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Allegheny General Hospital, WPAHS, Temple University School of Medicine, wpahs division of nephrology and hypertension Allegheny general hospital, wpahs, temple university school of medicine, Luis M. Ortega, luis M Ortega, Swati Arora" "autores" => array:5 [ 0 => array:3 [ "nombre" => "WPAHS" "apellidos" => "Division of Nephrology and Hypertension. Allegheny General Hospital, WPAHS, Temple University School of Medicine" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "wpahs" "apellidos" => "division of nephrology and hypertension Allegheny general hospital, wpahs, temple university school of medicine" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 2 => array:4 [ "nombre" => "Luis M." 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WPAHS, Temple University School of Medicine, Pittsburgh, Pennsylvania, USA, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "nephrology and hypertension, Allegheny general hosptial.WPAHS,Temple University School of Medicine, Pittsburgh, Pennsylvania, USA, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Acidosis metabólica y avance de la enfermedad renal crónica: incidencia, patogénesis y opciones terapéuticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11515_16025_38600_en_t211515i_copia.jpg" "Alto" => 2005 "Ancho" => 2166 "Tamanyo" => 927107 ] ] "descripcion" => array:1 [ "en" => "Randomized prospective trials in the use of oral bicarbonate in patients with CKD" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold"> </span></span></p><p class="elsevierStylePara">Metabolic acidosis traditionally defined as a reduction in serum bicarbonate (HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">-3</span></span>) concentration often associated with a reduction in blood PH, is a common accompaniment of progressive chronic kidney disease (CKD)<span class="elsevierStyleSup">.<span class="elsevierStyleSup">1</span></span> It originates from the reduced capacity of the kidney to synthesize ammonia (NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span>) and excrete hydrogen (H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>) ions. It can have adverse consequences on protein, muscle and bone metabolism through negative nitrogen balance, increased protein degradation and decreased albumin synthesis, leading to protein energy malnutrition, loss of lean body mass and muscle weakness. It can also affect bone turnover due to its buffer effect compensating for excess acid. This action interferes with vitamin D metabolism, developing osteomalacia and renal osteodytrophy in patients with renal impairment. The mechanisms underlying these effects appear to be complex, involving several different pathways.</p><p class="elsevierStylePara">There is a high incidence of CKD in the general population based on a cross-sectional analysis of the most recent National Health and Nutrition Examination survey (NHANES, from 1988-94 and 1990-2004).<span class="elsevierStyleSup">2</span> There is also a correlation between decreased GFR and decrease plasma HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> based on the concept of nephron loss and impairment of ammoniagenesis. The question is if metabolic acidosis could be linked to the progression of kidney disease and if so can its correction delay CKD progression.<span class="elsevierStyleSup">3</span> Metabolic acidosis may be corrected by oral HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> supplementation in CKD and dialysis patients by increasing the HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration in dialysis solutions. The absolute benefits of the correction of acidosis are not clearly identified and it is important to review the evidence. This evidence is very limited in pre-end-stage renal disease (ESRD) patients with lack of past or recent randomized control trials (RCT’s). Long term use of oral sodium HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> has not been evaluated in patients at risk for sodium overload especially nephrotic syndrome, hypertension or heart failure. Randomized control trials are needed to determine the benefits and risks of HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> therapy in preventing progression of CKD in pre-ESRD patients, targeting ideal HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span><span class="elsevierStyleSup"> </span>levels to initiate therapy with alkali agents. Di Iorio and colleagues in Italy will be conducting a prospective, multicenter, randomized, controlled trial looking at the correction of metabolic acidosis with oral HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> use and its influence in the progression of kidney disease. Randomization will involve 600 patients with CKD stages 3b and 4. Three hundred patients will receive oral sodium HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> or citrate.<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">EPIDEMIOLOGY</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Twenty six million Americans have evidence of kidney disease.<span class="elsevierStyleSup">2</span> A major determinant of serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> levels is kidney function. The exact prevalence of metabolic acidosis in patients with CKD is unknown. The Third National Health and Nutrition Examination Survey (NHANES III) analysis found a decrease in plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration with estimated glomerular filtration rate (eGFR)<span class="elsevierStyleSup">5</span> < than 20mL/min1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>. If hypobicarbonatemia caused by metabolic acidosis develops when eGFR is less < than 25% of normal parameters, it would be predicted that 300,000 to 400,000 individuals in the United States might have metabolic acidosis associated with CKD.<span class="elsevierStyleSup">6</span> After patients reach age 60 plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration is less than normal (12% of the population) and a great number of individuals could develop CKD related metabolic acidosis.<span class="elsevierStyleSup">7</span> Eighty percent of patients will manifest hypobicarbonatemia when GFR decreases to less than 20-25% of normal. The metabolic acidosis is mild in degree, with plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration between 12mEq/L and 22mEq/L.<span class="elsevierStyleSup">8</span> It is rare to have plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> values < than 12mEq/L in the absence of increments in dietary acid load or superimposed tubular defect in bicarbonate absorption or generation.<span class="elsevierStyleSup">9</span> On the other hand, 10 to 20% with stage 5 CKD, many of whom have diabetes, have a plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration close to 23mEq/L.<span class="elsevierStyleSup">10</span></p><p class="elsevierStylePara">There could be an inverse correlation between plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration and renal function. Widmer et al., evaluated forty one patients retrospectively showing an inverse linear relationship between serum carbon dioxide (CO<span class="elsevierStyleInf"><span class="elsevierStyleInf">2</span></span>) and serum creatinine, with a lower limit for serum CO<span class="elsevierStyleInf"><span class="elsevierStyleInf">2</span></span><span class="elsevierStyleInf"> </span>of 11mEq/L at a serum creatinine of 12 mg/dL.<span class="elsevierStyleSup">11</span> Data from the NHANES III<span class="elsevierStyleSup">12</span> showed that HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span>levels of 22mEq/L or less were present in 19% of those with eGFR of 15 to 29mL/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>. However, the exact prevalence of metabolic acidosis caused solely by CKD remains to be determined. Shah et al.<span class="elsevierStyleSup">13</span><span class="elsevierStyleSup"> </span>studied data from 5,422 patients with different comorbidities (diabetes 21%, HTN 41%) race (African-american 45%, Hispanics 11%) and gender (women 69%). Nine percent had GFR <60ml/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>. The lowest quartile of serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> (≤22 mEq/L) was associated with a 54% increased hazard of progression of kidney disease. After adjusting for potential confounders, the relative hazard ratio (rHR) for progression of kidney disease was 1.54 (95% confidence interval (CI) 1.13-2.09). The study was observational making causality difficult and lack of blood gas analysis could not rule out a respiratory component.</p><p class="elsevierStylePara">Lower serum HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> levels are associated with higher all-cause mortality in patients with moderate and advanced CKD. Kovesdy et al.<span class="elsevierStyleSup">14</span> evaluated a cohort of 1240 CKD patients (eGFR % 27.5±5.5 to 45.9±19.1). Multivariable-adjusted Cox models showed a U-shaped association with the highest mortality rate with serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> <22 mmol/L (95%CI) and the lowest mortality with serum bicarbonate of 26-29mmo/L, even after controlling for the confounding effect of nutritional status and inflammation. In 1094 patients,<span class="elsevierStyleSup">15</span> from the African American Study of Kidney Disease and Hypertension (AASK) cohort trial study, each 1mmo/L increase in serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> was associated with reduced risk of death (HR 0.942). One may speculate that protein-energy malnutrition may be related to acidemia and represents a risk factor for poor outcome in renal failure. Despite different clinical scenarios and covariants there is a correlation between worsening renal function and acidosis in the pre-ESRD population.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATHOGENESIS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleBold"> </span></span></p><p class="elsevierStylePara">An important function of the kidney is ammoniagnesis. Ammonia is produced in the proximal tubule from glutamine at a high rate. One half of renal NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> produced leaves via renal veins and the remainder is eliminated in the urine. </p><p class="elsevierStylePara">Patients with CKD present with normal and increased anion-gap metabolic acidosis at early and late stages respectively.<span class="elsevierStyleSup">9</span> The mechanism is the impaired renal bicarbonate generation with and without concomitant decreased bicarbonate absorption<span class="elsevierStyleSup">16</span> and retention of H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> ions.<span class="elsevierStyleSup">14</span> Total ammonium (NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>) excretion begins to fall when GFR <40 to 50mL/min. Widmer et al.,<span class="elsevierStyleSup">11</span> evaluated 41 patients in two different creatinine value groups in an ambulatory setting and 39 patients as controls (Table 1). The renal failure group presented with serum creatinine between 2, 4mg/dL (moderate renal failure subgroup), and 14.4mg/dl (severe renal failure subgroup) respectively. The control group’s serum creatinine ranged from 0.6 to 1.7mg/dl. Serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration was significantly lower in the moderate and severe groups in comparison with controls. Decrements in CO2 were proportional to the increment in serum creatinine and associated with increments in unmeasured anions, especially in the group with serum creatinine above 4mg/dl. There was no increment of unmeasured anions in the control group. In the other hand, serum Chloride (Cl‾ ) remained unchanged. In a retrospective analysis of 911 patients, Hakim et al.<span class="elsevierStyleSup">8</span> noted mixed normal and high anion gap metabolic acidosis, even early in the course of CKD. Dietary differences or abnormalities in gastrointestinal or renal absorption of organic/inorganic anions could account for the lower than expected anion gap in the early stages of renal failure. In fact serum anion gap could be altered by the accumulation of cations (calcium, magnesium or paraproteins).<span class="elsevierStyleSup">17</span> Kidney disease associated with more severe tubulointerstitial damage can be accompanied by more severe acidosis in the early stages of renal failure.<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara">Metabolic acidosis develops due to reduced renal mass and inability of the remaining nephrons to excrete the daily acid load through ammoniagenesis. The renal tubular production of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> is stimulated by intracellular acidosis. When the systemic acid load is modestly increased, balance is maintained by increase in NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> production and excretion. Failure to excrete sufficient NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> leads to the net retention of H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> ions and the development of metabolic acidosis. Defects in the ability to secrete NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> (proximal tubule) or H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> ions (distal tubule, type A intercalated cells), will translate into tubular acidosis through a pH dependent mechanism. Hyperkalemia, on the other hand, can induce intracellular alkalosis and also competes with potassium in the Na<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>/K<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>/2Cl<span class="elsevierStyleSup"><span class="elsevierStyleSup">‾</span></span> pump located in the thick ascending loop of Henle, diminishing NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> formation and preventing excretion of the acid load in the collecting tubules. As stated before single-nephron ammoniagenesis increases as compensation for decreased functioning nephrons.<span class="elsevierStyleSup">19</span> Generation of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> per nephron is increased but global ammoniagenesis is reduced. Decrease in urine NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> excretion is a reflection of decreased proximal renal tubular glutamine uptake and subsequent generation of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">4</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> and bicarbonate from α-ketoglutarate.<span class="elsevierStyleSup">20</span> Decreased in HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> generation from glutamine metabolism leaves the kidney dependent on bicarbonate generation from titratable acid excretion, which is later reduced in later stages of renal failure. Other mechanisms generating metabolic acidosis are: HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> wasting due to decrease absorption, with bicarbonate excretion ranging from 4.25% to 17.65% in uremic patients,<span class="elsevierStyleSup">21</span> hyporeninemic hypoaldosteronism, and impaired distal renal acidification.<span class="elsevierStyleSup">22</span></p><p class="elsevierStylePara">Several factors have been implicated in the progression of renal failure, in particular intraglomerular hypertension.<span class="elsevierStyleSup">23</span> Experimental studies in Wistar rats, subject to 5/6 nephrectomies, indicated that metabolic acidosis of CKD could have a role in exacerbating proteinuria, tubulointerstitial injury, and worsening renal failure.<span class="elsevierStyleSup">24</span> This data has not been confirmed in other animal studies where the presence of metabolic acidosis delayed the progression of renal failure through prevention of calcium phosphate deposits and increased renal clearance of phosphate and lesser degree of hyperparathyroidism.<span class="elsevierStyleSup">25</span></p><p class="elsevierStylePara">The levels of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> in vascular and cortical tissues are increased when maximally produced by the renal tubule. The factors which influence the production of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> in the kidney are angiotensin II, potassium and aldosterone, whose levels are increased in entities like renovascular hypertension.<span class="elsevierStyleSup">26</span> Increased concentration of angiotensin II stimulates ammoniagenesis as well as gluconeogenesis. Potassium depletion and administration of aldosterone may also increase ammoniagenesis.<span class="elsevierStyleSup">27</span></p><p class="elsevierStylePara">Four mechanisms have been suggested to explain acidosis induced renal injury:</p><p class="elsevierStylePara">1) Increased in NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span><span class="elsevierStyleBold"><span class="elsevierStyleBold"> </span></span>production<span class="elsevierStyleSup">28</span> and activation of the alternative complement pathway with generation of inflammatory mediators as well as alkalinization of the interstitium.<span class="elsevierStyleSup">29</span> Increased intrarenal ammonia reacts with the thioester bond in C3 and then induces C3b-like properties (form C3 covertase). Subsequent activation of the alternative pathway results in peritubular deposition of C3 and the membrane attack complex C5b-9 generating chemoattractants of tissue injury.<span class="elsevierStyleSup">30</span> On the other hand, there is lack of inflammation in the area of the renal medulla where there is increase NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"> </span>concentration<span class="elsevierStyleSup">.</span> High urea concentration can dissipate the cytotoxic effect of complement activated my NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span>. </p><p class="elsevierStylePara">2) H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> retention induces endothelin and aldosterone mediated GFR decline even before metabolic acidosis, as demonstrated in 2/3 nephrectomized rat models. Dietary alkali better preserved GFR than both endothelin and aldosterone receptor antagonist.<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">3) Acidosis induced aminoacid degradation through ubiquitin-proteasome with increased renal excretion of NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span>.</span><span class="elsevierStyleSup">32</span></p><p class="elsevierStylePara">4) Ammoniagenesis may cause renal injury by stimulating the hypertrophy of renal tubular cells.<span class="elsevierStyleSup">27</span></p><p class="elsevierStylePara">Renal damage through cell mediated immunity, involving the interaction of cross reacting antigens and antibodies with Tamm-Horsfall glycoproteins in the tubule has been described in patients with renal tubular acidosis with a concomitant urinary tract infection or autoimmune liver disease.<span class="elsevierStyleSup">33</span></p><p class="elsevierStylePara">As patient approaches ESRD plasma bicarbonate concentration tend to stabilize between 12-20mEq/L. A small number of this patients have a normal plasma HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> concentration and anion gap maybe due to decreased protein intake (decreased sulfate generation) and/or increased fruit intake (citrate)<span class="elsevierStyleSup">.<span class="elsevierStyleSup">34</span></span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">TREATMENT</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Bicarbonate supplementation preserves renal function in experimental CKD. Administration of either citrate or sodium bicarbonate to rats with CKD decreased the severity of tubulointerstitial disease and or the decline in GFR compared with controls receiving sodium chloride<span class="elsevierStyleSup">.<span class="elsevierStyleSup">28 </span></span>The chronic administration of base to Han.S-PRD rats (an animal model of polycystic kidney disease) decreased cyst enlargement and prevented development of interstitial inflammation, chronic fibrosis, and severe renal failure.<span class="elsevierStyleSup">35</span> The mechanisms underlying the decline in GFR with metabolic acidosis was examined in rats by Nath et al.<span class="elsevierStyleSup">28</span> These investigators provided evidence for a link between acidosis induced stimulation of renal NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> production by the kidney and progressive tubulointerstital injury, an effect initiated by activation of the complement cascade. Others have suggested that the stimulation of new HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> production in the kidney alkalinizes the interstitium encouraging precipitation of calcium in the kidney and renal injury.<span class="elsevierStyleSup">29</span> Finally, studies in rats using the remnant kidney model of CKD indicated that the decline in GFR was mediated in part by the actions of excess aldosterone and endothelin, the latter acting via activation of endothelin A receptors.<span class="elsevierStyleSup">36</span> The above mentioned studies suggest that metabolic acidosis when present can contribute to progression of CKD, and therefore base (alkali) treatment is warranted. Few studies have examined the effects of amelioration of metabolic acidosis on renal function in humans with CKD, not on renal replacement therapy (only three randomized underpowered controlled trials in ESRD).<span class="elsevierStyleSup">37</span> In short term studies, oral sodium HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> given to patients with moderate renal failure led to reduced protein catabolism, NH<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> production, and tubular damage.<span class="elsevierStyleSup">38</span></p><p class="elsevierStylePara">Three recently published studies tried to address this hypothesis (Table 2). Brito-Ashurst et al.,<span class="elsevierStyleSup">39</span> randomized 134 patients with creatinine clearance (CrCl) between 15-30ml/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span> and serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> 16 to 20mmol/L to either oral sodium HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> (600mg three times a week) or no treatment. Average age 54.7 years, mostly diabetics and hypertensives, 50% on an angiotensin converting inhibitor or angiotensin receptor blocker. Baseline blood pressure 124/75.5 in both groups, urinary protein g/24h 1.8-1.7 grams, in the control and HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> groups respectively. Two year follow up. Primary end point was rate of CrCl decline (>3 ml/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>) and ESRD (CrCl<10 ml/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>). Secondary end point was dietary protein intake. Decline in GFR was slower with HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> supplementation (CrCl 5.93 vs 1.88ml/min/1.73m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>; P<.0001). Fewer patients in the treated group developed ESRD (6.5% vs 33%). There was no mayor difference in the incidence of edema in both groups (30 and 39%). More patients in the supplementation group required hypertensive therapy adjustments (61 vs 48%); this can introduce a bias element since blood pressure elevation could alter glomerular filtration. Bicarbonate supplementation was also associated with increased dietary intake, and decreased protein catabolism and increased lean body mass. Lack of a placebo controlled group, a double blind-design and single center, difficults reproducibility.</p><p class="elsevierStylePara">Phisitkul et al.<span class="elsevierStyleSup">40</span> evaluated 59 patients with hypertensive nephropathy and metabolic acidosis in a prospective interventional study. His group randomized 59 patients to sodium (Na<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>) citrate (30) and no therapy (29). The hypothesis was that oral Na<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span>citrate (1mEq of bicarbonate/kg body weight per day in three divided doses) reduces endothelin production and tubulointerstitial injury in subjects with low GFR. Primary outcome was urine endothelin excretion (ET-1), secondary outcomes were changes in GFR by MDRD (modification in diet in renal disease) formula and by cystatin C derived GFR (GFRcys) (using the CKD-EPI equation). Urine N-acetyl-β-<span class="elsevierStyleInf"><span class="elsevierStyleInf">D</span></span>-glucosaminidase excretion was measured as a marker of tubulointerstitial injury. Baseline GFR was 33.4±8.4 and 33.0±8.5 in both groups. Average systolic blood pressure at 6 months was 132.1±6.3 and 132.4±6.2 in controls and treated patients respectively. At 30 months GFR MDRD and GFRcys declined in both groups but was lower in controls (GFR MDRD ml/min: 24.9±9.7 vs 29.5±8.8 and GFRcys ml/min: 23.0±6.05 vs 27.8±7.4 p-value <.0001). Urine endothelin excretion was lower in the Na<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> citrate group than in controls (4.83±1.47 vs 6.92±1.67 ng/g Cr P<.0001 at 30 months). No differences was noted in tubulointerstitial injury, as measured by urine N-acetyl-β-<span class="elsevierStyleInf"><span class="elsevierStyleInf">D</span></span>-glucosaminidase excretion (8.±2.92 vs 9.01±92.07U/g Cr). The study suggested that treatment of metabolic acidosis associated with low GFR due to hypertensive nephropathy ameliorates progressive kidney injury. Limitations were the lack of randomization of Na<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> citrate and the small population studied.</p><p class="elsevierStylePara">The same group<span class="elsevierStyleSup">41</span> randomized 120 patients to placebo, sodium chloride (NaCl) and sodium bicarbonate (NaHCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span>) in a prospective placebo controlled blinded interventional 5 year study. Approximate average GFR was 75.5±6.3ml/min, values that were lower in cysGFR determination. Systolic blood pressure ranged between 152.6±14.7 to 155.3±12.6 ml/min.</p><p class="elsevierStylePara">The GFR rate of change in the NaHCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleInf"> </span>group was lower than the placebo and NaCl groups (-1.47±0.19 ml/min per year, -2.13±0.19 ml/min per year, P=.014, -2.05±0.19 ml/min, P=.029, respectively). GFR was statistically higher in the NaHCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span><span class="elsevierStyleInf"><span class="elsevierStyleInf"> </span></span>group as compared with placebo but not with the NaCl group. By contrast, cysGFR was higher in the NaHCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleInf"> </span>group overall. Of interest, the net acid urinary excretion was lower in the NaHCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleInf"> </span>group in comparison with the placebo and NaCl groups respectively (19.2±5.4, 24.4±5.6, 24.9±5.9) which can explain that the HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> treated group had decreased intracellular acid generation, endothelin production and tubulointertitial injury. Limitations were again small groups and alkali effect on kidney creatinine and/or cystatin C handling, illustrating the need for a large scale study.</p><p class="elsevierStylePara">The magnitude of the hypobicarbonatemia present in patients with CKD is variable and, as stated previously, some patients can actually have normal serum HCO<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span><span class="elsevierStyleSup"><span class="elsevierStyleSup">-</span></span> even in the face of severe renal failure.<span class="elsevierStyleSup"><span class="elsevierStyleSup">34</span></span> Therefore, the threshold for initiation of base therapy in patients with CKD is important to establish. To address this point Wesson et al.<span class="elsevierStyleSup"><span class="elsevierStyleSup">31</span></span> examined the effect of alkali on the progression of renal failure in rats with <span class="elsevierStyleSup">2</span>/<span class="elsevierStyleInf"><span class="elsevierStyleInf">3</span></span> nephrectomy who had CKD without significant hypobicarbonatemia. Alkali therapy slowed the decline in GFR, an effect which was related to increased endothelin and aldosterone production. Renal H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> content in these rats was greater than that of Sham-operated controls, observations consistent with tissue acid retention despite the absence of a reduced serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span>. As mentioned before<span class="elsevierStyleSup">41</span> subsequent studies have corroborated the benefitial effects of sodium bicarbonate in the preservation of GFR. Wesson and collegues<span class="elsevierStyleSup">42</span> again examined weather human subjects with stage 2 CKD (GFR 60-90ml/min) with macroalbuminuria but not hypobicarbonatemia had evidence of H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> retention and increased levels of endothelin-1 and aldosterone compared with those with a GFR of >90 ml/min. Levels of these hormones were reduced after 30 days of bicarbonate therapy. They were not able to assess the acid content of the kidney but they indirectly evaluated acid content of tissues by the impact of a HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> bolus on serum HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> and urinary net acid excretion. These results suggest that tissue acid retention was greater in the CKD 2 group. Certain assumptions were made including similar total body buffering capacity in both groups. However based on their previous studies it is not unreasonable to expect H<span class="elsevierStyleSup"><span class="elsevierStyleSup">+</span></span> retention in humans as renal function declines even if serum bicarbonate is in normal values. It appears that in both animals and humans as renal function and the ability to eliminate the daily acid load decline, acid retention occurs, which secondarily stimulates endothelin and aldosterone production that contributes to a further decline in GFR.<span class="elsevierStyleSup">43</span> The effects of excess endothelin and aldosterone on the kidney might not be the only mechanism by which metabolic acidosis contributes to a decline in GFR. Provision of dietary alkali better preserves GFR than administration of endothelin and aldosterone receptor antagonists.<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">The trials mentioned above are the only human studies to date in patients with pre-ESRD that showed oral HCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span> as a therapeutic option with minimal side effects, inexpensive and with potential benefit in delaying progression of CKD.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">There is a high incidence of CKD in the general population.<span class="elsevierStyleSup">2</span> Metabolic acidosis presents early in kidney disease and could be associated with worsening renal function due to perhaps an immunological process, and increased mortality due to protein catabolism. Bicarbonate supplementation represents a therapeutic option easy to apply, economical, and almost devoided of side effects.</p><p class="elsevierStylePara">Alkali therapy could protect against the progression of CKD, especially in early stages with normal serum bicarbonate levels. The mechanisms by which NaHCO<span class="elsevierStyleSup"><span class="elsevierStyleSup">3</span></span><span class="elsevierStyleInf"> </span>therapy ameliorates nephropathy progression in unclear but nephrectomized animal models with reduced GFR provided insight to the hypothesis. Animals with reduced nephron mass and low GFR have acid retention compared with those with intact nephron mass despite no differences in serum acid-base parameters.<span class="elsevierStyleSup">44</span> Acid retention induces GFR decline mediated by tubulointerstitial injury through endothelin receptors.<span class="elsevierStyleSup">45</span></p><p class="elsevierStylePara">The paucity of well designed clinical trials in human subjects is counteracted by the good results obtained in these studies. The optimal therapeutic target as well as its efficacy and safety needs to be determined. The current situation, forces us to use the most practical resources in our armamentarium to try to delay, not to prevent unfortunately, the progression of kidney disease.</p><p class="elsevierStylePara">If confirmed by follow-up studies, implementation of this inexpensive and well tolerated therapy in at risk subjects could yield overall population and health system benefits by delaying the onset of kidney failure with its devastating effects on patient’s wellbeing and health care costs.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflict of interest</span></p><p class="elsevierStylePara">The authors declare that there is no conflict of interest associated with this manuscript.</p><p class="elsevierStylePara"><a href="grande/11515_16025_38600_en_t211515i_copia.jpg" class="elsevierStyleCrossRefs"><img src="11515_16025_38600_en_t211515i_copia.jpg" alt="Randomized prospective trials in the use of oral bicarbonate in patients with CKD"></img></a></p><p class="elsevierStylePara">Table 2. Randomized prospective trials in the use of oral bicarbonate in patients with CKD</p><p class="elsevierStylePara"><a href="grande/11515_16025_38602_en_t111515i_copia.jpg" class="elsevierStyleCrossRefs"><img src="11515_16025_38602_en_t111515i_copia.jpg" alt="Correlation of serum bicarbonate to changes in serum creatinine"></img></a></p><p class="elsevierStylePara">Table 1. Correlation of serum bicarbonate to changes in serum creatinine</p>" "pdfFichero" => "P1-E544-S3765-A11515-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437019" "palabras" => array:1 [ 0 => "Amoniaco" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437021" "palabras" => array:1 [ 0 => "Bicarbonato sódico" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437023" "palabras" => array:1 [ 0 => "ERC" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437025" "palabras" => array:1 [ 0 => "Acidosis metabólica" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437027" "palabras" => array:1 [ 0 => "Mortalidad" ] ] ] "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437020" "palabras" => array:1 [ 0 => "Ammonium" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437022" "palabras" => array:1 [ 0 => "Sodium bicarbonate" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437024" "palabras" => array:1 [ 0 => "CKD" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437026" "palabras" => array:1 [ 0 => "Metabolic acidosis" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437028" "palabras" => array:1 [ 0 => "Mortality" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">Hay una prevalencia importante de la acidosis metabólica en los pacientes que padecen enfermedad renal crónica, presentándose en niveles tempranos de pérdida de filtrado glomerular. La patogénesis se basa en la falta de síntesis de bicarbonato sérico con la acumulación de ácidos de naturaleza orgánica e inorgánica, ocasionando daño tubulointersticial a través de la retención de amoniaco y el depósito de complemento, aunque esta última hipótesis se ha cuestionado en el pasado. El uso empírico de bicarbonato oral representa una opción terapéutica interesante que ha sido utilizada en estudios clínicos recientes. La disponibilidad de bicarbonato de sodio oral en sus diversas formas representa una opción barata y simple de utilizar para decelerar la progresión de la enfermedad renal, sin mencionar las mejoras en el catabolismo proteico, la osteodistrofia renal y la mortalidad.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">In the chronic kidney disease population metabolic acidosis is prevalent presenting already in the early stages of renal dysfunction. The pathogenesis associates the lack of bicarbonate production with the accumulation of organic/inorganic acids and the development of tubulointerstitial damage through ammonium retention and complement deposition. The empiric use of oral sodium bicarbonate represents an interesting therapeutic option that has been documented in a few clinical trials in human subjects. The availability of oral sodium, in its diverse forms, represents an inexpensive and simple way of treating an entity that could hasten the progression of kidney disease, as well as protein catabolism, bone disease and mortality.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11515_16025_38600_en_t211515i_copia.jpg" "Alto" => 2005 "Ancho" => 2166 "Tamanyo" => 927107 ] ] "descripcion" => array:1 [ "en" => "Randomized prospective trials in the use of oral bicarbonate in patients with CKD" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11515_16025_38602_en_t111515i_copia.jpg" "Alto" => 307 "Ancho" => 2166 "Tamanyo" => 181512 ] ] "descripcion" => array:1 [ "en" => "Correlation of serum bicarbonate to changes in serum creatinine" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kraut JA, Kurtz I. 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Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors. Kidney Int 2008;73:192-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17978813" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003200000006/v0_201502091602/X2013251412002346/v0_201502091603/en/main.assets" "Apartado" => array:4 [ "identificador" => "35445" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Short Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003200000006/v0_201502091602/X2013251412002346/v0_201502091603/en/P1-E544-S3765-A11515-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251412002346?idApp=UINPBA000064" ]
Year/Month | Html | Total | |
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2024 November | 11 | 10 | 21 |
2024 October | 67 | 51 | 118 |
2024 September | 135 | 66 | 201 |
2024 August | 150 | 89 | 239 |
2024 July | 118 | 68 | 186 |
2024 June | 155 | 59 | 214 |
2024 May | 143 | 57 | 200 |
2024 April | 125 | 57 | 182 |
2024 March | 100 | 39 | 139 |
2024 February | 93 | 41 | 134 |
2024 January | 74 | 35 | 109 |
2023 December | 77 | 37 | 114 |
2023 November | 88 | 45 | 133 |
2023 October | 79 | 51 | 130 |
2023 September | 67 | 43 | 110 |
2023 August | 98 | 33 | 131 |
2023 July | 87 | 87 | 174 |
2023 June | 103 | 54 | 157 |
2023 May | 104 | 60 | 164 |
2023 April | 67 | 31 | 98 |
2023 March | 69 | 33 | 102 |
2023 February | 76 | 25 | 101 |
2023 January | 75 | 30 | 105 |
2022 December | 96 | 43 | 139 |
2022 November | 74 | 38 | 112 |
2022 October | 96 | 59 | 155 |
2022 September | 79 | 45 | 124 |
2022 August | 84 | 62 | 146 |
2022 July | 74 | 50 | 124 |
2022 June | 74 | 48 | 122 |
2022 May | 81 | 48 | 129 |
2022 April | 133 | 64 | 197 |
2022 March | 166 | 58 | 224 |
2022 February | 205 | 69 | 274 |
2022 January | 145 | 46 | 191 |
2021 December | 101 | 53 | 154 |
2021 November | 101 | 53 | 154 |
2021 October | 115 | 60 | 175 |
2021 September | 104 | 52 | 156 |
2021 August | 108 | 37 | 145 |
2021 July | 136 | 41 | 177 |
2021 June | 100 | 44 | 144 |
2021 May | 153 | 50 | 203 |
2021 April | 664 | 51 | 715 |
2021 March | 222 | 55 | 277 |
2021 February | 157 | 28 | 185 |
2021 January | 138 | 41 | 179 |
2020 December | 116 | 24 | 140 |
2020 November | 121 | 38 | 159 |
2020 October | 74 | 38 | 112 |
2020 September | 73 | 18 | 91 |
2020 August | 73 | 20 | 93 |
2020 July | 92 | 15 | 107 |
2020 June | 147 | 59 | 206 |
2020 May | 153 | 25 | 178 |
2020 April | 122 | 28 | 150 |
2020 March | 162 | 29 | 191 |
2020 February | 133 | 30 | 163 |
2020 January | 132 | 30 | 162 |
2019 December | 150 | 34 | 184 |
2019 November | 222 | 34 | 256 |
2019 October | 215 | 30 | 245 |
2019 September | 290 | 67 | 357 |
2019 August | 189 | 50 | 239 |
2019 July | 178 | 44 | 222 |
2019 June | 218 | 36 | 254 |
2019 May | 202 | 35 | 237 |
2019 April | 309 | 60 | 369 |
2019 March | 250 | 47 | 297 |
2019 February | 121 | 26 | 147 |
2019 January | 136 | 45 | 181 |
2018 December | 239 | 39 | 278 |
2018 November | 204 | 25 | 229 |
2018 October | 182 | 19 | 201 |
2018 September | 189 | 11 | 200 |
2018 August | 192 | 17 | 209 |
2018 July | 110 | 7 | 117 |
2018 June | 128 | 19 | 147 |
2018 May | 135 | 17 | 152 |
2018 April | 120 | 6 | 126 |
2018 March | 149 | 24 | 173 |
2018 February | 84 | 9 | 93 |
2018 January | 102 | 10 | 112 |
2017 December | 65 | 15 | 80 |
2017 November | 111 | 13 | 124 |
2017 October | 86 | 16 | 102 |
2017 September | 79 | 19 | 98 |
2017 August | 68 | 30 | 98 |
2017 July | 73 | 15 | 88 |
2017 June | 55 | 11 | 66 |
2017 May | 93 | 18 | 111 |
2017 April | 82 | 24 | 106 |
2017 March | 82 | 26 | 108 |
2017 February | 130 | 10 | 140 |
2017 January | 52 | 13 | 65 |
2016 December | 67 | 5 | 72 |
2016 November | 133 | 7 | 140 |
2016 October | 130 | 8 | 138 |
2016 September | 221 | 5 | 226 |
2016 August | 229 | 2 | 231 |
2016 July | 188 | 9 | 197 |
2016 June | 153 | 0 | 153 |
2016 May | 148 | 0 | 148 |
2016 April | 136 | 0 | 136 |
2016 March | 99 | 0 | 99 |
2016 February | 131 | 0 | 131 |
2016 January | 121 | 0 | 121 |
2015 December | 107 | 0 | 107 |
2015 November | 87 | 0 | 87 |
2015 October | 105 | 0 | 105 |
2015 September | 75 | 0 | 75 |
2015 August | 92 | 0 | 92 |
2015 July | 93 | 0 | 93 |
2015 June | 57 | 0 | 57 |
2015 May | 89 | 0 | 89 |
2015 April | 7 | 0 | 7 |