The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies

Abstract

G ross defects in glomerular capillary function manifested as heavy proteinuria and severely reduced glomerular filtration rates occur with long-standing diabetes mellitus. However, substantial changes in glomerular function appear even at an early phase of this metabolic disorder, and studies of these early alterations have begun to yield insights into potential mechanisms of the late, overt injury. In 1959, Stalder and Schmid [l] demonstrated supernormal glomerular filtration rate values in diabetic children and young adults, a finding confirmed by Ditzel and Schwartz [2] and extensively investigated in recent years by Mogensen [3,4]. Mogensen [3] described a 40 percent increment in glomerular filtration rate in 11 patients with newly diagnosed juvenile diabetes when compared to values in 31 normal subjects of similar age. This remarkable hyperfiltration was shown to be related to the patient’s metabolic status, since reduction of blood sugar levels over several days to weeks by standard insulin therapy tended to return glomerular filtration rate to normal or near-normal values. Indeed, recent studies by Christiansen et al. [5] have demonstrated that with reduction in blood glucose levels to normal by continuous insulin infusion, glomerular filtration rate also declines from elevated to near-normal values in a matter of hours. A number of clinical studies have been performed, largely by these and other Danish investigators, in an attempt to dissect the particular component or components of the diabetic state responsible for these early elevations in glomerular filtration rate. One factor that has been incriminated is hyperglycemia per se. Indeed, acute elevations of glomerular filtration rate occur in response to glucose infusion in normal subjects [ 6-81. While the structural hypertrophy observed in kidneys of diabetic humans and animals, best documented by $sterby, Gunderson and co-workers [ 9, lo], has also been proposed to contribute to the augmented glomerular filtration rate, this process would be unlikely to explain the relatively rapid changes in glomerular filtration rate that occur with insulin therapy. Augmented levels of glucagon and growth hormone are usual accompaniments of diabetic hyperglycemia, and each of these hormones is capable of inducing a rise in glomerular filtration rate in normal subjects at plasma levels comparable to those found in hyperglycemic diabetic patients [ 1 l-141. However, increments in glomerular filtration rate achieved by these hormones are substantially less than the usual increment observed in the early insulin-dependent diabetic patient. Finally, changes in circulating and tissue levels of classic vasoactive hormones such as angiotensin II, catecholamines and prostaglandins have been demonstrated in a variety of circumstances in diabetes [ 1% 171. Also, changes in responsiveness to angiotensin II and catecholamines have been demonstrated in several extrarenal vascular beds in diabetic patients and animals [ 18,191. Whether changes in the levels of these hormones or the vascular response to them contribute to the hyperfiltration is as yet unknown. In any case, a variety of factors present in the diabetic state may contribute to hyperfiltration, and no single factor appears to account fully for this phenomenon. Although insights into the stimuli responsible for diabetic hyperfiltration have been forthcoming from such