Renal Resistive Index as a Marker of Severity and Treatment Outcomes in Lupus Nephritis

LN is known to be one of the most serious complications of SLE and it is the major predictor of poor prognosis. In the United States, approximately 35% of adults with SLE have clinical evidence of nephritis at the time of diagnosis; with an estimated total of 50 to 60% developing nephritis during the first 10 years of disease. Lupus nephritis is diagnosed by either the presence of proteinuria (>0.5 g/day), active urinary sediment (with red blood cell, granular, tubular and/or mixed casts), or an unexplained rise in serum creatinine (S Cr). A kidney biopsy is the gold standard to diagnose LN as it provides information regarding the pattern and severity of renal involvement as well as the stage, activity and chronicity. These are all important considerations influencing treatment decisions. However, the invasive nature make it contraindicated in certain situation like bleeding tendency. In one report, five of seven patients with significant bleeding after renal biopsy were patients with LN. Serial biopsy may be needed to monitor progression and treatment. This will increase risk of complication and may be not practical.

The renal arterial resistive index (RRI) is a sonographic index to assess for renal arterial disease. It is measured as:

RRI = (peak systolic velocity - end diastolic velocity) / peak systolic velocity .The RRI was introduced in 1950, and was initially proposed for the semi-quantitative assay of intra-renal vascular resistance by Gosling and Pourcelot in 1974. RRI is and markedly affected by renal determinants such as renal interstitial and venous pressure. In humans in vivo, the acute increase of renal interstitial pressure by hydronephrosis or of venous pressure by venous thrombosis, or of both by abdominal hypertension, results in a linearly related increase in RRI. Increases in the RRI have been observed in a number of pathological conditions, which increase renal interstitial and venous pressure such as renal allograft acute rejection, parenchymal nephropathies, acute kidney injury, renal artery stenosis, chronic kidney disease (CKD), diabetic nephropathy, obstructive nephropathy. Remarkably, interstitial fibrosis closely correlates to renal function and long term prognosis, and may underlie the role of RRI as an independent marker of renal and clinical outcome in chronic renal diseases. No standard, validated, cut-off to distinguish normal from high RRI has been identified to date. RRI values between 0.7 and 0.85 have been associated with renal functional impairment in patients with chronic kidney disease and stenosis of the renal artery. Previous data have revealed a significant correlation between the increased RRI value (RRI>0.7) and renal functional parameters (creatinine and blood urea nitrogen levels) and/or histological finding, such as glomerulosclerosis, tubulointerstitial damage and vascular lesions. Few studies evaluate the role of RRI as marker of severity in LN and its potential use as non-invasive marker in the assessment of the outcomes and in treatments response. To date, the usefulness of RRI in monitoring the progression and treatment of LN is controversial.

Type of the study: : observational analytic cross sectional study - cohort study (the part of the study in which the patients of LN are followed for six month receiving the usual treatment according to KDIGO( Kidney Disease: Improving Global Outcomes) guidelines 2012 to demonstrate the response to treatment in patient with pathological RRI compared to with normal RRI) - Study Setting: Assiut University Hospital (internal medicine departments)

All patients with SLE that will be admitted in internal medicine department from August 2019 to January 2021 are eligible to be targeted and included in the study. The diagnosis of SLE will be according to the 1997 American college of Romatology revised criteria (Hochberg 1997). SLE patients with lupus nephritis will take kidney biopsy for standard care of management according to American college of Romatology guidelines 2012. The study will include three groups as follow:

1 - SLE patients with lupus nephritis. 2- SLE patients without lupus nephritis 3-A group of age and sex matched healthy individuals. The first group will represent the study group while the second and third groups group will be taken as control group .

Sample Size technique: total coverage The ratio of controls to study group will be 2:1.

Study methods:

A-The study group will be subjected to:-

1. History taking and complete physical examination.
2. Laboratory testing: complete blood counting (CBC), blood urea nitrogen (BUN), serum creatinine(S Cr), serum albumin( ALB) estimated glomerular filtration rate (eGFR) (using CKD-EPI(Chronic Kidney Disease Epidemiology Collaboration) Equation) and 24 h urinary protein excretion. These investigations will be taken at the beginning of the study and every month for sex months to determine degree of response to treatment according to KDIGO guidelines 2012.
3. Renal biopsy will be taken according American college of Romatology guidelines 2012. The renal biopsy samples were evaluated by renal pathologists, according to the Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis 2017. Briefly, chronicity index will be calculated as follows: glomerulosclerosis (GS) <25% of the glomeruli =1; GS = 26-50% of the glomeruli= 2; GS > 50% of the glomeruli =3. Fibrous crescents: Fibrous crescents in <25%of the glomeruli=1, Fibrous crescents in 25-50% of the glomeruli =2, Fibrous crescents in >50% of the glomeruli =3. Tubular atrophy: tubular atrophy in <25% of the cortical tubules=1, tubular atrophy in 25-50% of the cortical tubules 2, tubular atrophy in >50% of the cortical tubules =3. Interstitial fibrosis: interstitial fibrosis in <25% of the cortex=1, interstitial fibrosis in 25-50% of the cortex 2, interstitial fibrosis in >50% of the cortex =3. The chronicity index score range from 0 to 12. Activity index will be calculated as follow Endocapillary hypercellularity: Endocapillary hypercellularity in <25% of glomeruli =1, 25%-50% of glomeruli =2, or >50% of glomeruli =3. Neutrophils/karyorrhexis : Neutrophils and/or karyorrhexis in <25% of glomeruli =1*2, 25%-50% of glomeruli =2*2 or >50 of glomeruli =3 *2.Fibrinoid necrosis : Fibrinoid necrosis in <25% of glomeruli =1*2,25%-50% of glomeruli =2*2 or >50% of glomeruli =3*2.Hyaline deposits: Wire loop lesions and/or hyaline thrombi in <25% of glomeruli =1,25%-50% of glomeruli =2 or >50% of glomeruli = 3. Cellular/fibrocellular crescents: Cellular and/or fibrocellular crescents in <25% of glomeruli=1, 25%-50% of glomeruli =2 or >50% of glomeruli =3. Activity index score range from 0 to 24.
4. Doppler ultrasonography. Ultrasound evaluation will be performed 24 h prior to the renal biopsy for all patients and healthy individuals. In the maximum long-axis section images, the largest diameter and width of each kidney will be measured. The participants will be scanned in a supine or decubitus position to achieve an ultrasound beam as close to parallel to the blood flow direction in the intrarenal artery as possible. An ultrasound probe covered with transmission gel will be gently placed on the skin over the kidneys. The PSV, EDV and RI will be measured.

B-The control group (non renal SLE patients and healthy individuals) will be subjected to history taking, physical examination and Doppler ultrasonography as the same as the study group.

Aims of the work:

1. Assessment of the renal resistive index in patients with lupus nephritis (LN), in SLE patients without lupus nephritis and in the healthy controls.
2. Comparing the renal resistive index values in SLE patients with lupus nephritis with the SLE patients without LN and healthy controls.
3. Assessment of the correlation between renal resistive index (RRI) and histological findings in renal biopsy in patients with lupus nephritis.
4. Assessment of the correlation between renal resistive index (RRI) and renal function parameters (BUN, S Cr and eGFR).
5. Evaluation of the role of RRI as predictor of treatment outcomes in patients with lupus nephritis.