Journal of Nephrology

, Volume 32, Issue 2, pp 297–306 | Cite as

Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury

  • Paolo Greco
  • Giuseppe RegolistiEmail author
  • Umberto Maggiore
  • Elena Ferioli
  • Filippo Fani
  • Carlo Locatelli
  • Elisabetta Parenti
  • Caterina Maccari
  • Ilaria Gandolfini
  • Enrico Fiaccadori
Original Article



The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI).


We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58–88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject’s serum concentration–time data to model post-SLED rebound and predict the need for further treatments.


Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6–75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5–15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5–22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels.


A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.


Metformin Lactic acidosis Acute kidney injury Sustained low-efficiency dialysis Pharmacokinetics 


Author contributions

Research idea and study design: PG, GR, UM, EnFi; data acquisition: PG, ElFe, FF, EP, CM, IG; data analysis/interpretation: UM, GR, PG; statistical analysis: UM, GR; supervision and mentorship: EnFi, GR. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.



Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study, involving human participants, were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

40620_2018_562_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 KB)
40620_2018_562_MOESM2_ESM.doc (34 kb)
Supplementary material 2 (DOC 34 KB)
40620_2018_562_MOESM3_ESM.doc (29 kb)
Supplementary material 3 (DOC 29 KB)


  1. 1.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al (2015) Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38:140–149CrossRefGoogle Scholar
  2. 2.
    Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA et al (2016) Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm. 2016 Executive summary. Endocr Pract 22:84–113CrossRefGoogle Scholar
  3. 3.
    Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589CrossRefGoogle Scholar
  4. 4.
    Lalau JD, Arnouts P, Sharif A, De Broe ME (2015) Metformin and other antidiabetic agents in renal failure patients. Kidney Int 87:308–322CrossRefGoogle Scholar
  5. 5.
    Lalau JD, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N (2017) Metformin-associated lactic acidosis (MALA): moving towards a new paradigm. Diabetes Obes Metab 19:1502–1512CrossRefGoogle Scholar
  6. 6.
    Weisberg LS (2015) Lactic acidosis in a patient with type 2 diabetes mellitus. Clin J Am Soc Nephrol 10:1476–1483CrossRefGoogle Scholar
  7. 7.
    Calello D, Liu KD, Wiegand TJ, Roberts DM, Lavergne V, Gosselin S et al (2015) Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the extracorporeal treatments in poisoning workgroup. Crit Care Med 43:1716–1730CrossRefGoogle Scholar
  8. 8.
    Palevsky PM, Liu KD, Brophy PD, Chawla LS, Parikh CR, Thakar CV et al (2013) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 61:649–672CrossRefGoogle Scholar
  9. 9.
    James M, Bouchard J, Ho J, Klarenbach S, LaFrance JP, Rigatto C et al (2013) Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 61:673–685CrossRefGoogle Scholar
  10. 10.
    Fiaccadori E, Regolisti G, Cademartiri C, Cabassi A, Picetti E, Barbagallo M et al (2013) Efficacy and safety of a citrate-based protocol for sustained low-efficiency dialysis in AKI using standard dialysis equipment. Clin J Am Soc Nephrol 8:1670–1678CrossRefGoogle Scholar
  11. 11.
    Regolisti G, Antoniotti R, Fani F, Greco P, Fiaccadori E (2017) Treatment of metformin intoxication complicated by lactic acidosis and acute kidney injury: the role of prolonged intermittent hemodialysis. Am J Kidney Dis 70:290–296CrossRefGoogle Scholar
  12. 12.
    Frid A, Sterner GN, Löndahl M, Wiklander C, Cato A, Vinge E et al (2010) Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 33:1291–1293CrossRefGoogle Scholar
  13. 13.
    D’Argenio DZ, Schumitzky A (1997) Adapt II release 4, user’s guide. In: Biomedical simulations resource. University of Southern California, Los AngelesGoogle Scholar
  14. 14.
    Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF (1981) Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 12:235–246CrossRefGoogle Scholar
  15. 15.
    Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546CrossRefGoogle Scholar
  16. 16.
    Luengo A, Sullivan LB, Heiden MG (2014) Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy. BMC Biol 12:82CrossRefGoogle Scholar
  17. 17.
    Boucaud-Maitre D, Ropers J, Porokhov B, Altman JJ, Bouanick B, Doucet J et al (2016) Lactic acidosis: relationship between metformin levels, lactate concentration and mortality. Diabet Med 33:1536–1543CrossRefGoogle Scholar
  18. 18.
    Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98CrossRefGoogle Scholar
  19. 19.
    Guideline development group (2015) Clinical Practice Guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR < 45 ml/min). Nephrol Dial Transpl 30(Suppl2):ii1–i142CrossRefGoogle Scholar
  20. 20.
    Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 84(3):1–150Google Scholar
  21. 21.
    National Institute for Health and Care Excellence. NICE guidelines [NG28] (2015) Type 2 diabetes in adults: management. Accessed 24 Nov 2017 (Published date: December 2015. Last updated: May 2017)
  22. 22.
    Inzucchi SE, Lipska J, Mayo H, Bailey CJ, McGuire DK (2014) Metformin in patients with type 2 diabetes and kidney disease, a systematic review. JAMA 312:2668–2675CrossRefGoogle Scholar
  23. 23.
    Lipska KJ, Bailey CJ, Inzucchi SE (2011) Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 34:1431–1437CrossRefGoogle Scholar
  24. 24.
    Lalau JD, Andrejak M, Morinière P, Coevoet B, Debussche X, Westeel PF et al (1989) Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int Clin Pharmacol Ther Toxicol 27:285–288Google Scholar
  25. 25.
    Xie F, Ke AB, Bowers GD, Zamek-Glisczynski MJ (2015) Metformin’s intrinsic blood-to-plasma partition ratio (B/P): reconciling the perceived high in vivo B/P> 10 with the in vitro equilibrium value of unity. J Pharmacol Exp Ther 354:225–229CrossRefGoogle Scholar
  26. 26.
    Heaney D, Majid A, Junor B (1997) Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transpl 12:1046–1047CrossRefGoogle Scholar
  27. 27.
    Chalopin JM, Tanter Y, Besancenot JF, Cabanne JF, Rifle G (1984) Treatment of metformin-associated lactic acidosis with closed recirculation bicarbonate buffered hemodialysis. Arch Intern Med 144:203–205CrossRefGoogle Scholar
  28. 28.
    Panzer U, Kluge S, Kreymann G, Wolf G (2004) Combination of intermittent haemodialysis and high-volume continuous haemofiltration for the treatment of severe metformin-induced lactic acidosis. Nephrol Dial Transpl 19:2157–2158CrossRefGoogle Scholar
  29. 29.
    Guo PY, Storsley LJ, Finkle SN (2006) Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 19:80–83CrossRefGoogle Scholar
  30. 30.
    Teutonico A, Libutti P, Lomonte C, Antonelli M, Casucci F, Basile C (2008) Treatment of metformin-associated lactic acidosis with sustained low-efficiency daily dialysis. NDT Plus 1:380–381Google Scholar
  31. 31.
    Angioi A, Cabiddu F, Conti M, Pili G, Atzeni A, Matta V et al (2018) Metformin associated lactic acidosis: a case series of 28 patients treated with sustained low-efficiency dialysis (SLED) and long term follow-up. BMC Nephrol 19:77CrossRefGoogle Scholar
  32. 32.
    Moioli A, Maresca B, Manzione A et al (2016) Metformin associated lactic acidosis (MALA): clinical profiling and management. J Nephrol 29:783–789CrossRefGoogle Scholar
  33. 33.
    Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Andréjak M, Lalau JD (2016) Unexpectedly long half-life of metformin elimination in cases of metformin accumulation. Diabet Med 33:105–110CrossRefGoogle Scholar
  34. 34.
    Seidowsky A, Nseir S, Houdret N, Fourrier F (2009) Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 37:2191–2196CrossRefGoogle Scholar
  35. 35.
    Chiew AL, Wright DFB, Dobos NM et al (2018) “Massive” metformin overdose. Br J Clin Pharmacol. Google Scholar

Copyright information

© Italian Society of Nephrology 2018

Authors and Affiliations

  • Paolo Greco
    • 1
  • Giuseppe Regolisti
    • 1
    Email author
  • Umberto Maggiore
    • 2
  • Elena Ferioli
    • 1
  • Filippo Fani
    • 1
  • Carlo Locatelli
    • 3
  • Elisabetta Parenti
    • 1
  • Caterina Maccari
    • 1
  • Ilaria Gandolfini
    • 2
  • Enrico Fiaccadori
    • 1
  1. 1.Acute and Chronic Renal Failure Unit, Department of Medicine and SurgeryUniversity of ParmaParmaItaly
  2. 2.Renal Transplant Unit, Department of Medicine and SurgeryUniversity of ParmaParmaItaly
  3. 3.Poison Control Centre and National Toxicology Information Centre, Toxicology UnitIstituti Clinici Scientifici Maugeri Spa-SB, IRCCS Pavia Hospital and University of PaviaPaviaItaly

Personalised recommendations