Recent studies have shown that not only an enhanced renin-angiotensin system, but also relative volume retention might contribute to hypertension even in the early phase of a two kidney, one-clip hypertensive model. To evaluate the role of renal depressor and natriuretic systems in the development of high blood pressure in the early phase of this model, we measured urinary excretion of kallikrein (uKAL), prostaglandin E₂ (uPGE₂), and dopamine (uDA) in male Sprague-Dawley rats instrumented with a 0.2 mm diameter clip on the left renal artery (2K1C) and compared the results with those of sham-operated rats (sham). We also measured ouabain-like factor (OLF) in the plasma (pOLF) and urine (uOLF) in both groups. In 2K1C, systolic blood pressure (SBP) progressively increased and plasma renin activity was higher than the sham in the 3rd week. UDA and uPGE₂ were not different between these groups, but uKAL attenuated in 2K1C in the 1st and 3rd week compared to the sham. There was a negative correlation between %ΔSBP and %ΔuKAL. On the other hand, uOLF increased in 2K1C in the 1st, 2nd and 3rd week compared to the sham. There was a positive correlation between SBP and uOLF. And pOLF was higher in 2K1C than in the sham. Furthermore there was a negative correlation between %uKAL and %ΔuOLF. These results indicated that even in the early phase, suppression of the renal kallikrein-kinin system would contribute to high blood pressure in part, and OLF might play a compensatory role against the impaired natriuretic system in the kidney. However, OLF might contribute to blood pressure elevation through vasoconstriction in 2K1C.

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Many diabetic patients with nephropathy show loss of the nocturnal decrease in blood pressure. However, the mechanism is not yet fully understood. Twenty-four-hour blood pressure in type II diabetic patients was evaluated by ambulatory blood pressure monitoring (with TM2425 A and D Co. Tokyo). The power spectrum of blood pressure was also analyzed as an index of autonomic cardiovascular modulation using the same device. The ratio of lower frequency (LF) to higher frequency (HF) of heart rate rhythmic oscillations was determined as an index of sympathovagal balance. Patients were divided into two subgroups (Diabetes mellitus group, serum creatinine level< 1.5 mg/dl, n=25 ; Renal failure group, serum creatinine level≥ 1.5 mg/dl, n=20) on the basis of renal function. Mean 24-hour, awake and asleep systolic blood pressure were 151.8± 18.3 (SD), 155.7±17.4 and 140.5±23.3 mmHg (Diabetes mellitus group) and 152.2±22.7, 152.6±22.1 and 150.0±26.5 mmHg (Renal failure group), respectively, which were higher (p < 0.01) than those (122.7 ±9.1, 126.0± 10.2 and 112.9±10.7 mmHg) in age- and sex- matched control subjects (n=20). The ratio between asleep and awake systolic blood pressure was 0.90±0.10 (Control group) and 0.90±0.11 (Diabetes mellitus group), which were lower (p < 0.01) than that (0.98±0.09) in the Renal failure group. The Control and Diabetes mellitus groups showed a high awake mean LF/HF power ratio (1.91±0.55 and 1.95±0.48) . On the other hand, the Renal failure group showed a low ratio (1.50±0.46) (p< 0.01), but each group showed no significant difference in the asleep mean LF/HF power ratio. These findings suggest that sympathovagal imbalance is worse in the waking hours in diabetic nephropathy patients with renal dysfunction, and this causes loss of the nocturnal decrease in blood pressure.

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Cystatin-C is a low-molecular-weight basic protein produced at a stable rate by all nucleated cells. It is freely filtered through the renal glomeruli and primarily catabolized in the proximal tubule cells. Since the serum cystatin-C concentration is not affected by muscle mass nor inflammation, it has been postulated to be an improved marker of glomerular filtration rate (GFR) compared with the serum creatinine level. To evaluate the clinical usefulness in terms of estimation of the glomerular filtration rate (GFR), we compared the serum cystatin-C concentration with other markers of GFR, such as serum levels of creatinine (SCr), a 1-microglobulin (α1MG), and β₂-microglobulin (β₂MG) . Their variations were analyzed based on 2-hour creatinine clearance (2hCCr) as a standard marker of GFR. The logarithmic value of serum cystatin-C level showed a stronger negative correlation (-0.959) with the logarithmic value of 2hCCr than that of other markers (-0.924, -0.942, -0.888 ; SCr, α1MG, β₂MG, respectively) . Although β₂ MG showed the next strongest correlation with 2hCCr, it had a significantly lower sensitivity when M detecting mild reduction of GFR. In addition, serum cystatin-C showed the greatest area under the curve of receiver operating characteristic (ROC) of all GFR markers at both higher (90 ml/min.) and lower (70 ml/min.) cut-off value of 2hCCr. These data suggest that serum cystatin-C is useful for estimating GFR, even if the reduction of GFR is very mild.

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