The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Age, renal perfusion and function in island-dwelling indigenous Kuna Amerinds of Panama.

BACKGROUND/AIMS: Among possible contributors to a progressive fall in renal perfusion and function with increasing age, some hypotheses have invoked the rise in blood pressure that occurs with age, and a high-protein diet typical of urban cultures. Kuna Amerinds residing in isolated islands off the Panamanian Coast have a very low protein intake and show no tendency for blood pressure to rise with age, thus providing an opportunity to test these hypotheses. METHODS: We measured renal plasma flow and glomerular filtration rate (PAH and inulin clearance) in 16 Kuna Indians ranging in age from 18 to 86 years (51 +/- 6 years) who have resided on Ailigandi, an isolated Panamanian island for all of their lives. Inulin and PAH were infused with a battery-driven pump for 60 min, and a metabolic clearance rate used to calculate inulin and PAH clearance. For comparison, we employed identical techniques in 29 residents of Boston, ranging in age from 19 to 79 years (52 +/- 4 years), all normotensive and free of disease or medication use. Twenty-four were Caucasian. RESULTS: The Bostonian controls showed the anticipated fall in PAH clearance with age (y = 806 - 4.9 x; r = -0.82; f = 38.0; p < 0.0001). Our hypothesis was that the absence of a blood pressure rise with age and the low protein intake would flatten the slope relating renal perfusion to Kuna age. Our finding was a numerically steeper slope relating age and renal plasma flow in the Kuna (y = 936 - 6.48x; r = -0.81; p < 0.001). Filtration fraction rose with age in both populations, and again the rise was steeper in the Kuna. GFR in the Kuna, on the other hand, was very much higher at any age (139 +/- 4 ml/min/1.73 m2) than in Bostonians (112 +/- 3 ml/min/1.73 m2; p < 0.001). CONCLUSION: The findings are not in accord with the hypothesis that age-related changes in renal perfusion and glomerular filtration rate reflect an important contribution from blood pressure rise and a high protein intake, typical of modern, urban life.

Aging, acculturation, salt intake, and hypertension in the Kuna of Panama.

The indigenous Kuna who live on islands in the Panamanian Caribbean were among the first communities described with little age-related rise in blood pressure or hypertension. Our goals in this study were to ascertain whether isolated island-dwelling Kuna continue to show this pattern, whether migration to Panama City and its environs changed the patterns, and whether the island-dwelling Kuna have maintained their normal blood pressure levels despite partial acculturation, reflected in an increased salt intake. We enrolled 316 Kuna participants who ranged in age from 18 to 82 years. In 50, homogeneity was confirmed by documentation of an O+ blood group. In 92 island dwellers, diastolic hypertension was not identified and blood pressure levels were as low in volunteers over 60 years of age as in those between 20 and 30 years of age. In Panama City, conversely, hypertension prevalence was 10.7% and exceeded 45% in those over 60 years of age (P < .01), blood pressure levels were higher in the elderly, and there was a statistically significant positive relationship between age and blood pressure (P < .01). In Kuna Nega, a Panama City suburb designed to maintain a traditional Kuna lifestyle but with access to the city, all findings were intermediate. Sodium intake and excretion assessed in 50 island-dwelling Kuna averaged 135 +/- 15 mEq/g creatinine per 24 hours, exceeding substantially other communities free of hypertension and an age-related rise in blood pressure. Despite partial acculturation, the island-dwelling Kuna Indians are protected from hypertension and thus provide an attractive population for examining alternative mechanisms.

Specificity of renal vasodilation with captopril: saralasin prevents the response in the DOCA-treated, salt-loaded rabbit.

A prominent action of converting enzyme inhibitors, such as captopril, is a reduction in angiotensin II formation, but interpretation of responses has been complicated by the potential for such agents to reduce bradykinin degradation and promote prostaglandin release. To assess the specificity of the action of captopril, we pretreated rabbits with desoxycorticosterone and a high sodium intake, to suppress the renin-angiotensin system and thus maximize the renal vascular responses which might be unrelated to angiotensin II. Captopril was infused intravenously in graded dosage from 10 to 3,000 microgram/kg, and renal blood flow measured with an electromagnetic flowmeter. Despite suppression of the renin system, captopril increased renal blood flow from 3.7 +/- 0.5 to 5.3 +/- 0.8 ml/g/min (p less than .001) in 7 rabbits. In 6 additional rabbits, captopril was superimposed on a saralasin infusion (1.0 microgram/kg/min) in a dose sufficient to block response to endogenous angiotensin II. Saralasin prevented entirely the renal vasodilator response to captopril. Two surprising conclusions derive from this study: first, the renal vasodilator response to captopril appears to be specific for a reduction in angiotensin II formation; second, endogenous angiotensin appears to contribute to renal vascular tone, at least when anesthesia is employed, even when the renin system has been suppressed by a combination of a high sodium intake and desoxycorticosterone.

Increased glomerular filtration rate after converting-enzyme inhibition in essential hypertension.

To test the influence of an inhibitor of angiotensin-converting enzyme, teprotide (SQ 20881), we administered it to seven patients with essential hypertension and normal renal function and nine with an unequivocal reduction in creatinine clearance, caused by bilateral renal-artery stenosis in two and by essential hypertension in seven. Despite the fall in blood pressure (112.7 +/- 4.5 to 100.3 +/- 3.9 mm Hg, mean +/- S.E.M., P less than 0.01), there were prompt increases in both creatinine clearance (95.9 +/- 10.5 to 109.9 +/- 9.5 ml per minute per 1.73 m2 of body-surface area, P less than 0.01) and sodium excretion (17.0 +/- 5.9 to 31.7 +/- 7.2 mumol per minute, P less than 0.01) in patients with essential hypertension. The increase in glomerular filtration rate was most striking, averaging 33 per cent (66.0 +/- 10.3 to 88.0 +/- 9.2 ml per minute per 1.73 m2, P less than 0.001) in patients in whom an initial reduction was evident and hypertension was more severe. These observations suggest that a functional element, perhaps involving angiotensin-mediated renal vasoconstriction, frequently has a role in the reduction in glomerular filtration rate that occurs in essential hypertension. This class of agent may improve renal excretory function as it controls hypertension.