Peter Jacobsen

INTRODUCTION AND AIMS:Introduction: In diabetes, one of the main features of progression to diabetic kidney disease is a pathological deposition of extracellular matrix components triggering renal fibrosis. The main structural component of the fibrotic core is collagen. One of the most prominent collagens is collagen type III (COL III), which is excessively synthesized and incorporated into the fibrotic extracellular matrix. Multiple studies in both humans and mice have suggested that MMP-9 activity is increased in diabetic kidney disease. Aim: We investigated whether a neo-epitope fragment of COL III generated by MMP-9 (C3M) was associated with deterioration of kidney function in a well-characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. .

To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model’s improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale. Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality. In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.

1Steno Diabetes Center Gentofte, Denmark2 Faculty of Health Science University of Aarhus Denmark

Diabetic nephropathy is a major cause of diabetes related morbidity and mortality. The first part of the current review was published in the last issue of this journal and discussed the impotant role of the renin-angiotensin system (RAS) in diabetic nephropathy and the genetic influence on development of end-stage renal disease (ESRD) in diabetic patients. This second part of the review focus on the potential improvement of the current treatment strategy to slow down the loss of kidney function using dual blockade of the RAS with both ACE-inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Substantial evidence from short-term studies using surrogate endpoints indicates a beneficial impact of dual blockade of the RAS, not obtainable with single agent blockade alone, both in diabetic and non-diabetic renal disease. This conclusion has been confirmed and extended in a longterm trial with regard to prevention of ESRD in non-diabetic renal disease. Results indicate that dual blockade of the RAS may further slow down, but not arrest progressive loss of renal function. However, studies defining the optimal dose of ACE-I / ARBs without additional adverse effects are essential to ensure relevant comparison with dual blockade therapy. Trials using primary renal endpoints in diabetic nephropathy are still needed, and will finally establish the role of dual blockade of the RAS in a clinical setting.

Diabetic nephropathy is a major cause of diabetes-related morbidity and mortality; however the clinical course of the disease and the renal prognosis is highly variable among individuals. The current review will discuss the genetic influence on the development of end stage renal disease (ESRD) in diabetic patients and potential improvements to the current treatment strategy to slow the loss of kidney function in these patients. In this first part, the growing evidence that glucose-induced activation of the intra-renal and systemic renin-angiotensin systems plays an essential role in processes leading to destruction of renal function is summarised. Genetic variations, especially the angiotensin-converting enzyme (ACE)/ID polymorphisms in the gene coding for ACE, are involved in activation of the renin-angiotensin system and seem to influence the clinical course of diabetic nephropathy during treatment with ACE inhibitors. In addition, this polymorphism may interact with other polymorphisms within the reninangiotensin system, leading to high risk of ESRD. As new genetic approaches and methods develop, further understanding of diabetic nephropathy will evolve and genotyping will help prevent ESRD in diabetic patients.

Antihypertensive treatment has improved renal prognosis and survival in diabetic nephropathy. The present review summarizes the current status of blockade of the renin-angiotensin system in diabetic nephropathy. Since the current treatment strategies reduce, but do not prevent, the progression of kidney disease, the research focus is directed towards the potential renoprotective effects of dual blockade of the renin-angiotensin system using both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Angiotensin-converting enzyme inhibitors are now a first-line therapy for patients with type 1 diabetes and diabetic nephropathy, whereas in patients with type 2 diabetes, angiotensin II receptor blockers have been shown to protect the kidney. The optimal doses of both types of drug remain to be determined, and the efficacy of each medication needs to be compared both in patients with type 1 diabetes and in those with type 2 diabetes. Experimental studies suggests that dual blockade of the renin-angiotensin system may offer additive beneficial effects relative to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. In agreement with this, short-term studies of patients with diabetes have suggested that further renal and cardiovascular protection is achieved using dual blockade of the renin-angiotensin system. Long-term trials will finally define the role of this new treatment concept in diabetic nephropathy. All diabetic patients with elevated urinary albumin excretion need blockade of the renin-angiotensin system by either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. In addition, albuminuria and elevated blood pressure should be treated aggressively with a view to achieving blood pressure readings below 130/80 mmHg and albuminuria values of less than 300 mg/24 h; this often necessitates multi-pharmacy. Dual blockade of the renin-angiotensin system may be helpful in reaching these goals in treatment-resistant patients with diabetic nephropathy.

: The impact of polymorphisms in the genes coding for angiotensinogen (M235T), ACE (ID), and angiotensin II type 1 receptor (A ¹¹⁶⁶→C) on decline in GFR and doubling of s-creatinine or development of ESRD in patients with type 1 diabetes and diabetic nephropathy (DN) was tested. From 1985, all patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR (⁵¹Cr-EDTA). In a Cox proportional hazards model corrected for other risk factors, the D allele (ACE/ID) was associated with time to doubling of s-creatinine/ESRD (rate ratio, 1.81 per allele; 95% confidence interval, 1.09 to 3.03; P = 0.02). A new interaction hypothesis was generated demonstrating that the following variables were associated with accelerated decline in GFR: albuminuria (estimate, 2.12 ml/min per yr per 10-fold increase in albuminuria; P < 0.001), mean BP (estimate, 0.88 ml/min per yr per 10 mmHg; P = 0.02), hemoglobin A_1c (estimate, 0.54 min/min per yr per 1%; P = 0.02), and number of M (M235T)/D (ID)/A (A ¹¹⁶⁶→C) alleles (estimate, 0.45 ml/min per yr per allele; P = 0.049). Number of M/D/A alleles also influenced time to doubling of s-creatinine or ESRD. In this study of patients with type 1 diabetes, the D allele of the ACE/ID polymorphism in addition to nongenetic risk factors independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies. E-mail: pkjacobsen@dadlnet.dk