Serum Hemoglobin Concentration and Risk of Renal Function Decline in Early Stages of Diabetic Kidney Disease

A Nationwide, Biopsy-Based Cohort Study

Masayuki Yamanouchi; Kengo Furuichi; Miho Shimizu; Tadashi Toyama; Yuta Yamamura; Megumi Oshima; Shinji Kitajima; Akinori Hara; Yasunori Iwata; Norihiko Sakai; Yuki Oba; Shusaku Matsuoka; Daisuke Ikuma; Hiroki Mizuno; Tatsuya Suwabe; Junichi Hoshino; Naoki Sawa; Yukio Yuzawa; Hiroshi Kitamura; Yoshiki Suzuki; Hiroshi Sato; Noriko Uesugi; Yoshihiko Ueda; Shinichi Nishi; Hitoshi Yokoyama; Tomoya Nishino; Kenichi Samejima; Kentaro Kohagura; Yugo Shibagaki; Hirofumi Makino; Seiichi Matsuo; Yoshifumi Ubara; Takashi Wada


Nephrol Dial Transplant. 2022;37(3):489-497. 

In This Article

Abstract and Introduction


Graphical Abstract

Background: Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin (Hb) concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression.

Methods: Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: age 56 (45–63) years; 62.6% men; Hb 13.3 (12.0–14.5) g/dL; eGFR 76.2 (66.6–88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio 534 (100–1480) mg/g Crea. Serum Hb concentration was divided into quartiles: ≤12, 12.1–13.3, 13.4–14.5 and ≥14.6 g/dL. The association between serum Hb concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum Hb concentration to the known risk factors of DKD was assessed.

Results: Serum Hb levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ = −0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second and third quartile (the fourth quartile was reference) were 2.74 [95% confidence interval (CI) 1.26–5.97], 2.33 (95% CI 1.07–5.75) and 1.46 (95% CI 0.71–3.64), respectively. Addition of the serum Hb concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global Chi-statistics increased from 55.1 to 60.8; P < 0.001).

Conclusions: Serum Hb concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.


Diabetic kidney disease (DKD) is not just the most prevalent form of chronic kidney disease (CKD) but also the leading cause of end-stage kidney disease (ESKD) worldwide.[1–3] It also accounts for an increase in cardiovascular disease (CVD) and mortality.[4] Since morbidity and mortality increase as the renal function declines,[5] the early identification of patients at high risk of CKD progression is important so that clinicians can provide intensive treatment that may ultimately alter the prognosis of DKD. Although some novel biomarkers have shown to be of prognostic value in patients with diabetes in the early stages of CKD,[6] it is too laborious for routine use. This predicament highlights the need for widely available, routinely measured markers that reflect early kidney damage for prognosticating the clinical course of DKD, especially in the earlier stages of CKD.

Anemia is common among patients with CKD[7] and it is associated with the risk of progression of kidney disease, CVD and mortality.[8–11] Although possible causes of anemia in CKD include iron and vitamin deficiency, the major cause of anemia in CKD is renal tubulointerstitial impairment that interferes with erythropoietin production.[12,13] Therefore, anemia is more common and severe in the later stages of CKD.[7] Meanwhile, anemia occurs in the earlier stages of CKD in patients with diabetes.[14] However, data on the association between anemia, tubulointerstitial lesions and renal prognosis are lacking in the early stages of CKD in patients with diabetes due to the fact that kidney biopsy is not always applicable for them.

Fortunately, the Ministry of Health, Labor and Welfare in Japan has currently established a nationwide biopsy-proven cohort of DKD, including patients in the early stages of CKD.[15,16] We therefore postulate that anemia in the early stages of CKD reflects incipient kidney injury due to tubulointerstitial damage, and thus serum hemoglobin (Hb) concentration in the early stages of CKD could be useful for prognosticating the clinical course of DKD. The objectives of our study were to: (i) evaluate the association between serum Hb concentration and tubulointerstitial lesions in kidney biopsy specimens and (ii) quantify the risk for progression of CKD, according to the serum Hb concentration, in patients with Type 2 diabetes and biopsy-proven DKD in the early stages of CKD.