The discovery of diabetic nephropathy: from small print to centre stage.

Until the early nineteenth century, diabetes mellitus was regarded as a disease of the kidney, in which there was an increase in the volume of urine and a wasting of the flesh. With the identification of glucose in blood and urine in the late eighteenth century, first it was re-framed as a disease of assimilation and only then became a metabolic disorder. Whilst these changing concepts were debated, it was noted in parallel that diabetics might show coagulable urine containing albumin, even before Bright and others had established this as a sign of kidney disease. Wilhelm Griesinger (1817-1868) was perhaps the first to suggest in 1859 that the diabetes might be causing the Bright's disease, with the latter as a 'complication'. During the next half-century the observation that as albuminuria appeared and increased, so glycosuria improved or might remit, with a parallel or subsequent evolution into uraemia. Glomerulosclerosis and arteriolosclerosis were described in occasional patients during the same period, but text-books of pathology ignored these observations. Thus it was only when diabetics began to survive longer using insulin treatment in the early 1920s that a diabetic nephropathy became widely recognized. After a few isolated descriptions which were ignored, the now famous paper of Paul Kimmelstiel and Clifford Wilson appeared in 1935 detailing nodular renal lesions in just 8 maturity-onset (48-68 year old) diabetics. They barely noted the association with diabetes however, and it was Arthur Allen in 1941 who clarified the association in 105 patients with diabetes, again all aged over 40. Despite the age of the patients in these early studies, diabetic nephropathy became thought of as a disease of young diabetics as a cohort of survivors of juvenile diabetes passed 15 years or more of disease and more than half developed nephropathy. In the 1950s the technique of renal biopsy was rapidly applied to the study of diabetics, and the early lesions defined using electron microscopy as well as optical methods. Then the role of diabetic nephropathy as a cause of renal failure changed: to begin with numbers of young insulin-requiring diabetics were small and infrequently referred for dialysis treatment or transplantation. Then in the 1970s and 1980s the proportion of such juvenile-onset diabetics developing renal failure gradually fell, but at the same time much larger numbers of older diabetics survived their vascular disease and required treatment for renal failure. World-wide, today diabetes accounts for 20-50% of patients entering established renal failure programs, and absolute numbers increase as greater longevity and western-style living has promoted an 'epidemic' of diabetes at all ages.