Silent diabetic nephropathy

doi:10.5527/wjn.v3.i1.6

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World Journal of Nephrology

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2220-6124

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Nephrol. Feb 6, 2014; 3(1): 6-15
Published online Feb 6, 2014. doi: 10.5527/wjn.v3.i1.6

Table 1 Clinical characteristics at renal biopsy n (%)

Total	n = 45
Age (yr) (range)	58.3 ± 13.3 (28-84)
Sex (men)	32 (71.1)
Diabetes type 2	38 (84.4)
Diabetes duration (yr) (range)	9.6 ± 7.8 (0-35)
BMI (kg/m²) (range)	29.3 ± 5.3 (27.8-47.8)
Obesity BMI > 30 kg/m²	18 (40.9)
Hypertension (yes)	42 (93.3)
Smoker, active or past (yes)	34 (75.6)
Dyslipidemic (yes)	33 (73.3)
Ischemic heart disease (yes)	7 (15.6)
CVA (yes)	6 (13.3)
Peripheral arterial disease (yes)	8 (17.8)
Any CVD	16 (35.6)
Hematuria (yes)	18 (41.9)
Serum albumin (g/dL) (range)	3.4 ± 0.7 (2-5)
HbA1c% (range)	6.5 ± 1.4 (4.1-9.3)
Total cholesterol (mg/dL)	177.9 ± 58.7
Previous nephrology care (yr) (range)	1.21 ± 2.4 (0-12)
RAASI treatment	40 (88.9)
Statin treatment	33 (73.3)
Antiplatelet drug treatment	21 (46.7)

BMI: Body mass index; CVD: Cardiovascular disease; RAASI: Renin-angiotensin aldosterone system inhibitor; CVA: Cerebrovascular accident.

Table 2 Renal parameters and evolution n (%)

		Previous renal data (n = 39)	Renal biopsy (n = 45)	End of follow-up (n = 24)
Time prior to biopsy (mo) (range)		7.3 ± 5.2
Time prior to biopsy (mo) (range)		(1.1-24.1)
Follow-up period (yr) (range)				3.4 ± 2.9
Follow-up period (yr) (range)				(0.2-11.8)
Renal biopsy indication	RPKI		8 (17.8)
	Nephrotic proteinuria		28 (62.2)
	CKD		9 (20)
Serum creatinine (mg/dL) (range)		1.6 ± 0.8	2.3 ± 1.5	2.3 ± 1.8
Serum creatinine (mg/dL) (range)		(0.8-4.5)	(0.8-6)	(0.7-9.1)
eGFR (mL/min per 1.73 m²) (range)		51.4 ± 20.9	39.1 ± 22.5	40.8 ± 25
eGFR (mL/min per 1.73 m²) (range)		(14.7-97.6)	(8.1-101.2)	(5.1-107.1)
¹eGFR category	G5 < 15		7 (15.6)	24 (53.3)
	G4 15-30		8 (17.8)	6 (13.3)
	G3b 30-45		15 (33.3)	5 (11.1)
	G3a 45-60		7 (15.6)	7 (15.6)
	G2 60-90		7 (15.6)	1 (2.2)
	G1 > 90		1 (2.2)	2 (4.4)
> 25% drop in eGFR prior to biopsy		13 (33.3)
²Proteinuria (range)		3.7 ± 3.4	4.5 ± 2.7
²Proteinuria (range)		(0-12.9)	(1-8.9)
³Proteinuria category	A1 < 150	3 (8.8)	0
	A2 150-500	2 (5.9)	4 (8.9)
	A3 > 500	29 (85.3)	41 (91.1)
RRT		2	5	21 (46.7)
⁴CKD progression				7 (15.6)
eGFR improvement > 25%				4 (8.9)
Exitus				5 (11.1)

¹GFR categories (mL/min per 1.73 m²): G1 = GFR ≥ 90; G2 = 60-89; G3a = 45-59; G3b = 30-44; G4 = 15-29; G5 < 15.

²Baseline proteinuria was measured using protein/creatinine ratio in spot urine (mg/g). Renal biopsy proteinuria was measured using excretion rate over 24 h (g/d).

³Proteinuria categories are described based on protein-to-creatinine ratio (mg/g) or protein excretion rate (mg/24 h) in: A1 ≤ 150, A2 = 150-500, A3 ≥ 500.

⁴CKD progression: 25% or greater eGFR decline, accompanied by a decrease in GFR category. RPKI: Rapidly progressive kidney injury; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; RRT: Renal replacement therapy.

Table 3 Clinical and histopathological findings according to glomerular classification of diabetic nephropathy n (%)

		I-IIa-IIb (n = 18)	III (n = 23)	IV (n = 4)
Age (yr)		59.9 ± 12.2	58.1 ± 14.1	52.3 ± 15.4
Years of diabetes		9.1 ± 7.4	9.3 ± 6.3	15.1 ± 18
BMI (kg/m²)		29 ± 4.9	30.1 ± 6	26.8 ± 2.4
Serum creatinine (mg/dL)		2 ± 1.2	2.2 ± 1.4	4.4 ± 1.9
eGFR (mL/min per 1.73 m²)		42.3 ± 21.9	40.4 ± 22.9	17.6 ± 12.3
HbA1c (%)		6.7 ± 1.4	6.3 ± 1.3	6.7 ± 2
Proteinuria (g/d)		3.1 ± 2.6	5.2 ± 4	4.7 ± 5.6
Serum albumin (g/dL)		3.6 ± 0.7	3.3 ± 0.7	2.9 ± 0.7
Serum cholesterol (mg/dL)		165.4 ± 71.6	191.5 ± 34.6	213 ± 0
Hypertension		16 (88.9)	22 (95.7)	4 (100)
Diabetic retinopathy		7 (38.9)	9 (39.1)	2 (50)
CVD		7 (38.9)	6 (26.1)	3 (75)
RPKI		0	6 (33.3)	7 (30.4)
Patients with renal events		9 (50)	15 (65.2)	4 (100)
RRT		6 (33.3)	11 (47.8)	4 (100)
¹Years from biopsy to renal event		4.2 ± 1.2	3.4 ± 1.4	0.4 ± 0.4
% of global glomerulosclerosis		18.1 ± 12.8	18.4 ± 15.1	77.3 ± 16.9
Interstitial fibrosis	0	1 (5.6)	0	0
and tubular atrophy	1	10 (55.6)	13 (56.5)	0
	2	5 (27.8)	9 (39.1)	1 (25)
	3	2 (11.1)	1 (4.3)	3 (75)
Interstitial inflammation	0	3 (16.7)	0	0
	1	14 (77.8)	22 (95.7)	4 (100)
	2	1 (5.6)	1 (4.3)	0
Arteriolar hyalinosis	0	1 (5.6)	1 (4.3)	1 (25)
	1	3 (16.7)	2 (8.7)	0
	2	14 (77.8)	20 (87)	3 (75)
Large vessel arteriosclerosis (yes)		17 (94.4)	19 (86.4)	4 (100)

¹Years from biopsy to renal event are expressed as medians ± SEs, estimated by Kaplan-Meier method. CVD: Cardiovascular disease; BMI: Body mass index; RPKI: Rapidly progressive kidney injury; RRT: Renal replacement therapy; eGFR: Estimated glomerular filtration rate.

Table 4 Clinical differences at the time of biopsy between silent and non-silent diabetic nephropathy n (%)

	Non-silent DN (n = 20)	Silent DN (n = 25)	P value
Age (yr)	55.8 ± 12.2	60.3 ± 14.1
Sex (women)	5 (25)	8 (32)
BMI (kg/m²)	30.9 ± 6.3	28 ± 4.1
T2 DM	17 (85)	21 (84)
Duration of diabetes (year)	12.5 ± 5.3	7 ± 8.9	0.005
Follow-up period (year)	3.4 ± 3.5	3.5 ± 2.7
Smoking, active or past	16 (80)	18 (72)
Retinopathy	8 (40)	10 (40)
CVD	6 (30)	10 (40)
HbA1c (%)	7 ± 1.2	6.2 ± 1.5	0.03
Serum creatine at biopsy (mg/dL)	1.8 ± 1	2.7 ± 1.6	0.03
eGFR at biopsy (mL/min per 1.73 m²)	47 ± 22.5	32.9 ± 20.8	0.04
Proteinuria (g/d)	3.5 ± 2.6	5 ± 4.3
Hematuria	8 (44.4)	10 (40)
RPKI	3 (15)	12 (48)	0.03
CKD progression	3 (15)	10 (50)	0.04
Renal events	8 (40)	20 (80)	0.01
Histopathological class AP III-IV	9 (45)	18 (72)
Glomerular sclerosis percentage	18.8 ± 14.3	27.2 ± 26.4
IFTA 0-1	12 (60)	12 (48)
IFTA 2	7 (35)	8 (32)
IFTA 3	1 (5)	5 (20)
Severe arteriolar hyalinosis	15 (75)	22 (88)
Large vessel arteriosclerosis	18 (94.7)	22 (88)
RAASI treatment	18 (90)	22 (88)
Statins treatment	15 (75)	18 (72)

IFTA: Interstitial fibrosis and tubular atrophy; CVD: Cardiovascular disease; RPKI: Rapidly progressive kidney injury; RRT: Renal replacement therapy; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; RAASI: Renin-angiotensin aldosterone system inhibitor; DN: Diabetic nephropathy; DM: Diabetes mellitus.

Table 5 Multivariate Cox proportional model of renal end point by the variable silent diabetic nephropathy

Variables in the equation	HR	95%CI
Variables in the equation	HR	Lower	Upper
CVD	3.943	1.649	9.429
HbA1c%	0.724	0.516	1.016
Silent DN	2.137	0.819	5.573

Silent DN: Histologic diagnosis of DN and RPKI without significant proteinuria (< 0.5 g/d) and/or a DM with less than 5 years of evolution and/or the need to begin RRT before 1.5 years after renal biopsy. CVD: Cardiovascular disease; DN: Diabetic nephropathy; HR: Hazard ratio; DM: Diabetes mellitus.

Table 6 Univariate Cox proportional hazard analysis of renal end point, according to clinical variables

	HR	95%CI		P value
	HR	Lower	Upper
Age (yr)	1.00	0.97	1.03	P value
Sex (men)	1.19	0.50	2.85
Diabetes type (2/1)	0.76	0.31	1.91
Diabetes duration (years)	1.01	0.95	1.07
BMI < 30 (yes/no)	2.94	1.09	7.69	0.03
Smoker (yes/no)	0.92	0.34	2.50
Hypertension (yes/no)	1.01	0.13	7.69
CVD (yes/no)	4.56	1.94	10.69	0.000
Retinopathy (yes/no)	1.24	0.56	2.75
Baseline Serum creatinine (mg/dL)	2.18	1.14	4.16	0.02
Baseline eGFR (mL/min per 1.73 m²)	0.98	0.95	1.00
¹Baseline proteinuria (g/g)	1.12	0.98	1.27
eGFR drop > 25% before biopsy	3.96	1.54	10.18	0.004
Serum creatinine (mg/dL) at biopsy	2.97	1.91	4.61	0.000
eGFR (mL/min per 1.73 m²) at biopsy	0.94	0.92	0.97	0.000
RPKI	2.74	1.21	6.24	0.02
²Proteinuria at biopsy (g/d)	1.09	0.97	1.23
Hematuria	1.65	0.72	3.82
Serum albumin (g/dL)	0.75	0.41	1.35
HbA1c % (< 7/≥ 7)	3.37	1.23	9.25	0.02
Total cholesterol (mg/dL)	0.98	0.96	1.01
RAASI treatment (yes/no)	0.59	0.22	1.59
Statin treatment	0.66	0.27	1.62
Silent DN	3.04	1.26	7.3	0.02

¹Baseline proteinuria was measured using protein/creatinine ratio in spot urine (g/g).

²Renal biopsy proteinuria was measured using excretion rate in 24 h (g/d). BMI: Body mass index; CVD: Cardiovascular disease; eGFR: Estimated glomerular filtration rate; RPKI: Rapidly progressive kidney injury; RAASI: Renin-angiotensin aldosterone system inhibitor; DN: Diabetic nephropathy.

Table 7 Univariate Cox proportional hazard analysis of renal end point, according to histological variables

		HR	95%CI		P value
Glomerular class	III/I-IIa-IIb	1.2	0.5	2.9
	IV/I-IIa-IIb	5.6	1.6	19.7	0.007
	IV/III	4.6	1.4	15.1	0.01
% of global glomerulosclerosis		1.0	1.0	1.0	0.01
IFTA	(> 25 ≤ 25%)	1.2	0.5	2.5
Arteriolar hyalinosis	Severe/mild	0.7	0.2	2.2
Large vessel arteriosclerosis (yes)	1-2/0	1.2	0.4	4.1

HR: Hazard ratio; IFTA: Interstitial fibrosis and tubular atrophy.

Table 8 Multivariate Cox proportional hazard model of renal end point, adjusted for age and sex

	HR	95%CI for HR		P value
	HR	Lower	Upper
CVD	2.75	1.07	7.11	P value	0.036
RPKI	1.29	0.46	3.64	0.626
eGFR (10 mL/min per 1.73 m²)	1.96	1.28	3.00	0.001
HbA1c% (< 7/≥ 7)	2.88	0.98	8.44	0.054

CVD: Cardiovascular disease; HR: Hazard ratio; RPKI: Rapidly progressive kidney injury; eGFR: Estimated glomerular filtration rate.

Citation: López-Revuelta K, Galdo PP, Stanescu R, Parejo L, Guerrero C, Pérez-Fernández E. Silent diabetic nephropathy. World J Nephrol 2014; 3(1): 6-15
URL: https://www.wjgnet.com/2220-6124/full/v3/i1/6.htm
DOI: https://dx.doi.org/10.5527/wjn.v3.i1.6