Role of Acid-Base Homeostasis in Diabetic Kidney Disease
Purpose of Review
Acid-base homeostasis is impaired in chronic kidney disease (CKD) and may contribute to disease progression. Diabetes, a major cause of CKD worldwide, may exacerbate acidosis further due to differences in acid production and excretion. Here, we review the role of abnormal acid-base homeostasis in the pathogenesis and progression of diabetes and diabetic kidney disease.
Acidosis and dietary acid loading may contribute to the development and worsening of insulin resistance and hypertension, thereby promoting diabetes and diabetic CKD. However, although metabolic acidosis associates with progression of CKD generally, the results in diabetic CKD are mixed. Data suggests that metabolic acid production in diabetes may be higher than would be predicted based on dietary intake alone, and new observational data suggests that this higher diet-independent acid production could potentially be protective.
The role of acid-base homeostasis in diabetic CKD progression is complex and must consider differences in endogenous acid production and excretion in diabetes. Ongoing observational and interventional studies in this field should consider the unique physiology of diabetes.
KeywordsAcid load Acidosis Insulin resistance Diabetes Diabetic nephropathy CKD CKD progression
This work is supported in part by K23DK095949 (JS) from the National Institute of Diabetes and Digestive and Kidney Diseases, a Stead Resident Research Award from the Duke University Department of Medicine (PK), and the Duke O’Brien Center for Kidney Research (P30DK096493).
Compliance with Ethical Standards
Conflict of Interest
Pascale Khairallah declares that she has no conflicts of interest relevant to the content of this work.
Julia J. Scialla reports personal fees from Ultragenyx and modest research support from Eli Lilly.
Human and Animal Rights and Informed Consent
Any reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.United States Renal Data System. 2015 USRDS annual data report: epidemiology of Kidney Disease in the United States. Bethesda, MD; 2015.Google Scholar
- 5.Pohl MA, Blumenthal S, Cordonnier DJ, De Alvaro F, Deferrari G, Eisner G, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am Soc Nephrol. 2005;16(10):3027–37.PubMedCrossRefGoogle Scholar
- 12.Goldenstein L, Driver TH, Fried LF, Rifkin DE, Patel KV, Yenchek RH, et al. Serum bicarbonate concentrations and kidney disease progression in community-living elders: the Health, Aging, and Body Composition (Health ABC) Study. Am J Kidney Dis. 2014;64(4):542–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 13.•• Schutte E, Lambers Heerspink HJ, Lutgers HL, Bakker SJ, Vart P, Wolffenbuttel BH, et al. Serum bicarbonate and kidney disease progression and cardiovascular outcome in patients with diabetic nephropathy: a post hoc analysis of the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study and IDNT (Irbesartan Diabetic Nephropathy Trial). Am J Kidney Dis. 2015;66(3):450–8. Among approximately 2600 patients with type 2 diabetes and kidney disease enrolled in clinical trials of angiotensin receptor blockers, lower serum bicarbonate at enrollment was not associated with risk of progression to ESKD or doubling of serum creatinine after adjustment for kidney function. Google Scholar
- 53.Bobulescu IA, Maalouf NM, Capolongo G, Adams-Huet B, Rosenthal TR, Moe OW, et al. Renal ammonium excretion after an acute acid load: blunted response in uric acid stone formers but not in patients with type 2 diabetes. Am J Physiol Renal Physiol. 2013;305(10): F1498-F503.Google Scholar
- 54.•• Scialla JJ, Asplin J, Dobre M, Chang AR, Lash J, Hsu CY, et al. Higher net acid excretion is associated with a lower risk of kidney disease progression in patients with diabetes. Kidney Int. 2017;91(1):204–15. In this study of 980 participants with CKD, higher urine net acid excretion was associated with lower risk of progression to ESKD or 50% decline in kidney function among participants with diabetes, but not those without. Higher urine net acid excretion was independently associated with lower serum bicarbonate suggesting that it represented a higher non-volatile acid load. Interestingly, diet-dependent acid load ascertained by food frequency questionnaire was not associated with progression of CKD among the participants with diabetes, suggesting that the risk associated with low acid excretion could be related to diet-independent acid production. Google Scholar
- 56.• Mandel EI, Taylor EN, Curhan GC. Dietary and lifestyle factors and medical conditions associated with urinary citrate excretion. Clin J Am Soc Nephrol. 2013;8(6):901–8. Using a subset of participants from the Health Professionals Follow up Study and the Nurses Health Study with 24-hour urine collections available, these investigators found an independent association between diabetes mellitus and higher urine citrate. Typically, urine citrate falls with metabolic acidosis and lower urine pH, both common in diabetes. This finding may suggest that the production or reabsorption of citrate is impaired in diabetes. Google Scholar
- 60.DeFronzo RA, Beckles AD. Glucose intolerance following chronic metabolic acidosis in man. Am J Phys. 1979;236(4):E328–34.Google Scholar
- 67.Reaich D, Graham KA, Channon SM, Hetherington C, Scrimgeour CM, Wilkinson R, et al. Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. Am J Phys. 1995;268(1 Pt 1):E121–6.Google Scholar
- 69.• Bellasi A, Di Micco L, Santoro D, Marzocco S, De Simone E, Cozzolino M, et al. Correction of metabolic acidosis improves insulin resistance in chronic kidney disease. BMC Nephrol. 2016;17(1):158. In this post hoc analysis of 145 participants with type 2 diabetes, kidney disease, and serum bicarbonate less than 24 mEq/L, treatment with sodium bicarbonate vs. control for 1 year resulted in improvements in glucose control (HgA1c) and insulin resistance (homeostatic model assessment of insulin resistance). Improvement in these parameters correlated with the degree of improvement in serum bicarbonate. PubMedPubMedCentralCrossRefGoogle Scholar
- 70.Frassetto LA, Shi L, Schloetter M, Sebastian A, Remer T. Established dietary estimates of net acid production do not predict measured net acid excretion in patients with type 2 diabetes on Paleolithic-Hunter-Gatherer-type diets. Eur J Clin Nutr. 2013;67(9):899–903.PubMedPubMedCentralCrossRefGoogle Scholar
- 87.•• Fagherazzi G, Vilier A, Bonnet F, Lajous M, Balkau B, Boutron-Rualt MC, et al. Dietary acid load and risk of type 2 diabetes: the E3N-EPIC cohort study. Diabetologia. 2014;57(2):313–20. Among over 60,000 women in this French cohort, the risk of a new diagnosis of diabetes over 14 years of follow-up was higher for women consuming diets with higher diet-dependent acid load independent of total calorie intake and other lifestyle variables. Diet was assessed by self-report with a food frequency questionnaire, and results were similar if acid load was quantified as the potential renal acid load or the net endogenous acid production. PubMedCrossRefGoogle Scholar
- 106.• Banerjee T, Crews DC, Wesson DE, Tilea AM, Saran R, Rios-Burrows N, et al. High dietary acid load predicts ESRD among adults with CKD. J Am Soc Nephrol. 2015;26(7):1693–700. This study evaluated the relationship between higher diet-dependent acid load and risk of CKD progression to ESKD using data from participants with CKD 3-4 in the National Health and Nutrition Examination Survey. Diet-dependent acid load was estimated from dietary recalls. They found higher independent risk of ESKD with higher baseline diet-dependent acid load using competing risk regression to account for death. The risk was most pronounced in the group with albuminuria. Although the study included approximately 30% of participants with diabetes, stratified results were not described in this subgroup. Google Scholar
- 107.• Rebholz CM, Coresh J, Grams ME, Steffen LM, Anderson CA, Appel LJ, et al. Dietary acid load and incident chronic kidney disease: results from the ARIC study. Am J Nephrol. 2015;42(6):427–35. In this analysis out of the Atherosclerosis Risk in Communities Study in over 15,000 individuals, higher diet-dependent acid load ascertained by a food frequency questionnaire associated with new onset CKD over 21 years of follow-up. The study population included ∼11% who had diabetes, but stratified results were not described. PubMedCrossRefGoogle Scholar