Low-Grade Proteinuria Does Not Exclude Significant Kidney Injury in Lupus Nephritis

Abstract

Kidney involvement is common in systemic lupus erythematosus (SLE) and is a major cause of morbidity and mortality.1Danila M.I. Pons-Estel G.J. Zhang J. et al.Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort.Rheumatology (Oxford). 2009; 48: 542-545Crossref PubMed Scopus (149) Google Scholar About 50% to 70% of adults and 37% to 82% of children with SLE develop lupus nephritis (LN).2Szymanik-Grzelak H. Kuźma-Mroczkowska E. Małdyk J. Pańczyk-Tomaszewska M. Lupus nephritis in children—10 years' experience.Cent Eur J Immunol. 2016; 41: 248-254Crossref PubMed Scopus (7) Google Scholar A kidney biopsy is generally performed to confirm a diagnosis of LN and to inform treatment in SLE patients who develop proteinuria with or without hematuria and/or impaired kidney function. Proteinuria is considered to be the key clinical diagnostic marker of LN, and in the absence of proteinuria above a certain threshold, kidney biopsies in SLE patients are often not performed. For example, the current American College of Rheumatology (ACR) guidelines suggest that a kidney biopsy be performed in patients with proteinuria >1.0 g/d, or proteinuria >0.5 g/d accompanied by hematuria or cellular casts.3Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar However, there have been a handful of reports describing significant kidney pathology in SLE patients with no or minimal proteinuria,4Mavragani C.P. Fragoulis G.E. Somarakis G. et al.Clinical and laboratory predictors of distinct histopathologic features of lupus nephritis.Medicine. 2015; 94: e829Crossref PubMed Scopus (33) Google Scholar,5Zabaleta-Lanz M.E. Muñoz L.E. Tapanes F.J. et al.Further description of early clinically silent lupus nephritis.Lupus. 2006; 15: 845-851Crossref PubMed Scopus (46) Google Scholar raising the question of what constitutes an appropriate threshold for performing a kidney biopsy. We examined proteinuria levels at the time of kidney biopsy in our LN population to determine whether the proteinuria threshold for biopsy should be <0.5−1 g/d. We characterized 222 SLE patients who underwent a kidney biopsy for suspicion of LN between 2008 and 2017 at the Hospital de Clinicas, University of Buenos Aires. Most patients (79%) had proteinuria ≥0.5g/d, and all except 7 patients had evidence of glomerular hematuria (acanthocytes) on examination of the urine sediment. However, 46 patients with a urine protein level <0.5 g/d underwent biopsy. All of these patients had glomerular hematuria, and 5 had a serum creatinine concentration >1 mg/dl (1.1−1.3 mg/dl). All patients were Hispanic and of European ancestry. The demographic and clinical characteristics of the patients with low (<0.5 g/d) proteinuria and the patients with proteinuria (≥ 0.5 g/d) are compared in Table 1, and the kidney biopsy findings are listed in Table 2. The subgroups of patients with low proteinuria plus a serum creatinine concentration >1 mg/dl and of patients with very low proteinuria (<0.25 g/d) are described in Table 3.Table 1Cohort demographics, clinical characteristics, and laboratory data at biopsyCohort characteristicsProteinuria <0.5 g/d (n = 46)Proteinuria ≥0.5 g/d (n = 176)P valueaComparing patients with proteinuria <0.5 g/d to patients with proteinuria ≥0.5 g/d.Female36 (78.3)155 (88)aComparing patients with proteinuria <0.5 g/d to patients with proteinuria ≥0.5 g/d.0.097Age, yr31.5 (18–65)32 (16–66)0.72Duration of lupus, mo12 (2–60)11 (1–168)0.64Glomerular hematuria present46 (100)169 (96)0.36Proteinuria, g/d0.23 (0.0–0.42)3.60 (0.5–20)<0.0001Serum creatinine, mg/dl0.70 (0.4–1.3)0.9 (0.46–7.8)<0.0001ANA-positive,46 (100)176 (100)—Anti-dsDNA–positive31 (67.4)114 (64.8)1C3, mg/dl66 (15–174)69 (14–180)0.97C4, mg/dl12 (1–43)9 (1–46)0.89ANA, anti-nuclear antibody; anti-dsDNA, anti−double-stranded DNA antibody; C3, complement C3; C4, complement C4.Data are expressed as number of patients (% of group) or median (range).a Comparing patients with proteinuria <0.5 g/d to patients with proteinuria ≥0.5 g/d. Open table in a new tab Table 2Histologic findings at biopsyHistologic parameterProteinuria <0.5 g/d (n = 46)Proteinuria ≥0.5 g/d (n = 176)P valueaComparing patients with proteinuria <0.5 g/d to patients with proteinuria ≥0.5 g/d.ISN/RPS class II5 (10.9)0— III14 (30.4)18 (10.2)0.002 IV21 (45.7)135 (76.7)0.0001 V2 (4.3)3 (1.7)— III or IV +V4 (8.7)19 (10.8)— VI01 (0.6)—Activity index6 (0−14)9 (1−21)<0.0001Chronicity index2 (0−4)3 (0−8)<0.0001ISN/RPS, International Society of Nephrology/Renal Pathology Society.Data are expressed as number of patients (% of group) or as median (range).a Comparing patients with proteinuria <0.5 g/d to patients with proteinuria ≥0.5 g/d. Open table in a new tab Table 3Demographic, clinical, and histologic findings of patients with very low levels of proteinuriaCohort characteristicsProteinuria <0.25 g/d (n = 25)Both proteinuria <0.25 g/d and serum creatinine≥1 mg/dl (n = 5)Both proteinuria <0.25 g/d and serum creatinine <1 mg/dl (n = 20)P valueaCompares patients with proteinuria <0.25 g/d with a serum creatinine level of ≥1 mg/dl and those with proteinuria <0.25 g/d and a serum creatinine of <1mg/dl. χ2, Mann–Whitney, and Fisher exact test used where appropriate.Female, %21 (84)5 (100)16 (80)NSAge, yr32 (18–65)24 (22–42)32 (18–65)NSDuration of lupus, mo12 (2–56)12 (4–44)5 (2–56)NSGlomerular hematuria present25 (100)5 (100)20 (100)NSProteinuria, g/d0.05 (0.05–0.23)0.20 (0.05–0.23)0.05 (0.05–0.22)NSSerum creatinine, mg/dl0.70 (0.5–1.1)1.0 (1.0–1.1)0.63 (0.5–0.9)0.0008ANA-positive25 (100)5 (100)20 (100)NSAnti-dsDNA–positive19 (76)4 (80)15 (75)NSC3, mg/dl64 (15–174)44 (15–79)87.5 (20–174)0.032C4, mg/dl12 (1–43)3 (1–14)12.5 (1–43)NSActivity index5 (0–10)6 (6–7)4 (0–10)NSChronicity index2 (0–4)2 (2–3)1 (0–4)NSISN/RPS class II5 (20)0 (0)5 (25)NSISN/RPS class III6 (24)1 (20)5 (25)ISN/RPS class III+V1 (4)0 (0)1 (5)ISN/RPS class IV12 (48)4 (80)8 (40)ISN/RPS class V1 (4)0 (0)1 (5)ANA, anti-nuclear antibody; anti-dsDNA, anti–double-stranded DNA antibody; C3, complement C3; C4, complement C4; ISN/RPS, International Society of Neurology/Renal Pathology Society; NS, not significant.Data are expressed as number of patients (% of group) or as median (range).a Compares patients with proteinuria <0.25 g/d with a serum creatinine level of ≥1 mg/dl and those with proteinuria <0.25 g/d and a serum creatinine of <1mg/dl. χ2, Mann–Whitney, and Fisher exact test used where appropriate. Open table in a new tab ANA, anti-nuclear antibody; anti-dsDNA, anti−double-stranded DNA antibody; C3, complement C3; C4, complement C4. Data are expressed as number of patients (% of group) or median (range). ISN/RPS, International Society of Nephrology/Renal Pathology Society. Data are expressed as number of patients (% of group) or as median (range). ANA, anti-nuclear antibody; anti-dsDNA, anti–double-stranded DNA antibody; C3, complement C3; C4, complement C4; ISN/RPS, International Society of Neurology/Renal Pathology Society; NS, not significant. Data are expressed as number of patients (% of group) or as median (range). About 85% of the patients with proteinuria <0.5 g/d and 76% with proteinuria <0.25 g/d had class III or IV (±V) LN. None of these patients had class I LN, and only 11% and 20% had class II in the <0.5/d and <0.25 g/d proteinuria groups, respectively. The patients with low proteinuria generally had moderate histologic activity, with only 7 (15%) having an activity index ≤1. In addition, despite no prior history of nephritis, most of the patients with low proteinuria had already accrued chronic kidney damage, and only 8 (17%) had a chronicity index of 0. Histologic activity and chronicity were significantly worse in the patients with >0.5 g/d proteinuria. In this group, 2 patients had an activity index of 1 and the rest were all ≥2. Similarly, 2 patients had a chronicity index of 0, and the rest were ≥1. Compared to the SLE patients with >0.5 g/d proteinuria, there were numerically more male patients in the low-proteinuria group, but this was not significant. The overall duration of SLE was the same for both groups, with a median of about 1 year, but a very wide range. LN was diagnosed within 2 months of an SLE diagnosis in 15% of the low-proteinuria patients and 20% of the patients with >0.5 g/d proteinuria. Patients at both levels of proteinuria were of similar age, all were anti-nuclear antibody–positive, and there were no differences between groups in complement consumption or the proportion of patients who were double-stranded DNA antibody–positive. However, patients with proteinuria <0.5 g/d did have significantly better kidney function than patients with proteinuria >0.5 g/d. These observations demonstrate that in patients with SLE and glomerular hematuria, the kidney may harbor significant pathology without much proteinuria. One interpretation of these findings is that the patients were identified very early in the course of their LN. Although that may be the case and although it cannot be determined from our cohort, their overall duration of SLE was 12 months, their kidney biopsy samples showed more than minimal histologic activity, and their kidneys already had evidence of chronic damage. These findings support making an early diagnosis of LN with rapid treatment to avoid chronic renal injury and progressive kidney dysfunction.6Esdaile J.M. Joseph L. MacKenzie T. et al.The benefit of early treatment with immunosuppressive agents in lupus nephritis.J Rheumatol. 1994; 21: 2046-2051PubMed Google Scholar,7Houssiau F.A. Vasconcelos C. D'Cruz D. et al.Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long term followup of patients in the Euro Lupus Nephritis Trial.Arthritis Rheum. 2004; 50: 3934-3940Crossref PubMed Scopus (329) Google Scholar It is important to emphasize that our patients do not have silent lupus nephritis, which describes patients with no urinary abnormalities and proteinuria ≤300 mg/24 h. Between 60% and 70% of patients with silent LN were found to have class I or II LN histology, whereas only 15% to 20% had class III or IV.5Zabaleta-Lanz M.E. Muñoz L.E. Tapanes F.J. et al.Further description of early clinically silent lupus nephritis.Lupus. 2006; 15: 845-851Crossref PubMed Scopus (46) Google Scholar,8Wakasugi D. Gono T. Kawaguchi Y. et al.Frequency of class III and IV nephritis in systemic lupus erythematosus without clinical renal involvement: an analysis of predictive measures.J Rheumatol. 2012; 39: 79-85Crossref PubMed Scopus (65) Google Scholar In contrast, class IV LN was the most common International Society of Nephrology/Renal Pathology Society (ISN/RPS) class found in our patients with glomerular hematuria (46%), closely followed by class III LN (30%). Similarly, class III or IV LN was found in 14 of 24 (58%) patients with SLE, proteinuria <0.25 g/d, and an active urine sediment,4Mavragani C.P. Fragoulis G.E. Somarakis G. et al.Clinical and laboratory predictors of distinct histopathologic features of lupus nephritis.Medicine. 2015; 94: e829Crossref PubMed Scopus (33) Google Scholar and in 57% of 21 patients who had a kidney biopsy for 24-h proteinuria <1 g/d with or without hematuria.9Christopher-Stine L. Siedner M. Lin J. et al.Renal biopsy in lupus patients with low levels of proteinuria.J Rheumatol. 2007; 34: 332-335PubMed Google Scholar This study has several limitations. It is a retrospective analysis and cannot be used to define the incidence or prevalence of proliferative LN in patients with minimal proteinuria. There were too few patients with class II or V LN to be able to identify predictors to differentiate LN classes in a population of patients with glomerular hematuria and low-grade proteinuria. Finally, and most importantly, all of the patients with class III and IV LN were treated aggressively with corticosteroids and an immunosuppressive agent (cyclophosphamide or mycophenolate mofetil), precluding any determination of whether patients with these characteristics may respond adequately to less intense immunosuppression. In summary, patients with lupus and evidence of an active urine sediment but low levels of proteinuria (<0.5 g/d) may have important kidney pathology that warrants aggressive treatment. Despite current guidelines that recommend a proteinuria threshold of >0.5 to 1 g/d, a diagnostic kidney biopsy in SLE patients with low-grade proteinuria should be considered. All the authors declared no competing interests. Download .pdf (.1 MB) Help with pdf files Supplementary File (PDF) Therapeutic Implications of Renal Biopsies to Detect Proliferative Lupus Nephritis in Patients With Low-Grade ProteinuriaKidney International ReportsVol. 5Issue 11PreviewIn their research letter, de Rosa et al.1 present important data in a cohort of patients with lupus nephritis (LN) with low-grade proteinuria. They demonstrate that a significant proportion of patients requiring intensive immunosuppressive therapy may be missed with a threshold of 500 mg/24 hours of proteinuria as an indication for renal biopsy, as suggested in the latest European League Against Rheumatism guideline.2 They show that 46 of 228 patients who underwent a renal biopsy had low-grade proteinuria and microscopic hematuria. Full-Text PDF Open AccessLetter to the EditorKidney International ReportsVol. 5Issue 11PreviewWe thank Plüß and colleagues1 for their letter supporting our finding that aggressive histological forms of lupus nephritis may be present in patients with very little proteinuria.2 Although we did not find serology helpful in discriminating these patients from among all patients with low-grade proteinuria, Plüß et al.1 reported that higher titers of anti–double-stranded DNA antibodies and lower levels of C3 and C4 were associated with proliferative lupus nephritis. Their findings support the premise that the decision to perform a kidney biopsy in patients with systemic lupus erythematosus should not be solely based on the level of proteinuria. Full-Text PDF Open Access

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