Capillaroscopic changes in patients with glomerular diseases: a case control study

doi:10.21203/rs.3.rs-4223620/v1

Background:

Glomerulonephritis is a heterogenous group of diseases which is diagnosed mainly by renal biopsy. This study aims to assess nailfold capillaroscopic changes in patients with glomerular diseases.

Patients and methods:

This study was conducted on 50 patients with glomerular disease confirmed by renal biopsy and 50 age and sex matched healthy controls. Clinical, laboratory evaluation and nailfold capillaroscopic examination were done for all participants. Statistical analysis was done andT test and one way ANOVA test were used for normally distributed variables, while Mann Whitney and Kruskal Wallis tests were used for non-normally distributed variables. Association between 2 continuous variables was done by Pearson’s correlation or spearman’s rank correlation.

Results:

Lupus nephritis was the most common pathological type among glomerulonephritis group (34%, n=17), followed by focal segmental glomerulosclerosis (18%, n= 9). Tortuous capillaries were significantly higher in patients with glomerular diseases (94%, n=47) (P<0.001). The diameter was significantly lower in patients with glomerular diseases (18.68 µm, 16.83 µm, P=0.021). Subpapillary venous plexus (22%, 6%, P 0.021) and capillary microhemorrhage (42%, P <0.001) were significantly more frequent in patients with glomerular diseases compared to the control group. Patients with lupus nephritis had higher capillary diameter (19.5, 15.6 µm, P 0.02), width (55.6, 44 µm, P 0.003) and microhemorrhage (64.7%, 32%, P 0.03) compared to patients with primary glomerulonephritis. There were no statistically significant differences between patients with different types of primary glomerulonephritis. There was a statistically significant difference as regard diameter (P=0.005) and length (P=0.02) between different classes of lupus nephritis.

Conclusion:

Nailfold capillaroscopy showed more tortious capillaries and lower capillary diameter in patients with glomerular disease compared to healthy persons. Lupus nephritis patients showed more dilated capillaries and more capillary microhemorrhage compared to primary glomerulonephritis patients.

Glomerulonephritis

Capillaroscopy

Lupus nephritis

Glomerulonephritis (GN) is a heterogenous group of diseases characterized by increased glomerular cellularity due to proliferation of glomerular cells and/or leukocyte infiltration which may lead to glomerular damage. If GN is not properly treated may progress to chronic kidney disease and end stage renal disease (ESRD) (1). GN is the most common cause of end stage renal disease in young people. The clinical presentation of GN is variable, ranging from asymptomatic proteinuria to rapidly progressive GN with hypertension, oliguria and uremia. The classic presentation of acute GN include edema, hypertension hematuria and sometimes oliguria. Patients may also present with nephrotic syndrome and generalized edema (2).

Renal biopsy is the gold standard for diagnosis of GN as it can differentiate it from other causes of kidney disease, can identify the histopathological type and differentiate active reversible lesions from chronic irreversible lesions. Renal biopsy should be evaluated by light microscopy, immunohistology and often by electron microscopy (2). GN can be classified according to the pathogenesis into immune-complex GN, pauci-immune GN, anti glomerular basement membrane antibody (anti-GBM) GN, monoclonal Ig GN, and C3 glomerulopathy (3).

Nailfold capillaroscopy (NFC) is an easy, noninvasive method for examination of nailfold capillaries. Normal nailfold capillaroscopy appear as homogenous parallel hairpin shaped capillaries (4). NFC is strongly recommended for patients with Raynaud’s phenomenon and is commonly used by rheumatologists in clinical practice and in research studies. Presence of giant capillaries, microhemorrhage, avascular areas and neo angiogenesis is helpful for diagnosis of scleroderma spectrum disorders (5).

In systemic sclerosis, NFC is included in the diagnostic criteria, can be used for early diagnosis and can identify the activity phase (either early, active or late pattern). In other connective tissue diseases as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), NFC changes are nonspecific but may provide support to the diagnosis. The utility of NFC in non-rheumatic diseases is not well studied (6). NFC may be helpful in assessment of microcirculation and endothelial dysfunction. Capillaroscopic changes in the form of decrease in capillary density was reported in association with chronic kidney disease (CKD) (7). Also more decrease in capillary density was found in CKD patients with diabetes mellitus (DM) than CKD patients without DM (8). Additionally, NFC changes was associated with disease severity in ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (9). However, no previous studies evaluated the capillaroscopic changes in patients with glomerular diseases.

This study aims to assess NFC changes in patients with glomerular diseases. This is a case control study which was conducted on 50 patients with glomerular disease who attended and/or referred to the nephrology or Rheumatology and Immunology units and outpatient clinics, Mansoura university hospital beside 50 healthy controls. The study was conducted from March 2022 to March 2023. This study was approved by Institutional Review Board of Mansoura university (IRB code number: MS.21.12.1777). The study was explained to all the participants and an informed consent was taken.

Patients older than 16 years who were diagnosed to have glomerular disease based on renal biopsy were included in this study. Patients less than 16 years and patients who did not take renal biopsy due to any cause were excluded from this study. Participants were divided into two groups. Group 1 included 50 patients diagnosed with glomerular disease, group 2 which included 50 age and gender matched healthy persons.

All participants were subjected to full history taking and examination including age, smoking and chronic illness. Investigations were done to the patients including complete blood count, serum creatinine, urine analysis, 24-hour urinary protein, ESR (erythrocyte sedimentation rate) and CRP (C reactive protein). The result of renal biopsy was revised and documented in all patients.

Capillaroscopic examination:

Capillaroscopic examination was done for all participants in this study using videocapillaroscope by Dino lite with 200X magnification. Participants were seated in a temperature-controlled (23–26 °C) room for 15-20 minutes for relaxation and acclimatization (10).

Capillaroscopic examination was done for eight fingers of both hands (excluding the thumbs) in each participant. Fingers with thick nailfolds and gangrenous fingers were not analyzed. A drop of vegetable oil was applied to the nailfold of each finger before examination to maximize the amount of light and improve the image quality (11). Care was taken not to exert too much pressure on the nail surface. Three adjacent fields were examined for nailfold of each finger by one Rheumatologist trained in this technique and was blinded to the clinical data of the patients (12). The images were analyzed using the software Dino Capture 2 version 1.5.47.B, in which measurements of the capillaries were made and the characteristics of the capillary microarchitecture were carefully visualized.

The parameters measured include capillary density, capillary width, capillary diameter and capillary length. Capillary density means the number of capillaries in a 1mm length of the distal row of each finger. Capillary width is the width of a capillary loop at its widest section. The diameter of capillaries at its widest sections were also measured. Capillaries are considered dilated if the largest diameter is more than 20 Um and considered giant if the largest diameter is more than 50 Um. Capillary length is the distance between the apex of a capillary loop and the point where the capillary loop is no longer visible (13). The average was calculated for each of the observed parameters in 24 images.

Capillary shape was evaluated, and regular hairpin shaped capillaries was considered normal (11). Tortious capillaries are capillaries which intersect like number eight with convex apex. Abnormal capillary shapes include branched, bushy and bizarre capillaries (14). If more than 50% of the existing capillaries were evaluated as being affected, they were scored as “present”. If less than 50% of capillaries were found to be affected, they were scored as “none”.

Patients were also evaluated for the presence of capillary microhemorrhage and subpapillary venous plexus into either present or absent. Capillary microhemorrhages mean presence of 2 or more punctate bleeds around a single capillary or hemosiderin deposit caused by the rupture of one or more capillaries in at least 2 fingers. The vascular network at the base of a finger nailfold into which capillaries drain is called the subpapillary plexus (13).

Statistical analysis:

The results were collected, sorted & tabulated using computer based spread sheet program. The collected data were analyzed by SPSS. Numerical data were presented as means ± standard deviation when they were parametric and median when they were non-parametric. Non numerical data were presented as frequencies & percentage. Data were tested for normality via Kolmogorov-Smirnov test. In the normally distributed variables, T test and one way ANOVA test were used; while in non-normally distributed variables, Mann Whitney and Kruskal Wallis tests were used.

Association between 2 continuous variables was done by Pearson’s correlation, whereas non-parametric associations were done by spearman’s rank correlation. Regression analysis models will be used to define independent predictors. P value ≤0.05 was considered statistically significant.

Patients with glomerular diseases were higher in hypertension (56%, 8%, P <0.001), 24-hour urinary protein (2.4, 0.02 gm/24hours P 0.005) and positive CRP (64%, 0, P<0.001) compared to healthy control group. Otherwise, there was no significant difference between both groups as regard demographic, clinical or laboratory data as shown in table 1. Lupus nephritis was the most common pathological type (34%, n=17), followed by focal segmental glomerulosclerosis (FSGS) (18%, n= 9) as demonstrated in figure 1.

There were no statistically significant differences between patients with glomerular diseases and the control groups as regards Capillary density, Capillary architecture, width or length. Hair pain shaped capillaries were higher in control group as in figure 2 (58%, n= 29), while tortuous capillaries were significantly higher in patients with glomerular diseases as in figure 3 (94%, n=47) (P<0.001). The diameter was significantly lower in patients with glomerular diseases (18.68 µm, 16.83 µm, P=0.021). Subpapillary venous plexus (22%, 6%, P 0.021) and capillary microhemorrhage (42%, P <0.001) were significantly more frequent in patients with glomerular diseases compared to the control group as illustrated in table (2).

There were no statistically significant differences between patients with primary glomerulonephritis and patients with lupus nephritis as regards demographic, clinical and laboratory data except for 24-hour urinary protein which was significantly higher in patients with primary glomerulonephritis (5 gm/24 hours, 2 gm/24 hours, P = 0.005) as demonstrated in table 3. There was no statistically significant difference between patients with primary glomerulonephritis and patients with lupus nephritis as regards capillary density, capillary shape, capillary architecture, length or subpapillary venous plexus. However, patients with lupus nephritis had higher capillary diameter (19.5, 15.6 µm, P 0.02), width as in figure 4 (55.6, 44 µm, P 0.003) and microhemorrhage as in figure 5 (64.7%, 32%, P 0.03) compared to patients with primary glomerulonephritis as illustrated in table 4.

There were no statistically significant differences between patients with different types of primary glomerulonephritis as illustrated in table 5. There was a statistically significant difference as regard diameter (P=0.005) and length (P=0.02) between different classes of lupus nephritis. While no significant difference was detected as regard the remaining capillaroscopic parameters as demonstrated in table 6.

There were no statistically significant correlations between proteinuria and all capillaroscopic parameters except for capillary hemorrhage which had a significant negative correlation with proteinuria (R=-0.4, P=0.006). In addition, there was a significant positive correlation between proteinuria and serum creatinine (R=0.4, P=0.004) as in table 7.

Table (1): Sociodemographic, clinical and laboratory characteristics of the studied groups:

	Control group N=50	Cases group N=50	P value
Age/years Mean ± SD	31.48±7.12	35.30±12.64	0.07
Gender Male n(%) Female n(%)	25(50) 25(50)	17(34) 33(66)	0.105
Hypertension n(%)	4(8.0)	28(56.0)	<0.001*
Diabetes n(%)	2(4.0)	7(14.0)	0.081
Smoking n(%)	0	4(8)	0.117
24 hour urinary protein (gm/day) Median (IQR)	0.02 (0.01- 0.04)	2.4 (0.97 – 6)	0.005*
Serum creatinine (mg/dl) Median (IQR)	0.9 (0.8-1)	1.1 (0.9 – 2)	0.5
Hemoglobin (gm/dl) Mean ± SD	12 (11 – 13)	10.48±2.12	0.6
CRP Positive n(%) Negative n(%)	- 50 (100)	32(64.0) 18(36.0)	0.001*

SD: standard deviation, IQR: interquartile range, CRP: C reactive protein.

*P value less than 0.05 is statistically significant.

Table (2): Difference in capillaroscopic characteristics between patients with glomerular diseases and the healthy control group:

Control group

N=50

Cases group

N=50

P value

Capillary density (capillary /mm)

Mean ± SD

7.24±1.12

7.17±2.16

p=0.835

Capillary shape

Hair pin n(%)

Tortious n(%)

Abnormal n(%)

29 (58%)

21 (42%)

-

1 (2%)

47 (94%)

2 (4%)

<0.001*

Capillary architecture

Normal n(%)

Disturbed n(%)

50(100)

0

49(98%)

1(2)

P=0.468

Diameter (µm)

Mean ± SD

18.86±3.85

16.83±4.78

p=0.021*

Length (µm)

Mean ± SD

270.14±88.88

255.84±102.03

p=0.457

Width (µm)

Mean ± SD

42.99±11.98

47.84±13.25

p=0.06

Subpapillary venous plexus n(%)

3(6.0%)

11(22.0%)

P=0.021*

Capillary hemorrhage n(%)

-

21 (42%)

<0.001*

SD: standard deviation, IQR: interquartile range.

*P value less than 0.05 is statistically significant.

Table (3): Difference in sociodemographic, clinical and laboratory characteristics between patients with primary glomerulonephritis and patients with lupus nephritis.

Primary glomerulonephritis

N=28

Lupus nephritis

N=17

P value

Age/years

Median (IQR)

36 (21-43.75)

36 (24 -40)

0.9

Sex

Male n(%)

Female n(%)

11(39.3%)

17 (60.7%)

3 (17.6%)

14(82.4%)

0.2

Hypertension n(%)

14(50%)

11(64.7%)

0.3

Diabetes n(%)

4(14.3%)

2(11.8%)

0.6

Smoking n(%)

2 (7.1%)

2(11.8%)

0.5

24 hour urinary protein (gm/day)

Median (IQR)

5 (1.53 – 6.85)

2 (.055-2.5)

0.005*

Serum creatinine (mg/dl)

Median (IQR)

1.3 (1 – 2)

1 (0.9 – 1.8)

0.5

Hemoglobin (gm/dl)

Mean ± SD

10.5 ± 2.1

10.3 ± 2.2

0.6

CRP

Positive n(%)

12 (42.6%)

4 (23.5%)

0.2

SD: standard deviation, IQR: interquartile range, CRP: C reactive protein.

*P value less than 0.05 is statistically significant.

Table (4): Difference in capillaroscopic characters between patients with primary glomerulonephritis and patients with lupus nephritis:

	Primary glomerulonephritis	Lupus nephritis	P value
Capillary density (capillary/mm) Mean ± SD	6.9 ±1	6.8 ± 0.7	0.9
Capillary shape Hair pin n(%) Tortious n(%) Abnormal n(%)	- 26 (92.9%) 2 (7.1%)	- 17 (100%) -	0.4
Capillary architecture Normal n(%) Disturbed n(%)	27 (96.4%) 1 (3.6%)	17 (100%) -	0.6
Diameter (µm) Mean ± SD	15.6 ± 3.5	19.5 ± 5.7	0.02*
Length (µm) Mean ± SD	230 (165– 354)	218 (156 – 318)	0.6
Width (µm) Mean ± SD	43.99±11	55.6 ±13.6	0.003*
Subpapillary venous plexus n(%)	8 (28.6%)	3 (17.6%)	0.3
Capillary hemorrhage n(%)	9 (32%)	11 (64.7%)	0.03*

SD: standard deviation, IQR: interquartile range.

*P value less than 0.05 is statistically significant.

Table (5): Difference in capillaroscopy between patients with different types of primary glomerulonephritis:

MPGN

N=5

Focal proliferative glomerulonephritis

N= 5

Minimal change disease

N= 3

FSGS

N= 9

Membranous nephropathy

N=6

P value

Capillary density (capillary/mm)

Mean ± SD

7±1.3

6.5 ± 1

8 ± 1

6.6 ± 0.7

7 ± 0.8

0.3

Capillary shape

Hair pin n(%)

Tortious n(%)

Abnormal n(%)

-

5 (100%)

-

4 (80%)

1 (20%)

3 (100%)

-

8 (88.9%)

1 (11.1%)

-

6 (100%)

0.7

Capillary architecture

Normal n(%)

Disturbed n(%)

4 (80%)

1 (20%)

5 (100%)

3 (100%)

9 (100%)

6 (100%)

0.3

Diameter (µm)

Mean ± SD

13.7 ± 2.3

15 ± 4.5

12.9 ± 3.3

17.3 ± 3.2

16.6 ± 3.3

0.2

Length (µm)

Mean ± SD

239 ± 65

209 ± 50

218 ± 109

315 ± 158

285 ± 97

0.7

Width (µm)

Mean ± SD

37.7 ± 7.5

48.6 ± 17.8

38.9 ± 4.6

44 ± 5.5

47.3 ± 14.5

0.8

Subpapillary venous plexus n(%)

3 (60%)

1 (20%)

-

1 (16.7%)

0.4

Capillary hemorrhage n(%)

2 (40%)

1 (33.3%)

3 (33.3%)

1 (16.7%)

0.9

SD: standard deviation, IQR: interquartile range.

*P value less than 0.05 is statistically significant

Table (6): Difference in capillaroscopy between patients with different classes of lupus nephritis:

	Class III N= 5	Class IV N=8	Class V N=3	P value
Capillary density (capillary/mm) Mean ± SD	7.1 ± 0.36	6.7 ± 0.7	6.7 ± 1.2	0.14
Capillary shape Hair pin n(%) Tortious n(%) Abnormal n(%)	5 (100%)	- 8 (100%)	- 3 (100%)	1
Capillary architecture Normal n(%) Disturbed n(%)	5 (100%)	8 (100%)	3 (100%)	1
Diameter (µm) Mean ± SD	15.5 ± 1.2	19.4 ± 3.4	28.2 ± 6.7	0.005*
Length (µm) Mean ± SD	162 ± 34	268 ± 101	322 ± 41	0.02*
Width (µm) Mean ± SD	44.8 ± 5.6	57.6 ± 10.6	70.3 ± 19.4	0.08
Subpapillary venous plexus n(%)	2 (40%)	8 (100%)	1 (33.3%)	0.2
Capillary hemorrhage n(%)	3 (60%)	4 (50%)	3 (100%)	0.3

SD: standard deviation, IQR: interquartile range.

*P value less than 0.05 is statistically significant.

Table (7): Correlation between proteinuria, capillaroscopic parameters and serum creatinine:

	Patients with glomerular diseases
Character	Rho	P
Capillary density	0.02	0.9
Capillary shape	0.02	0.9
Capillary architecture	0.05	0.7
Capillary diameter	0.09	0.5
Capillary length	0.03	0.9
Capillary width	-0.3	0.06
Capillary hemorrhage	-0.4	0.006*
Subpapillary venous plexus	0.08	0.6
Serum creatinine	0.4	0.004*

*P value less than 0.05 is statistically significant.

Glomerular diseases are relatively rare kidney diseases which can lead to CKD and ESRD. Kidney biopsy is the diagnostic procedure of choice (15). This study was conducted on 50 patients with glomerular diseases who were compared to 50 healthy control participants. Nailfold capillaroscopic examination was done for all participants. The commonest GN type was lupus nephritis followed by FSGS and membranous nephropathy. Capillaroscopic characteristics showed significant differences between GN patients and control group as regard capillary shape, diameter, subpapillary venous plexus and capillary hemorrhage. There was statistically significant difference between lupus nephritis patients and patients with primary glomerulonephritis as regard diameter, width and capillary hemorrhage. However, there was no significant difference in capillaroscopic changes between different types of primary glomerular diseases. There was a significant negative correlation between proteinuria and capillary hemorrhage.

Hypertension was significantly higher in patients with GN than in healthy control group. The high incidence of hypertension is primarily due to sodium retention leading to fluid overload, as evidenced by suppression of the renin-angiotensin-aldosterone (RAAS) system (16). Almost all patients develop hypertension when the glomerular filtration rate (GFR) declines (17). Other studies reported a strong association between GN and the incidence of hypertension (16) (18).

In the present study, lupus nephritis was the commonest cause for GN. In agreement with this, recent Egyptian study on 140 Egyptian GN patients reported that lupus nephritis was the commonest cause for secondary GN and FSGS was the commonest primary cause for GN (21.4%) (19). Similarly, other studies reported that lupus nephritis was the most common cause of glomerulonephritis (20) (21) (22). The most common primary GN in the current study was FSGS followed by membranous nephropathy. Similar to this, other studies reported that FSGS was the most frequent primary GN (22) (23). Membranous nephropathy was the most common primary GN in other studies (21)(24). While, in a recent Japanese study, minimal change disease was the commonest GN representing 56.7% followed by membranous nephropathy then FSGS (25). These different results may be related to difference in the ethnicity between patients in different studies.

In the present study, there were no statistically significant age and sex differences between primary glomerulonephritis and lupus nephritis patients. In agreement with this, two other studies reported similar results (26) (27). On contrary, marked female preponderance was noted for lupus nephritis and thin basement membrane nephropathy, whereas a modest male predominance was noted for acute post-infectious GN, FSGS and IgA nephropathy (28). Also, Jegatheesan et aldemonstrated that primary GN was more frequent in males while lupus nephritis had higher prevalence among females (29).

Primary glomerulonephritis patients had higher median values of 24- hour urinary protein than lupus nephritis patients and this was similar to the results of a previous study (27). On contrary, another study did not find statistically significant difference between primary GN and lupus nephritis as regard urinary protein levels (26). There were no statistically significant differences between primary glomerulonephritis and lupus nephritis as regard serum creatinine in the current study. On the other hand, two other studies reported higher serum creatinine in patients with secondary GN and lupus nephritis than patients with primary GN (26) (27). This may be attributed to lower median serum creatinine in patients included in the current study.

In the present study, capillaroscopic characteristics between GN patients and control group were compared. No previous studies evaluated the capillaroscopic characteristics of glomerulonephritis patients. However, some studies evaluated these characteristics among rheumatic diseases , diabetic nephropathy and chronic kidney disease patients (30) (31) (7).

As regards capillary density and architecture there was no significant difference between GN and control groups in the current study. Similarly, there was no statistically significant differences between hemodialysis patients, renal transplant recipients and control groups as regard capillary density and architecture (32). On contrary, Thang et al found significantly lower capillary density in ESRD patients compared to healthy control (33). In another study conducted on 96 CKD patients, capillary density was also lower in CKD patients compared to healthy control and capillary density was found to decrease with CKD progression (7). This may explain the absence of difference between GN patients and healthy control group in this study as most of our patients have normal kidney function and the mean serum creatinine was 1.1 mg/dl.

In the present study there was statistically significant difference between GN and control group as regard capillary shape with higher percent of tortious capillaries among GN group. This was in concordance with the results of previous study conducted on 144 patients with diabetic nephropathy and reported that patients with proteinuria had higher incidence of tortious capillaries than normoalbuminuric patients and healthy control group (31). In other two studies, tortious capillaries had higher prevalence in patients with diabetic nephropathy and diabetic microangiopathy than healthy control (34) (35).

The current study showed significantly lower capillary diameter in patients with GN compared to healthy control group. This result was different from previous two studies which demonstrated no difference in capillary diameter between patients with renal disease and diabetic nephropathy on one side and healthy control (32) (36). In the current study, subpapillary venous plexus was significantly more common in GN patients than healthy control group. On the other hand, Bakirci et aldid not find statistically significant difference between diabetic nephropathy group and non- diabetic nephropathy group as regard percent of subpapillary venous plexus (36).

Capillary hemorrhage was more frequent in patients with GN than healthy control group and this was similar to the results of previous study which demonstrated significant difference in capillary hemorrhage between diabetic patients with proteinuria and those without proteinuria (31). However other studies failed to demonstrate significant difference between patients with renal disease and diabetic nephropathy in one hand and healthy control group in the other hand (32) (36) (34). This difference can be explained by the difference in the cause of renal disease between the studies.

Comparison between primary glomerulonephritis and lupus nephritis as regard capillaroscopic changes showed that lupus nephritis patients had more aggressive changes than primary glomerulonephritis especially in capillary diameter, width, and hemorrhage. This was in agreement with what was reported by Raeeskarami et al that SLE patients had lower capillary density than healthy control (30). Other studies reported high frequency of tortious capillaries among SLE patients (37) (38) (39). Also, capillary diameter was significantly higher in SLE patients than healthy control in multiple studies (40) (30). However, Fatemi et al reported no significant difference in capillary density between SLE patients and healthy control group (41).

With advancement of lupus nephritis classes, capillary diameter and length increased significantly in this study. Another studyshowed that capillary abnormalities were very common in patients with SLE and some changes may be associated with disease activity as elongated capillary loops which were seen more often in patients with renal involvement (42). Similarly, Hamza et al found that progression of NFC score had been directly related to lupus activity and internal organ involvement especially nephritis (37). Another study showed that NFC abnormalities were correlated with disease activity in Egyptian SLE patients (43).

The significant difference between lupus nephritis and other GN as regard capillaroscopic changes could be explained by the add on effect of SLE disease itself. As reported in multiple studies, SLE was associated with significant capillaroscopic changes as low capillary density, increased capillary tortuosity and increased capillary diameter (37) (41) (38). The capillaroscopic changes in SLE patients were attributed to increased VEGF (vascular endothelial growth factor) levels and interleukin- 18 levels in SLE causing endothelial hyperplasia and damage leading to microcirculatory changes (38).

The present study showed significant negative correlation between proteinuria and capillaroscopic changes especially capillary hemorrhage. In agreement with this, Cutolo et al reported statistically significant inverse correlation between Capillaroscopic changes and degree of proteinuria in SLE patients (44). Similarly, another study showed that capillaroscopic changes were significantly correlated with markers of SLE activity and 24- hour urinary protein (45). In this study, there were no statistically significant correlations between serum creatinine and any of capillaroscopic changes in glomerular disease patients. This was similar to the results of previous studies which failed to demonstrate statistically significant correlation between serum creatinine and capillaroscopic findings in SLE patients (30) (42) (46).

The current study showed statistically significant positive correlation between serum creatinine and 24- hour urinary protein. In agreement with this, a statistically significant correlation between serum creatinine and urinary protein was found in studies conducted on GN, nephrotic syndrome and CKD patients (47) (48) (49). Additionally, Braga et alshowed that serum creatinine and 24- hour urinary protein are surrogate markers for renal diseases in GN patients and both markers are associated with renal impairment (50). Another study reported absence of statistically significant correlation between proteinuria and serum creatinine among GN patients (51). However, Hirja et alfound that rising of serum creatinine was associated with significant decline in proteinuria. This had an explanation as rise of serum creatinine is associated with increased renal fibrosis and scarring of the kidney which IN turn is associated with decreased glomerular filtration rate and filtration of protein (52). This was not found in this study as included patients had better kidney function.

The main advantage of this study is that it is the first study to evaluate the capillaroscopic findings in GN patients. Another advantage is that the study compared capillaroscopic changes between GN and healthy control and between primary GN and lupus nephritis. The main limitation of this study is the small number of patients in each group of primary GN. Another limitation is that the effect of treatment and improvement of proteinuria was not evaluated in this study. Further studies are required on larger groups of patients with different types of primary GN to demonstrate if there is a specific capillaroscopic pattern in each type. Also, further longitudinal studies are required to study the effect of improvement of proteinuria on capillaroscopy.

Capillaroscopy may be helpful in the diagnosis of type and cause of glomerular disease. There were significant differences between GN patients and control group as regard capillary shape, diameter, subpapillary venous plexus and capillary hemorrhage. There were statistically significant differences between lupus nephritis patients and patients with primary GN as regard diameter, width and capillary hemorrhage. However, there was no significant difference in capillaroscopic changes between different types of primary glomerular diseases. There was a significant positive correlation between proteinuria and capillary hemorrhage.

CKD: chronic kidney disease

CRP: C reactive protein

DM: diabetes mellitus

ESR: erythrocyte sedimentation rate

ESRD: end stage renal disease

FSGS: segmental glomerulosclerosis

GN: Glomerulonephritis

NFC: Nailfold capillaroscopy

RA: rheumatoid arthritis

SLE: systemic lupus erythematosus

Ethical approval:

This study was approved by Institutional Review Board of Mansoura university (IRB code number: MS.21.12.1777). The study was explained to all the participants and an informed consent was taken.

Consent for publication:

Consent for publication of this manuscript was taken from all the authors.

Availability of data and materials:

All data generated or analyzed during this study are included in this published article.

Competing interests:

I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Funding: not applicable

Authors contribution:

Hend Adel: collecting data and writing the manuscript.

Fatma Hamdy: collecting data and writing the manuscript.

Ahmed A Eldeeb: revising the manuscript.

Acknowledgement: not applicable.

Authors information:

Hend Adel

Resident of Internal medicine (nephrology) Mansoura university

Fatma Hamdy

Lecturer of Internal Medicine (Rheumatology and Immunology), Mansoura University

Ahmed A Eldeeb:

Assistant professor of Internal Medicine (nephrology). Mansoura University.

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No competing interests reported.

Capillaroscopic changes in patients with glomerular diseases: a case control study

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Version 1