treatment for 8 days in both PH and PC animals at 6 months old via metabolic function studies and by renal histological analysis. Results: Inulin clearance and other renal function parameters were similar in PH and PC animals at 3 and 6 months old. Nevertheless, the PH group showed significant differences with regard to histological analysis despite a similar number of glomeruli. The glomerular area of PH animals was significantly smaller than that measured in PC animals, and the fractional interstitial area was significantly larger in PH animals than that measured in PC animals at 3 months old. With regard to nicotine treatment, we observed a trend for a reduction in creatinine clearance in both PC and PH groups, but only PH animals showed hypomagnesemia and the highest fractional interstitial area. Conclusions: The offspring exposed to a high cholesterol milieu during intrauterine and neonatal life may show a silent kidney injury at adulthood that may be aggravated by nicotine exposure if hypomagnesemia occurs.

Study of Erythrocyte ATPases in Infants Evaluated during the Recovery Phase of Severe Dehydration Caused by Diarrhea

Background/Aims: Patients severely dehydrated from diarrhea are at risk of developing hyperkalemia consequent to fluid therapy treatment. In parallel with the regulation of external potassium balance by the kidney and gastrointestinal tract, plasma potassium is rapidly regulated by redistribution of potassium between the extracellular and intracellular compartments. Erythrocytes contain ATPases that play a role in this potassium movement. In this study, erythrocyte ATPase effectiveness was evaluated in infants dehydrated from diarrhea and compared to that of healthy infants. Methods: Blood samples were collected from dehydrated and healthy infants. The activity of Na+,K+-ATPase and of an ouabain-insensitive K+-ATPase were assessed. Serum electrolytes and blood pH were also determined. Results: No hyperkalemia was found, even in dehydrated infants presenting with severe hyperchloremic metabolic acidosis. In the erythrocytes of dehydrated infants, Na+,K+-ATPase activity was increased correlating positively with the amount of sodium administered. High K+-ATPase activity in the erythrocytes correlated with low plasma potassium. The K+-ATPase activity correlated positively with the amount of potassium administered to dehydrated infants. Conclusion: These findings suggest that the erythrocytes Na+,K+-ATPase and K+-ATPase both protect against plasma potassium abnormalities in dehydrated infants. In such infants, the risk of hyperkalemia is probably low.

Erratum by the Publisher – Announcement

In continuation of our tradition of joint congresses, the meeting in Feiburg will focus on new experimental and clinical data. The program, consisting of posters, free contributions, and invited reviews, will have three focuses: (1) basic research; (2) experimental clinical science, and (3) lectures on hot clinical topics. The congress also encompasses free symposia, plenary sessions, and a social program. The major topics will be defined by the Joint Program Committee of the Gesellschaft für Nephrologie and the Deutsche Arbeitsgemeinschaft für Klinische Nephrologie. The congress language will be German. Free communications or posters should be submitted by using the specific abstract form which, together with the preliminary program, will be available in February 1999. The success of the meeting will depend firstly on broad participation of nephrologists and those interested in nephrology and secondly on the contributions submitted. We will try to generate an interesting program and secure sufficient time also for social activities.