Diabetologia

, Volume 57, Issue 6, pp 1249–1256 | Cite as

Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study

  • Abd A. Tahrani
  • Kiran Dubb
  • Neil T. Raymond
  • Safia Begum
  • Quratul A. Altaf
  • Hamed Sadiqi
  • Milan K. Piya
  • Martin J. Stevens
Article

Abstract

Aims/hypothesis

The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes.

Methods

We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR) < 60 ml min−1 1.73 m−2. CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability.

Results

Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (−9.0 ± 17.8% vs −3.3 ± 10.3%, p = 0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (β = −3.5, p = 0.03). Spectral analysis variables were also independent predictors of eGFR decline.

Conclusions/interpretation

CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.

Keywords

Albuminuria Autonomic neuropathy Cohort study Diabetic nephropathy Estimated glomerular filtration rate Macroalbuminuria Microalbuminuria Type 2 diabetes 

Abbreviations

ACR

Albumin/creatinine ratio

CAN

Cardiac autonomic neuropathy

CKD

Chronic kidney disease

DN

Diabetic nephropathy

E/I

Expiratory/inspiratory

ESRD

End-stage renal disease

HRV

Heart rate variability

LFa

Low-frequency area

pNN50

Percentage of adjacent R–R intervals that varied by more than 50  ms

RAAS

Renin–angiotensin–aldosterone system

RFa

Respiratory-frequency area

RMSSD

Square root of the mean squared differences of successive RR intervals

RRT

Renal replacement therapy

SDNN

Standard deviation of normal RR intervals

Supplementary material

125_2014_3211_MOESM1_ESM.pdf (853 kb)
ESM(PDF 853 kb)

References

  1. 1.
    Leiter LA (2005) The prevention of diabetic microvascular complications of diabetes: is there a role for lipid lowering? Diabetes Res Clin Pract 68:S3–S14PubMedCrossRefGoogle Scholar
  2. 2.
    Bakris GL (2011) Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc 86:444–456PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Dronavalli S, Duka I, Bakris GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract End Metab 4:444–452CrossRefGoogle Scholar
  4. 4.
    Afghahi H, Cederholm J, Eliasson B et al (2011) Risk factors for the development of albuminuria and renal impairment in type 2 diabetes—the Swedish National Diabetes Register (NDR). Nephrol Dial Transplant 26:1236–1243PubMedCrossRefGoogle Scholar
  5. 5.
    Low PA, Benrud-Larson LM, Sletten DM et al (2004) Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 27:2942–2947PubMedCrossRefGoogle Scholar
  6. 6.
    Gæde P, Vedel P, Larsen N, Jensen GVH, Parving HH, Pedersen O (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383–393PubMedCrossRefGoogle Scholar
  7. 7.
    Ziegler D, Mayer P, Mühlen H, Gries FA (1991) The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34:822–829PubMedCrossRefGoogle Scholar
  8. 8.
    Valensi P, Pariès J, Attali JR (2003) Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications the French multicenter study. Metabolism 52:815–820PubMedCrossRefGoogle Scholar
  9. 9.
    Joles JA, Koomans HA (2004) Causes and consequences of increased sympathetic activity in renal disease. Hypertension 43:699–706PubMedCrossRefGoogle Scholar
  10. 10.
    Kuehl M, Stevens MJ (2012) Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol 8:405–416PubMedCrossRefGoogle Scholar
  11. 11.
    Maser RE, Lenhard MJ (2005) Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab 90:5896–5903PubMedCrossRefGoogle Scholar
  12. 12.
    Spallone V, Gambardella S, Maiello MR, Barini A, Frontoni S, Menzinger G (1994) Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients. Diabetes Care 17:578–584PubMedCrossRefGoogle Scholar
  13. 13.
    Sundkvist G, Lilja B (1993) Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care 16:773–779PubMedCrossRefGoogle Scholar
  14. 14.
    Kempler P, Amarenco G, Freeman R et al (2011) Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes. Diabetes Metab Res Rev 27:665–677CrossRefGoogle Scholar
  15. 15.
    Salman IM, Ameer OZ, Sattar MA et al (2011) Renal sympathetic nervous system hyperactivity in early streptozotocin-induced diabetic kidney disease. Neurourol Urodyn 30:438–446PubMedCrossRefGoogle Scholar
  16. 16.
    Luippold G, Beilharz M, Mühlbauer B (2004) Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 19:342–347PubMedCrossRefGoogle Scholar
  17. 17.
    Pop-Busui R, Kirkwood I, Schmid H et al (2004) Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 44:2368–2374PubMedCrossRefGoogle Scholar
  18. 18.
    Moran A, Palmas W, Field L et al (2004) Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes. Diabetes Care 27:972–977PubMedCrossRefGoogle Scholar
  19. 19.
    Sterner NG, Nilsson H, Rošen U, Lilja B, Sundkvist G (1997) Relationships among glomerular filtration rate, albuminuria, and autonomic nerve function in insulin-dependent and non-insulin-dependent diabetes mellitus. J Diabetes Complicat 11:188–193PubMedCrossRefGoogle Scholar
  20. 20.
    Smulders YM, Jager A, Gerritsen J et al (2000) Cardiovascular autonomic function is associated with (micro-)albuminuria in elderly Caucasian subjects with impaired glucose tolerance or type 2 diabetes: the Hoorn Study. Diabetes Care 23:1369–1374PubMedCrossRefGoogle Scholar
  21. 21.
    Duvnjak L, Vuckoviç S, Car N, Metelko Ž (2001) Relationship between autonomic function, 24-h blood pressure, and albuminuria in normotensive, normoalbuminuric patients with type 1 diabetes. J Diabetes Complicat 15:314–319PubMedCrossRefGoogle Scholar
  22. 22.
    Lafferty AR, Werther GA, Clarke CF (2000) Ambulatory blood pressure, microalbuminuria, and autonomic neuropathy in adolescents with type 1 diabetes. Diabetes Care 23:533–538PubMedCrossRefGoogle Scholar
  23. 23.
    Poulsen PL, Ebbehøj E, Hansen KW, Mogensen CE (1997) 24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients. Diabetologia 40:718–725PubMedCrossRefGoogle Scholar
  24. 24.
    Forsén A, Kangro M, Sterner G et al (2004) A 14-year prospective study of autonomic nerve function in type-1 diabetic patients: association with nephropathy. Diabet Med 21:852–858PubMedCrossRefGoogle Scholar
  25. 25.
    Piya MK, Shivu GN, Tahrani A et al (2011) Abnormal left ventricular torsion and cardiac autonomic dysfunction in subjects with type 1 diabetes mellitus. Metabolism 60:1115–1121PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Colombo JP, Shoemaker WCM, Belzberg HM, Hatzakis GM, Fathizadeh PM, Demetriades DM (2008) Noninvasive monitoring of the autonomic nervous system and hemodynamics of patients with blunt and penetrating trauma. J Trauma Inj Infect Crit Care 65:1364–1373CrossRefGoogle Scholar
  27. 27.
    Vinik AI, Ziegler D (2007) Diabetic cardiovascular autonomic neuropathy. Circulation 115:387–397PubMedCrossRefGoogle Scholar
  28. 28.
    Spallone V, Ziegler D, Freeman R et al (2011) Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 27:639–653CrossRefGoogle Scholar
  29. 29.
    Bernardi L, Spallone V, Stevens M et al (2011) Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev 27:654–664CrossRefGoogle Scholar
  30. 30.
    Ziegler D, Laux G, Dannehl K et al (1992) Assessment of cardiovascular autonomic function: age-related normal ranges and reproducibility of spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses. Diabet Med 9:166–175PubMedCrossRefGoogle Scholar
  31. 31.
    Levey AS, Coresh J, Greene T et al (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–254PubMedCrossRefGoogle Scholar
  32. 32.
    Tahrani AA, Ali A, Raymond NT et al (2013) Obstructive sleep apnea and diabetic nephropathy: a cohort study. Diabetes Care 36:3718–3725PubMedCrossRefGoogle Scholar
  33. 33.
    Chronic Kidney Disease Prognosis Consortium (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375:2073–2081CrossRefGoogle Scholar
  34. 34.
    Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG (2006) Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 69:2057–2063PubMedCrossRefGoogle Scholar
  35. 35.
    Pugliese G, Solini A, Fondelli C et al (2011) Reproducibility of albuminuria in type 2 diabetic subjects. Findings from the Renal Insufficiency and Cardiovascular Events (RIACE) study. Nephrol Dial Transplant 26:3950–3954PubMedCrossRefGoogle Scholar
  36. 36.
    Molitch ME, Steffes M, Sun W et al (2010) Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care 33:1536–1543PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Zoppini G, Targher G, Chonchol M et al (2012) Predictors of estimated GFR decline in patients with type 2 diabetes and preserved kidney function. Clin J Am Soc Nephrol 7:401–408PubMedCrossRefGoogle Scholar
  38. 38.
    Abbott CA, Chaturvedi N, Malik RA et al (2010) Explanations for the lower rates of diabetic neuropathy in Indian Asians versus Europeans. Diabetes Care 33:1325–1330PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Tahrani AA, Askwith T, Stevens MJ (2010) Emerging drugs for diabetic neuropathy. Expert Opin Emerg Drugs 15:661–683PubMedCrossRefGoogle Scholar
  40. 40.
    Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625PubMedCrossRefGoogle Scholar
  41. 41.
    Krishnan AV, Kiernan MC (2007) Uremic neuropathy: clinical features and new pathophysiological insights. Muscle Nerve 35:273–290PubMedCrossRefGoogle Scholar
  42. 42.
    Nasrallah MP, Ziyadeh FN (2013) Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney. Semin Nephrol 33:54–65 (Abstract)PubMedCrossRefGoogle Scholar
  43. 43.
    Kramer HJNQ (2003) Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 289:3273–3277PubMedCrossRefGoogle Scholar
  44. 44.
    Tahrani AA, Ali A, Raymond NT et al (2012) Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med 186:434–441PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Abd A. Tahrani
    • 1
    • 2
  • Kiran Dubb
    • 1
  • Neil T. Raymond
    • 3
  • Safia Begum
    • 2
  • Quratul A. Altaf
    • 2
  • Hamed Sadiqi
    • 2
  • Milan K. Piya
    • 4
    • 5
  • Martin J. Stevens
    • 1
    • 2
  1. 1.Centre of Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, The Medical SchoolUniversity of BirminghamBirminghamUK
  2. 2.Department of Diabetes and EndocrinologyHeart of England NHS Foundation trustBirminghamUK
  3. 3.Division of Health Sciences, Warwick Medical SchoolUniversity of WarwickCoventryUK
  4. 4.Division of Metabolic and Vascular Health, Warwick Medical SchoolUniversity of WarwickCoventryUK
  5. 5.Warwickshire Institute for the Study of Diabetes, Endocrinology and MetabolismUniversity Hospitals Coventry and Warwickshire NHS TrustCoventryUK

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