International Society Of Nephrology/Renal Pathology Society Research Articles

Prognosis of proliferative lupus nephritis subsets in the Louvain Lupus Nephritis inception Cohort

The objective of this paper is to evaluate whether the different International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes of proliferative lupus nephritis (LN) have a distinct baseline presentation, short-term response to immunosuppression (IS) and long-term prognosis. Ninety-eight patients with new onset (first renal biopsy) ISN/RPS proliferative LN (Class III: n=24; IV-S: n=23; IV-G: n=51) were diagnosed at our institution between 1995 and 2012 (Louvain Lupus Nephritis inception Cohort). Their baseline renal parameters, primary response to IS at one year, survival and long-term renal outcome (mean follow-up: 77 months) were compared. At baseline, serum creatinine and 24-hour proteinuria were higher in Class IV-G, as was activity index on renal biopsy in Class IV-S and IV-G compared to III. Upon treatment, renal parameters improved with the same kinetics and to the same extent in the three pathological classes. On repeat renal biopsies (n=43), activity indices dropped similarly. Poor outcomes (death, end-stage renal disease, renal impairment defined by an eGFR <60 ml/min/1.73 m(2)) did not statistically differ between groups, although there was a trend toward more renal impairment at follow-up in Class IV-G compared to IV-S and III. Finally, the presence of even mild chronic lesions on baseline biopsy was clearly predictive of late renal outcome. Subsetting proliferative LN into Class III, IV-S and IV-G provides less clinically discriminant prognostic information than baseline chronicity index.

Long-term outcome of biopsy-proven lupus nephritis in Iran

This study was conducted to evaluate the survival of patients with lupus nephritis (LN) in two different lupus clinics in Iran. This was a retrospective cohort study covering 82 patients diagnosed with biopsy-proven LN hospitalized between 1994 until 2010. Demographic, clinical, laboratory, therapeutic and end-point data were collected. Renal biopsies were categorized according to the 2004 classification of the International Society of Nephrology/Renal Pathology Society (ISN/RPS). Survival plots, univariate and multivariate Cox regression analyses were applied. Female/male ratio was 65/17. Mortality rate was 6.1% (five patients). Fifty-five (67%), 18 (22%), and four (4.9%) patients had complete/partial remission, chronic renal failure (CRF) and end-stage renal disease (ESRD), respectively. Renal biopsies showed 0, three (3.7%), 18 (22%), 58 (70.7%), two (2.4%) and 0 patients with ISN/RPS classes I, II, III, IV, V and VI, respectively, and one patient (1.2%) with mixed class (IV and V). The 5, 10 and 15 year survival rates for living patients were 97%, 92% and 69%, respectively. When CRF, ESRD and death were considered as one category of poor patient outcome, the 5, 10 and 15 year survival rates for remission were 87%, 47% and 35%, respectively. Multivariate analysis demonstrated the following independent protectives against poor outcome: class II nephritis (hazards ratio [HR] = 0.67; 95% confidence interval [CI], 0.57-0.85), class III nephritis (HR = 0.002; 95% CI, 0-0.036) and time passed since SLE diagnosis (HR = 0.006; 95% CI, 0-0.1). Survival rates of Iranian patients with LN were comparable with those of developed countries.

The clinical significance of serial kidney biopsies in lupus nephritis

Objectives. Repeated kidney biopsies are increasingly recognized to be pivotal in the management of various phases of lupus nephritis. The aim of this retrospective study was to examine the shift in activity index and chronicity index among International Society of Nephrology/Renal Pathology Society (ISN/RPS) class patients with lupus nephritis who undergo a triple kidney biopsy.Methods. Eleven patients with lupus nephritis and 3 biopsies each were assessed and reclassified based on ISN/RPS classification.Results. The mean creatinine level increased from 74 (± 38) μmol/l at baseline to 129 (± 116) μmol/l at the second biopsy and to 204 (± 200) μmol/l at the last biopsy. Among 11 kidney biopsies, 7 (63.7%) had a different ISN/RPS class in the second biopsy. The third biopsy showed that six kidney biopsies had a different ISN/RPS class compared to the second biopsy. Even among patients who stayed in the same ISN/RPS class, the second and third biopsies gave a different activity and/or chronicity index. The median activity index (range) was 3.1 (0–14), 4 (0–13) and 3 (0–14) for the first, second and third biopsies, respectively. The median chronicity indices (range) were 2.5 (0–8), 7 (0–8) and 5 (0–10), respectively.Conclusion. My study has shown that lupus nephritis is a shifting disease, and repeated biopsies are a pivotal policy in its management.

Interstitial inflammation and long-term renal outcomes in lupus nephritis

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification criteria of lupus nephritis are limited to glomerular injury. Although the tubulointerstitium is commonly involved, the importance of such involvement is not well defined. The major objective of this study was to evaluate the association of interstitial inflammation with the long-term outcomes of patients with lupus nephritis. A total of 73 patients who were diagnosed with lupus nephritis between 1996 and 2012 were analyzed. The follow-up data were obtained, and the analysis was conducted to determine the effect of interstitial inflammation on the rate of the doubling of serum creatinine or end-stage renal disease (ESRD) in patients with lupus nephritis. Of the patients included in the cohort, 63 underwent a second biopsy. The degree of interstitial inflammation was positively correlated with the serum creatinine level at the time of biopsy (p = 0.005) but not at the end of the follow-up period (p = 0.9). The complements level, anti-dsDNA, ANA, and proteinuria were not related to the degree of interstitial inflammation. There was no relationship between the probability of remission and the severity of interstitial infiltrate. The rate of no remission was 40% among those without interstitial infiltrate, 34.6% in those with mild infiltrate and 23.5% among those with moderate-to-severe infiltrate (p = 0.6). There was no relationship between interstitial inflammation at the baseline biopsy and worsening of renal function (p = 0.17). There was a strong relationship between interstitial inflammation at the repeat biopsy and renal survival (p = 0.005). The recovery of interstitial inflammation in lupus nephritis correlated with a favorable outcome in the patients with interstitial inflammation at baseline that had resolved at the repeated biopsy (p = 0.047). The persistence of interstitial inflammation is associated with poor renal outcome among patients with lupus nephritis. A comprehensive histological assessment of inflammation in lupus nephritis including interstitial inflammation may provide better prognostic information.

Rare transformation in repeat renal biopsies suggests a different pathogenesis of segmental and global lesions in proliferative lupus nephritis

Heterogeneous histological findings in the renal biopsies of patients with systemic lupus erythematosus were distinguished early into different types of lupus nephritis with different outcomes. The effort to unify the terminology resulted in six classes of the World Health Organization (WHO) classification published in 1982 [1]. Having apart biopsies with normal histology (Class I) and advanced sclerotic lesions (Class VI), it became apparent that there are two main types of lupus nephritis: membranous (Class V) and proliferative (Classes III and IV), although there were also patients with a combination of both membranous and proliferative lesions. Membranous lupus nephritis was shown early to have better outcome than proliferative lupus nephritis, but the relation between focal (Class III) and diffuse (Class IV) lesions remained uncertain. Segmental lesions typical for Class III lupus nephritis resemble the lesions present in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and are very different from global lesions typical for Class IV which, on the other hand, may resemble the immune complex-mediated lesions present, e.g. in idiopathic membranoproliferative glomerulonephritis. According to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classification [1] segmental lesions may be present both in Class III (focal lupus nephritis) if affecting 50% of glomeruli. The ISN/RPS Class IV category thus mixes together segmental lesions in >50% of glomeruli (Class IV-S) and diffuse proliferative lesions (Class IV-G) affecting >50% of glomeruli [2]. Although some authors argued that focal segmental lesions may evolve into diffuse global lesions and both of them may regress (after treatment) into mesangial (Class II) lupus nephritis, other authors referred that there are significant differences between WHO Classes III and IV (and ISN/RPS Class IV-S and IV-G) lupus nephritis both concerning the histological characteristics, clinical presentation and outcome, and that the pathogenesis of segmental and global proliferative lesions may be different [3]. In this issue of NDT Pagni et al. evaluated 142 patients with lupus nephritis and repeat biopsies. Although their original main aim was to look at the role of repeat renal biopsies in routine clinical practice, their paper also adds an important contribution to our understanding of the putatively different pathogenesis of different histological classes of (proliferative) lupus nephritis. Patients with IV-G class of lupus nephritis had, at presentation compared with segmental forms of lupus nephritis (Classes III and IV-S), higher proteinuria, serum creatinine and blood pressure and more mesangial proliferation, wire loops and tuft necrosis in the biopsy. The disease was more severe in both first and repeat biopsy in Class IV-G compared with Class III and IV-S patients and repeat renal biopsy predicted better trend of serum creatinine and proteinuria than the first biopsy. Most importantly, although the transitions between different histological classes were quite frequent (40.8%), the transition between segmental (III/IV-S) and mesangial (II/IV-G) forms was extremely rare, strongly suggesting that really both forms may have not only different clinical and histological features, but also different pathogenesis. Important differences in the histology between IV-G and IV-S patients were repeatedly (and relatively consistently) described. Patients with IV-S class had, compared with IV-G class, e.g. fewer glomeruli with wire loops [3, 4] and hyalin thrombi [3], more frequent fibrinoid necrosis [4–7], lower endocapillary proliferation [6], significant trend to the higher proportion of crescents [4], less frequent infiltration of glomeruli with monocyte/macrophages, lower interstitial inflammation [6] and less IgG (or even complete absence of IgG) on immunofluorescence [3]. Histologic differences may be translated into some differences in the clinical presentation. Class IV-G lupus nephritis was shown to present, compared with Class IV-S, with higher serum creatinine, worse proteinuria [4–6] and higher diastolic blood pressure [4, 7] and also lower C3 [5, 6] and lower proportion of patients with the positivity of anticardiolipin antibodies [6]. Patients with Class III were also shown to have a lower prevalence of the positivity of anti-C1q compared with Class IV patients [8] and patients with segmental lesions (Classes III and IV-S) have the lowest levels of complement factor H in SLE and lupus nephritis patients [9]. IN F O C U S

The value of repeat biopsy in the management of lupus nephritis: an international multicentre study in a large cohort of patients

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification represents the gold standard for the histological evaluation of Systemic Lupus Erythematosus (SLE) nephritis. A repeat biopsy (RB) might be an important tool to provide information on long-term renal outcomes and optimal therapy. Aims of this study were to evaluate the use of the ISN/RPS classification and the role of RB in routine clinical practice. A total number of 142 patients with SLE nephritis and with adequate reference and RB samples were included in this multicentre retrospective study. A meticulous histological examination was centrally performed on first and RB and compared with clinical variables and follow-up data. Morphological features of the ISN/RPS classification: at first and RB, significant differences were observed between segmental classes (III, IV-S) and Class IV-G in mesangial proliferation, wire loops and tuft necrosis. Clinical features and ISN/RPS classification: the correlation between serum creatinine, proteinuria, blood pressure levels and histological classes at first and RB demonstrated more severe renal disease in Class IV-G, both at first and RB. Agreement between ISN/RPS classification at first and RB: 40.8% of patients changed the histological class. Fifty per cent of Class II (mild mesangial form) were reclassified as Class IV-G at RB, whereas 18.9% of Class IV-G were reclassified as Class II. The transition among segmental (III/IV-S) and mesangial forms (II/IV-G) was extremely rare. The comparison between the clinical parameters at the final follow-up and the ISN/RPS classification confirmed that the trend of serum creatinine and proteinuria between the different classes was better described at the RB (higher in Class IV-G) than on the first biopsy. The histopathological data suggest that morphological differences between segmental and global forms do exist, possibly due to different pathogenetic mechanisms. An RB strategy could provide additional information on long-term renal outcomes. A strategy of protocol biopsies could be useful in perspective future trials to better understand the therapeutic response and the natural history of this disease.

An observational study of outcome in SLE patients with biopsy-verified glomerulonephritis between 1986 and 2004 in a defined area of Southern Sweden: the clinical utility of the ACR renal response criteria and predictors for renal outcome

Objectives: To test the utility of the World Health Organization (WHO) and International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria for lupus nephritis (LN) in systemic lupus erythematosus (SLE) and the American College of Rheumatology renal response criteria (ACR-RRC) for renal follow-up in an observational cohort.Method: All 52 biopsy-verified cases of LN during 19 years were identified, and glomerular filtration rate (GFR), serum creatinine, proteinuria, haematuria, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and complement were retrieved at diagnosis of nephritis, after 6 and 12 months, and at the latest visit. Forty-five renal biopsies were available for re-evaluation with the ISN/RPS criteria. Outcome was defined by the ACR-RRC and the final GFR.Results: The mean follow-up time was 9 years; complete renal response (CRR) was achieved in 11 cases, end-stage renal disease (ESRD) in four, and nephrotic syndrome (NS) in one. The final GFR decreased with increasing age at biopsy (p < 0.01) and with interstitial manifestations added to the ISN/RPS classification (p < 0.05). The final GFR correlated with the decrease of proteinuria or casts and actual serum creatinine after 6 months of treatment (all p < 0.05). The outcome defined by ACR-RRC correlated with the nephrological components of SLEDAI-2K after 6 months of therapy (p < 0.01) and with the presence of antibodies to C1q at biopsy (p < 0.05).Conclusions: Renal outcome is correlated with the response to treatment after 6 months and with the addition of interstitial changes to the ISN/RPS classification, which might add useful information for prediction. The ACR-RRC offers a defined alternative to categorize renal response.

Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids

ObjectivesLupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We...

Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions

The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification system of lupus nephritis specified the importance of vascular damage and indicated this should be included in the diagnostic summary. Few pathological studies of lupus nephritis, however, focus on the patterns of renal vascular involvement. Here we assessed renal vascular lesions in lupus nephritis based on the 2003 ISN/RPS classification system and evaluated their association with clinical and pathological data in a large cohort from a single center in China. Among 341 patients with lupus nephritis, 279 were diagnosed with single or multiple renal vascular lesions that included 253 with vascular immune complex deposits, 82 with atherosclerosis, 60 with thrombotic microangiopathy, 13 with noninflammatory necrotizing vasculopathy, and 2 with true renal vasculitis. Patients with thrombotic microangiopathy had the poorest renal outcome. In multivariate Cox hazard analysis after inclusion of renal vascular lesions, the new chronicity index score became a significantly better independent risk factor for renal outcome (hazard ratio 2.32). Thus, renal vascular lesions are common in lupus nephritis and closely correlate with clinical disease activity and renal outcome. Inclusion of a detailed description of renal vascular lesions in the ISN/RPS classification of lupus nephritis may strengthen its predictive value for renal outcome.

Impact of recurrent lupus nephritis on lupus kidney transplantation

This study was conducted to delineate the frequency of recurrent lupus nephritis in a Chinese kidney transplant cohort and to estimate its impact on long-term transplant outcomes. A total of 32 lupus transplant patients were enrolled in this study, and the medical records were retrospectively reviewed. Patients with unexplained graft abnormalities were subjected to allograft biopsy. Recurrent lupus nephritis was diagnosed by light microscopy, immunofluorescence, and electron microscopy. In addition, to determine the clinical manifestations of recurrent lupus GN in these patients, serum original systemic lupus erythematosus disease activity index (SLEDAI) scores while undergoing allograft biopsy were evaluated. In total, six out of 32 patients (18.8%; mean age, 40.5 ± 9.1 years) were diagnosed as having recurrent lupus nephritis and the mean time at diagnosis was 5.1 ± 4.9 years post-transplantation. According to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 criteria, three of the six cases (50%) were defined as class I, one was class II, one was class IV, and one was class III + V. The graft and patient survival rates of recurrent lupus nephritis (n = 6) were not different from those of patients with other diagnostic entities. Although recurrent lupus nephritis was not uncommon, it did not appear to have a strong negative impact on long-term outcome in Chinese kidney transplant patients. The recurrence was potentially treatable and should not be precluded for receiving transplantation.

Frequency of Class III and IV Nephritis in Systemic Lupus Erythematosus Without Clinical Renal Involvement: An Analysis of Predictive Measures

To determine the frequency of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis in patients with systemic lupus erythematosus (SLE) without clinical renal involvement. We investigated the renal pathology of 195 patients with SLE, including 86 patients without clinical renal involvement. Lupus nephritis other than class I was found in 58% of the patients without clinical renal involvement, and class III and IV nephritis was found in 15% of these patients. To reveal the predictive measures involved in class III or IV lupus nephritis, we explored the clinical measures in patients with SLE who did not have clinical renal involvement. Anti-dsDNA antibody titers were significantly higher (p = 0.0266) and C3 values were significantly lower (p = 0.0073) in patients with class III or IV lupus nephritis than in patients without class III or IV lupus nephritis. The sensitivity and specificity values were 77% and 73%, respectively, for cutoff levels of both 40 IU/ml for anti-dsDNA antibodies and 55 mg/dl for C3 (OR 8.8, p = 0.0011). The frequency of nephritis, including ISN/RPS class III and IV, was unexpectedly high in SLE patients without clinical renal involvement. ISN/RPS class III or IV lupus nephritis could be hidden in patients with SLE who present both a high titer of anti-dsDNA antibody and a low concentration of C3, even when they have clinically normal urinary findings and renal function.

Discrepancies in glomerular and tubulointerstitial/vascular immune complex IgG subclasses in lupus nephritis

Lupus nephritis is characterized by glomerular and extraglomerular immune complex deposition in the kidney. It is unclear whether the same circulating immune complexes deposit in the glomeruli and in extraglomerular structures, or whether they are pathogenetically different. Differences in the IgG subclass composition may point towards different pathways in the formation of glomerular and extraglomerular immune complexes. Therefore we investigated IgG subclass distribution in the immune complex deposits at these anatomic sites. A total of 84 biopsies diagnosed as lupus nephritis and classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification, were examined by direct immunofluorescence staining for IgG subclasses. The IgG subclass composition in the glomerular, tubular basement membrane (TBM) and vascular wall deposits was compared. We also correlated the presence/absence of interstitial inflammation and IgG subclasses in the TBM and vascular deposits. Lastly, we looked for correlation between staining for IgG subclasses and complement C1q and C3 staining. IgG staining was present in the TBM in 52/84 biopsies, and in the vascular walls in 40/84 biopsies. IgG subclass distribution was discrepant between glomerular and TBM deposits in 36/52 biopsies, and between glomerular and vascular deposits in 27/40 biopsies. Interstitial inflammation did not correlate with the presence of IgG staining or distribution of IgG subclasses in the TBM. Interstitial inflammation was more common in biopsies of African-American patients than Caucasian patients. The IgG subclass staining correlated with C1q staining in all the three compartments. The antibody composition of the glomerular and extraglomerular immune complex deposits appear to differ from each other. They may not represent the same preformed immune complexes from the circulation. It is likely that their pathogenesis and site of formation are different.

Simultaneous presentation of systemic lupus erythematosus and lupus nephritis in mother and son

The pathogenesis of systemic lupus erythematosus (SLE) has been attributed to complex interactions between genetic, hormonal and environmental factors. The influence of a genetic predisposition to SLE is supported by family aggregation and a high concordance rate in monozygotic twins. Here we present a rare case of simultaneous presentation of SLE and lupus nephritis in a mother and son. Both patients had nephrotic-range proteinuria, and the renal pathological classifications of the son and his mother were Class IV-G (A) and Class III (A/C), respectively, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis. Apart from the renal involvement, both patients had leucopenia and anemia, and the mother also had typical cutaneous lesions and secondary Sjögren's syndrome. This case supports the genetic role in the etiology of SLE, and displayed different clinical presentations and disease severity in familial SLE patients of different gender and age.

Efficacy and safety of tacrolimus for induction therapy in patients with active lupus nephritis

After the completion of a double-blind placebo-controlled trial, tacrolimus (TAC) was approved for the treatment of lupus nephritis (LN) in Japan. However, the approved maximal dose, 3 mg/day, is almost half the dose used for induction therapy outside Japan. In this study, we retrospectively evaluated the efficacy and safety of low-dose TAC (≤3 mg/day) for induction therapy in 13 adult patients (2 men and 11 women) with active LN. Eight patients were treated for LN flares. Twelve patients underwent renal biopsies: 8 with class IV, 2 with class III + V, 1 with class IV + V, and 1 with class V renal histology, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. The mean initial doses of prednisone and TAC were 34.6 ± 14.5 and 2.7 ± 0.6 mg/day, respectively. All the patients achieved a complete remission (CR) at 7.7 ± 6.7 months (mean ± SD) after the last administration of TAC, except for 2 patients who discontinued TAC treatment; 1 because of worsening systemic lupus erythematosus and 1 because of hypertension. Two patients experienced a flare-up after achieving CR. The mean blood TAC concentration 12 h after the last administration (C12) was significantly lower among the patients with flare-ups than among those with a sustained CR (1.5 ± 1.5 vs. 5.1 ± 1.9 ng/mL, P = 0.034). These data showed that low-dose TAC was effective for induction therapy in patients with active LN, although a lower TAC concentration may be associated with a poor outcome.

Outcome of reclassification of World Health Organization (WHO) class III under International Society of Nephrology-Renal Pathology Society (ISN-RPS) classification: retrospective observational study

The outcome of systemic lupus erythematosus (SLE) is largely influenced by the existence of lupus nephritis (LN), and its histologic classification guides the treatment and prognosis of SLE. International Society of Nephrology-Renal Pathology Society (ISN-RPS) announced a revised classification of LN in 2004. The present study investigated the differential outcome of World Health Organization (WHO) class III LN when reclassified according to ISN-RPS classification. Forty-three patients with biopsy-proven WHO class III LN at a single tertiary hospital were included in the study. Baseline characteristics at the time of renal biopsy and clinical data during follow-up were obtained from medical records. Renal response to treatment at one-year follow-up was analyzed in three ways; complete response (CR), partial response (PR), and no response (NR). Of 43 patients with previous WHO class III LN, 12 cases were reclassified into ISN-RPS class IV (9 cases of class IV-S and 3 cases of IV-G). Baseline characteristics at the time of renal biopsy were not different between the reclassified class IV and remaining class III LN group except activity index on renal histology, which was significantly elevated in the reclassified class IV group (4.90 vs. 6.75; P = 0.02). Significantly higher number of patients with remaining class III LN achieved CR to treatment than those with reclassified class IV LN at one-year follow-up since initial biopsy (CR: PR: NR; 16:7:7 vs. 3:1:8; P = 0.032). Our study suggests that the ISN-RPS classification is more advantageous in predicting renal outcome and guiding treatment when evaluating previously classified WHO class III LN.

Identification of urinary metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal segmental glomerulosclerosis

IntroductionSystemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS).MethodsMetabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis.ResultsUrinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001).ConclusionsThis pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.

Efficacy and safety of tacrolimus for induction therapy in patients with active lupus nephritis

After the completion of a double-blind placebo-controlled trial, tacrolimus (TAC) was approved for the treatment of lupus nephritis (LN) in Japan. However, the approved maximal dose, 3 mg/day, is almost half the dose used for induction therapy outside Japan. In this study, we retrospectively evaluated the efficacy and safety of low-dose TAC (≤3 mg/day) for induction therapy in 13 adult patients (2 men and 11 women) with active LN. Eight patients were treated for LN flares. Twelve patients underwent renal biopsies: 8 with class IV, 2 with class III + V, 1 with class IV + V, and 1 with class V renal histology, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. The mean initial doses of prednisone and TAC were 34.6 ± 14.5 and 2.7 ± 0.6 mg/day, respectively. All the patients achieved a complete remission (CR) at 7.7 ± 6.7 months (mean ± SD) after the last administration of TAC, except for 2 patients who discontinued TAC treatment; 1 because of worsening systemic lupus erythematosus and 1 because of hypertension. Two patients experienced a flare-up after achieving CR. The mean blood TAC concentration 12 h after the last administration (C12) was significantly lower among the patients with flare-ups than among those with a sustained CR (1.5 ± 1.5 vs. 5.1 ± 1.9 ng/mL, P = 0.034). These data showed that low-dose TAC was effective for induction therapy in patients with active LN, although a lower TAC concentration may be associated with a poor outcome.

Late onset lupus nephritis: analysis of clinical manifestations and renal pathological features in Chinese patients

The objectives of the study are to analyze the clinical and pathological features of 35 Chinese patients with late onset lupus nephritis (LN) in a single center. All the LN patients followed-up in our lupus clinic center from 1986 to 2008 were enrolled in this retrospective study. Thirty-five patients with a disease onset beyond the age of 50 years were identified. One hundred systemic lupus erythematosus (SLE) patients who had their disease onset before the age of 50 years were randomly recruited as controls. All of them received renal biopsy. The histological classifications were categorized according to 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. All of patients were Han Chinese. The mean age of onset of SLE for late onset and the control groups were 55.7 ± 6.5 years (range: 50-76) and 28.9 ± 7.6 years (range:18-48).The female to male ratio was smaller in the late onset SLE group, 2.9-1, compared with 7.3-1 in the control. The patients with hypertension in late onset LN were much more than that in control group. The renal histological classes showed no significant difference between the two groups. Classes IV, V, IV + V were common in late onset LN patients. There were no significant differences in extra renal manifestations except for a lower prevalence of malar rash, a higher leukopenia and skin vasculitis in the late onset patients. As to the immunological features, serum antineutrophil cytoplasmic antibodies (ANCA) and SSA positivity were more common in late onset LN patients. The patients with hypertension in late onset LN were much more than that in control group. The renal histological classes showed no significant difference between the two groups. Leukopenia and serum ANCA were more common. The results suggest a more severity of the disease in late onset LN.

Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system

The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) system for classifying patients with lupus nephritis was based on glomerular lesions exclusively, despite the fact that lupus nephritis affects all compartments of the kidney. Hence, we analyzed the tubulointerstitial lesions in patients with lupus nephritis within the different classes and subclasses of the 2003 ISN/RPS system. Among 313 patients from five centers in northern China with lupus nephritis, interstitial inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis were severe in 170 patients with class IV, moderate in 55 with class III, and mild in 19 with class II and in 69 with class V disease, each with significance. The severity of tubulointerstitial lesions in classes IV-segmental and III was similar, whereas the score of interstitial inflammatory cell infiltration in patients with subclass IV-global was significantly higher than that in those with subclass IV-segmental. Interstitial fibrosis and tubular atrophy were each significantly more prominent in patients with both active and chronic lesions than in those with active lesions alone. The correlation coefficient ranged from 0.222 to 0.811 comparing glomerular and tubulointerstitial indices. In multivariate Cox hazard analysis of tubulointerstitial lesions, indices of interstitial infiltration, tubular atrophy, and interstitial fibrosis were confirmed as significant independent risk factors for renal outcome. Thus, we found that the 2003 ISN/RPS classification system of lupus nephritis, based on glomerular lesions, could also reflect related tubulointerstitial lesions. Hence, we suggest that the extent of tubulointerstitial lesions may be helpful in predicting renal outcome in patients with lupus nephritis.

Classification of lupus nephritis

Lupus nephritis manifests as diverse patterns of immune complex-mediated renal disease affecting glomerular, tubulointerstitial, and vascular compartments. This review will focus on the most recent classification, the 'International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis', and will briefly discuss other types of renal disease seen in patients with systemic lupus erythematosus. The ISN/RPS 2003 Classification of lupus nephritis includes multiple changes from its predecessors, most notably removal of the subclasses of lupus nephritis class V (i.e. Va-Vd), elimination of the normal category (WHO class I), clearer definitions for all classes, a standard approach to sclerotic glomeruli, and the division of lupus nephritis class IV into subcategories based on whether the endocapillary involvement is predominantly segmental (lupus nephritis IV-S) or global (lupus nephritis IV-G). These changes have led to a higher level of interobserver reproducibility and a significant increase in the number of cases of class IV, with a reciprocal decline in lupus nephritis class III and lupus nephritis class V. Multiple studies have found that lupus nephritis class IV-S has similar or better outcomes than lupus nephritis class IV-G. The ISN/RPS 2003 classification of lupus nephritis is gaining widespread acceptance and appears to be achieving its goals of reproducibility and clinical relevance.