A 32-year-old man with type 1 diabetes, modest renal impairment (serum creatinine 212 µmol/L) and clinical nephropathy had a BP of 170/110 mmHg when he first presented in 1994. His diabetic control was poor and he would only take insulin once a day in an unusual mixture of lente and ultralente preparations. He was started on enalapril 10 mg bd with an immediate response; his BP fell to 120/80 mmHg.
Although there was an initial increase in his serum creatinine, this stabilised and now 15 years later he is still independent of dialysis. His inverse creatinine chart is shown in Figure 16.12.
During this time his BP has always been < 140/90 mmHg and usually much less than that. He was working until 5 years ago as a scaffolder but had to stop because of postural dizziness due to autonomic neuropathy. His HbA1c has varied between 8% and 11% over this time; he is now on twice-daily premixed insulin (after ultralente was withdrawn).
Comment: The renal response to therapy in this man is striking and was achieved despite poor glycemic control. This under-scores the primacy of BP in driving progression of diabetic nephropathy once it is established. The initial increase in serum creatinine is significant but still within a 35% change that is acceptable when commencing RAS-blocking drugs. His blood pressure response was dramatic which supports the role of angiotensin II in nephropathy-related hypertension.
Although eGFR is a useful reminder of kidney function, a reciprocal serum creatinine chart like this is also helpful in monitoring progression and the impact of any interventions, especially once the level is > 150 µmol/L.
Handbook of Diabetes, 4th Ed., Excerpt #15: Diabetic Nephropathy
The glomerular barrier normally retains most circulating proteins of the size and charge of albumin. Glycation of the glycocalyx proteins, disruption of the GBM lattice by matrix accumulation, and podocyte loss allow filtration of increasing amounts of albumin and larger macromolecules which characterize progressive nephropathy. There is evidence that the increased presentation of proteins in the filtrate to tubular cells leads to tubulointerstial inflammation and fibrosis, contributing to declining GFR.
Prospective observational studies have shown a consistent association between glycemia and known duration of diabetes, and development of nephropathy.
The role of hypertension has been mentioned earlier; blood pressure rises as nephropathy develops in type 1 and plays a more causative role in type 2 diabetes.
A meta-analysis of studies of directly measured GFR in type 1 diabetes found a significant link between hyperfiltration and later development of nephropathy but there was marked heterogeneity and the relationship was weakened when glycemic control was taken into account.
Ethnicity plays an important but ill-understood role. Rates of nephropathy are much higher in Native American, South Asian, some Pacific Islanders, non-Ashkenazi Jewish and Afro-Caribbean diabetic patients compared to their white Europid age- and duration-matched controls. Some of this increased risk relates to increased rates of hypertension (e.g. in Afro-Caribbean patients), and some may be related to the low birthweight (thrifty phenotype) hypothesis (see Chapter 7 ) which has been linked to higher blood pressures and nephropathies generally as well as to type 2 diabetes per se.
Sibling studies in multiplex families with type 1 diabetes have shown an increased incidence of nephropathy in siblings of a proband with the condition compared to those of a proband with normal albuminuria (Figure 16.7). These observations do not completely rule out environmental factors but the heritability of a risk for nephropathy is supported by the observation that a positive family history of hypertension and cardiovascular disease is more likely in the parents of type 1 patients with nephropathy compared to those of patients without. Extensive search for candidate genes and genome-wide screening have so far yielded some positive associations (with polymorphisms in genes related to the RAS) but on the whole, these relationships are not very strong and no major gene effect has yet been identified.
The DCCT/EDIC Study and UKPDS provide incontrovertible evidence that good glycemic control can prevent the development of microalbuminuria and this benefit was apparent for at least 8 – 10 years after the studies concluded (Figure 16.8). There is very little evidence to suggest that it can prevent or delay the progress of nephropathy once it is established. This is probably because after nephropathy has been initiated (by largely glucose-dependent mechanisms), it is continued by pathways that are no longer sensitive to changes in glycemia. Intriguingly, though, in a small group of type 1 pancreas transplant recipients, renal pathology improved in their native kidneys after 10 (but not 5) years of normoglycemia, implying that not only is complete normalization of blood glucose required, but also the lesions take almost as long to resolve as they do to develop. Good glycemic control, however, will continue to benefit other complications such as retinopathy.