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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 1  |  Page : 32-43
Study of the relationship between urinary level of uromodulin, renal involvement and disease activity in patients with systemic lupus erythrematosus


1 Department of Chemical Pathology, Medical Research Institute, Alexandria University, Egypt
2 Department of Internal Medicine, Kafr ElSheikh University, Egypt
3 Department of Experimental and Clinical Internal Medicine, Medical Research Institute, Alexandria University, Egypt
4 Department of Internal Medicine, Faculty of Medicine, Alexandria University, Egypt

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Date of Submission06-Feb-2019
Date of Decision13-Mar-2019
Date of Acceptance16-Mar-2019
Date of Web Publication3-Mar-2020
 

   Abstract 


Systemic lupus erythematosus (SLE) is a multifactorial chronic inflammatory autoimmune connective tissue disease. Lupus nephritis (LN) is a common and serious complication of SLE which can progress to end-stage renal disease. Renal biopsy is the gold standard in the diagnosis and classification of LN, but since it is an invasive procedure, it is neither desirable nor applicable for all cases. This has led to the search for an alternative, noninvasive, site-specific, and immune process-related biomarkers. Uromodulin (Tamm-Horsfall glycoprotein) is the most abundant urinary protein expressed exclusively by the thick ascending limb cells and released into urine of healthy controls. Studies showed that it may act as a danger signaling molecule eliciting an inflammatory response following conditions that damage the nephron integrity and leading to uromodulin release into the interstitial space. This study aimed to assess uromodulin as a screening biomarker of tubulointerstitial involvement in patients with SLE and to elucidate its correlation with disease activity and progression. The study was conducted on 70 patients divided into two groups: control group (Group I) consisted of 20 apparently healthy volunteers of comparable age and sex to the patients’ group, and 50 SLE patients (Group II) diagnosed according to the 2012 Systemic Lupus Collaborating Clinics (SLICC) classification criteria. Group II was further subdivided into 23 patients without manifestations of LN (Group II A) and 27 patients with manifestations of LN (Group II B). Urinary uromodulin level showed statistically significant difference among the studied groups, being lowest among the LN patients with a mean value 5.6 ± 3.4, in SLE patients without nephritis 9.9 ± 5.2 and 12.9 ± 4.6 in the control group. Urinary uromodulin also correlated positively with estimated glome- rular filtration rate. A negative correlation was found between urinary uromodulin and serum creatinine, 24 h urinary proteins and SLICC renal activity score. No statistically significant correlation was found between urinary uromo- dulin and SLE disease activity index. Thus, decreasing urinary uromodulin levels can be a marker for renal involvement and tubulo- interstitial nephritis in active SLE patients and a marker for chronic kidney disease and nephron loss in the absence of activity markers.

How to cite this article:
Bedair RN, Amin Ismail MM, Gaber EW, Kader Mahmoud RA, Mowafy MN. Study of the relationship between urinary level of uromodulin, renal involvement and disease activity in patients with systemic lupus erythrematosus. Saudi J Kidney Dis Transpl 2020;31:32-43

How to cite this URL:
Bedair RN, Amin Ismail MM, Gaber EW, Kader Mahmoud RA, Mowafy MN. Study of the relationship between urinary level of uromodulin, renal involvement and disease activity in patients with systemic lupus erythrematosus. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Oct 31];31:32-43. Available from: https://www.sjkdt.org/text.asp?2020/31/1/32/279959



   Introduction Top


Systemic lupus erythematosus (SLE) is a heterogeneous inflammatory chronic autoimmune disorder characterized by progressive involvement of multiple organ systems with clinical exacerbations and remissions.[1] Lupus nephritis (LN) is a serious complication in patients with SLE. Approximately 40% to 70% of patients with SLE will develop LN, and of these about one out of 10 will develope chronic or end-stage renal disease (ESRD).[2] Renal biopsy is the gold standard in the diagnosis and classification of LN.[3] Since it is an invasive procedure, renal biopsy is neither desirable nor applicable in many conditions. Therefore; the search for an alternative, noninvasive, site-specific, and immune-related biomarkers is needed.

Uromodulin or Tamm-Horsfall glycoprotein (THG) is the most abundant protein excreted in urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine through proteolytic cleavage.[4] It is synthesized exclusively and abundantly in the thick ascending limb (TAL) of the loop of Henle. Its biologic function remains somewhat unclear for more than a century after its first description in 1895.[5] Uromodulin contains the most varied array of glycans of any human glycoprotein, which suggests a capacity for adhesion to a variety of ligands. Indeed, uromodulin has been shown to bind cells, crystals, ions, immunoglobulins, myeloma proteins, and cytokines. It has been hypothesized that uromodulin may serve a physiologic role in the binding and excretion of a variety of potentially injurious products from the tubular fluid.[6]

The role of uromodulin in the kidney’s innate immunity has been demonstrated in several studies that showed that uromodulin interacts with components of the immune system through the facilitation of neutrophil attachment, induction of pro-inflammatory cytokine release from human monocytes, and activation of myeloid dendritic cells to acquire full maturation. Furthermore, it may play a role in renal inflammation through binding with high affinity to IgG,[8] complement factors (C1, C1q and C3) and cytokines, such as: tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) beta, and IL-8.[9]

Those studies suggested that uromodulin may act as a danger-signaling molecule, able to elicit an inflammatory response following conditions that damage the nephron integrity leading to uromodulin release into the interstitial space, with the decrease in its urinary excreted levels. Moreover, recent studies demonstrated that urinary uromodulin level was decreased in conditions affecting kidney function and/or integrity, positively correlated with the estimated glomerular filtration rate (eGFR) and could represent a useful biomarker for the development of chronic kidney disease (CKD). Moreover, Genome-wide association studies have successfully identified common variants in the uromodulin gene that have been asso-ciated with the risk of CKD.[10],[11]

The aim of the current study was to assess the urinary level of uromodulin as a marker of renal involvement in patients with SLE and to elucidate its correlation with disease activity.


   Subjects and Methods Top


Subjects

The study was conducted on 70 subjects divided into two groups: Control group (Group I) included 20 apparently healthy volunteers of comparable age and sex to the patients group. Group II included 50 SLE patients diagnosed according to the 2012 Systemic Lupus Collaborating Clinics (SLICC) Classification criteria for SLE.[12] This group was further subdivided into:

Group IIA: included 23 patients without manifestations of LN.

Group IIB: included 27 patients with manifestations of LN (in which 20 were proven by renal biopsy and 7 of them refused the procedure).

All patients were randomly selected from the Medical Research Institute, Alexandria University, Alexandria, Egypt, during the period of 2014 and 2015.

Patients with diabetes, gout, urinary tract infections, and renal stones were excluded from the study.

According to the Helsinki declaration, written consent was taken from every patient before sampling after thorough explanation of the procedure. The study was approved by the ethical committee at the Faculty of Medicine, Alexandria University.

Methods

All participants were subjected to detailed history taking including sociodemographic history (age, sex, residency, and marital status), with specific stress on disease-related manifestations such as the presence or absence of constitutional manifestations (fever, malaise, myalgia, or weight loss), significant hair fall or alopecia, skin rash, oral ulcers, photosensi- tivity, and thromboembolic manifestations. Analysis of joint, pulmonary, cardiovascular, gastrointestinal, renal, hematological, ophthal- mological, and neuro-psychiatric-related complaints were done. Careful drug, menstrual, and family histories were taken.

A thorough systemic physical examination was done including blood pressure measurement, skin, and mucosal examination for the presence of malar rash, vasculitis, purpura, alopecia, pallor, lower limb edema, and oral or nasal ulcers. Cardiac, pulmonary, abdominal and neurological, eye, joint, and lymph nodes examination were all performed.

Assessment of disease activity by SLE disease activity index (SLEDAI) scoring system13 was done for each patient (minimum score is 0 and the maximum is 105). Assessment of disease damage by SLE disease damage index (DI) [SLICC/American College of Rheumatology DI (ACR DI)][14] was done.

Disease damage was defined as: non reversible change, not related to active inflammation, occurring since the diagnosis of SLE, ascertained by clinical assessment and present for at least six months. Repeated episodes must occur at least six months apart to score 2 and the same lesion cannot be scored twice. Minimum score is 0 and the maximum is 47.

The assessment of renal activity by the SLICC renal activity score was also done.[15] Renal activity within the LN patients group was assessed by the SLICC renal activity score which is computed as follows: Proteinuria 0.5-1 g/day = 3 points Proteinuria >1-3 g/day = 5 points Proteinuria >3 g/day = 11 points Urine red blood cell count >10/hpf = 3 points Urine white blood cell count >10/hpf = 1 point Laboratory investigations were done and included routine investigations (Complete blood picture, erythrocyte sedimentation rate, serum alanine aminotransferase and aspartate aminotransferase activities, serum urea and Cr, complete urine analysis, 24-h urinary proteins and eGFR).

Specific immunological investigations were done and included the antinuclear antibody (ANA) and anti-double-stranded DNA (anti- dsDNA) titers and complement (C3) level.

Radiological investigations were done and included plain X-ray chest, abdominal ultra- sonography, and echocardiography (were done to complete the assessment for SLEDAI and SLICC/ACR DI scores)

Urinary level of uromodulin was determined using the Biovendor Human Uromodulin ELISA Kit.[16]

A sterile container was used to collect urine samples. Any particulates were removed by centrifugation for 15 min, and samples were stored at -80°C. Repeated freeze/thaw cycles were avoided. Samples were centrifuged again before assaying to remove any additional precipitates that appeared after storage.

Urine samples required dilution just before the assay with dilution buffer which is achieved by adding 5 μL of sample into 195 i!L of dilution buffer and mix well, then add 5μ1 of the previously diluted sample into 245 μL of dilution buffer to prepare the final dilution and mix well (Dilution factor = 2000, final results were expressed as pg/mL).


   Statistical Analysis Top


Descriptive statistics were calculated as number and percentage for qualitative variables and mean ± standard deviation for quantitative variables.

Analysis of variance and Chi-square test were used for testing difference between the three studied groups. Receiver operating characteristic (ROC) curve analysis, sensitivity, and specificity were done for urinary uromodulin as a screening test. The level of significance <0.05 was adopted statistically significant. The IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA) and Medcalc version 15.0 (MedCalc Software, Ostend, Belgium) were used.


   Results Top


Immunological investigations showed that not a single case of the control group was positive for ANA, anti-dsDNA or consumed C3 [Table 1]. While 87% and 77.8% were positive for ANA in both patients groups, respectively, with very high statistical significant difference between the three groups (χ = 40.01, P = 0.000). Positive anti-dsDNA was present in 34.8% and 55.6% of both patients groups, respectively, with very high statistically significant difference between the three groups (χ = 16.13, P = 0.000). About 21.7% and 48.14%, respectively, of patients groups had consumed C3 showing very high statistically significant difference between the three groups (χ[2] = 14.37, P = 0.000).
Table 1: Distribution of immunological investigations results among the three studied groups.

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Calculated scores done to patients groups including SLEDAI, SLICC/ACR DI, and SLICC renal activity score, [Table 2] shows that on studying disease activity between patients groups according to the SLEDAI, the percentage of active patients were 26.1 and 55.6, respectively, with statistically significant difference (χ = 4.4, P = 0.35). Organ damage among patients groups was assessed according to the SLICC/ACR DI and showed that 21.7% and 51.9%, respectively, suffered from organ damage from SLE, with no statistically significant difference between the two groups. Renal activity at the time of the study was scored according to the SLICC renal activity score, and the results showed that all first group patients scored zero while the second group ranged from 0 to 16 with mean value 7.0 ± 5.4 which denotes very high statistical significant difference between the two groups (t-test = 6.2, P = 0.000).
Table 2: Distribution of Systemic lupus erythematosus disease activity index, systemic lupus collaborating clinics/American College of Rheumatology damage index and Systemic Lupus Collaborating Clinics renal activity score results among the patients' groups.

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As regards urinary uromodulin levels in all groups, its level among the three studied groups ranged 4.8-21.0, 3.1-19.0, and 1.012.0, respectively, mean values were 12.9 ± 4.6, 9.9 ± 5.2, and 5.6 ± 3.4, respectively. The difference between the three groups was very highly significant (F = 15.5, P<0.0001) [Table 3] and [Figure 1].
Figure 1: Urinary uromodulin levels distribution among the three studied groups.

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Table 3: Urinary uromodulin levels distribution among the three studied groups.

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It was found that urinary uromodulin correlated positively and statistically significantly with eGFR (r = 0.25, P = 0.03), [Figure 2]. A negative correlation was found between urinary uromodulin on one hand and serum creatinine (SCr) levels [Figure 3], 24-h urinary proteins values [Figure 4] and SLICC renal activity score [Figure 5] on the other hand, with high statistical significance with Cr levels (r = -0.42, P = 0.001) and very high statistical significance with 24-h urinary proteins values and SLICC renal activity score (r = -0.567, P = 0.000) and (r = -0.526, P = 0.000), respectively. No statistically significant correlation was found between urinary uromodulin and SLEDAI [Table 4].
Figure 2: A scatter plot showing positively and statistically significant correlation between urinary uromodulin and estimated glomerular filtration rate.

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Figure 3: A scatter plot showing negatively and highly statistically significant correlation between urinary uromodulin and serum creatinine.

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Figure 4: A scatter plot showing negatively and very highly statistically significant correlation between urinary uromodulin and 24-h urinary proteins.

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Figure 5: A scatter plot showing negatively and very highly statistically significant correlation between urinary uromodulin and Systemic Lupus Collaborating Clinics Renal Activity Score.

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Table 4: Correlations between urinary uromoduin and estimated glomerular filtration rate, serum creatinine, 24-h urinary proteins, systemic lupus collaborating clinics renal activity score, and systemic lupus erythematosus disease activity index among all groups.

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The ROC analysis of uromodulin as a screening test for renal damage showed that urinary uromodulin level of 3.05 ug/mL has a corresponding sensitivity of 100% and the specificity of 33% (with an area under the curve = 0.76, which is diagnostic with a + LR >1.0) [Figure 6].
Figure 6: The receiver operating characteristic analysis of uromodulin as a screening test for renal damage with area under the curve = 0.076. Urinary uromodulin level of 3.05, the corresponding sensitivity was 100% and the specificity was 33% (with an area under the curve = 0.76, which is diagnostic with a + LR >1.0).

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   Discussion Top


LN is a common and serious complication of SLE.[17] Almost one-third of patients may progress to ESRD.[18] Uromodulin has been studied as one of the urinary proteins proved to be involved in conditions causing renal damage.[7],[8],[9] Immunological testing for both patients groups showed high ANA prevalence, representing 87% in SLE patients without nephritis and 77.8% in LN group, whereas for anti-dsDNA, it represented 34.8% and 55.6%, respectively. Higher prevalence of anti-dsDNA antibodies among LN patients supports theories of their pathogenic role in LN, and that their levels tend to rise and fall with disease activity.[19] This is in agreement with Farid et al[20] who studied 88 SLE patients divided as 44 patients with biopsy-proven LN and 44 patients without LN, they found that anti-dsDNA was higher in the LN group (84.09%) compared with the non-LN group (70.45%), showing that patients with active LN often have raised levels of anti-dsDNA antibodies.

The negative cases can be explained as reported by Marto et al, [21] who stated that their findings may have been influenced by the fact that some of the serum samples were taken in the first four months after the beginning of immune-supportive treatment, as anti-dsDNA values fall very rapidly after treatment.[22]

As for the C3 level, a higher percentage of LN patients had lowered C3 level compared to non LN, 48.1% versus 21.7%, similarly Sharifipour et al,[23] stated that C3 levels were significantly lower in patients with nephritis than in patients without nephritis. On the contrary, Farid et al,[20] and Rubinstein et al,[24] both found no statistically significant difference between LN and non-LN SLE patients regarding C3.

SLEDAI showed high statistical difference between both patients groups (P = 0.007**), being higher in LN patients, which matches the study done by Zabaleta-Lanz et al,[25] and concluded that SLEDAI is significantly higher among LN patients. Pitashny et al[26] and El- Shehaby et al[27] also reached the same conclusion.

Generally, there is very high statistical significant difference regarding SLICC renal activity score between both patients groups, as it involves proteinuria, urinary RBCs and WBCs, which are totally absent in SLE patients without nephritis.

Although the SLICC/ACR DI was represented by 51.9% in LN group versus 21.7% in the nonnephritis group, there was no statistically significant difference between the two groups meanwhile (P = 0.102), which could be explained by the fact that 18.5% were newly diagnosed LN at the time of the study, while SLICC/ACR DI necessitates six months period of persistence to be scored.

In this study, the urinary uromodulin level studied among the three groups showed very high statistical difference (P <0.0001), being lowest among the LN patients with mean 5.6 ± 3.4, 9.9 ± 5.2 in SLE patients without nephritis and 12.9 ± 4.6 in the control group.

The fact that SLE patients without LN manifestations showed lower levels than the healthy control group can be explained by and categorized under the term “silent LN” showed by studies, in which renal biopsy was performed in patients without any clinical manifestations of renal involvement, in which mesangial, focal, or diffuse proliferative glo- merulonephritis in some patients were found.[28] These findings were supported by Wakasugi et al[29] who performed kidney biopsy to all patients with SLE seen at a Japanese hospital over an 11-year period, whether or not clinical signs of renal disease were present, the results showed, out of the 195 patients who had adequate biopsies, 86 had no clinical renal involvement, of these 86 patients without clinical renal disease, 13 (15%) had either Class III or IV LN, and nine (10 %) had Class V (membranous) disease.[29]

Thus, we can consider that mild renal inflammatory process is ongoing in these patients with mild tubular cell injury and release of uromodulin into the interstitium decreasing the total amount excreted in urine, mild enough to not be clinically evident (i.e., proteinuria is <500 mg/day and a bland urine sediment), justifying why they have lower values than normal individuals. Those patients should be closely followed for evidence of progressive disease such as increasing proteinuria, the emergence of active sediment, and/or an increase in SCr. These manifestations suggest transformation to a more severe lesion and warrant renal biopsy, yet there are not enough data to suggest that every lupus patient should have a kidney biopsy.

In this study, very highly significant negative correlation was found between urinary uromo- dulin levels and renal activity as assessed by the SLICC renal activity score. Similarly, Tsai et al,[30] compared between urinary uromodulin levels in active and inactive LN patients and found that its excretion was lower in patients with active LN and tubulointerstitial inflammation as compared with patients with inactive LN or normal individuals. Moreover, among 15 patients with active LN, there were nine patients with intense cellular infiltration in the interstitium (++ or +++); the uromodulin excretion in the urine of these patients was significantly lower than that of the other 6 patients without significant interstitial cell infiltration. His results have suggested that both glomerular and tubular lesions exist in LN and that the lesions are more prominent in active nephritis. In addition, both proximal and distal renal tubule functions are impaired in patients with LN, and the impairment seems to be relevant to the severity of glomerular as well as tubulointerstitial inflammation in the kidney. Moreover, since uromodulin is synthesized exclusively by the epithelial cells of the TAL of Henle’s loop, its quantitation in urine may be a good alternative way for evaluation of the distal tubular damage in LN.

Furthermore, Prajczer et al[31] wanted to test the hypothesis suggesting that high levels of interstitial uromodulin potentially trigger inflammation, so they correlated serum uromo- dulin concentration from healthy volunteers and CKD patients with serum concentrations of pro-inflammatory cytokines and growth factors. TNF-alpha, IL-6, IL-8, and IL-1 beta all correlated positively with serum uromo- dulin. Thus, a link between serum uromodulin and inflammation was established. To confirm this, they used an in vitro system where purified uromodulin was applied to whole blood from healthy volunteers. Uromodulin resulted in a dose-dependent increase in TNF- alpha, IL-6, IL-8, and IL-1 beta. Therefore, leakage of uromodulin into the interstitium is likely to result in renal inflammation.

Abulaban et al[32] studied urinary biomarkers and their role in predicting the future development of renal functional loss with LN in children and adults and concluded that uromo- dulin is a marker of disease activity but not predictive of renal function loss. In addition, an experimental study done by Boenisch et al[33] using MRL-lpr/lpr mice as a model of human SLE, suggested that the urinary excretion of uromodulin is a good indicator of the severity of renal inflammation and has therapeutic implications in monitoring the disease activity in mice with SLE. They performed a comparative urinary and kidney protein profiling in a MRL-lpr/lpr mouse model of membranopro- liferative glomerulonephritis and found a negative correlation between THG excretion in the urine of these mice and disease level, as it was significantly lower (4-fold) than that of the other mice without nephritis, on the contrary, a positive correlation of THG levels in the kidneys and disease level was found. These findings may be related to early complement- dependent alterations in tubular protein expression which may play critical roles in the development of tubulointerstitial disease and provide experimental support for the use of urinary proteomic profiling of renal injury and/or kidney failure.[33]

In our study, urinary uromodulin levels were also correlated positively with eGFR and negatively with SCr levels, as the lowest values were presented in CKD patients with low eGFR. Similarly, many previous studies correlated between low urinary uromodulin levels and CKD progression.[4],[10],[11] From those conducted on SLE patients, Prajczer et al[31] who conducted a study on CKD patients including LN patients and found that urinary uromodulin is an indicator of renal disease, correlating negatively to SCr and positively to eGFR. Taking this data together with the in vitro study mentioned before, they concluded that a significant shift of soluble uromodulin from the lumen to the intersitium could accelerate CKD progression due to severe inflammation and destruction of the TAL. CKD patients with high serum uromodulin may respond to anti-inflammatory therapy to slow uromodulin-orchestrated chronic renal disease progression.

Thus, from all of the above data, we can conclude that, the increase in renal inflammation specifically tubulointerstitial inflammation which almost always accompany glome- rular inflammation can be represented by decrease in the urinary uromodulin levels.

As renal injury and TAL damage leads to leakage of uromodulin into the interstitium which in turn resulting in more tubular damage, with decrease in the urinary excreted levels. In mild conditions the response is appropriate, and tubular damage is repaired. In severe cases or in cases of delay in treatment, sustained leakage of uromodulin into the interstitium would finally result in a decrease of TAL cell numbers, eventually to the point where neither urinary nor serum uromodulin can be detected with the deterioration of renal functions and progression to ESRD.

In this study, urinary uromodulin levels and 24 h urinary proteins were negatively correlated with very high statistical difference. This finding was supported by Boenisch et al,[33] in their experimental study using MRL-lpr/lpr mice as a model of human SLE, as they determined the urinary uromodulin excretion and proteinuria in the mice before and after treatment which concluded that the urinary excretion of uromodulin in mice with a higher proteinuria level was significantly lower than that in normal or in cyclophosphamide-treated subjects. This also supports the theory of its therapeutic implications in monitoring the disease activity and response to treatment in SLE. No correlation was found between urinary uromodulin levels and SLEDAI in our study, and to our knowledge, there are no published studies correlating between them, which can be accepted as SLEDAI score even if high might not include renal involvement.

Thus, from the results of this study and other previous studies in literature, we can state that decreasing urinary uromodulin levels can be a marker for renal activity in SLE patients and a good tool to monitor treatment response and can also be a marker for CKD and nephron loss in the absence of activity markers.

From the current study, we can conclude that urinary uromodulin or THG can be used as a biomarker for renal involvement in SLE patients. Urinary uromodulin levels were found to decrease with the increase of renal activity in LN patients; thus, it can be used to monitor disease activity and treatment response. Decreased urinary uromodulin levels can be a marker for CKD and nephron loss in the absence of activity markers in LN patients. Patients with decreased urinary uromodulin levels would be expected to be more susceptible to UTI and stone formation.

We recommend further studies on large numbers of SLE and LN patients to reach a cut-off value for renal involvement in lupus patients through measuring urinary uromo- dulin levels. Close monitoring of SLE patients not showing clinical manifestations of renal involvement, but have lower urinary uromo- dulin levels. We also recommend further studies to elucidate the relation between urinary uromodulin levels and different treatment protocols. Long-term studies and follow up are recommended to test urinary uromo dulin as a marker for prediction of the possibility of CKD progression.

Conflict of interest: None declared.



 
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Correspondence Address:
Rania Nabil Bedair
Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria
Egypt
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DOI: 10.4103/1319-2442.279959

PMID: 32129195

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    Tables

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