{'fraction_non_alphanumeric': 0.016034710431993962, 'fraction_numerical': 0.007357102433503113, 'mean_word_length': 5.586335403726708, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Diabetic nephropathy without the diabetes: If not hyperglycaemia, then what? (Editorial)

In recent years, diabetic nephropathy has emerged as the major causative pathology in patients entering end-stage kidney disease programmes. In most cases, the diagnosis will have been determined on clinical grounds, with few patients undergoing a diagnostic renal biopsy. Those who do generally have atypical features present that are at odds with accepted clinical profile of increasing urinary protein and progressive renal impairment in the setting of long-standing diabetes, hypertension and associate retinopathy. Therapeutic efforts are centred on control of hyperglycaemia and blood pressure control that uses renin-angiotensin blockade, treatments only partially effective at controlling the progression of disease. Clearly our understanding of the underlying pathogenetic mechanisms of diabetic nephropathy is still poor. This is highlighted in the current issue by a report by Sanai et al., in which classic histological appearance of diabetic nephropathy and subsequent progressive renal impairment are described in a cohort of patients who, on the whole, exhibit only a minor degree of disordered insulin metabolism. What Sanai and colleagues describe in this issue highlights the importance of non-hyperglycaemic mechanisms in the development of diabetic nephropathy. This is not a new phenomenon, but it is a cogent reminder that although hyperglycaemia may be regarded as necessary, in itself it is not a sufficient factor for the development of kidney disease. It begs the question as to what other factors may be contributing to the development and progression of diabetic kidney disease. That only a fraction of patients with type 2 diabetes develop diabetic nephropathy further illustrates the variable role that hyperglycaemia plays in the development of microvascular disease. Epidemiological analyses of patient populations with type 2 diabetes have identified phenotypic risk factors for the development of renal complications, such that it is now generally accepted that the aetiology of the structural and functional changes of diabetic nephropathy is multifactorial. Other studies have challenged the notions that diabetic nephropathy develops often after a decade of poor control, and occurs in association with other microvascular complications such as retinopathy. Hans-Henrik Parving and his colleagues undertook a biopsy study of patients with type 2 diabetes with evidence of proteinuria, in the absence of retinopathy. Although there was evidence of non-diabetic renal pathology, in 70% of cases diabetic nephropathy was the predominant lesion. Familial aggregation of kidney disease in diabetic populations is considered an important factor in the development of disease. Recognition of inherited difference in renal susceptibility has led to a large number of studies searching for genetic polymorphisms that may confer abnormal glomerular haemodynamics and permselectivity. As a result, a number of possible mediators have been identified, particularly angiotensin-converting enzyme polymorphisms, although findings are sometimes contradictory. It has been postulated that insufficient power in some of the studies, and the presence of racial variation, are possible explanations for the contradictory findings. Nonetheless, these studies of genetic susceptibility in humans offer important insights into the potential mechanisms of disease. An example of the significance of identifying potential mediators of disease through genotypic analysis is the study of inflammation in pathogenesis of diabetic kidney disease. A number of pro-inflammatory cytokine polymorphisms have been identified in patients with an increased rate of renal involvement. The beneficial effects of the antiinflammatory activity of ruboxistaurin, a novel agent that blocks PKC-b activation, have been demonstrated in both a rodent model of diabetic nephropathy, and more recently in a phase 2 clinical trial. The inflammatory nature of diabetic nephropathy is emerging, and a new therapeutic agent may be on the horizon. A major obstacle to the development of new therapies for diabetic kidney disease has been the ability to fully study kidney tissue from human subjects. Although techniques such as immunohistology and electron microscopy have refined the diagnostic capabilities of the kidney biopsy by adding to the structural information gleaned with conventional histology, the information is still limited in that it lacks predictive strength and therapeutic consequence. However, recent advances in molecular analysis of very small pieces of tissue have enabled the development of new approaches to the information stored within each kidney biopsy. Traditionally, the techniques available for the study of molecular mechanisms of disease have mandated the collection of larger amounts of tissues. However, over the last few years, several remarkable breakthroughs in the development of highly effective gene technologies have allowed the rapid and accurate study of gene expression, even in very small tissue samples such as renal biopsies with gene array analysis possible from as few as three glomeruli. It is envisaged that NEPHROLOGY 2007; 12, 67–68 doi:10.1111/j.1440-1797.2006.00744.x