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Practical Diabetes Care, 3rd Ed., Excerpt #15: Diabetic Renal Disease Part 4 of 5

David Levy, MD, FRCP

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Other management problems in diabetic nephropathy

Glycemic control
Once nephropathy is established, good control of blood pressure and lipids is probably more important than glycemic control. Observational studies abound and show that, for example, patients with advanced renal failure entering renal replacement programmes survive longer with a low HbA1c, orthathemodialysis patients with HbA1c above 8%(64 mmol/mol) have an increased risk of sudden death but not myocardial infarction compared with those with HbA1c of 6% (42 mmol/mol) or less [16]. Since nearly all patients with diabetic nephropathy will have advanced macrovascular disease, the cautions of ACCORD should probably be heeded more than observations, and reasonable control (e.g. HbA1c 7.5–8.5%, 59–69 mmol/mol), avoiding hypoglycemia, will probable serve patients well until formal RCTs of glycemic control in advanced diabetic renal disease are reported. Regardless, glycemic control is often difficult to achieve in renal impairment because of….

  • other diabetic complications associated with long-duration diabetes (e.g. hypoglycemia unawareness, gastroparesis);
  • decreasing insulin requirements with progressing renal impairment (due to decreased renal insulin clearance and degradation, though it is not a sufficiently reliable factor that insulin doses can be prophylactically reduced as renal impairment progresses, partly because renal failure is itself an insulin-resistant state);
  • changes in insulin requirements during and after dialysis sessions;
  • the need to discontinue or change doses of non-insulin drugs, and increasing reliance on insulin;
  • long-term poor control, partly responsible for the renal impairment itself.

In some, poor nutrition and appetite, decreased muscle and fat mass, and belated awareness of the need for good glucose control conspire to cause very low HbA1c levels. These cannot now be considered safe, but neither can double-figure HbA1c values.

Blood pressure
The benefits of blood pressure treatment in advanced CKD are not established, but home systolic blood pressure readings between dialysis sessions probably give better prognostic information than readings taken in the dialysis unit. Optimum systolic blood pressure is probably 120–130 mmHg, with increased cardiovascular mortality occurring with systolic blood pressure measurements above 180 or below 110–120 mmHg [17]. Antihypertensive treatment is surprisingly well tolerated in these patients. Angiotensin-blocking agents, beta-blockers and calcium channel blockers are all suitable; many patients will be taking loop diuretics.

Cardiac disease
Coronary artery disease is common but dyspnoea or atypical chest symptoms are more common than classical angina in these patients with very limited exercise tolerance. At the onset of dialysis, about 30% of patients have ischemic heart disease, and heart failure and concentric left ventricular hypertrophy (LVH) are very common. Events are distressingly frequent: type 2 hemodialysis patients have an 8% annual rate of myocardial infarction or coronary death, higher than the 6.6% rate reported in the placebo group of the pioneering 4S study. There is concern that repeated episodes of myocardial stunning during hemodialysis sessions may contribute to heart failure and poor survival. Heavy coronary artery and cardiac valvular calcification is very common, and nearly all type 1 patients have significant coronary artery disease, often with heavy calcification. As in patients with normal renal function, the best algorithm for investigation and management is not known. Resting ECG remains important, but few patients can do standard exercise tolerance tests. Routine two-dimensional echocardiography is limited but certain measurements (e.g. height-indexed left atrial volume) may be of prognostic value. Dobutamine stress echo is not currently recommended for patients with advanced CKD, but stress myocardial perfusion imaging and eventually cardiac MRI may be valuable. Pretransplantation coronary angiography is now routine, as is carotid Doppler scanning.

Lipids (see Chapter 12)
Any patient with any degree of albuminuria or renal impairment must take a statin in the long term. The cardiovascular benefits are at least as great as in patients with normal renal function. Early vigorous treatment, aiming for LDL 1.7–1.8 mmol/L (65–70 mg/dL) and probably lower, is needed. Delaying statin treatment until dialysis does not reduce the very high cardiovascular event rates (4D study, atorvastatin 20 mg daily, 2005; AURORA, rosuvastatin 10 mg daily, 2009), but most patients will have been treated for many years before entering ESRD. There was no excess of serious statin-related muscle side-effects in these studies (i.e. myositis and rhabdomyolysis), and although new proteinuria may occur in a very small proportion, it is tubular proteinuria that does not impact on renal function. In RCTs, statins (especially simvastatin in the HPS, and atorvastatin in CARDS) have a mildly beneficial effect on eGFR, reducing the rate of fall compared with placebo-treated patients. These benefits seem to be particularly great in proteinuric patients, although statins do not reduce new-onset proteinuria or increase regression to normoalbuminuria [18].

However, one study found that in heavily proteinuric non-diabetic patients treated with angiotensin blockers, atorvastatin halved proteinuria from about 2 g per 24 hours to 1 g per 24 hours over a year.

Other agents
Ezetimibe 10 mg daily combined with simvastatin 20 mg daily is safe and effective in pre-dialysis patients, although there are no end-point studies, but avoid fibrates, especially gemfibrozil, and statin–fibrate combinations. Fibrates, much less used now, increase serum creatinine. If increased creatinine synthesis is the reason (one view), then there should be no effect on renal function; another view is that they may decrease production of vasodilatory prostaglandins, and therefore have a real effect on renal function. Serum creatinine may increase by up to 30%, in which case the drug should be withdrawn. Fibrates and angiotensin-blocking agents used together can therefore cause an alarming increase in serum creatinine, especially in patients with impaired renal function; the fibrate should be withdrawn, as it is unlikely to be of prognostic value. High-dose w-3 fatty acids (e.g. Omacor 4 g daily) improve postprandial lipemia in the nephrotic syndrome.

Peripheral vascular disease
Peripheral vascular disease and neuro-ischemic foot lesions are common in patients with nephropathy and ESRD. Medial arterial calcification is widespread and leads to spuriously high systolic blood pressure measurements on Doppler testing (and is responsible for the severe systolic hypertension that is so difficult to manage). Absent foot pulses on clinical examination is the most reliable indicator of peripheral vascular disease in these patients, but the presence of peripheral oedema (stasis, venous disease, heart failure and hypoalbuminemia) makes evaluation of peripheral vasculature difficult. Assess ischemic limbs for suitability for angioplasty or vascular bypass. Small and medium arteries can be affected by a specific form of calcification known as calciphylaxis, usually occurring in dialysis patients. Severe skin necrosis and distal limb gangrene can occur. It is very difficult to treat; hyperbaric oxygen might help.

Neuropathy
Most patients with renal impairment will have advanced, though not always symptomatic, peripheral neuropathy. Many will have additional peripheral vascular disease, putting their feet at very high risk of ulceration and gangrene. Regular podiatrist supervision with intensification of input where required and education in foot care can reduce the frequency of serious foot lesions.

Retinopathy
This is extremely common. Type 1 patients may have ‘burned out’, previously laser-treated, but currently inactive retinopathy. Others suffer recurrent bleeding from proliferative retinopathy, with vitreous and preretinal hemorrhages, frustratingly even in the presence of good glycemic and blood pressure control. Maculopathy, with or without proliferative changes, with its associated risk of progressive and severe visual loss, is common in type 2 patients.

Renal bone disease
Difficult territory for the non-specialist, but now encompasses disturbed mineral metabolism, abnormalities of bone histology (renal osteodystrophy) and extraskeletal features, such as vascular calcification [19]. These all require specialist management, but significant bone disease can occur relatively early in diabetic CKD and both primary and secondary care teams need to be aware of it, as abnormalities of mineral metabolism and cardiovascular disease may be linked. Secondary hyperparathyroidism may occur as early as stage 2 CKD. Perform bone screen, including PTH, once eGFR is below 60mL/min (i.e. CKD stage 3 or worse), along with routine diabetes blood work. The spectrum of renal bone disease is wide, from adynamic bone disease and osteomalacia, associated with low PTH levels, to severe secondary hyperparathyroidism and classical osteitis fibrosa with high PTH levels, contributing to vascular calcification and increased fracture risk. Both syndromes are common, but adynamic bone disease is very frequent in stage 5 CKD patients, and vitamin D analogues and phosphate binders are partly responsible.

The aims are to reduce the calcium X phosphate product and to normalize PTH levels. Vitamin D analogues are used where serum calcium is low, but there is much interest in calcimimetics (e.g. cinacalcet) that significantly reduce PTH and the calcium X phosphate product. The hope is that cinacalcet, now used widely, may have a more consistent long-term effect than vitamin D analogues, and may reduce soft-tissue and vascular calcification.

Anemia
The normochromic anemia of erythropoietin deficiency occurs earlier, i.e. at a higher eGFR, in diabetic nephropathy than in non-diabetic renal disease. By CKD stage 3, about 20% of patients have Hb below 11 g/dL [20]; anemia may be more common in men. Prospective non-RCT data strongly linked anemia with hard end points (e.g. in RENAAL, Hb < 13.8 g/dL was associated with progression to ESRD, and Hb < 11.3 g/dL with both ESRD and death). Guidelines therefore suggested achieving Hb of 11–13 g/dL using one of the erythropoietin-stimulating agents (ESAs).

The most used, recombinant human erythropoietin, is usually given by weekly subcutaneous injection, in the hope that it will improve quality of life, reduce the risk of progression to LVH in pre-dialysis CKD patients, decrease hospitalization in end-stage renal failure, and reduce the incidence of cardiovascular events.

In 2006, two non-placebo-controlled studies (CHOIR and CREATE) that compared achievement of mean Hb of 13 versus 11 g/dL were published. Neither showed the expected major advantages of full anemia correction, with no decrease in cardiovascular risk but possibly improved quality of life. The definitive placebo-controlled TREAT study (2009) used another ESA, darbepoetin, in type 2 patients with moderate renal impairment and anemia (eGFR ∼30 mL/min, Hb 10.4 g/dL) to raise mean Hb to 12.6 g/dL (placebo 10.6 g/dL). Overall, cardiovascular events were not increased, but the risk of stroke was doubled in the darbepoetin group. Reported hypertension, and both venous and arterial thromboembolic events, were more common. Quality-of-life measures barely changed. Partial correction of anemia to about 11 g/dL is therefore warranted.

Coexisting iron deficiency is very common and must be fully corrected to maximize the benefit of ESAs. In view of the new lower target level many patients will require only iron treatment (and possibly folate and vitamin B12). Oral and intravenous routes are equally effective in correcting iron deficiency in CKD, but intravenous iron is quicker, is better tolerated and may have a greater effect on quality of life. It can easily be given as a single outpatient infusion, is relatively inexpensive and should be used more than it is [21]. Target ferritin is above 100 µg/L. If an ESA is needed once patients are iron replete, refer to the renal team. ESAs require frequent monitoring, including blood pressure, which can rise. From the diabetes point of view, ESAs increase the number of young red cells, which, less exposed to ambient glycemia, may cause a factitious fall in HbA1c.

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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)