David Levy, MD, FRCP
Management of diabetic nephropathy
- Mid-stream urine if leucocytes on routine urinalysis.
- Renal tract ultrasound scan:
- a. Normal renal length is about 11 cm, correlating weakly with height and BMI; it is about 10 cm in South Asian and oriental subjects. Kidneys are large in the poorly controlled, hyperfiltering patient (see above) and the level of proteinuria is related to kidney size. Even in advanced diabetic renal disease the kidneys are not particularly small (∼10 cm), compared with the typically shrunken kidneys (∼8 cm) of advanced chronic non-diabetic renal disease. Adult polycystic kidney disease may coexist with diabetes, though the two conditions are not associated.
- b. Obstruction (stones, tumour, prostatic enlargement, papilla).
- c. Discrepancy in kidney size: if marked (i.e. > 1 cm), suggests renal artery stenosis (see below).
- d. Bladder size and residual volume (neuropathic bladder).
- Full blood count, CRP, ferritin, vitamin B12, folate, prostate-specific antigen.
- Fasting lipids.
- Bone screen, including parathyroid hormone (PTH) when eGFR
- 150 µmol/L (1.7 mg/dL). 12-lead ECG. Any hint of ischemia should be investigated early, though standard treadmill tests may be unhelpful because of the extensive diffuse coronary artery disease that occurs in diabetes, and poor exercise tolerance. The best non-invasive investigations in this group of patients are not known, and stress echocardiography, radionuclide scanning and CT scan for coronary artery calcium score all have their advocates.
- Regular measurement of albuminuria. An increase may herald nephrotic syndrome; a decrease may signify response to treatment….
Most guidelines suggest referral to a renal physician when eGFR is 40–50 mL/min or serum creatinine reaches about 150 µmol/L (2 mg/dL). Whether all these patients should remain under nephrology care, as opposed to only those with major risk factors for progression of renal impairment, is debated (see above). Younger or ethnic minority patients with heavy proteinuria or uncontrolled blood pressure should be prioritized. The greater problem is patients with rapidly progressing renal impairment, and many patients are referred far too late, with 30–40% of diabetic patients fulfilling the criterion for ‘late referral’, i.e. requiring renal replacement therapy within 4 months of referral. Many first attend the renal clinic with poorly controlled glycemia and blood pressure, and taking suboptimal angiotensin blockade treatment and lipid-lowering treatment. Anemia and renal bone disease are common.
Renal artery stenosis
Atherosclerotic renal artery stenosis affecting the ostium or proximal renal artery is common in type 2 diabetes. It is usually asymptomatic and considered where there is widespread macrovascular disease, hypertension, renal impairment and renal asymmetry on ultrasound. ‘Flash’ pulmonary oedema is characteristic, related to activation of the renin–angiontensin–aldosterone pathway. Duplex ultrasound (including assessment of intrarenal resistive index) and magnetic resonance arteriography are definitive investigations.
Longitudinal studies and historical fashion hinted that revascularization could slow the rate of decline in renal function (though there was no long-term benefit on blood pressure). However, the ASTRAL trial (2009) found that well-defined outcomes after revascularization (renal function or event(s), blood pressure, cardiovascular outcomes or death) were no different from a group given optimum medical treatment . The similar CORAL study has not yet reported, but the era of invasive management of atherosclerotic renal artery stenosis is probably coming to an end.
Proteinuria reduction and management of hypertension (Table 8.4)
Trial data in proteinuric type 1 patients is limited and quite old. Reducing blood pressure to less than 130/75 mmHg should result in remission or regression of proteinuria in 20–30% of patients, so long as full-dose ACE-i treatment is used.
In type 2 diabetes, two large-scale trials reporting in 2001 give clearer guidance. Full-dose ARB treatment (irbesartan in the IDNT study; losartan in the RENAAL study) significantly reduced progression from proteinuria to ESRD, with relatively modest achieved blood pressure (140/75, target < 135/85 mmHg), using on average three to four antihypertensive agents. In IDNT, the renal benefits of irbesartan were not matched by a group treated with amlodipine, despite similar blood pressure levels; amlodipine is an effective antihypertensive agent but does not reduce proteinuria. ACE inhibitors and ARBs have not been directly compared, though they are probably equally effective in reducing renal and cardiovascular end points, but there is some uncertainty over dose equivalents. In the AMADEO trial (2007), telmisartan 80 mg daily was slightly more effective and had a longer-lasting effect in reducing proteinuria than losartan 100 mg daily, but these differences are unlikely to be important in the individual.
However, patients in the IDNT and RENAAL studies had severe diabetic renal disease. Each year about 10% died, progressed to ESRD or doubled their serum creatinine. At baseline, they had moderate renal impairment (serum creatinine 150–170 µmol/L, 1.7–1.9 mg/dL), heavy proteinuria (ACR 140 mg/mmol, 1.25 g/g; or 2 g albumin per 24 hours). Lipids, blood pressure and glycemia were all poorly controlled. In IDNT, there was a clear relationship between the degree of albuminuria above 1 g per 24 hours and the rate of decline in renal function. Conversely, the greater the fall in proteinuria, the better the renal outcome. Unfortunately, these remain observations, and the factors influencing the response to angiotensin blockade are not known.
In addition to blood pressure control and angiotensin blockade with a single agent, more complex drug strategies have been used, but so far not in major RCTs. They are worth considering when responses to conventional management are not sufficiently effective, but they are not yet licensed.
High-dose ARB treatment
Proteinuria continues to fall more than blood pressure at very high ARB doses, three or four times the standard doses (e.g. irbesartan 900 mg daily, valsartan 640 mg daily). They appear to be safe and without increased risks of hyperkalemia or hypotension, but currently would be prohibitively expensive.
Lisinopril 40 mg daily has additional proteinuria- and blood pressure-reducing effects compared with 20 mg daily in proteinuric type 1 patients, and without increased adverse effects . This regimen is likely to be safer than combined ARB and ACE-i treatment (see below).
Low-dose spironolactone (25 mg daily) in addition to angiotensin blockade reduces proteinuria by about a further 30% in heavy proteinuria, but some of the effect may be related to blood pressure reduction. Hyperkalemia is a problem, but carefully monitored this may be a valuable agent in some patients. The selective aldosterone blocker eplerenone 50–100 mg daily also additionally reduces proteinuria, but is not licensed in diabetes, because of the high risk of hyperkalemia.
Combined ACE-i and ARB treatment
This combination was fashionable a few years ago in the management of both hypertension and proteinuria, based on a small study in diabetes that was not confirmed. A major clinical trial (VA NEPHRON-D) is studying the effects of losartan plus lisinopril versus losartan alone on the progression of diabetic nephropathy to hard renal end points. The ONTARGET study (2008) found that telmisartan and ramipril together reduced proteinuria more than ramipril alone, but hard renal end points (dialysis, doubling of serum creatinine and death) were increased on dual therapy and eGFR fell quicker. However, this was in a mixed population, albeit huge, and not primarily proteinuric diabetic patients. Although a cautious trial of combination treatment is worthwhile in heavy proteinuria that has not responded to maximum treatment with a single agent, it should not be used routinely and should be initiated and supervised by a specialist team. Near-complete blockade of the renin–angiotensin–aldosterone system may compromise physiological responses to acute hypovolemia, for example bleeding, vomiting or diarrhoea, with a risk of acute kidney injury. Advise patients taking combination therapy to stop both if there is vomiting or diarrhoea, and present to the emergency department.
Combined ARB and direct renin inhibitor (aliskiren) treatment
In the AVOID study (2008), aliskiren 300 mg and losartan 100 mg daily reduced ACR by 20% more than placebo, for a similar decrease in blood pressure (to 135/78 mmHg) . This is an encouraging combination, as is aliskiren and irbesartan 300 mg each daily, but the cardio-renal endpoint ALTITUDE study is not expected to report until 2012. Like combined ACE-i and ARB treatment, it may be worth a trial in individuals with heavy proteinuria, especially those who suffer ACE-i side-effects.
- Burrows NR, Li Y, Geiss LS. Incidence of treatment for end-stage renal disease among individuals with diabetes in the U.S. continues to decline. Diabetes Care 2010;33:73–7. PMID: 20040673.
- Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225–32. PMID: 12472787.
- Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol 2007;27:322–8. PMID: 17495429.
- Romão JE, Haiashi AR, Elias RM et al. Positive acute-phase inflammatory markers in different stages of chronic kidney disease. Am J Nephrol 2006;26: 59–66. PMID: 16508248.
- Houlihan CA, Tsalamandris C, Akdeniz A, Jerums G. Albumin to creatinine ratio: a screening test with limitations. Am J Kidney Dis 2002;39:1183–9. PMID: 12046029.
- Stoycheff N, Stevens LA, Schmid CH et al. Nephrotic syndrome in diabetic kidney disease: an evaluation and update of the definition. Am J Kidney Dis 2009;54:840–9. PMID: 19556043.
- Fonseca V, Thomas M, Katrak A, Sweny P, Moorhead JF. Can urinary thyroid hormone loss cause hypothyroidism? Lancet 1991;338:475–6. PMID: 1678446.
- Bilous R, Chaturvedi N, Sjølie AK et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 2009;151:11–20. PMID: 19451554.
- Ruggenenti P, Fassi A, Ilieva AP et al. Preventing microalbuminuria in type 2 diabetes. Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) investigators. N Engl J Med 2004;351:1941–51. PMID: 15516697.
- Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285–93. PMID: 12788992.
- Gæde P, Lund-Andersen H, Parving HH, Pederson O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–91. PMID: 18256393.
- House AA, Eliasziw M, Cattran DC et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 2010;303:1603–9. PMID: 20424250.
- The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009;361:1953–62. PMID: 19907042.
- Schjoedt KJ, Astrup AS, Persson F et al. Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 2009;52:46–9. PMID: 18974967.
- Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathy. AVOID Study Investigators. N Engl J Med 2008;358:2433–46. PMID: 18525041.
- Drechsler C, Krane V, Ritz E, März W, Wanner C. Glycemic control and cardiovascular events in diabetic hemodialysis patients. Circulation 2009;120:2421–8. PMID: 19948978.
- Agarwal R. Blood pressure and mortality among hemodialysis patients. Hypertension 2010;55:762–8. PMID: 20083728.
- Colhoun HM, Betteridge DJ, Durrington PN et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54:810–19. PMID: 19540640.
- Gal-Moscovici A, Sprague SM. Bone health in chronic kidney disease–mineral and bone disease. Adv Chronic Kidney Dis 2007;14:27–36. PMID: 17200041.
- New JP, Aung T, Baker PG et al. The high prevalence of unrecognized anaemia in patients with diabetes and chronic kidney disease: a population-based study. Diabetic Med 2008;25:564–9. PMID: 18445169.
- Agarwal R, Rizkala AR, Bastani B, Kaskas MO, Leehey DJ, Besarab A. A randomized controlled trial of oral versus intravenous iron in chronic kidney disease. Am J Nephrol 2006;26:445–54. PMID 17035697.
- Shapiro AMJ, Ricordi C, Hering BJ et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318–30. PMID: 17005949.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)