Predictors of non-diabetic kidney disease in diabetics: A Saudi Arabian perspective

Table 1 Histological spectrum of non-diabetic kidney diseases vs mixed lesions, n (%)

Biopsy category	NDKD	NDKD + DKD	Total
Interstitial nephritis	12 (29.2)	-	12 (18.2)
FSGS	10 (24.4)	3 (13.0)	13 (20.3)
Immune complex glomerulonephritis	5 (12.2)	6 (26.1)	11 (17.2)
IgA	2 (4.9)	4 (17.4)	6 (9.4)
Membranous	4 (9.8)	2 (8.7)	6 (9.4)
Lupus nephritis	4 (9.8)	-	4 (6.2)
Chronic pyelonephritis	-	2 (8.7)	2 (3.1)
Minimal change disease	3 (7.3)	-	3 (4.7)
Multiple myeloma	1 (2.4)	1 (4.3)	2 (3.1)
C1Q nephropathy	-	1 (4.3)	1 (1.6)
C3 glomerulopathy	-	1 (4.3)	1 (1.6)
Fibrillary glomerulonephritis	-	1 (4.3)	1 (1.6)
Pauci-immune vasculitis	-	1 (4.3)	1 (1.6)
Post-infectious glomerulonephritis	-	1 (4.3)	1 (1.6)
Total	41 (100.0)	23 (100.0)	64 (100.0)

DKD: Diabetic kidney diseases; NDKD: Non-diabetic kidney diseases; FSGS: Focal segmental glomerulosclerosis; IgA: Immunoglobulin A.

Table 2 Biopsy classification in the diabetic kidney disease group (n = 39)

DKD classification	n (%)
Class 4	16 (41.0)
Class 3	15 (38.5)
Class 2	7 (17.9)
Class 1	1 (2.6)

DKD: Diabetic kidney diseases.

Table 3 Baseline demographic and clinical characteristics, n (%)

Variable	DKD (n = 39)	DKD + NDKD (n = 23)	NDKD (n = 41)	P value
Gender				0.3518
Male	20 (51.3)	16 (69.6)	25 (61.0)
Female	19 (48.7)	7 (30.4)	16 (39.0)
Age, median (IQR)	53.0 (42.0-66.0)	69.0 (61.5-74.0)	50.0 (46.0-61.0)	0.0003
Diabetes diagnosis				1.0000
Yes	39 (100.0)	23 (100.0)	41 (100.0)
Diabetes type				0.0020
Type 1	10 (26.3)	1 (4.3)	1 (2.4)
Type 2	28 (73.7)	22 (95.7)	40 (97.6)
Duration of diabetes (months)	168.0 (120.0-240.0)	180.0 (36.0-216.0)	60.0 (12.0-108.0)	< 0.0001
Haemoglobin A1c level	7.1 (5.9-8.3)	7.2 (6.3-9.2)	6.8 (6.3-9.2)	0.5502
Retinopathy				0.0070
Yes	23 (59.0)	9 (39.1)	10 (24.4)
No	16 (41.0)	14 (60.9)	31 (75.6)
Hypertension				0.3005
Yes	34 (91.9)	20 (100.0)	35 (97.2)
No	3 (8.1)	0 (0.0)	1 (2.8)
Dyslipidaemia				0.9336
Yes	23 (60.5)	13 (59.1)	22 (56.4)
No	15 (39.5)	9 (40.9)	17 (43.6)
Neuropathy				0.0003
Yes	22 (61.1)	11 (55.0)	2 (9.1)
No	14 (38.9)	9 (45.0)	20 (90.9)
Coronary artery disease				0.0000
Yes	23 (65.7)	8 (42.1)	1 (4.2)
No	12 (34.3)	11 (57.9)	23 (95.8)
Peripheral artery disease				< 0.0001
Yes	30 (85.7)	12 (63.2)	1 (4.0)
No	5 (14.3)	7 (36.8)	24 (96.0)
Stroke				0.0001
Yes	28 (77.8)	12 (63.2)	5 (20.8)
No	8 (22.2)	7 (36.8)	19 (79.2)
Blood pressure-lowering medications				0.5112
≥ 1 medication	36 (92.3)	19 (82.6)	36 (87.8)
0 medication	3 (7.7)	4 (17.4)	5 (12.2)
ACE inhibitor use				0.1394
Yes	11 (30.6)	3 (13.0)	6 (14.6)
No	25 (69.4)	20 (87.0)	35 (85.4)
ARBs use				0.6285
Yes	21 (56.8)	11 (47.8)	19 (46.3)
No	16 (43.2)	12 (52.2)	22 (53.7)
Statin use				0.6736
Yes	29 (78.4)	19 (82.6)	30 (73.2)
No	8 (21.6)	4 (17.4)	11 (26.8)
Insulin use				0.000
Yes	29 (76.3)	15 (65.2)	11 (26.8)
No	9 (23.7)	8 (34.8)	30 (73.2)
Oral hypoglycemics				0.2538
Yes	17 (45.9)	8 (34.8)	23 (56.1)
No	20 (54.1)	15 (65.2)	18 (43.9)
SGLT2 inhibitor use				0.8871
Yes	2 (5.7)	1 (4.3)	3 (7.3)
No	33 (94.3)	22 (95.7)	38 (92.7)
Creatinine at biopsy (µmol/L)	295.0 (166.0-596.5)	323.0 (193.5-547.5)	210.0 (105.0-580.0)	0.3004
Creatinine at 1 year	483.5 (211.0-694.8)	352.5 (157.0-551.2)	124.0 (89.5-182.5)	0.0000
Creatinine at 2 years	491.0 (243.0-891.0)	302.0 (134.0-561.0)	122.0 (92.0-169.0)	0.0002
eGFR at 1 year	16.0 (11.0-25.5)	34.0 (19.5-44.5)	45.5 (22.8-77.2)	0.0056
eGFR at 2 years	19.0 (15.0-22.0)	30.5 (13.0-47.8)	55.0 (32.0-77.0)	0.0372
Hemoglobin (g/dL)	10.0 (9.1-11.1)	11.1 (9.8-14.5)	12.1 (10.4-78.3)	0.0013
Yes (Hb < 12)	30 (76.9)	14 (60.9)	18 (43.9)
No (Hb ≥ 12)	9 (23.1)	9 (39.1)	23 (56.1)
PTH (pmol/L)	20.4 (15.0-33.0)	11.1 (7.5-25.9)	20.4 (11.3-28.2)	0.0634
Calcium (mmol/L)	2.06 (1.90-2.15)	2.03 (1.90-2.31)	2.11 (1.96-2.22)	0.3066
Phosphate (mmol/L)	1.41 (1.28-1.64)	1.50 (1.23-1.96)	1.47 (1.26-1.73)	0.9176
Total protein (g/L)	58.0 (51.0-67.0)	58.0 (51.2-66.0)	64.0 (56.0-75.0)	0.1400
Albumin (g/L)	30.0 (26.0-33.0)	27.5 (23.8-32.0)	31.0 (27.0-37.0)	0.1404
Proteinuria = yes > 3.5 g/day	21.0 (47.7)	10.0 (22.7)	13.0 (29.5)
Proteinuria = no < 3.5 g/day	16.0 (30.2)	12.0 (22.6)	25.0 (47.2)
Proteinuria, median (IQR)	4.6 (2.2-7.8)	3.3 (0.8-7.0)	2.1 (0.9-5.0)	0.1859
Indication for biopsy				0.0243
Sudden renal decline	12 (30.8)	12 (52.2)	24 (58.5)
Proteinuria rise	20 (51.3)	7 (30.4)	7 (17.1)
Systemic markers	2 (5.1)	1 (4.3)	0 (0.0)
Hematuria (Indication)	5 (12.8)	3 (13.0)	10 (24.4)
Hematuria presence				0.2809
Present	27 (69.2)	17 (73.9)	23 (56.1)
Absent	12 (30.8)	6 (26.1)	18 (43.9)
Total glomeruli count	19.0 (12.0-28.0)	18.0 (10.5-32.5)	10.0 (8.0-17.0)	0.0154
Global sclerosis (count)	5.0 (2.0-11.0)	4.0 (2.2-5.8)	2.0 (1.0-3.2)	0.0007
Global sclerosis ratio	0.3 (0.1-0.6)	0.2 (0.1-0.4)	0.1 (0.1-0.4)	0.0212
Segmental sclerosis (count)	3.0 (0.5-6.0)	1.0 (0.0-5.0)	1.0 (0.0-2.5)	0.0399
Segmental sclerosis ratio	0.1 (0.0-0.2)	0.0 (0.0-0.2)	0.0 (0.0-0.2)	0.6571
Crescent presence				0.0567
Present	0 (0,0)	5 (21.7)	5 (12.2)
Absent	39 (100)	18 (78.3)	36 (87.8)
IFTA presence (≥ 25)				0.0073
Present	16 (41.0)	17 (77.3)	23 (69.7)
Not present	23 (59.0)	5 (22.7)	10 (30.3)
IFTA severity score				0.0019
Absent < 10	5 (12.8)	2 (9.1)	3 (9.1)
Mild 10-24	11 (28.2)	15 (68.2)	20 (60.6)
Moderate 25-50	13 (33.3)	5 (22.7)	10 (30.3)
Severe > 50	10 (25.6)	0 (0.0)	0 (0.0)
Median (IQR)	2.0 (1.0-2.5)	1.0 (1.0-1.0)	1.0 (1.0-2.0)
Arteriosclerosis presence				0.2367
Present	19 (50.0)	9 (42.9)	10 (71.4)
Absent	19 (50.0)	12 (57.1)	4 (28.6)
Arteriosclerosis severity (0-3)				0.2508
None	19 (50.0)	12 (57.1)	4 (28.6)
Mild 25	6 (15.8)	4 (19.0)	7 (50.0)
Moderate 26-50	9 (23.7)	3 (14.3)	2 (14.3)
Severe > 50	4 (10.5)	2 (9.5)	1 (7.1)
Arteriosclerosis median (IQR)	0.5 (0.0-2.0)	0.0 (0.0-1.0)	1.0 (0.2-1.0)
Hyalinosis severity (0-3)				0.3221
None	8 (20.5)	6 (28.6)	4 (22.2)
Mild	15 (38.5)	10 (47.6)	10 (55.6)
Moderate	15 (38.5)	3 (14.3)	4 (22.2)
Severe	1 (2.6)	2 (9.5)	0 (0.0)
Hyalinosis median (IQR)	1.0 (1.0-2.0)	1.0 (0.0-1.0)	1.0 (1.0-1.0)
Podocyte effacement				0.0042
Diffuse > 50	10 (26.3)	6 (30.0)	13 (52.0)
Focal ≤ 50	3 (7.9)	4 (20.0)	9 (36.0)
None	2 (5.3)	1 (5.0)	0 (0.0)
Not reported	23 (60.5)	9 (45.0)	3 (12.0)
Podocyte effacement median (IQR)	4.0 (1.2-4.0)	2.5 (1.0-4.0)	1.0 (1.0-2.0)
ANA (antinuclear antibodies)				0.5140
Positive	5 (13.5)	4 (20.0)	8 (24.2)
Negative	32 (86.5)	16 (80.0)	25 (75.8)
Anti-dsDNA Antibodies				0.3852
Positive	0 (0.0)	1 (12.5)	1 (4.2)
Negative	18 (94.7)	7 (87.5)	23 (95.8)
C3 complement (low vs normal)				0.1198
Low	0 (0.0)	4 (33.3)	7 (19.4)
Normal	11 (100.0)	8 (66.7)	29 (80.6)
C4 complement (low vs normal)				0.6700
Low	1 (4.2)	0 (0.0)	2 (5.6)
Normal	23 (95.8)	14 (100.0)	34 (94.4)
C-ANCA (cytoplasmic ANCA)				0.6378
Positive	0 (0.0)	1 (0.0)	0 (0.0)
Negative	35 (100)	16 (100.0)	15 (100.0)
P-ANCA (perinuclear ANCA)				1.0000
Positive	0 (0.0)	1(6.25)	(0.0)
Negative	35 (100.0)	15 (93.75)	14 (100.0)
Kidney failure (as per study definition)	38 (97.4)	15(65.2)	25 (61.0)	0.0002
Mortality				0.2038
Yes	8 (20.5)	7 (30.4)	5 (12.2)
No	31 (79.5)	16 (69.6)	36 (87.8)

DKD: Diabetic kidney diseases; NDKD: Non-diabetic kidney diseases; IQR: Interquartile range; ACE: Angiotensin converting enzyme; ARBs: Angiotensin II type 1 receptor blockers; SGLT2: Sodium-glucose cotransporter 2; eGFR: Estimated glomerular filtration rate; PTH: Parathyroid hormone; IFTA: Interstitial fibrosis and tubular atrophy; ANA: Antinuclear antibody; ANCA: Antineutrophil cytoplasmic antibodies.

Table 4 Multinomial logistic regression (Non-diabetic kidney diseases vs diabetic kidney diseases and mixed vs diabetic kidney diseases)

Group	Predictor	OR (95%CI)	P value	Significance
A clinical + lab-based model
NDKD vs DKD	Proteinuria > 3.5 g/day	0.02 (0.00-0.22)	0.0015	Significant
	Haemoglobin < 12 g/dL	9.56 (1.68-54.30)	0.0107	Significant
	Retinopathy present	0.04 (0.00-0.38)	0.0067	Significant
	DM duration ≥ 10 years	0.01 (0.00-0.12)	0.0002	Significant
	Age	1.01 (0.94-1.08)	0.8127	Not significant
	Creatinine > 180 μmol/L	18.68 (2.26-154.80)	0.0063	Significant
Mixed vs DKD	Proteinuria > 3.5 g/day	0.66 (0.08-5.70)	0.7030	Not significant
	Haemoglobin < 12 g/dL	1.90 (0.31-11.51)	0.4850	Not significant
	Retinopathy present	0.35 (0.05-2.58)	0.3049	Not significant
	DM duration ≥ 10 years	0.07 (0.01-0.71)	0.0249	Significant
	Age	1.13 (1.04-1.23)	0.0055	Significant
	Creatinine > 180 μmol/L	1.48 (0.13-16.50)	0.7483	Not significant
A histopathological model
NDKD vs DKD	Global sclerosis ratio	0.13 (0.01-3.21)	0.2108	Not significant
	Podocyte effacement	0.06 (0.01-0.39)	0.0033	Significant
	IFTA moderate to severe	0.22 (0.04-1.26)	0.0893	Borderline
Mixed vs DKD	Global sclerosis ratio	0.38 (0.04-3.73)	0.4048	Not significant
	Podocyte effacement	0.30 (0.08-1.19)	0.0870	Borderline
	IFTA moderate to severe	0.19 (0.05-0.77)	0.02	Significant

OR: Odds ratios; CI: Confidence interval; DKD: Diabetic kidney diseases; NDKD: Non-diabetic kidney diseases; DM: Diabetes mellitus; IFTA: Interstitial fibrosis and tubular atrophy.

Table 5 The multivariable Cox proportional hazards model (kidney failure and mortality)

Variable	HR	95%CI	P value	Significance
Multivariable Cox proportional hazards model (Kidney failure)
Age	1.04	1.01-1.07	0.01	Significant
Creatinine	1.01	1.01-1.01	< 0.005	Significant
RAS blocker (ACEi/ARBs)	0.43	0.21-0.89	0.02	Protective factor
Arteriosclerosis	1.56	1.11-2.19	0.01	Significant
IFTA	1.85	1.26-2.72	< 0.005	Significant
Retinopathy	1.60	0.79-3.25	0.19	Not significant
Multivariable Cox proportional hazards model (Mortality)
Age	1.05	1.00-1.09	0.04	Significant
Creatinine	1.01	1.00-1.01	< 0.005	Significant
Hemoglobin < 12 g/dL	2.25	0.66-7.72	0.20	Not significant
Albumin < 30 g/L	4.26	1.09-16.61	0.04	Significant
Retinopathy	3.66	1.05-12.72	0.04	Significant
Arteriosclerosis	2.47	1.36-4.50	< 0.005	Significant

HR: Hazard ratio; CI: Confidence interval; RAS: Renin-angiotensin system; ACEi: Angiotensin converting enzyme inhibitors; ARBs: Angiotensin II type 1 receptor blockers; IFTA: Interstitial fibrosis and tubular atrophy.