Urinary ammonia and long-term outcomes in chronic kidney disease
Authors: Marion Vallet, Marie Metzger, Jean-Philippe Haymann, Martin Flamant, Cédric Gauci, Eric Thervet, Jean-Jacques Boffa, François Vrtovsnik, Marc Froissart, Bénédicte Stengel, Pascal Houillier
Journal: Kidney International (2015)

Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1–4. All patients had measured glomerular filtration rate (mGFR) by 51Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m2. Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06–3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98–3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes. Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1–4. All patients had measured glomerular filtration rate (mGFR) by 51Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m2. Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06–3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98–3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes. In chronic kidney disease (CKD), the ability of the kidney to excrete the daily acid load declines1.Relman A.S. Renal acidosis and renal excretion of acid in health and disease.Adv Intern Med. 1964; 12: 295-347PubMed Google Scholar, 2.Schwartz W.B. Hall 3rd, P.W. Hays R.M. et al.On the mechanism of acidosis in chronic renal disease.J Clin Invest. 1959; 38: 39-52Crossref PubMed Google Scholar, 3.Wrong O. Davies H.E. The excretion of acid in renal disease.Q J Med. 1959; 28: 259-313PubMed Google Scholar and the prevalence of metabolic acidosis increases with the severity of the disease.4.Moranne O. Froissart M. Rossert J. et al.Timing of onset of CKD-related metabolic complications.J Am Soc Nephrol. 2009; 20: 164-171Crossref PubMed Scopus (326) Google Scholar,5.Clase C.M. Kiberd B.A. Garg A.X. Relationship between glomerular filtration rate and the prevalence of metabolic abnormalities: results from the Third National Health and Nutrition Examination Survey (NHANES III).Nephron Clin Pract. 2007; 105: c178-c184Crossref PubMed Scopus (58) Google Scholar The results of prospective studies suggest that alkali-based therapy efficiently delays CKD progression in patients with6.Phisitkul S. Khanna A. Simoni J. et al.Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR.Kidney Int. 2010; 77: 617-623Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar,7.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (630) Google Scholar or without overt metabolic acidosis.8.Goraya N. Simoni J. Jo C.H. et al.Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.Kidney Int. 2014; 86: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar,9.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar In cohort studies, a low plasma bicarbonate concentration is associated with increased mortality.10.Raphael K.L. Zhang Y. Wei G. et al.Serum bicarbonate and mortality in adults in NHANES III.Nephrol Dial Transplant. 2013; 28: 1207-1213Crossref PubMed Scopus (63) Google Scholar, 11.Kovesdy C.P. Anderson J.E. Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD.Nephrol Dial Transplant. 2009; 24: 1232-1237Crossref PubMed Scopus (199) Google Scholar, 12.Navaneethan S.D. Schold J.D. Arrigain S. et al.Serum bicarbonate and mortality in stage 3 and stage 4 chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 2395-2402Crossref PubMed Scopus (124) Google Scholar However, whether a low plasma bicarbonate level is a risk factor for a faster decline in the glomerular filtration rate (GFR) remains uncertain.11.Kovesdy C.P. Anderson J.E. Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD.Nephrol Dial Transplant. 2009; 24: 1232-1237Crossref PubMed Scopus (199) Google Scholar, 13.Kanda E. Ai M. Yoshida M. et al.High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients.BMC Nephrol. 2013; 14: 4Crossref PubMed Scopus (24) Google Scholar, 14.Menon V. Tighiouart H. Vaughn N.S. et al.Serum bicarbonate and long-term outcomes in CKD.Am J Kidney Dis. 2010; 56: 907-914Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 15.Shah S.N. Abramowitz M. Hostetter T.H. et al.Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Scialla et al.16.Scialla J.J. Appel L.J. Astor B.C. et al.Net endogenous acid production is associated with a faster decline in GFR in African Americans.Kidney Int. 2012; 82: 106-112Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar have recently studied in the AASK trial the association between net endogenous acid production (NEAP), the balance between fixed acid and alkali precursors in diet, and CKD progression. A higher NEAP was associated with a significantly faster decline in GFR. This could indicate that the daily acid load itself and/or the inability of the kidney to cope with the acid load is a risk factor for disease worsening in CKD patients. So far, most of the published studies have focused on the link between plasma bicarbonate level, a surrogate marker of the status of acid balance, and the decline in GFR. None has tested whether the impaired ability of the kidney to excrete the daily net acid load is an independent risk factor for the progression of CKD. Kidneys excrete the daily acid load mainly by generating and excreting ammonia (ammonia refers to the sum of NH4+ and NH3; as NH3 concentration is negligible in urine, ammonia concentration virtually equals that of NH4+) and to a lesser extent by excreting hydrogen ions as titratable acid (TA). Urinary excretion of ammonia decreases in parallel to GFR, whereas TA excretion is maintained until very advanced CKD stages.2.Schwartz W.B. Hall 3rd, P.W. Hays R.M. et al.On the mechanism of acidosis in chronic renal disease.J Clin Invest. 1959; 38: 39-52Crossref PubMed Google Scholar, 3.Wrong O. Davies H.E. The excretion of acid in renal disease.Q J Med. 1959; 28: 259-313PubMed Google Scholar, 17.Pitts R.F. The renal regulation of acid base balance with special reference to the mechanism for acidifying the urine. II.Science. 1945; 102: 81-85Crossref PubMed Scopus (7) Google Scholar We made the assumption that a low urinary ammonia excretion might be an earlier marker of the propensity to develop a positive acid balance (and hence metabolic acidosis) compared with plasma bicarbonate concentration. Therefore, we calculated the balance of fixed acid and compared the associations between plasma total CO2 (tCO2) level or urinary ammonia excretion and long-term outcomes including the rate of decline in GFR, the incidence of end-stage renal disease (ESRD), and mortality, in the NephroTest study cohort. Patients' mean age was 60±15 years and most were men (70.6%) (Table 1). Eighty per cent were on angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment at baseline. Median measured glomerular filtration rate (mGFR) was 37.6 ml/min per 1.73 m2 (interquartile range (IQR) 27.6–51.4). Fifty-four percent of the patients had CKD stage 3 and 31% had stage 4. Mean venous tCO2 concentration was 26±3 mmol/l, and only 8.3% of the patients had overt metabolic acidosis (defined by a venous tCO2 concentration below 22 mmol/l). Median NEAP was 56.3 mEq/24 h (IQR 44.4, 73.7). Median urinary 24-h ammonia excretion was 1.70 mEq/mmol creatinine (IQR 1.17–2.42) and median fasting ammonia concentration was 12.3 mEq/l (IQR 7.5–20.0). NEAP was not associated with mGFR, whereas 24-h ammonia excretion and fasting urinary ammonia concentration significantly decreased with decreasing baseline mGFR (Figure 1). Fasting urinary pH was inversely related to urinary ammonia excretion. No relation between body mass index (BMI), urinary phosphate or urinary urea nitrogen, and 24-h urinary ammonia excretion was observed in our study population.Table 1Population characteristics, mean±s.d., median (Q1–Q3), or % (n)NAll patientsSub-group of patients with ≥ 2 visitsSub-group of patients with 1 visitSub-group of patients with acid balance1065711354160Demographic Men70.6 (752)69.9 (497)72.0 (255)70.6 (113) Age, year60.1±14.958.9±14.862.4±14.762.2±13.9 Sub-Saharan African origin11.5 (118)11.4 (80)11.5 (38)9.4 (15) BMI26.5±5.026.2±4.927.0±5.026.1±4.1 Systolic/Diastolic BP, mm Hg138±21/75±12137±21/75±11139±21/75±12139±21/76±11 Diabetes29.0 (309)27.0 (192)33.1 (117)18.1 (29) History of cardiovascular disease20.5 (216)18.7 (131)24.1 (85)14.5 (23) History of smoking, past/current35.4 (377)/16.0 (170)36.1 (257)/17.0 (121)33.9 (120)/13.8 (49)40.6 (65)/13.1 (21)Renal function mGFR, ml/min per 1.73 m237.6 (27.6–51.4)37.7 (27.6–50.6)37.4 (27.5–53.4)39.1 (26.7–49.5) ≥6015.4(164)14.3 (102)17.5 (62)13.8 (22) 45–5920.8(221)21.7 (154)18.9 (67)21.3 (34) 30–4432.7(348)33.9 (241)30.2 (107)31.9 (51) 15–2931.2(332)30.1 (214)33.3 (118)33.1 (53) ACR, mg/mmol9.0 (1.8–47.9)9.8 (2.0–44.0)7.5 (1.7–60.4)7.2 (1.4– 31.7) PCR, mg/mmol30.0 (11.1–110.0)30.0 (11.8–102.3)29.0 (10.0–120.0)18.3 (9.9–60.2)Acid-base homeostasis Fasting urinary NH4 concentration, mEq/l12.3 (7.5–20.0)12.1 (7.3–19.8)13.0 (7.6–20.7)13.6 (8.7–18.9) Fasting urinary osmolality, mOsm/kgH2O487±139489±138483±143472±134 24-h urinary NH4 excretion, mEq/24 h18.5 (12.1–27.2)18.2 (12.0–26.6)18.9 (12.4–27.7)20.7 (15.7–29.1) 24-h urinary creatinine excretion, mmol/24 h11.6±4.311.8±4.211.1±4.412.9±5.4 24-h urinary NH4/creatinine mEq/mmol1.70 (1.17–2.42)1.66 (1.11–2.33)1.80 (1.28–2.53)1.74 (1.32–2.37) Venous total CO2, mmol/l26.0±3.026.0±2.926.1±3.125.9±3.0 Acidosis, tCO2<22 mmol/l8.3 (88)7.5 (53)9.9 (35)8.8 (14)Treatments Loop diuretics treatment33.9 (361)32.9 (234)35.9 (127)18.8 (30) Phosphate binders treatment1.0 (11)1.1(8)0.8(3)0.6 (1) ACEi or ARB treatment80.2 (854)82.7 (588)75.1 (266)91.3 (146)Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate; PCR, urinary protein-creatinine ratio; tCO2, total CO2. Open table in a new tab Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate; PCR, urinary protein-creatinine ratio; tCO2, total CO2. In a subset of our study population (n=160, Table 1), we measured 24-h net acid excretion (NAE) and calculated acid balance (Figure 2). Both urinary ammonia and TA excretions decreased with mGFR (r=0.30, P<0.0001 and r=0.16, P=0.05, respectively). NAE also significantly decreased with mGFR (r=0.22, P=0.004), mainly because of the decrease in ammonia excretion. Acid balance was not different from zero in patients with CKD stages 1 and 2 (P=0.2); it increased as mGFR declined (r=-0.28, P=0.0003), eventually being significantly positive in patients with CKD stage 4 (P<0.001) when most patients still had a normal blood tCO2 concentration. Acid balance was inversely and significantly related to urinary ammonia excretion (r=-0.38, P<0.0001) but not to venous tCO2 concentration (r=-0.12, P=0.13). During a median follow-up of 4.3 years (IQR 2.37, 6.53), 201 patients (18.9%) reached ESRD. A lower venous tCO2 level at baseline was associated with a higher risk of ESRD before and after stratification on mGFR, but this association was no longer significant after adjustment for other covariates (Figure 3; Table 2). Patients with overt metabolic acidosis were not at higher risk for ESRD after stratification on mGFR (Table 2).Table 2Hazard-ratios of ESRD according to venous total CO2 levels, 24-h urinary NH4/creatinine ratio, or fasting urinary NH4 concentration in all patientsNn eventsModel 0Model 1Model 2Model 3Venous total CO2, mmol/l ≥27.2379400.70 (0.46, 1.06)1.10 (0.72, 1.68)1.09 (0.71, 1.69) [24.8–27.2]336511 (ref)1 (ref)1 (ref) <24.83501102.32 (1.67, 3.24)1.50 (1.08, 2.11)1.26 (0.89, 1.79) P for trend<0.00010.040.3 P Wald test<0.00010.040.4 AcidosisaAcidosis: venous total CO2<22 mmol/l. No9771681 (ref)1 (ref)1 (ref) Yes88332.56 (1.76, 3.73)1.37 (0.93, 2.01)1.08 (0.72, 1.61)24-h NH4/creatinine ratio, mEq/mmol ≥2.11356381 (ref)1 (ref)1 (ref) [1.33, 2.11]355440.98 (0.63, 1.51)0.90 (0.58, 1.40)0.80 (0.51, 1.26) <1.333541192.78 (1.93, 4.01)1.52 (1.05, 2.20)1.41 (0.96, 2.08) P for trend<0.00010.0070.02Fasting NH4 concentration, mEq/l ≥17.0357221 (ref)1 (ref)1 (ref)1 (ref) [9.0–17.0]357562.66 (1.62, 4.35)1.53 (0.93, 2.53)1.48 (0.88, 2.47)1.37 (0.80, 2.34) <9.03511236.19 (3.93, 9.74)2.27 (1.42, 3.62)2.07 (1.27, 3.36)1.82 (1.06, 3.13) P for trend<0.00010.00020.0010.02Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate.Model 0: crude hazard ratio, Model 1: stratified for mGFR (15–20, 20–30, 30–40, 40–50, 50–60, >60 ml/min per 1.73 m2), Model 2: Model 1+adjustment for covariates: age, gender, sub-Saharan African origin, BMI (<25, 25–30, >30 kg/m2), BP>140/90 mm Hg (0,1), diabetes, history of cardiovascular disease, smoking (never, past, current), ACEi or ARB treatment, ACR (<3, 3–30, >30 mg/mmol), center. Model 3: Model 2+fasting urine osmolality.a Acidosis: venous total CO2<22 mmol/l. Open table in a new tab Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate. Model 0: crude hazard ratio, Model 1: stratified for mGFR (15–20, 20–30, 30–40, 40–50, 50–60, >60 ml/min per 1.73 m2), Model 2: Model 1+adjustment for covariates: age, gender, sub-Saharan African origin, BMI (<25, 25–30, >30 kg/m2), BP>140/90 mm Hg (0,1), diabetes, history of cardiovascular disease, smoking (never, past, current), ACEi or ARB treatment, ACR (<3, 3–30, >30 mg/mmol), center. Model 3: Model 2+fasting urine osmolality. The Kaplan–Meier survival curves showed a higher risk of ESRD in patients with urinary ammonia in the lowest tertile (Figure 3). Crude hazard ratio (HR) of ESRD was significantly higher in patients in the lowest 24-h urinary ammonia/creatinine ratio tertile as compared with patients in the first tertile (Table 2). This association remained statistically significant after taking mGFR and other covariates into account. The risk of ESRD associated with urinary ammonia/creatinine ratio was not linear, with the highest risk for patients with the lowest values of the ratio (Figure 4). Similar trend was observed when ammonia excretion was expressed in mEq/24 h. Regarding fasting urinary ammonia concentration, we observed a strong graded negative relationship with the risk of ESRD that remained statistically significant after stratification on mGFR and adjustment for the same covariates and fasting urine osmolality. Every 10 mEq/L decrease in fasting NH4 concentration was associated with a 43% increase in the risk of ESRD after stratification on mGFR and adjustment (HR 1.43, 95% confidence interval (CI) 1.09–1.86). In contrast with urinary 24-h ammonia/creatinine ratio, the linearity of the relationship between fasting urinary NH4 and ESRD risk was confirmed using regression splines (Figure 5). The HRs of ESRD and pre-ESRD mortality according to fasting NH4 concentration and adjustment covariates are shown in Supplementary Table 2. Further adjustment for nephropathy type did not significantly change the adjusted HR of ESRD. Download .doc (.06 MB) Help with doc files Supplementary Tables During follow-up, 160 patients (15%) died of whom 114 died before reaching ESRD. There was no association between venous tCO2 concentration and overall mortality before (HR 1.31, 95% CI 0.80–2.14) or after stratification on mGFR and adjustment for covariates (HR 0.96, 95% CI 0.80–2.14). Pre-ESRD mortality was significantly higher in patients with metabolic acidosis (HR 1.83, 95% CI 1.04–3.21), but this association was no longer significant after adjustment (HR 1.29, 95% CI 0.71–2.34). We did not find any association between urinary ammonia/creatinine ratio or fasting urinary ammonia concentration with mortality (data not shown). In patients with at least two mGFR measurements, mean time between the first and last mGFR was 3.9±2.0 years and the mean number of measures was 4.4±2.4. They were slightly younger and had less often diabetes mellitus and cardiovascular disease than those with one single mGFR measurement, but the two groups did not significantly differ with respect to baseline mGFR or acid-base status (Table 1). The median follow-up to events or census date was significantly higher in the former group than in the latter, 4.92 (2.95–7.00) vs. 2.92 years (1.49–5.33). Median slope of mGFR over time was -1.79 ml/min/year (IQR -3.82, 0.14), and median percent change was -4.39% per year (IQR -10.47, 0.25). One hundred and eighty-nine patients (26.6%) had a rate of decline in mGFR higher than 10% per year (fast rate of decline in mGFR). The odds ratio (OR) of fast mGFR decline was significantly higher in the lowest venous tCO2 tertile as compared with the middle tertile both before and after adjusting for mGFR and other covariates (Table 3). Regarding fasting ammonia concentration, there was a strong graded association with fast rate of decline in mGFR, similar to that observed for ESRD risk, which was also attenuated, but remained statistically significant after adjusting for covariates and further adjustment for fasting urinary osmolality (Table 3). It is worth noting that adding venous tCO2 in model 3 strengthened the association of both venous tCO2 and fasting ammonia concentration with fast mGFR decline: adjusted ORs for fasting ammonia concentration middle and first vs. last tertile, 1.85 (1.05–3.27) and 2.00 (1.05–3.82), respectively, and for venous tCO2 first and last vs. middle tertile, 2.02 (1.25–3.28) and 1.52 (0.91–2.56), respectively. Repeating the analysis using an absolute cutoff value of 4 ml/min/year instead of 10% per year yielded similar associations with slightly reduced OR for model 2: 1.52 (0.94, 2.47) for middle vs. last tertile of urinary fasting ammonium and 1.73 (1.03, 2.91) for first vs. last tertile.Table 3Odds ratio (95% CI) of fast mGFR decline (>10%/year) according to venous total CO2 levels, 24-h urinary NH4/creatinine ratio, or fasting urinary NH4 concentration in the subgroup of 711 patients with ≥2 visitsNn eventsModel 0Model 1Model 2Model 3Venous total CO2, mmol/l ≥27.2247510.98 (0.63, 1.52)1.53 (0.94, 2.47)1.55 (0.93, 2.59) [24.8–27.2]233491 (ref)1 (ref)1 (ref) <24.8231892.35 (1.56, 3.55)1.74 (1.12, 2.70)1.88 (1.17, 3.03) P for trend<0.00010.40.3 P Wald test<0.00010.040.03AcidosisaAcidosis: venous total CO2<22 mmol/l. No6581621 (ref)1 (ref)1 (ref) Yes53273.18 (1.80, 5.61)1.71 (0.93, 3.14)1.71 (0.89, 3.31)24-h NH4/creatinine ratio, mEq/mmol ≥2.11224541 (ref)1 (ref)1 (ref) [1.33, 2.11]229490.86 (0.55, 1.33)0.67 (0.42, 1.09)0.62 (0.37, 1.03) < 1.33258861.57 (1.05, 2.35)0.87 (0.56, 1.36)0.78 (0.48, 1.29) P for trend0.020.70.4Fasting NH4 concentration, mEq/l ≥17.0234291 (ref)1 (ref)1 (ref)1 (ref) [9.0–17.0]239652.64 (1.63, 4.28)1.79 (1.07, 2.98)1.89 (1.10, 3.23)1.76 (1.00, 3.08) <9.0238954.70 (2.94, 7.49)2.01 (1.20, 3.36)2.13 (1.23, 3.70)1.84 (0.98, 3.48)P for trend<0.00010.010.010.08Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARBs, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate.Model 0: crude odd ratio. Model 1: adjusted for mean mGFR. Model 2: Model 1+adjustment for covariates: age, gender, sub-Saharan African origin, BMI, mean blood pressure, diabetes, history of cardiovascular disease, smoking (never, past, current), ACEi or ARB treatment, ACR (<3, 3–30,>30 mg/mmol), center. Model 3: Model 2+fasting urine osmolality.a Acidosis: venous total CO2<22 mmol/l. Open table in a new tab Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, urinary albumin-creatinine ratio; ARBs, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; mGFR, measured glomerular filtration rate. Model 0: crude odd ratio. Model 1: adjusted for mean mGFR. Model 2: Model 1+adjustment for covariates: age, gender, sub-Saharan African origin, BMI, mean blood pressure, diabetes, history of cardiovascular disease, smoking (never, past, current), ACEi or ARB treatment, ACR (<3, 3–30,>30 mg/mmol), center. Model 3: Model 2+fasting urine osmolality. In our cohort of adult patients with CKD stages 1–4, urinary ammonia and NAE decrease with GFR, whereas NEAP does not. Therefore, patients with CKD develop a positive acid balance as CKD worsens. A lower urinary ammonia excretion or concentration is associated with a significantly higher risk of progression toward ESRD, and a lower concentration is also associated with fast mGFR decline. By contrast, a lower plasma tCO2 concentration is related with higher risk of mGFR decline but not with ESRD risk. We did not observe a relationship between the risk of death and venous tCO2 concentration or urinary ammonia excretion or concentration. The question whether patients with a low level of plasma tCO2 have a higher risk of CKD progression is still discussed. Several cohort studies found a significant association between low plasma bicarbonate levels and poorer renal outcomes.10.Raphael K.L. Zhang Y. Wei G. et al.Serum bicarbonate and mortality in adults in NHANES III.Nephrol Dial Transplant. 2013; 28: 1207-1213Crossref PubMed Scopus (63) Google Scholar, 13.Kanda E. Ai M. Yoshida M. et al.High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients.BMC Nephrol. 2013; 14: 4Crossref PubMed Scopus (24) Google Scholar, 15.Shah S.N. Abramowitz M. Hostetter T.H. et al.Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 18.Dobre M. Yang W. Chen J. et al.Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) Study.Am J Kidney Dis. 2013; 62: 670-678Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 19.Raphael K.L. Wei G. Baird B.C. et al.Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.Kidney Int. 2011; 79: 356-362Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Menon et al.14.Menon V. Tighiouart H. Vaughn N.S. et al.Serum bicarbonate and long-term outcomes in CKD.Am J Kidney Dis. 2010; 56: 907-914Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar in the Modification of Diet in Renal Disease cohort found an association that was, however, not independent of baseline mGFR value. In our study, the increased risk of ESRD associated with low venous tCO2 was independent of mGFR, but strongly attenuated by other confounders, whereas the risk for fast mGFR decline was independent of these factors. Within the last years, several interventional studies have tested the effect of alkali therapy (sodium bicarbonate or sodium citrate) or fruit and vegetable-enriched diet on the rate of decline in GFR.6.Phisitkul S. Khanna A. Simoni J. et al.Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR.Kidney Int. 2010; 77: 617-623Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 7.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (630) Google Scholar, 8.Goraya N. Simoni J. Jo C.H. et al.Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.Kidney Int. 2014; 86: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 9.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar Most studies have been conducted on small groups of patients and have used estimated rather than measured GFR; in addition, some of them were not randomized controlled trials. Every study found a protective effect of alkali therapy on the course of kidney function. The renal protective effect of alkali therapy was also observed in patients with early hypertensive nephropathy without overt metabolic acidosis.9.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar This protective effect of alkali therapy could be due to the attendant increase in plasma bicarbonate concentration or to the decrease in net acid load and acid balance. In accordance with the latter, higher NEAP associated with a faster rate of decline in GFR in patients with CKD16.Scialla J.J. Appel L.J. Astor B.C. et al.Net endogenous acid production is associated with a faster decline in GFR in African Americans.Kidney Int. 2012; 82: 106-112Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar and higher dietary acid load associated with reduced eGFR in the NHANES cohort.20.Banerjee T. Crews D.C. Wesson D.E. et al.Dietary acid load and chronic kidney disease among adults in the United States.BMC Nephrol. 2014; 15: 137Crossref PubMed Scopus (88) Google Scholar Moreover, lowering dietary acid load, by bicarbonate therapy or by fruit and vegetable-enriched diet, reduced the urinary indices of kidney injury in patients with hypertensive nephropathy stage 38.Goraya N. Simoni J. Jo C.H. et al.Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.Kidney Int. 2014; 86: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar or early stages of CKD.21.Goraya N. Simoni J. Jo C. et al.Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glome