To determine whether life-long reduction in the GH/IGF-I activity could be renoprotective and attenuate renal damage, we examined the kidneys of transgenic strain of rats whose GH gene was suppressed by an antisense GH transgene. Male rats homozygote for the transgene (tg/tg) had a reduced number of pituitary GH-secreting cells, and 53% less plasma concentration of IGF-I, compared with wild-type (wt/wt) rats at 6 months of age. We compared the kidneys obtained from male wild-type young (6 months) and old (24 months) rats with male homozygote transgenic young (6 months) and old (24 months) rats. The wild-type rats showed features of renal damage as they grew older, including glomerulosclerosis (higher sclerosis index at 24 months; P<0.0001), tubulointerstitial widening (increased interstitial volume at 24 months; P<0.0001), and presence of phenotypically altered myofibroblasts and increased accumulation of collagens. Life-long suppression of GH/IGF-I activity resulted in prevention of age-associated renal diseases in homozygote transgenic rats at 24 months (sclerosis index: 1.65+/-0.11 in wild-type vs. 0.463+/-0.061 in transgenic rats; interstitial volume: 34.2+/-0.82 in wild-type vs. 12.8+/-0.32 in homozygote transgenic rats at 24 months; P<0.0001). Such reno-protective effects in transgenic rats were associated with decreased renal accumulation of ED-1-positive macrophages, and less renal expression of pro-fibrogenic factors, including connective tissue growth factor and heat shock protein 47. Our in vivo genetic manipulation study provides direct evidence of reno-protective effects of life-long suppression of GH/IGF-I system, by reducing renal infiltration of inflammatory cells, and by suppressing the synthesis of profibrogenic factors and accumulation of extracellular matrix protein.

Aim: The aim of this study was to determine the effects of kidney pathology on overall survival and longevity and the combined effects of chronic suppression of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity and lifelong caloric restriction on age-associated nephropathy. Methods: We analyzed the kidneys of rats with suppressed GH activity through genetic manipulation with an antisense GH transgene. Rats were fed normally or with a 30% calorie-restricted diet for 24–26 months. The kidneys of male wild-type young (6 months) and old (24–26 months) rats were compared with male hemizygote transgenic young (6 months) and old (24–26 months) rats fed with either regular diet or 30% calorie-restricted diet for their entire life span. Results: The transgenic rats had relatively less pituitary GH-secreting cells, and the plasma levels of IGF-1 were decreased by 53% in homozygote rats (tg/tg) and by 28% in hemizygote rats (tg/wt) compared to wild-type rats (wt/wt) of the same age (6 months). Wild-type rats fed the regular diet developed age-associated nephropathy as they aged, showing severe inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. In addition, about 83% of the wild-type rats allowed to survive naturally showed signs of nephropathy. In contrast, only 26% of the naturally surviving hemizygote rats showed features of nephropathy, despite the fact that these rats lived 8% longer (maximum survival 171 weeks) than the wild-type rats (maximum survival 158 weeks). When chronic suppression of GH/IGF-1 activity was combined with lifelong caloric restriction, however, age- associated nephropathy was nonexistent in hemizygote transgenic rats, and they showed about 30% increase in survival (maximum survival 204 weeks). There was no significant difference in the rate of neoplastic or nonneoplastic lesions (other than in the kidney) in the regularly fed wild-type rats or in the calorie-restricted hemizygote transgenic rats that survived longer. Conclusion: We concluded that kidney pathology is an important determinant of overall survival, and that prevention of kidney pathology by dietary restriction, combined with chronic suppression of GH/IGF-1 activity, significantly extends overall survival and longevity.

Background It is unclear whether short‐term blood pressure variability is associated with renal outcomes in patients with chronic kidney disease. Methods and Results This study analyzed data from participants in the C‐ STRIDE (Chinese Cohort Study of Chronic Kidney Disease) who had chronic kidney disease stages 1 to 4. Short‐term blood pressure variability was measured by calculating the weighted SD (w‐ SD ) of systolic blood pressure ( SBP ). Renal outcomes were defined as dialysis initiation and/or transplantation. Risk factors associated with w‐ SD of SBP were evaluated by linear regression. Associations of short‐term SBP variability with renal outcomes were evaluated by Cox regression. In total, 1421 patients with chronic kidney disease were included in this study (mean age, 49.4±13.6 years; 56.2% men; estimated glomerular filtration rate, 50.5±29.3 mL/min per 1.73 m 2 ; proteinuria, 0.9 [0.3–2.0] g/d). Mean w‐ SD of SBP was 12.6±4.4 mm Hg. w‐ SD of SBP was independently associated with older age, 24‐hour SBP , blood pressure circadian pattern, and angiotensin II receptor blocker treatment. During a median follow‐up of 4.9 years, 237 patients developed renal outcomes (37.01 per 1000 patient‐years). The incidence rate increased across the quartiles of w‐ SD (log‐rank P =0.005). w‐ SD of SBP was associated with an increased risk of renal outcomes, both as a continuous variable (hazard ratio [HR], 1.47; 95% CI, 1.09–1.99) and as a categorical variable (quartile 4 versus quartile 1: HR, 1.60; 95% CI, 1.08–2.36), independent of 24‐hour SBP , daytime SBP , and nighttime SBP . Conclusions Short‐term SBP was independently associated with the risk of dialysis initiation and/or transplantation in patients with chronic kidney disease .

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