The present study is the first, large-scale, multicenter, prospective cohort study in Japanese patients with CKD under nephrology care, which aimed at identifying risk factors for CKD progression to ESRD. Our study disclosed the following facts: (1) elevated SBP and increased UACR, both at baseline, were significantly associated (HR 1.203, 95 % CI 1.099–1.318 and HR 4523, 95 % CI 3.098–6.604; P < 0.0001, respectively) with the primary endpoint; and (2) the deterioration of a powerful predictor of ESRD, proteinuria (which was translated into higher UACR), accelerated CKD progression to ESRD extensively. These findings are in concert with previous clinical studies indicating that lower eGFR and higher UACR are independently associated with the increased risks of CVD and ESRD.
Numerous previous studies have indicated that hypertension is one of the important risk factors for renal impairment. In the present study, SBP at baseline was significantly associated with both the primary and secondary endpoints. On the other hand, DBP was not associated with a decline in renal function. Furthermore, the primary endpoint was analyzed according to two patterns of BPs. Consequently, the number of patients who developed a primary endpoint renal event increased in parallel with the severity of hypertension at baseline—a finding that is concordant with a previous study [9]. Statistical analyses according to two patterns of BPs revealed that patients with isolated systolic hypertension, which prevails in the elderly, showed no marked changes in the primary endpoint.
In the present study, increased UACR was significantly associated with the rate of decline in eGFR from baseline. In general, proteinuria, considered to reflect the severity of glomerular damage and to be a risk factor for systemic angiopathy, has also been reported to be a risk factor for renal impairment or CVD [10]. A massive health checkup program was conducted to annually follow up ≥120,000 Japanese individuals in the general population to examine time-course changes in eGFR for not less than 10 years [11]. The study showed an annual average decrease of 0.36 mL/min/1.73 m2 in eGFR and revealed that hypertension, proteinuria, and low eGFR at baseline accelerated the decline in the renal function of investigated patients. On the other hand, the results from the present study indicate that the rate of decline in eGFR from baseline in Japanese patients with CKD increased in parallel with CKD progression; the rate was >tenfold greater in patients with CKD stage G5. In the US, Yang et al. [12] conducted a large-scale, prospective cohort study (the CRIC study) in patients with CKD. Regarding ESRD and eGFR halving from baseline, the HRs in the highest proteinuria category compared to the lowest counterpart were 11.83 (95 % CI 8.40–16.65) and 11.19 (95 % CI 8.53–14.68), respectively. They considered that proteinuria was a strong risk factor for the latter two endpoints only. CKD differs between the US and Japan with respect to its background factors, e.g., the proportion of underlying disease, the complication rate of CAD, and BMI. Nevertheless, we also verified the association of higher UACR, an index for ESRD, with declined eGFR. We established three categories of UACR to examine Alb excretion in spot urine samples in reference to the guideline [7]. Consequently, multivariate analysis revealed that P < 0.0001 was calculated not for UACR >300 mg/g Cre, the guideline’s category A3, but for UACR ≥1000 mg/g Cre, an arbitrary category. This novel finding indicates that CKD patients with increased UACR are at greater risk of experiencing CKD progression to ESRD compared to those with UACR 300–999 mg/g Cre among those with a high UACR.
De Nicola et al. [13] examined the renal prognosis of patients with CKD stages G1–G4 who were under nephrology care. They used the composite outcome of ESRD or a ≥40 % decline in eGFR from baseline and established the therapeutic target values for BPs, anemia, and urine proteins to care for 729 patients. They found a significant association (HR 1.96) of DM with combined renal endpoints when using hypertensive nephropathy as reference. However, we did not find any strong association between concurrent DM and the primary endpoint in the present study. Not all of patients, who had DM as underlying disease, developed diabetic nephropathy; the proportion of the relevant patients was no more than 55 %, a figure that had been described in our prior study [2]. The present study seems to have included a number of diabetic patients whose underlying disease was nephrosclerosis, which probably led to failure in extracting DM as a risk factor. We speculate that this unexpected finding is presumably attributable to the fact that many patients with DM have hypertensive nephropathy concurrently.
Voormolen et al. [14] reported a significant association (HR 0.178) between serum phosphorus level and the rate of decline in eGFR from baseline in patients with stage 4/5 CKD and conjectured that the association was attributable to the progression of arteriosclerosis caused by protein and phosphorus loads. In the present study, however, we did not find any significant association of elevated serum phosphorus level with the primary or secondary endpoints. Furthermore, we detected significant associations (HRs 1.050–1.090) between elevated BMI and the primary endpoint and some secondary endpoints. Of significance was the fact that elevated BMI was extracted as a risk factor similar to a previous study in Japan [15] even in a cohort of patients with CKD whose mean BMI was as low as 23.5 kg/m2. Also, we consider that the present study is clinically relevant in that the primary and secondary endpoints were examined in patients with CKD who were under nephrology care; not less than 80 % of them received ARBs and/or ACEIs, and their BPs (132 ± 19 mmHg in SBP/76 ± 12 mmHg in DBP) were under control to the levels at which the target BPs were almost reached. Our study is distinguishably featured by the precise assessment of renal events, including the rate of decline in eGFR from baseline, through the more meticulous care (e.g., frequent blood collections) of patients as compared with previous studies in Westerners.
Our study has several limitations. First, patient characteristics were determined only at baseline and once. Second, the GFR to assess the renal function of patients was not precisely calculated based on inulin clearance but was estimated with the serum creatinine-based equation. Third, selection bias cannot be ruled out, because patients were mostly enrolled at large-sized hospitals that can provide nephrology care.
In conclusion, elevated SBP and increased UACR were the risk factors significantly associated with CKD progression to ESRD in Japanese patients with CKD. Therefore, clinicians should constantly give heed, in the routine clinical setting, especially to advanced CKD patients with poorly controlled hypertension and increased UACR in an attempt to curb CKD progression to ESRD.