Handbook of Diabetes, 4th Ed., Excerpt #15: Diabetic Nephropathy
Target blood pressure for people with diabetes has been set at < 130/80 mmHg by most guidelines, with some suggesting < 120/75 in those with nephropathy and proteinuria > 1 g/day. Improved control of blood pressure is probably the main reason why the median duration of clinical nephropathy prior to ESRD has risen from 7 to 14 years since 1980 (Figure 16.9).
Because of the involvement of angiotensin II in the glomerular hemodynamic changes in diabetes, agents which block the RAS feature as first-line therapy in most guidelines. These drugs also reduce albuminuria which would help ameliorate any tubulointerstitial insult caused by increased protein trafficking across the tubular epithelium. Meta-analysis in normotensive patients with type 1 diabetes and microalbuminuria confirms that angiotensin-converting enzyme inhibitors (ACEI) can reduce the numbers developing clinical nephropathy by around 60%, with those having higher levels of albuminuria at baseline showing the most benefit (Figure 16.10).
However, there is little evidence that RAS blockade can prevent primary development of microalbuminuria in type 1 diabetes and may only be effective in patients with type 2 diabetes who are already hypertensive or at high cardiovascular risk.
Most patients with nephropathy will require two or more agents to achieve blood pressure targets. For more details of blood pressure management, please see Chapter 19.
There is evidence from intervention trials that patients who have a greater reduction in proteinuria in response to treatment do better in terms of rate of decline in renal function.
This observation has led to the proposal that reduction of proteinuria to < 1 g/day should be a therapeutic target. This is not widely accepted, but studies of multiple blockade of the RAS using combinations of ACEI, angiotensin type 1 receptor blockers, aldosterone antagonists and renin inhibitors have shown greater reductions in albuminuria compared to the use of individual agents alone. However, there is a real risk of hyperkalemia and acute deterioration in renal function (see Chapter 19).
In experimental diabetes, dietary protein restriction reduces albuminuria and progression to renal failure. Studies in humans have been variable in duration and endpoint. A systematic review has shown a modest reduction in the rate of decline of GFR in type 1 diabetes with a restriction of dietary protein intake to 0.7 – 1.1 g/kg bodyweight/day. Only one study used mortality and ESRD as endpoints and found a relative risk of 0.23 (95% CI 0.07 – 0.72). For type 2 diabetes the data were not significant. The National Kidney Foundation guideline recommends a dietary protein intake of 0.8 g/kg bodyweight/day for diabetic patients and CKD stages 1 – 4.
Anemia secondary to erythropoietin (EPO) deficiency is a feature of CKD generally and some studies suggest that it occurs earlier at a higher GFR in people with diabetes. Hospital clinic-based surveys suggest prevalence rates of WHO-defined anemia ( < 12 g/dL women, < 13 g/dL men) of 15 – 25%, and many cases were in patients with an eGFR > 60 mL/min/1.73 m2. Several large trials of anemia correction using various preparations of EPO have suggested no benefit (and possibly some harm) of achieving a hemoglobin concentration > 13 g/dL. Below this level, patients feel better but no conclusive impact on rate of decline in GFR or cardiovascular morbidity/mortality has been demonstrated. Current NICE guidance has set an intervention threshold of 11 g/dL and a target of 10.5 – 12.5 g/dL for all patients with CKD and adequate iron stores.
Cardiovascular risk factor management
There are no conclusive trial data to support aspirin or lipid-lowering therapy specifically in diabetic nephropathy. Thus targets are the same as for diabetes generally.
The Steno 2 Study of multifactorial cardiovascular risk intervention in type 2 patients with microalbuminuria at baseline showed a major impact on mortality, development of nephropathy and ESRD, as well as cardiovascular complications including myocardial infarction and amputation (Figure 16.11). The protocol for the intensive arm was for RAS-blocking drugs in all, lipid-lowering therapy with a target total cholesterol < 4.5 mmol/L, intensive glycemic control with a target HbA 1c < 6.5% (48 mmol/mol), low-dose aspirin, antioxidants (vitamins C and E) and lifestyle changes including stopping smoking, weight reduction and increasing exercise. As with the DCCT/EDIC and UKPDS, these benefits continued beyond the end of the trial but it was not possible to determine which were the most effective interventions.
Thus the patient with nephropathy should have intensive management of all known cardiovascular and diabetic complication risk factors.