Pediatr Nephrol DOI 10.1007/s00467-014-2873-9
REVIEW
Acidosis: progression of chronic kidney disease and quality of life Ione de-Brito Ashurst & Emma O’Lone & Tarun Kaushik & Kieran McCafferty & Muhammad M. Yaqoob
Received: 2 February 2014 / Revised: 23 May 2014 / Accepted: 30 May 2014 # IPNA 2014
Abstract Metabolic acidosis (MA) is relatively common in patients with chronic kidney disease (CKD) particularly in stages 4 and 5. It is assumed to play a contributory role in the development of several complications including bone disease, skeletal muscle wasting, altered protein synthesis, and degradation. Recent evidence also suggests that even mild acidosis might play a role in progressive glomerular filtration rate loss. Experimental and clinical studies suggest that correction of acidosis by alkali therapy attenuates these complications and improves quality of life. Despite several recent small and single-center studies supporting this notion, more robust evidence is required with regard to the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate.
Introduction Metabolic acidosis (MA) is relatively common in patients with advanced chronic kidney disease (CKD), particularly when the glomerular filtration rate falls below 30 ml/min and may affect approximately 30–50 % of such patients [1]. Progressive loss of renal function in CKD results in loss of the tubular capacity to generate sufficient ammonia to excrete the approximately 1 mmol/kg body weight of hydrogen ions produced daily in adults at physiological pH. When the excretory capacity of hydrogen ions by kidneys is sub-optimal, a I. de-Brito Ashurst : E. O’Lone : T. Kaushik : K. McCafferty : M. M. Yaqoob Department of Renal Medicine and Transplantation, Barts Health NHS Trust, Cardiovascular Biological Research Unit and William Harvey Research Institute, London, UK M. M. Yaqoob (*) Royal London Hospital, Whitechapel, E1 1BB London, UK e-mail: [email protected]
new steady state is achieved at the expense of a permanent reduction in blood pH, resulting in MA with an approximate positive acid balance of between 10 and 20 mmol/day. Metabolic acidosis adversely affects protein and muscle metabolism, bone turnover, and contributes to mineral bone disorders of uremia. MA is also associated with increased inflammatory mediators, insulin resistance, increased corticosteroid production, and parathyroid hormone (PTH) production. These metabolic consequences of MA may result in stunted growth in children, loss of bone and muscle mass, negative nitrogen balance and possible acceleration of progression to chronic renal failure due to hormonal and cellular abnormalities [2]. There is good experimental but limited clinical evidence suggesting that MA may lead to protein energy wasting (PEW) disorder in CKD patients [3] by several mechanisms, such as elevated protein catabolism from upregulation of the ubiquitin–proteasome system [4, 5], increased oxidation of branched chain amino acids [6], and reduced synthesis of visceral proteins, including albumin [7]. Several small and short-duration clinical trials conducted predominantly in patients with end-stage kidney disease (ESKD) have suggested that correction of acidosis is associated with increased concentrations of serum albumin and pre-albumin, a reduction in the normalised protein catabolic rate (nPCR) [8–10] and an increase in the levels of both branched chain and total essential amino acids [11, 12].
Evidence from pre-clinical studies Experimental studies in a few rodent models of CKD have indicated that MA is associated with the development and worsening of proteinuria, tubulo-interstitial fibrosis and acceleration in the rate of decline in renal function [13–15]. Mechanisms underlying the pathogenesis of progressive renal damage due to MA remain largely speculative. Excessive
Pediatr Nephrol
single-nephron ammonia production is a normal compensatory mechanism to excrete increased acid load per nephron in the setting of progressive renal mass loss. Excessive ammonia production per nephron results in a non-enzymatic activation of the alternative complement pathway in the renal interstitium, resulting in a chronic inflammatory state [14, 16]. This observation was subsequently borne out in a rat model of polycystic kidney disease (PKD). Rats with PKD demonstrated abnormal renal handling of citrate and ammonia. Citrate salts, which have alkalinising properties and have been shown to reduce ammonia generation, preserve renal function, reduce cyst growth. and prolong the life span of these animals [17]. In a different set of experiments, rats with CKD induced by surgical renal mass reduction given a casein diet developed MA and was associated with rapid decline of glomerular filtration rate (GFR). Interestingly, endothelin receptor A inhibitor was beneficial in raising the issue of acidosis-induced excessive endothelin production as another potential mechanism [18]. However, other studies in rats failed to reproduce the beneficial effect of alkali therapy on the rate of progression of chronic renal failure. In a 5/6 nephrectomy rodent model of CKD on a high dietary acid load, no beneficial effect of sodium bicarbonate on proteinuria, interstitial fibrosis or the rate of decline of renal function was seen [19]. By comparison, in rodents with CKD on high phosphate intake, MA was in fact reno-protective as it reduced the rate of progression of renal failure. This unusual but interesting finding was possibly due to the inhibition of calcium phosphate deposits in the kidney by acidosis [20, 21]. Moreover, correction of acidosis in the presence of hyperphosphatemia may theoretically promote extra-osseous ectopic calcification.
Evidence from clinical observations There is a paucity of studies examining the effects of MA correction by alkali or reducing dietary acid load on renal function in humans. In an earlier report from 1931, Lyon and Stewart [22] treated 17 CKD patients with both lowacid diets and sufficient oral supplementation with sodium bicarbonate and potassium citrate to maintain an alkaline urine pH for a few weeks to months. This observation formed the basis of a new concept with regard to strategies to reduce the acid burden on the kidney in order to stabilise or temporarily improve renal function. In a subsequent short-term study, administration of oral sodium bicarbonate to patients with mild to moderate renal failure led to reduced renal tubular peptide catabolism and ammonia production, resulting in attenuation of proximal tubular damage as assessed by urinary biomarkers [23]. Because of the short-term follow-up, no substantial impact on renal function could be demonstrated. In a recent small prospective observational study that we undertook, MA was independently associated with
acceleration of renal failure in CKD patients over a 2-year follow-up period (unpublished data). In a separate retrospective cohort study, over 5,000 adult CKD patients attending an outpatient setting were followed up for 5 years and assessed for the rate of decline of GFR longitudinally [24]. Progression of CKD was defined as either a fall in estimated GFR by 50 % or developing ESKD (n=337). In this ethnically diverse group of CKD patients with heterogeneous causes, bicarbonate levels of 22 mEq/L or less were associated with an increased risk of primary renal endpoints. However, the retrospective observational nature of this study fell short of establishing a cause and effect relationship between MA and progression of CKD. We have recently reported the results of a randomised controlled clinical trial examining the effect of oral sodium bicarbonate supplementation on progression of CKD in patients with non-dialysis-dependent CKD [25]. In this singlecenter study, we randomised 134 patients with CKD and mean creatinine clearance (CrCl) of around 20 ml/min to either standard care (control group) or additional administration of oral sodium bicarbonate titrated to reach a serum bicarbonate level of greater than 23 mmol/l (intervention group). The two groups were similar in their baseline demographic characteristics and clinical and biochemical parameters, including blood pressure control and proteinuria. At 24 months the mean rate of decline in CrCl was significantly lower in the intervention group than in the controls (−1.88±0.38 vs −5.93±0.39, P
REVIEW
Acidosis: progression of chronic kidney disease and quality of life Ione de-Brito Ashurst & Emma O’Lone & Tarun Kaushik & Kieran McCafferty & Muhammad M. Yaqoob
Received: 2 February 2014 / Revised: 23 May 2014 / Accepted: 30 May 2014 # IPNA 2014
Abstract Metabolic acidosis (MA) is relatively common in patients with chronic kidney disease (CKD) particularly in stages 4 and 5. It is assumed to play a contributory role in the development of several complications including bone disease, skeletal muscle wasting, altered protein synthesis, and degradation. Recent evidence also suggests that even mild acidosis might play a role in progressive glomerular filtration rate loss. Experimental and clinical studies suggest that correction of acidosis by alkali therapy attenuates these complications and improves quality of life. Despite several recent small and single-center studies supporting this notion, more robust evidence is required with regard to the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate.
Introduction Metabolic acidosis (MA) is relatively common in patients with advanced chronic kidney disease (CKD), particularly when the glomerular filtration rate falls below 30 ml/min and may affect approximately 30–50 % of such patients [1]. Progressive loss of renal function in CKD results in loss of the tubular capacity to generate sufficient ammonia to excrete the approximately 1 mmol/kg body weight of hydrogen ions produced daily in adults at physiological pH. When the excretory capacity of hydrogen ions by kidneys is sub-optimal, a I. de-Brito Ashurst : E. O’Lone : T. Kaushik : K. McCafferty : M. M. Yaqoob Department of Renal Medicine and Transplantation, Barts Health NHS Trust, Cardiovascular Biological Research Unit and William Harvey Research Institute, London, UK M. M. Yaqoob (*) Royal London Hospital, Whitechapel, E1 1BB London, UK e-mail: [email protected]
new steady state is achieved at the expense of a permanent reduction in blood pH, resulting in MA with an approximate positive acid balance of between 10 and 20 mmol/day. Metabolic acidosis adversely affects protein and muscle metabolism, bone turnover, and contributes to mineral bone disorders of uremia. MA is also associated with increased inflammatory mediators, insulin resistance, increased corticosteroid production, and parathyroid hormone (PTH) production. These metabolic consequences of MA may result in stunted growth in children, loss of bone and muscle mass, negative nitrogen balance and possible acceleration of progression to chronic renal failure due to hormonal and cellular abnormalities [2]. There is good experimental but limited clinical evidence suggesting that MA may lead to protein energy wasting (PEW) disorder in CKD patients [3] by several mechanisms, such as elevated protein catabolism from upregulation of the ubiquitin–proteasome system [4, 5], increased oxidation of branched chain amino acids [6], and reduced synthesis of visceral proteins, including albumin [7]. Several small and short-duration clinical trials conducted predominantly in patients with end-stage kidney disease (ESKD) have suggested that correction of acidosis is associated with increased concentrations of serum albumin and pre-albumin, a reduction in the normalised protein catabolic rate (nPCR) [8–10] and an increase in the levels of both branched chain and total essential amino acids [11, 12].
Evidence from pre-clinical studies Experimental studies in a few rodent models of CKD have indicated that MA is associated with the development and worsening of proteinuria, tubulo-interstitial fibrosis and acceleration in the rate of decline in renal function [13–15]. Mechanisms underlying the pathogenesis of progressive renal damage due to MA remain largely speculative. Excessive
Pediatr Nephrol
single-nephron ammonia production is a normal compensatory mechanism to excrete increased acid load per nephron in the setting of progressive renal mass loss. Excessive ammonia production per nephron results in a non-enzymatic activation of the alternative complement pathway in the renal interstitium, resulting in a chronic inflammatory state [14, 16]. This observation was subsequently borne out in a rat model of polycystic kidney disease (PKD). Rats with PKD demonstrated abnormal renal handling of citrate and ammonia. Citrate salts, which have alkalinising properties and have been shown to reduce ammonia generation, preserve renal function, reduce cyst growth. and prolong the life span of these animals [17]. In a different set of experiments, rats with CKD induced by surgical renal mass reduction given a casein diet developed MA and was associated with rapid decline of glomerular filtration rate (GFR). Interestingly, endothelin receptor A inhibitor was beneficial in raising the issue of acidosis-induced excessive endothelin production as another potential mechanism [18]. However, other studies in rats failed to reproduce the beneficial effect of alkali therapy on the rate of progression of chronic renal failure. In a 5/6 nephrectomy rodent model of CKD on a high dietary acid load, no beneficial effect of sodium bicarbonate on proteinuria, interstitial fibrosis or the rate of decline of renal function was seen [19]. By comparison, in rodents with CKD on high phosphate intake, MA was in fact reno-protective as it reduced the rate of progression of renal failure. This unusual but interesting finding was possibly due to the inhibition of calcium phosphate deposits in the kidney by acidosis [20, 21]. Moreover, correction of acidosis in the presence of hyperphosphatemia may theoretically promote extra-osseous ectopic calcification.
Evidence from clinical observations There is a paucity of studies examining the effects of MA correction by alkali or reducing dietary acid load on renal function in humans. In an earlier report from 1931, Lyon and Stewart [22] treated 17 CKD patients with both lowacid diets and sufficient oral supplementation with sodium bicarbonate and potassium citrate to maintain an alkaline urine pH for a few weeks to months. This observation formed the basis of a new concept with regard to strategies to reduce the acid burden on the kidney in order to stabilise or temporarily improve renal function. In a subsequent short-term study, administration of oral sodium bicarbonate to patients with mild to moderate renal failure led to reduced renal tubular peptide catabolism and ammonia production, resulting in attenuation of proximal tubular damage as assessed by urinary biomarkers [23]. Because of the short-term follow-up, no substantial impact on renal function could be demonstrated. In a recent small prospective observational study that we undertook, MA was independently associated with
acceleration of renal failure in CKD patients over a 2-year follow-up period (unpublished data). In a separate retrospective cohort study, over 5,000 adult CKD patients attending an outpatient setting were followed up for 5 years and assessed for the rate of decline of GFR longitudinally [24]. Progression of CKD was defined as either a fall in estimated GFR by 50 % or developing ESKD (n=337). In this ethnically diverse group of CKD patients with heterogeneous causes, bicarbonate levels of 22 mEq/L or less were associated with an increased risk of primary renal endpoints. However, the retrospective observational nature of this study fell short of establishing a cause and effect relationship between MA and progression of CKD. We have recently reported the results of a randomised controlled clinical trial examining the effect of oral sodium bicarbonate supplementation on progression of CKD in patients with non-dialysis-dependent CKD [25]. In this singlecenter study, we randomised 134 patients with CKD and mean creatinine clearance (CrCl) of around 20 ml/min to either standard care (control group) or additional administration of oral sodium bicarbonate titrated to reach a serum bicarbonate level of greater than 23 mmol/l (intervention group). The two groups were similar in their baseline demographic characteristics and clinical and biochemical parameters, including blood pressure control and proteinuria. At 24 months the mean rate of decline in CrCl was significantly lower in the intervention group than in the controls (−1.88±0.38 vs −5.93±0.39, P
