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Chloride anions are the most abundant in humans. For many years, it has been believed that chloride is simply a counterion of all other cations, ensuring the electroneutrality of the extracellular space. Recent data suggests that chloride anions possess a broad spectrum of important activities that regulate vital cellular functions. It is now evident that, apart from its contribution to the electroneutrality of the extracellular space, it acts as an osmole and contributes to extracellular and intracellular volume regulation. Its anionic charge also contributes to the generation of cell membrane potential. The most interesting action of chloride anions is their ability to regulate the activity of with-no-lysine kinases, which in turn regulate the activity of sodium chloride and potassium chloride cotransporters and govern the reabsorption of salt and excretion of potassium by nephron epithelia. Chloride anions seem to play a crucial role in cell functions, such as cell volume regulation, sodium reabsorption in the distal nephron, potassium balance, and sodium sensitivity, which lead to hypertension. All of these functions are accomplished on a molecular level via complicated metabolic pathways, many of which remain poorly defined. We attempted to elucidate some of these pathways in light of recent advances in our knowledge, obtained mainly from experimental studies., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Koulouridis and Koulouridis.)

Background: In the last two decades, progress in cytogenetic and genome research has enabled investigators to unravel the underlying molecular mechanisms of inherited tubulopathies such as Bartter's and Gitelman's syndromes and helped physicians to better understand not only these two pathologic entities but also renal pathophysiology and salt sensitive hypertension., Data Sources: Articles collected from PubMed and open access journals included original articles, research articles, and comprehensive reviews. They were evaluated by the authors with an special emphasis on originality and up to date information about molecular pathophysiology., Results: Bartter's and Gitelman's syndromes are two different inherited salt loosing tubulopathies. They are characterized by various inability of distal nephron to reabsorb sodium chloride with resultant extarcellular volume contraction and increased activity of the renin angiotensin aldosterone system. Hypokalemic metabolic alkalosis is a common feature of these two forms of tubulopathies. Hypercalciuria characterizes the majority of Bartter's syndrome, and hypomagnesemia with hypocalciuria characterizes Gitelman's syndrome. Low blood pressure is a common feature among patients who suffered from these tubulopathies. Bartter's syndromes encompass a heterogeneous group of ion channels defects localized at the thick ascending limp of Henle's loop with resultant loss of function of sodium-potassium-2 chloride cotransporter. These defects result in the impairment of the countercurrent multiplication system of the kidney as well as calcium, potassium and acid base disturbances which in the majority of cases are proved lethal especially in the antenatal and/or immediate postnatal life period. The underlying pathology in Gitelman's syndrome is defined to the distal convoluted tubule and is related to loss of function of the sodium-chloride cotransporter. The results of this defect encompass the inability of extracellular volume homeostasis, magnesium and potassium conservation, and acid base disturbances which are generally mild and in the majority of cases are not life-threatening., Conclusions: Recent advances in molecular pathophysiology of Bartter's and Gitelman's syndromes have helped physicians to better understand the underlying mechanisms of these pathologic entities which remain obscure. Data collected from experiments among genetically manipulated animals enable us to better understand the pathophysiology of mammalian kidney and the underlying mechanisms of salt sensitive hypertension and to lay a foundation for the future development of new drugs, especially diuretics and antihypertensive drugs.

The first description of the renal tubules is attributed to Lorenzo Bellini in 1662 and four years later Marcello Malpighi described the glomerulus. In 1842 Sir William Bowman described the capsule that surrounds the Malpighian body and its connection with the renal tubule and introduced the "excretory" hypothesis of urine formation. In the same year, Carl Ludwig introduced the "filtration-reabsorption" hypothesis of urine formation. Bowman's hypothesis was accepted by the so-called "vitalists" and Ludwig's hypothesis by the so-called "mechanists". In the middle of this confliction, Jacob Henle described in 1862 the homonymous "U" shaped loop but his discovery has neglected. In 1942 Werner Kuhn, a physical chemist, proposed that the loop of Henle may be the natural analog of the hairpin countercurrent multiplication system which concentrates urine in mammalian kidneys. In 1951 Kuhn, Hargitay and Wirz showed experimentally that the loop of Henle was the most important part of the countercurrent multiplication system of urine-concentrating mechanism in mammalian kidneys. The new theory was accepted by English-speaking scientists later, in 1958, when Carl Gottschalk and Margaret Mylle published their experimental work and proved that Kuhn's theory was correct. Gottschalk summarized the evidence of the accumulated knowledge in 1962, three centuries after the first description of renal tubules and one century after description of Henle's loop.

The possible deleterious effect of meet consumption upon deterioration of renal disease was speculated from Lionel Beale as early as 1869. The first attempt to apply a very low protein diet in humans is attributed to Millard Smith who prescribed a diet consisting of 300 mg protein per day in a volunteer medical student for 24 days. Unfortunately, in early 20(th) century, prescribing very low protein diets among patients suffering from renal disease complicated with malnutrition and the medical practice of this era turned to the recommendation of high protein diets because it was believed that protein consumption is coupled with the strength of civilized man. In mid sixties Giordano and Giovanetti introduced low protein diets in the treatment of uremic patients but their efforts did not accepted from the medical community. Meanwhile the evolution of haemodialysis, peritoneal dialysis and transplantation as effective methods of treating end stage renal disease guided doctors and patients far from privative diets in the era of plenty. The rapidly increasing number of end stage renal disease patients needed substitution of renal function produced a tremendous increase of financial burden upon public health system expenditure and alternative measures of therapy, prevention and delaying chronic kidney disease searched. Unfortunately MDRD study failed to show convincing results of food protein restriction and blood pressure lowering in ameliorating deterioration of renal function and the majority of physicians turned to the practice of early dialysis in an attempt to avoid malnutrition. Despite the increasing knowledge and the appliance of certain guidelines in treating end stage renal disease patients, the morbidity and mortality remain high among this population. The search toward other possible toxic substances showed that phosphorus consumption with diet is another dangerous element exerting its deleterious effect in deteriorating renal function as well as increasing morbidity and mortality. Recently published epidemiological data suggest a very poor outcome of elderly patients, older than 80 years of age, undergoing substitution of renal function by dialysis or peritoneal dialysis and a lot of skepticism arise concerning the beneficial effect of diet and a rigorous effort of rehabilitation of these patients instead of substitution of renal function by either method.

The aim of this study was to seek the possible relationship between estimated glomerular filtration rate (e-GFR) and anthropometric indexes, lipids, insulin sensitivity, and metabolic syndrome risk factors among healthy children and adolescents. Sufficient evidence suggest that obesity is related with a novel form of glomerulopathy named obesity-related glomerulopathy (ORG) among adults, children, and adolescents. Glomerular filtration rate was estimated from serum creatinine in 166 healthy children and adolescents [79 males, 87 females; age 10.6 +/- 3.3 (3-18) years]. Anthropometric indexes and systolic and diastolic blood pressure were measured. Fasting insulin, glucose, creatinine, uric acid, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides were estimated. Insulin sensitivity was estimated from known formulas. The presence of certain metabolic syndrome risk factors was checked among the studied population. Boys showed higher e-GFR rates than girls (f = 8.49, p = 0.004). We found a strong positive correlation between e-GFR and body weight (r = 0.415), body mass index (BMI) (r = 0.28), waist circumference (r = 0.419), hip circumference (r = 0.364), birth weight (r = 0.164), systolic blood pressure (SBP) (r = 0.305), and mean arterial pressure (MAP) (r = 0.207). A negative correlation was found between e-GFR and fasting glucose (r = -0.19), total cholesterol (r = -0.27) and LDL-cholesterol (r = -0.26). Clustering of metabolic syndrome risk factors among certain individuals was correlated with higher e-GFR rates (f = 3.606, p = 0.007). The results of this study suggest that gender, anthropometric indexes, and SBP are strong positive determinants of e-GFR among children and adolescents. Waist circumference is the most powerful determinant of e-GFR. Fasting glucose and lipid abnormalities are negative determinants of e-GFR among the studied population. Clustering of metabolic syndrome risk factors is coupled with higher e-GFR rates.

Objective: To investigate the incidence of increased blood pressure among children and adolescents and its relation with the anthropometric indexes, fasting insulin, insulin sensitivity indexes and lipid levels., Background: Sufficient evidence suggests that the incidence of essential hypertension among children and adolescents is rapidly increased parallel to the incidence of obesity among these subjects., Methods: We investigated 154 school-aged children; 77 males and 77 females, aged 11.28+/-2.99 (4-18) years old. After an overnight (12 h) fasting, we measured the following: anthropometric parameters, insulin (micro units/ml), glucose (mg/dl), cholesterol (mg/dl), cholesterol-HDL (mg/dl), cholesterol-LDL (mg/dl), triglycerides (mg/dl), uric acid (mg/dl), systolic and diastolic blood pressure (BP) (mmHg), HOMA-R index, QUICKI index and estimated glomerular filtration rate (eGFR)., Results: Boys showed greater body weight than girls as well as greater height and waist circumference. High normal systolic and diastolic BP measurements were more frequent among boys (HN-SBP: 27.2% vs. 16.8%, P=0.002. HN-DBP: 23.3% vs. 16.8%, P=0.05), but girls showed a higher frequency of systolic and diastolic high BP (H-SBP: 5.2% vs. 3.8%, P=0.6 (NS). H-DBP: 10.4% vs. 3.8%, P=0.05). Girls showed higher insulin levels and HOMA-R index values than boys, as well as higher levels of total cholesterol, triglycerides and LDL-cholesterol. Boys exhibited greater values of estimated glomerular filtration rate than girls. The most important factors influencing systolic and diastolic BP were the waist circumference (central obesity) and the body weight. Fasting insulin levels showed a biphasic effect upon systolic and, especially, diastolic BP. Normoinsulinemia exhibited a positive effect upon systolic and diastolic BP but high insulin levels exhibited a negative effect upon diastolic BP. No considerable effect of lipid parameters was found upon BP., Conclusions: Our results suggest that anthropometric indexes, particularly central obesity and body weight play the most important role in BP control among children and adolescents. Girls exhibit greater frequency of high BP than boys, as well as greater frequency of other metabolic syndrome risk factors. Insulin levels and insulin sensitivity are important factors influencing BP control. Insulin, per se, plays a pivotal role in BP control, normoinsulinemia produce a positive effect upon BP, but high insulin levels exert a hypotensive action.

The prevalence of obesity among modern communities increases dramatically and trends to achieve the characteristics of an epidemic. Obesity is the result of a sedentary life style and increased food intake, which characterises western communities. Obesity is closely related to insulin resistance and hyperinsulinemia and the very frequent combination of obesity and NIDDM is characterised as "Diabesity". The behaviour of man in seeking food and the amount of food consumption is a complicated situation, which is regulated by the CNS and especially in the arcuate nucleus of the hypothalamus. A repertoire of neurohormonal actions, generated in peripheral tissues and integrated in the CNS, encompasses many peptides with orexigenic and anorexigenic actions. Two main hormones, insulin and leptin, accomplish the fine-tuning of these peptides action at the critical level of body weight and energy control. The high prevalence of insulin resistance and hyperinsulinemia in obesity indicates a causative relationship between these two situations. It seems likely that insulin resistance in muscle cells is the prime "defect" which renders individuals vulnerable to obesity. The high prevalence of insulin resistance, about 25%, among otherwise healthy subjects indicates that this genetically determined "defect" may be the result of an evolutionary selection which rendered mankind capable of surviving during long periods of famine, in his long journey from the hunter-gatherer period of his life to the present time of plenty.

Background: Mild to moderate hyperhomocysteinemia is very common among patients undergoing haemodialysis. There is sufficient evidence that hyperhomocysteinemia is an independent risk factor for cardiovascular and or atheromatous disease in end stage renal failure patients. Vitamin supplementation such as vitamin B6, B12 or folate has been proposed to correct this metabolic disturbance and it is to be proved if this intervention benefit these patients, but there is no agreement whether oral folate supplementation is capable to normalize homocysteine levels in end stage renal failure patients., Methods: In 53 patients, undergoing haemodialysis, homocysteine levels (Hcy), folate, vitamin B12, ferritin and C-reactive protein (CRP) were estimated before and after dialysis, without folate supplementation. Thirty voluntary blood donors were used as controls to compare homocysteine levels. After four weeks of oral folate supplementation (10 mg/24 hours) the levels of homocysteine, serum folate and intra-erythrocyte folate were estimated again. Eighteen months later the survival rate of our patients was recorded and analyzed in relation to Hcy and CRP levels., Results: The results showed that haemodialysis patients exhibited, almost, fourfold higher homocysteine levels than controls (27.39 +/- 11.54 vs 7.38 +/- 3.5, t = -8.2, p = 0.000000). Folate levels, vitamin B12 and CRP increase significantly after haemodialysis where as homocysteine levels decrease (Hcy1 vs. Hcy2: z = 2.08, p = 0.03). Fourteen (14) patients suffered from coronary heart disease (CHD) and they exhibited the higher levels of homocysteine (Hcy1 vs. CHD: z = -3.4, p = 0.0006). All estimations performed revealed a negative correlation between homocysteine levels and plasma or intra-erythrocyte folate. No other variable exhibited any significant influence upon homocysteine levels. After folate supplementation homocysteine levels in the whole number of patients were unchanged (Hcy(before) vs. Hcy(after): 27.39 +/- 11.54 vs. 26.95 +/- 8.22, z = 0.3, p = 0.7, NS). When patients with homocysteine levels higher than 24 micromol/L were selected, a significant decrease was observed (34.77 +/- 9.32 vs. 30.0 +/- 8.05, z = 2.09, p = 0.02). Forty-two patients were treated with erythropoietin for their anemia and we found a positive correlation between C-reactive protein levels and rhu-Epo dose (CRP vs. Epo: r = 0.45, p = 0.002). Homocysteine levels did not exhibit any significant influence upon short-term survival (U = -0.37, p = 0.3, NS) where as CRP levels exhibit a significant influence upon short-term survival (U = 2.15, p = 0.005)., Conclusions: Homocysteine levels in haemodialysis patients are fourfold higher than healthy controls. Folate, vitamin B12 and CRP increases significantly after dialysis. Patients with coronary heart disease exhibit the highest levels of homocysteine. The homocysteine levels are inversely related with the folate levels. The exogenous folate supplementation increase the serum folate levels but decreases homocysteine only in patients with higher than mild hyperhomocysteinemia. Hcy doesn't exert any significant effect upon the short-term survival of the haemodialysis patients but CRP level is a god predictor of the short-term survival of these patients.

Insulin dependent diabetes mellitus (IDDM) is a disease predominantly affecting children and young adults. Over the last few decades, there has been an increase in the number of patients with IDDM which has almost doubled the incidence per generation. Evidence suggests that autoimmunity plays an important role in its pathogenesis. Diabetic nephropathy is a serious complication of IDDM, affecting about one-third of patients. It is accompanied by generalized micro- and macroangiopathy, neuropathy and arterial hypertension. Diabetic nephropathy is characterized by a long evolution, starting from microalbuminuria and, over 10-20 years, leading to end stage renal failure (ESRD). Microalbuminuria in children is reversible and by no means necessitates evolution to ESRD. Conversely, overt albuminuria inevitably progresses to ESRD irrespective of any known treatment. The principal pathogenic factors of diabetic nephropathy are glucose metabolic derangement and genetic predisposition, but to date no definite candidate gene(s) have been established as predisposing to the disease. Once diabetic nephropathy is established, it carries a high risk of morbidity and mortality because of the concurrent occurrence of other functional abnormalities, some of them life-threatening. Hemodialysis, peritoneal dialysis and renal transplantation are effective treatments of ESRD due to diabetic nephropathy, but recurrence of the disease in the renal transplant is very common among patients with IDDM unless renal transplantation is accompanied bypancreatic transplantation.

Objective: The long-term effects of the replacement of conventional heparin by low-molecular weight heparin (LMWH) on lipid parameters were examined in a large group of hemodialysis patients., Experimental Design: One-year prospective investigation., Setting: Renal units., Patients: A total of 93 patients aged 12-63 years old receiving hemodialysis for 51 (1-172) months were studied. None of the patients had primary hyperlipidemia, diabetes mellitus, or other secondary causes of dyslipidemia., Interventions: In all patients administration of LMWH was introduced in doses 2500-5000 units., Measures: Baseline values of lipoprotein profile prior to the intervention were compared with results obtained after 3, 6 and 12 months of LMWH., Results: During of LMWH treatment a small but statistically significant decrease of total and HDL cholesterol (from 200 +/- 45 mg/dl to 185 +/- 42 mg/dl, p < 0.01, and from 45 +/- 11 mg/dl to 42 +/- 10 mg/dl, p < 0.05, respectively), as well as Apo B (from 128 +/- 36 mg/dl to 121 +/- 35 mg/dl, p < 0.001) was noticed. Moreover, triglycerides decreased significantly (from 175 +/- 73 mg/dl to 146 +/- 62 mg/dl, p < 0.001). The beneficial effects of LMWH were more pronounced in patients with dyslipidemia (total cholesterol > 200 mg/dl, or triglycerides > 200 mg/dl) before the replacement of conventional heparin., Conclusion: The long-term use of LMWH instead of conventional heparin for anticoagulation during dialysis has beneficial effects on the lipoprotein profile, especially in patients with dyslipidemia.

Chronic hemodialysis (CHD) patients have a high incidence and prevalence of atherosclerotic disease which may be related to numerous atherosclerotic risk factors. Among them dyslipidemia plays a significant role. Elevated Lp(a) levels, which are strongly associated with atherosclerosis, have been reported recently in uremic patients. The aim of our study was the determination of the levels of lipid parameters including Lp(a) in 151 CHD patients (76 male) aged 57 (12-81) years, who were on hemodialysis for a mean of 44.3 (range 1 to 189) months. Eighty-four normal individuals age and sex matched were used as controls. The median serum Lp(a) concentration in hemodialysis patients was 13 mg/dL compared with 6.5 mg/dL in healthy controls, p < 0.001 by distribution-free Mann-Whitney test. The prevalence of subjects with Lp(a) levels above 25 mg/dL was significantly higher in CHD patients compared to normal subjects (30% vs. 8%, p < 0.001). Even if CHD patients were matched for fasting lipid levels, they showed Lp(a) levels significantly higher than controls. No significant correlation was found between Lp(a) levels and either the age of the patients or the duration of hemodialysis. The etiology of primary renal disease did not influence the Lp(a) levels.