Introduction
Nephrotic syndrome (NS) is one of the clinical syndromes that lead to various complications, such as edema and hyperlipidemia. The definition of this syndrome includes massive proteinuria of more than 40 mg/m2 per hour, which leads to hypoalbuminemia of less than 30 g/L, caused by increased permeability of the basal membrane damaged in the kidney glomeruli, primarily due to infectious or thromboembolic factors. It can occur primarily due to a kidney-specific disease, or may develop as a result of glomerular permeability abnormality due to diabetes, congenital infections, neoplasia, systemic lupus erythematosus, or a particular use of a drug. There is a trigger factor such as an upper respiratory tract infection in nearly 50% of the cases, an allergic reaction in one-third, and less frequently, an insect bite, treatment with psychiatric drugs, and vaccination. The first causes include focal glomerulosclerosis, minimal change nephropathy, hereditary nephropathies, and membranous nephropathy. Diabetes mellitus (DM) is the second cause. Immune causes include antibody vasculitis, systemic lupus erythematosus, Goodpasture’s syndrome, Berger’s disease, membranoproliferative or extramembranous glomerulonephritis, acute infectious glomerulonephritis, toxicity (non-steroidal anti-inflammatory drugs), alloantibodies due to enzyme replacement therapy, and thrombotic microangiopathy. Infectious causes include hepatitis B and C virus, hepatitis, HIV, immunodeficiency, toxoplasmosis, cytomegalovirus, and parvovirus B1. In addition, preeclampsia, paraproteinemia, and amyloidosis can be counted among the causes. The most common cause of NS in children is minimal changes in glomerulonephritis; in white adults, it is membranous nephropathy. However, in African populations, the main cause is focal segmental glomerulosclerosis. Clinical data shows that the NS could be frequently recurrent, steroid-sensitive, steroid-resistant, and steroid-dependent. The creation of phospholipase antibodies, the deposition of the immune complex, or the formation of alloantibodies are among the causes of NS syndrome (1,2,3,4,5,6).
C-reactive protein (CRP) is a major acute phase reactant that is seen to rise acutely and rapidly in case of infection and tissue damage in the human body which is among the non-specific laboratory findings. It triggers hepatic production in cases of various tissue damage, infection and inflammation. The American Heart Association recommends determining serum hs-CRP levels in all patients at risk for cardiovascular disease. Normal levels of CRP are mostly 2 mg/L or less. Standard methods make it possible to measure CRP in the range of 3-8 mg/L. It is possible to detect CRP levels below this limit with current “high sensitivity” (hs-CRP) methods. Today, hs-CRP measurements are used in risk determination. The diagnostic value of CRP, which is one of the non-specific indicators for inflammation, is quite high in many clinical situations. In line with today’s accepted values; a CRP value below 1 mg/L is low risk, 1-3 mg/L is moderate risk, and above 3 mg/L is high risk. In many studies, CRP is used as an activity indicator and clinical course predictor for different diseases (7,8,9,10).
Material and Methods
A total of 1440 patient files hospitalized with the NS diagnosis and followed up and treated in the Nephrology Service of Dicle University between 2000 and 2010 were retrospectively analyzed. One hundred-four patients, with sufficient data, were included in the study. Informed consent was obtained from all patients. This research, which is a thesis study, was carried out following the Local Ethics Committee of Batman University approval dated 04.02.2021 and numbered 3671 and the Declaration of Helsinki.
Inclusion Criteria:
- Those with NS with a histopathological diagnosis based on primary or secondary causes.
- Diabetic patients with proteinuria in the nephrotic range.
- Patients with adequate parameters for the study.
Exclusion Criteria:
- Patients without histopathological diagnosis.
- Patients with malignancy.
- Patients with signs of acute coronary syndrome or heart failure.
- Patients with cerebrovascular disease.
- Patients with active connective tissue disease.
- Patients with a chronic inflammatory disease with acute exacerbation.
- Patients with signs of infection.
Study parameters include; histopathological diagnoses, demographic data, amount of fluid taken in and out from clinical admission until discharge, arterial blood pressure, blood count parameters [hemoglobin, white blood cell (WBC), platelet, hematocrit], biochemical parameters [glucose, urea, uric acid, sodium (Na), calcium (Ca), creatinine (Kr), chlorine (Cl), magnesium (Mg), potassium (K), aspartate transaminase (AST), phosphorus (P), alanine transaminase, lactate dehydrogenase (LDH), high-density lipoprotein (HDL), cholesterol, triglyceride (TG), albumin, low-density lipoprotein (LDL), CRP, total protein], fibrinogen, immunoglobulin panel [immunoglobulin M (IgM), immunoglobulin A (IgA), immunoglobulin G (IgG)], complement proteins (C3, C4), erythrocyte sedimentation rate (ESR), 24-hour urine protein, urine analysis (urine leukocytes, protein, erythrocytes and urine density), echocardiogram findings [ejection fraction (EF), left atrium thickness (LAD), interventricular septum thickness (EA), left ventricular posterior wall thickness (SVPDK)] and length of hospital stay. All study parameters are shown in Table 1.
We divided the patients into two groups: CRP level >5 mg/L in group 1 and CRP level ≤5 mg/L in group 2. Data collected from both groups were compared and analyzed. In addition, the serum CRP and other study variables of the patients at admission to hospital and discharge were compared within each group, and the relationship between them was analyzed.
Ethical statement: The Non-Interventional Clinical Research Ethics Committee of Batman University approved the permission for this study with a letter dated 04/02/2021 and numbered 3671, and the study was carried out following the Helsinki Declaration criteria.
Statistical Analysis
Study data were analyzed in computer virtual environment with SPSS for Windows 20.0 software program. For comparisons between groups, chi-square and Student’s t-tests were used for independent variables, and Wilcoxon signed-rank test (Wilcoxon signed-rank test) was used for dependent variables. Pearson correlation analysis was used to compare dependent variables and serum CRP levels. Data were expressed as mean ± standard deviation. Data were analyzed with a 95% confidence interval. The p-value <0.05 was considered statistically significant.
Results
The study participation includes a total of 104 patients. Of the study participants, 53% (55) were female, and 47% (49) were male. While the mean serum CRP level in group I was 31.70±21.75 mg/L, it was 2.21±1.58 mg/L in group II.
The difference between the groups was statistically significant (p<0.001). The age range of the patients was determined as 18-80 years. The patients’ mean age with normal serum CRP level (group 2) and high CRP level (group 1) were 35.92±16.25 years and 46.68±20.34 years, respectively. It was observed that those with higher serum CRP levels were older, and the difference was statistically significant (p=0.004). Renal histopathological reports of 104 patients who were diagnosed between 2000-2010 and whose data matched the research criteria were also obtained. Distribution of cases according to the NS subtype is shown in the table (Table 2).
Daily amount of proteinuria (p=0.003), albumin (p=0.001), Ca (p=0.001), total protein (p=0.035), HGB (p=0.032) and HDL (p=0.038) serum level at hospitalization were statistically significantly lower in group 1 than in group 2 (Table 3).
Again, Length of hospital stay (p=0.030), age (p=0.004), creatinine (p=0.009), platelets (p=0.005), LDH (p=0.006), ESR (p<0.001), spot urine protein (p=0.038), C4 (p<0.001) and 24-hour proteinuria (p<0.001) levels in group I were statistically significantly higher than group II. However, although serum LDL (p=0.051) levels were high, there was no significant difference between the groups (Table 2).
Serum CRP (p<0.001), diastolic blood pressure (DBP) (p=0.018), systolic blood pressure (SBP) (p<0.001), cholesterol (p<0.001), urea (p=0.031), TG (p<0.001), LDL (p<0.001) and proteinuria (p=0.001) levels measured at hospital admission in group 1 were found to be significantly higher than the values measured at discharge (Table 3).
When the values at hospital admission were compared with values at discharge in group 2, statistically significant elevation in variables such as CRP (p=0.002), DBP (p=0.001), SBP (p<0.001), TG (p=0.039), cholesterol (p=0.002), LDL (p=0.009), daily proteinuria was found (Table 3).
In the evaluation of correlation analysis of serum CRP level with other study variables, a positive correlation was found between CRP elevation and creatinine (p=0.003), urea (p=0.015), LDH (p=0.015), ESR (p=0.004), WBC (p=0.004), C4 (p=0.023), urinary erythrocyte (p=0.041), urinary leukocytes (p=0.032), daily proteinuria (p=0.044) levels. However, a negative correlation was found between CRP elevation and 24-hour urine (p=0.043). The relationship between echocardiography findings (EF, LAD, SVPDK, EA) and serum CRP level in patients with NS is not statistically significant (p>0.05).
Discussion
As an acute phase reactant, CRP increases secondary to infection and tissue damage. The values, which reach the peak levels within 1-2 days, decrease to the normal level with the restoration of the tissue structure and function (11). CRP is used to determine the response to treatment, to evaluate the course of the infection, and to detect the inflammatory response in chronic rheumatological diseases such as vasculitis and rheumatoid arthritis (12). High serum CRP level was associated with macro and microalbuminuria independent of hypertension, DM and other potential factors (p<0.001) (13). Our study found a positive correlation between spot urine protein and serum CRP levels (p=0.038). Similar to our study, it has been determined in another study that the increase in serum CRP level is associated with the incidence and prevalence of proteinuria (p=0.042) (14). In other studies, the rate of nephropathy was higher and the development time of nephropathy was shorter in diabetic patients with high hsCRP levels than those with normal hsCRP levels (15). High CRP levels in type 2 diabetic patients have been associated with an increased prevalence of albuminuria (16). Hs-CRP was found to be independently associated with diabetic nephropathy (17). The diabetic nephropathy patients’ hs-CRP concentrations were significantly higher than the control group, which includes DM patients without nephropathy and healthy people. Moreover, hs-CRP concentration in the macro albuminuria group was significantly higher compared to the microalbuminuria group and the non-albuminuria group (18). Diabetic patients with complications had significantly higher hs CRP and microalbuminuria than uncomplicated diabetic patients and the control group (19). the results showed that patients with decreased hs-CRP have a lower risk of decline in kidney development and function of proteinuria (20). It has been understood in our study that the amount of 24-hour urine protein was significantly higher in the high CRP value group than the low CRP value group (<0.001). A positive correlation was found between CRP and proteinuria (p=0.044), urea (p=0.015), creatinine (p=0.003) levels in cases with nephrotic proteinuria. Low-grade inflammatory markers (hsCRP, IL-6) have been associated with diabetic nephropathy in type 1 diabetic patients (21). One study showed that both MBL and hsCRP concentrations are associated with progression of kidney disease in type 1 diabetes (22). The hs-CRP cumulative exposure has been associated with following CKD increased risk and is helpful in risk estimation (23). In a different study, CRP, serum amyloid A and IL-6, which are acute phase indicators, were associated with diabetic nephropathy and glomerular basement membrane thickness (p<0.005) (24). However, in a study of Tencer et al. (25), no statistically significant relationship was found between the increase in proteinuria and the CRP level in 166 cases with glomerulonephritis (MPGN, MN, IgAN) (p>0.005). hs-CRP, s-albumin, and WBC are inflammatory markers and studies have been conducted showing them to be associated with the progression of IgAGN (26). Previous studies show the significant role of inflammation in increasing the risk of cardiovascular diseases. Regarding hs-CRP, some studies show that this inflammatory index can predict long-term cardiovascular risk, enriches traditional risk assessment with prognostic information, and predict cardiovascular risk not reflected by traditional risk factors (27). In one study, high plasma hs-CRP and IL-6 levels were found to be associated with LVH and systolic dysfunction in patients with CKD (28). Independent of cardiovascular risk factors, high hs-CRP level was associated with microalbuminuria. Additionally, high hs-CRP levels were associated with an increased risk of developing microalbuminuria in people with CVD risk factors (29). The relationship between CRP and echocardiography indicators (LAD, EA, SVPDK, EF) was not statistically significant (p>0.05). In the study, it was observed that the systolic (p<0.001) and diastolic (p=0.018) blood pressure values measured before discharge in high CRP levels patients were significantly lower than the values measured during their hospitalization. It is thought that the fact that the patients are in the active phase of NS and the use of diuretic, anti-proteinuric and reno-protective drugs in addition to immunosuppressive drugs during the hospitalization period may also be effective. Ueland et al. (30) observed that the hs-CRP level is significantly increased in patients with familial hypercholesterolemia. It was observed that hs-CRP level remained high in these cases, despite the anti-hyperlipidemic treatment (pravastatin 20-40 mg/g) (30). On the other hand, it was observed in this study that cholesterol (p=0.081), TG (p=0.423), LDL (p=0.051) levels were higher in patients with high CRP levels compared to patients with normal CRP levels. However, this relationship was not found to be statistically significant. In our study, it was determined that the cholesterol, TG, LDL levels measured during the discharge process of the patients in group I were significantly lower than the values measured during the hospitalization period (p<0.001). It is thought that this may be associated with the significant decrease in the level of CRP and proteinuria due to anti-hyperlipidemic and immunosuppressive treatment given during hospitalization. It was also determined that a positive correlation is between CRP level and the length of stay in the hospital rather than a statistically significant relationship (r=0.134, p=0.178).
Conclusion
The present study found that an increase in proteinuria, deterioration in kidney functions, decrease in daily urine volume, prolonged hospitalization and decrease in serum albumin levels in adult NS patients are associated with high serum CRP level and CRP level can be used as a fine parameter for the follow-up of patients. In our study, it was determined that the relationship between the level of CRP and cardiac parameters measured by Echocardiography (LAD, EA, SVPDK, EF) was not statistically significant.
Ethics
Ethics Committee Approval: The Non-Interventional Clinical Research Ethics Committee of Batman University approved the permission for this study with a letter dated 04/02/2021 and numbered 3671, and the study was carried out following the Helsinki Declaration criteria.
Informed Consent: Informed consent was obtained from all patients.
Peer-review: Internally and externally peer-reviewed.
Authorship Contributions
Concept: İ.Y., M.E.Y., Design: İ.Y., Z.K., M.E.Y., Data Collection or Processing: İ.Y., Analysis or Interpretation: İ.Y., Literature Search: İ.Y., Z.K., Writing: İ.Y., Z.K., M.E.Y.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.