Barry M. Brenner

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

IT is now more than 30 years since Addis suggested that protein intake be restricted in patients with chronic renal insufficiency.1 His aim was not to reduce uremic symptoms but rather to prevent an increase in the "workload" of surviving nephrons of diseased kidneys in order to minimize further loss of renal function. With the development and increasingly widespread availability of dialysis and transplantation in the past three decades, relatively little attention has been paid to the influence of diet on the progression of renal disease, despite general awareness that renal disease typically follows an inexorably progressive course. In this . . .

CONTENTS: BACKGROUND AND HISTORICAL ASPECTS: Hypertension: Definitions, Natural Histories, and Consequences Sir George Pickering Afterword to Chapter 1: Modern Definitions and Expressions of Hypertension Thomas G. Pickering The Goldblatt Experiment: A Conceptual Paradigm Peter J. Goldblatt The Vascular Fault in Hypertension: Byrom's Work Revisited John M. Ledingham. EPIDEMIOLOGICAL DIMENSIONS OF HYPERTENSION: Does Hypertension Predispose to Coronary Disease? Conflicting Epidemiological and Experimental Evidence Austin E. Doyle Genetic Epidemiology of Blood Pressure Ryk Ward Low Birth Weight as a Risk Factor for Juvenile and Adult Hypertension Glenn M. Chertow and Barry M. Brenner Hypertension, Other Risk Factors, and the Risk of Cardiovascular Disease William B. Kannel and Peter W. F. Wilson Human Population Biology and Blood Pressure: Evolutionary and Ecological Considerations and Interpretations of Population Studies Gary D. James and Paul Baker Impact of Systolic and Diastolic Blood Pressure on Cardiovascular Mortality James D. Neaton, Lewis Kuller, Jeremiah Stamler, and Deborah N. Wentworth Epidemiology and Treatment of Hypertension in Older Persons Adrian M. Ostfeld, Richard J. Havlik, and Jack Guralnik Hypertension in Women Ellen Cohen, Mary E. (Polly) Wheat, Deborah M. Swiderski, and Pamela Charney High Blood Pressure in Blacks: Salt, Slavery, Survival, Stress, and Racism Clarence E. Grim, James P. Henry, and Hector Myers Childhood Hypertension Alan R. Sinaiko Hypertension in the Elderly Richard L. Byyny Public Health Issues in Hypertension Control: What Has Been Learned from Clinical Trials Jeffrey A. Cutler, Bruce M. Psaty, Stephen MacMahon, and Curt D. Furberg. DIET AND HYPERTENSION: Blood Pressure and Sodium Intake Olaf F. Simpson Dietary Sodium Restriction in Hypertension John D. Swales Dietary K $PL, Na, and Cardiovascular Integrity in Experimental Models of Hypertension Louis Tobian Blood Pressure and K $PL Intake R. C. Morris, Jr., and Anthony Sebastian The Role of Dietary Protein in Hypertensive Disease: The Japanese Experience: Clinical Implications Walter M. Lovenberg and Yukio Yamori. CIRCULATORY AND TARGET ORGAN PATHOPHYSIOLOGY OF HYPERTENSIVE DISEASE: Hemodynamic Patterns of Untreated Hypertensive Disease Per Lund-Johansen and Per Omvik Evaluation of Arterial Waveforms in Hypertension and Normotension Michael F. O'Rourke and Raymond P. Kelly Blood Viscosity as a Factor in Human Hypertension Shu Chien and Ann Chabanal Vascular Compliance and Blood Volume in Essential Hypertension Michael E. Safar, G erard E. Plante, and G erard M. London Red Blood Cell Mass/Erythropoietin and Blood Pressure: Lessons from Patients with Renal Disease Joseph W. Eschbach and Robert C. Davidson Interactions Between the Sympathetic Nervous System and the Renin-Angiotensin System Guiseppe Mancia, Antonio Saino, and Guido Grassi Hypertensive Cardiac Hypertrophy: Pathophysiologic and Clinical Characteris

Micropuncture studies were performed in three groups of male Munich-Wistar rats 1 wk after surgery: group I, eight control rats that underwent laparotomy and were fed a normal diet; group II, nine rats that underwent right nephrectomy and segmental infarction of five-sixths of the left kidney and were fed a normal diet; and group III, seven rats that underwent the same renal ablative procedure and were fed a low protein diet. Single nephron glomerular filtration rate (SNGFR) was higher in the remnant kidney of group II rats compared with group I rats due to higher average values for mean glomerular transcapillary hydraulic pressure difference (delta P) and initial glomerular plasma flow rate (QA) in group II. Glomeruli in remnant kidneys of group II showed striking alterations in morphology, including epithelial cell protein reabsorption droplets, foot process fusion, and mesangial expansion. Group III rats demonstrated a mean SNGFR not statistically different from that of group I, but significantly less than that of group II rats. This lack of absolute hyperfiltration in remnant glomeruli of group III rats relative to group I obtained because QA and delta P did not increase above values found in group I. The glomerular structural lesions seen in group II were also largely attenuated in group III. These studies demonstrate that alterations in glomerular hemodynamics associated with renal ablation are accompanied by structural lesions and suggest that sustained single nephron hyperfiltration may have maladaptive consequences by damaging remnant glomeruli.