Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis

Aim: The role of the tumour necrosis factor‐like weak inducer of apoptosis (TWEAK)/Fn14 and interferon‐inducible protein (IP‐10)/CXCR3 axis in the pathogenesis of lupus nephritis were studied. Methods: The mRNA expression of TWEAK, Fn14, IP‐10 and CXCR3 were quantified in the glomerulus and tubulointerstitium of 42 patients with lupus nephritis (LN group) and 10 healthy controls. Results: As compared to controls, LN patients had higher glomerular expression of TWEAK and Fn14, but glomerular CXCR3 expression was lower in the LN group. Similarly, the LN group had higher tubulointerstitial expression of TWEAK and Fn14, but lower tubulointerstitial expression of CXCR3, than controls. Glomerular TWEAK expression of class V nephritis was significantly higher than class IV nephritis. Glomerular expression of CXCR3 significantly correlated with proteinuria (r = ?0.532; P = 0.019), whereas tubulointerstitial CXCR3 significantly correlated with serum creatinine (r = ?0.447; P = 0.029). Conclusion: In patients with lupus nephritis, there is an increase in intra‐renal expression of TWEAK and Fn14, and a decrease in CXCR3 expression. Intra‐renal expression of CXCR3 correlates with proteinuria and renal function. Our findings suggest that the TWEAK/Fn14 and IP‐10/CXCR3 axis may contribute to the pathogenesis of lupus nephritis.     

Dyslipidaemia in patients with lupus nephritis

Aim: There is little data on the prevalence and severity of dyslipidaemia in Asian patients with lupus nephritis (LN). Whether the dyslipidaemia in LN patients differs from subjects with comparable levels of renal impairment also remains undefined. Methods: Lipid profiles of 100 Chinese patients with quiescent LN (age 46.3 ± 9.3 years, 83% female, maintenance prednisolone dose 5.80 ± 2.43 mg/day) were studied and compared with 100 controls who had non‐lupus non‐diabetic chronic kidney diseases (CKD), matched for sex, age and renal function. Results: LN patients and CKD controls had similar renal function and proteinuria, while blood pressure was higher in controls. Twenty‐five percent of LN patients and 17% of controls were receiving statin treatment. Despite this, 59% of LN patients and 46% CKD controls showed abnormal lipid parameters (P = 0.066). LN patients showed higher levels of total cholesterol (TC) and triglycerides (TG) than controls (5.28 ± 0.12 vs 4.86 ± 0.08 mmol/L, P = 0.004; and 1.62 ± 0.12 vs 1.20 ± 0.07 mmol/L, P = 0.002, respectively). More LN patients had abnormal TC, TG or low‐density lipoprotein cholesterol (LDL‐C) (54%, 16% and 38%; P = 0.016, = 0.005 and = 0.021, respectively). Hydroxychloroquine (HCQ) treatment was associated with lower TC, LDL‐C and HDL‐cholesterol. Conclusion: Dyslipidaemia is prevalent in LN patients and is more severe than controls with a similar degree of CKD despite disease quiescence, low steroid dose and low level of proteinuria. Concomitant corticosteroid and renal impairment are likely contributing factors. HCQ treatment is associated with reduced severity of dyslipidaemia in LN patients.     

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis

AIM: Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. METHOD: Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. RESULTS: All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). CONCLUSION: From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.     

Clinical significance of renal biopsies showing mixed mesangial and global proliferative lupus nephritis

Renal biopsies of 70 children with systemic lupus erythematosus were categorized, according to the World Health Organization classification, as normal (five, 7%), mesangial (23, 33%), focal segmental proliferative (11, 16%), diffuse global proliferative (20, 29%) (ie, greater than or equal to 80% of glomeruli showing mesangioendothelial cell proliferation and/or deposition of immune complexes along the subendothelial margin of glomerular capillaries), and membranous (six, 8%) lupus nephritis (LN). In addition, five (7%) biopsies showed global proliferative LN in less than 80% of glomeruli and mesangial LN in the others. We assessed the renal status of these five patients at the time of renal biopsy and at outcome following prednisone treatment, with or without azathioprine. Four patients improved and later had either a normal urinalysis or only trace proteinuria. A low chronicity index was calculated on the biopsies of these patients. The fifth patient, whose condition did not improve, demonstrated a high chronicity index on renal biopsy. Overall, the renal status at outcome in the patients showing mixed mesangial and global proliferative LN more closely resembled that of patients with mesangial than diffuse global proliferative LN.     

Lupus nephritis in children: prognostic significance of clinicopathological findings

BACKGROUND: We aimed to review our experience with childhood lupus nephritis (LN) in respect to the analysis of the clinical and histopathological presentation of LN and prognostic factors affecting the kidney and patient outcomes. METHOD: Forty-three children (39 girls, 4 boys) with biopsy-proven LN were included in the study. The mean age of the children was 12.0 +/- 2.8 years. Based on the renal histopathology and clinical presentation, patients were treated with oral prednisone, intravenous pulses of methylprednisolone or intravenous cyclophosphamide. The final clinical status was classified as follows: (1) renal and extrarenal remission; (2) clinically active renal disease, or (3) adverse outcome, i.e., end-stage renal failure (ESRF) or death. RESULTS: The mean duration of follow-up was 7.2 +/- 2.8 years (1 month to 14.2 years). All 43 children had hematuria and 53.5% had proteinuria at admission. Fourteen children were in nephrotic status at the onset of disease. Class IV (diffuse proliferative) nephritis was observed in 29 patients as the most frequent histopathology (67.4%). The patients with class IV nephritis had a tendency to develop nephrotic syndrome, heavy proteinuria, increased Cr levels and persistent hypertension at initial evaluation. Thirty-two of 43 children (74.4%) were in renal remission at the last visit. Five-year kidney and patient survival rates from the time of diagnosis to the endpoints of ESRF or death were 83.7 and 90.7% respectively in the whole group while it was 75.9 and 86.2% respectively in the class IV group. Adverse outcome was significantly associated with the persistent hypertension, anemia, high serum Cr level, heavy proteinuria, nephrotic syndrome and class IV nephritis at presentation. CONCLUSION: We can conclude that the prognosis of LN in children is primarily dependent on the histopathological lesions. Severity of the clinical renal disease at admission and presence of persistent hypertension are the main poor prognostic factors rather than age, gender, low C3 and C4 levels, ANA positivity and the treatment modalities in Turkish children.     

Treatment of lupus nephritis with cyclosporine - an outcome analysis

BACKGROUND: The optimal therapy for lupus nephritis (LN), including the role of cyclosporine (CsA), still lacks scientifically valid clinical experience. We evaluated the efficacy of CsA in the induction and maintenance treatment of patients with biopsy-proven LN. PATIENTS AND METHODS: A total of 31 patients (25 women, 6 men, mean age 29.5 years) were enrolled in the study. The majority had proliferative LN. The mean follow-up was 85.6 +/- 24.7 months. RESULTS: CsA was used as first-line treatment in 38.7% of patients and as second-line treatment in 61.3% of patients. Complete remission was achieved in 93.5% of patients. The relapse rate was 45.2%. The mean disease-free interval was 33 months. At the end of follow-up, a total of 67.9% of the patients were in remission. The treatment led to significant improvement in proteinuria (p = 0.001) and stabilization of renal function. CONCLUSION: CsA might be an appropriate and a less toxic alternative drug for LN both as a first-choice and rescue therapy.     

Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis

Aim: MicroRNAs (miRNAs) play important roles in the pathogenesis of autoimmune diseases. We studied the intra‐renal expression of miRNA targets that were reported to be differentially expressed in peripheral blood or urine between lupus nephritis (LN) patients and normal controls. Methods: We quantified the expression of in glomerulus and tubulointerstitium of miR‐146a, miR‐155, miR‐198 miR‐638 and miR‐663 in 42 patients with LN and 10 healthy controls. Results: As compared with controls, LN patients had lower glomerular expression of miR‐638 (P < 0.001) but higher tubulointerstitial expression of this target (P = 0.001). Both glomerular and tubulointerstitial expression of miR‐198 were higher in LN patients than controls (P < 0.001). For miR‐146a, LN patients only had higher expression in glomerulus (P = 0.005) but not in tubulointerstitium. Tubulointerstitial miR‐638 expression was significantly correlated with proteinuria (r = 0.404; P = 0.022) and disease activity score (r = 0.454; P = 0.008), while glomerular miR‐146a expressions were correlated with estimated GFR (r = 0.453; P = 0.028) and histological activity index (r = 0.494; P = 0.027). Conclusion: We found that intra‐renal expression of miR‐638, miR‐198 and miR‐146a are differentially expressed between LN patients and normal controls. Furthermore, the degree of change in glomerular miR‐146a and tubulointerstitial miR‐638 expression correlated with clinical disease severity. The results suggested that these miRNA targets may play a role in the pathogenesis of lupus nephritis.     

Recurrent lupus nephritis in renal transplant recipients revisited: it is not rare

BACKGROUND: Although recurrent lupus nephritis (RLN) after kidney transplantation is reported to be rare (1%-4%), recent studies suggest a higher incidence. The purpose of this study was to determine the incidence of RLN in a large cohort of renal transplant recipients with systemic lupus erythematosus (SLE). METHODS: The records of 54 renal transplant recipients with SLE were reviewed. Thirty-one patients underwent biopsy because of worsening renal function and proteinuria. All biopsy specimens were evaluated by light microscopy, immunofluorescence (IF), and electron microscopy (EM). RESULTS: Among the 50 patients with at least 3 months of follow-up, RLN was present in 15 (52% of patients who underwent biopsy, 30% of total patients): mesangial lupus nephritis (LN) (class II) in eight, focal proliferative LN (class III) in four, and membranous LN (class Vb) in three patients. One patient had graft loss because of RLN (class II) at 10.5 years. The duration of dialysis before transplantation was not different between patients with RLN compared to patients without RLN (P=0.40). Overall patient survival (n=50) was 96% at 1 year and 82% at 5 years, and graft survival was 87% at 1 year and 60% at 5 years. Graft survival was worse in patients who underwent biopsy compared with patients who never underwent biopsy (P<0.01). CONCLUSIONS: RLN is more common than previously reported, but in our series, graft loss because of RLN was rare. Aggressive use of allograft biopsies and morphologic evaluation with IF and EM are important factors in the diagnosis of RLN. The impact of new immunosuppressive agents on the incidence of RLN remains to be seen.     

Lupus nephritis: an update

Lupus nephritis (LN) is an inflammatory condition of the kidneys that encompasses various patterns of renal disease including glomerular and tubulointerstitial pathology. It is a major predictor of poor prognosis in patients with systemic lupus erythematosus (SLE). Genetic factors, including several predisposing loci, and environmental factors, such as EBV and ultraviolet light, have been implicated in the pathogenesis. It carries a high morbidity and mortality if left untreated. Renal biopsy findings are utilized to guide treatment. Optimizing risk factors such as proteinuria and hypertension with renin-angiotensin receptor blockade is crucial. Immunosuppressive therapy is recommended for patients with focal or diffuse proliferative lupus nephritis (Class III or IV) disease, and certain patients with membranous LN (Class V) disease. Over the past decade, immunosuppressive therapies have significantly improved long-term outcomes, but the optimal therapy for LN remains to be elucidated. Cyclophosphamide-based regimens, given concomitantly with corticosteroids, have improved survival significantly. Even though many patients achieve remission, the risk of relapse remains considerably high. Other treatments include hydroxychloroquine, mycofenolate mofetil, and biologic therapies such as Belimumab, Rituximab, and Abatacept. In this paper, we provide a review of LN, including pathogenesis, classification, and clinical manifestations. We will focus, though, on discussion of the established as well as emerging therapies for patients with proliferative and membranous lupus nephritis.     

Clinical course of lupus membranous glomerulonephritis in children

Background. Lupus nephritis (LN) is not a common renal disorder of childhood. Few pediatric nephrologists, except for those in a large center, see enough patients with LN to build up a substantial amount of experience. Membranous glomerulonephritis (MGN) associated with systemic lupus erythematosus (SLE), so-called lupus membranous glomerulonephritis (LMGN), is also rare in patients with LN. Methods. In 36 children with SLE, we investigated the clinical course of 4 children (1 boy and 3 girls) who showed MGN. Their mean age at presentation was 7.8 years and the mean follow-up period was 7.1 years. Results. Presenting symptoms were chance hematuria and proteinuria (H and P) in 2 children, edema in 1, and petechiae and thrombocytopenia in 1. The initial biopsy showed MGN in 3 children and diffuse proliferative glomerulonephritis in 1 child, in whom transition to MGN was observed. Two patients, who presented with chance H and P and showed MGN on the initial biopsy, later developed clinical signs of SLE, 3 and 5 years after presentation, respectively. During the course, all patients developed nephrotic syndrome, but at the last follow-up, H and P was detected in 1 child and proteinuria in 1 child. Urinalysis results were normal in 2 children. No patient had nephrotic syndrome or developed renal failure. Conclusions. The clinical course of LMGN in the 4 children seemed to be favorable. Two patients with MGN developed clinical signs of SLE several years after the renal manifestation. Received: May 10, 2000 / Accepted: March 10, 2001     

Ⅴ型狼疮肾炎的诊断与治疗

系统性红斑狼疮(SLE)是最常见的自身免疫性疾病,狼疮肾炎(LN)是SLE患者临床较常见且严重的并发症,至少50%以上的SLE患者临床上有肾脏受累的证据。Ⅴ型狼疮肾炎,又称膜性狼疮肾炎,在肾活检确诊LN中的比例为8%～20%。目前Ⅴ型LN的治疗尚无统一方案。所有Ⅴ型LN患者都应尽早开展以减少蛋白尿、控制血压、降低血脂、抗凝治疗为主的非免疫抑制治疗,其中肾素-血管紧张素系统阻断剂起重要作用。伴有严重蛋白尿、肾功能损害或非免疫抑制治疗无效的患者,需接受免疫抑制治疗,具体方案为糖皮质激素联合硫唑嘌呤或烷化剂或钙调磷酸酶抑制剂或吗替麦考酚酯。免疫抑制治疗的方案选择及疗效仍需大样本临床研究进一步证实。     

Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up.

BACKGROUND: Whether corticosteroid and immunosuppressive therapy may be safely withdrawn in patients with proliferative lupus nephritis is still unclear. METHODS: In 32 patients with biopsy-proven proliferative lupus nephritis previously put into remission, therapy was gradually tapered off. RESULTS: When immunosuppressive therapy was stopped (median: 38 months; 25th-75th percentile: 24-81 months, after biopsy), 24 patients were in complete remission and eight had a median proteinuria of 1.05 g/24 h (25th-75th percentile: 0.91-1.1 g/24 h) with normal renal function. After stopping therapy, patients were followed for a median of 203 months (25th-75th percentile: 116-230 months). Fifteen patients (Group 1) never developed lupus activity. The other 17 patients (Group 2) developed lupus exacerbations in a median of 34 months (25th-75th percentile: 29-52 months) after stopping therapy and were re-treated. The only significant differences between the two groups were the longer median durations of treatment, 57 months (25th-75th percentile: 41.5-113.5 months) vs 30 months (25th-75th percentile: 18-41 months; P<0.009), and remission, 24 months (25th-75th percentile: 18-41) vs 12 months (25th-75th percentile: 7-20 months; P<0.02), before stopping therapy in Group 1 than in Group 2. At last follow-up, 12 patients of Group 1 were in complete remission, two had mild proteinuria and one had died. In Group 2, one patient died, 14 were in complete remission, one had mild proteinuria and in another patient serum creatinine doubled. CONCLUSIONS: Some patients with severe lupus nephritis who enter stable remission can be maintained without any specific treatment for many years. Those patients who have new flares can again go into remission with an appropriate treatment. The longer the treatment and remission before withdrawal, the lower the risk of relapse.     

Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis

Background: The aim of the present study was to evaluate the efficacy of mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Methods: Forty‐four patients from eight centres with newly diagnosed lupus nephritis World Health Organization class III or IV were randomly assigned to either mycophenolate mofetil (MMF) 2 g/day for 6 months or intravenous cyclophosphamide (IVC) 0.75–1 g/m² monthly for 6 months in addition to corticosteroids. Results: Remission occurred in 13 out of 25 patients (52%) in the IVC group and 11 out of 19 patients (58%) in the MMF group (P = 0.70). There were 12% in the IVC group and 26% in the MMF group that achieved complete remission (P = 0.22). Improvements in haemoglobin, the erythrocyte sedimentation rate, serum albumin, serum complement, proteinuria, urinary activity, renal function and the Systemic Lupus Erythematosus Disease Activity Index score were similar in both groups. Twenty‐four follow‐up renal biopsies at the end of therapy showed a significant reduction in the activity score in both groups. The chronicity index increased in both groups but was only significant in the IVC group. Adverse events were similar. Major infections occurred in three patients in each group. There was no difference in gastrointestinal side‐effects. Conclusions: MMF in combination with corticosteroids is an effective induction therapy for moderately severe proliferative lupus nephritis.     

Minimal change disease in systemic lupus erythematosus

We report the clinical and pathologic findings in 7 patients with systemic lupus erythematosus and minimal change disease. All 7 patients presented with full nephrotic syndrome including peripheral edema, nephrotic range proteinuria (mean 9.6 g/day), and hypoalbuminemia (mean 1.8 g/dl). In all cases, renal biopsy revealed diffuse foot process effacement in the absence of significant peripheral capillary wall immune deposits, findings consistent with minimal-change disease. In addition, 5 cases displayed mesangial electron-dense deposits, with or without associated mesangial proliferation, consistent with underlying lupus nephritis class II. In all cases, steroid therapy induced a rapid remission of nephrotic syndrome. Minimal change disease is an underrecognized and readily reversible form of nephrotic syndrome in systemic lupus erythematosus. Because it may occur superimposed on mild mesangial proliferative lupus nephritis, this entity may be misinterpreted as an atypical presentation of lupus nephritis class II. Proper recognition of this entity requires careful integration of the renal biopsy immunofluorescence and electron microscopic findings.     

Role of intravenous cyclophosphamide in lupus nephritis patients with renal impairment

Summary: Twenty-three patients with lupus nephritis (21 diffuse proliferative glomerulonephritis and two with focal proliferative glomerulonephritis) with impaired renal functions were evaluated for their response to pulse cyclophosphamide. Diagnosis of lupus nephritis was based on American rheumatism association criteria or on the basis of renal manifestations with high anti dsDNA antibody titres. Cyclophosphamide was given in dosage of 900mg/m² as infusion in 500 mL of 5% dextrose (reduced by 25% if serum creatinine was more than 6 mg/dL) once every month for 6 months then 3 monthly for a minimum of 3 years. Response was defined by 24h protein excretion less than 500mg and serum creatinine less than 1.4mg/dL. Nine patients (group I) had normal function (serum creatinine 1.16 ± 0.21mg/dL) and 14 patients (group II) had impaired renal function at presentation (serum creatinine 3.72 ± 4.06 mg/dL). Both groups were compared for response to therapy. All patients in group I were in complete remission at last follow up of 44.6 ± 8.3 months (serum creatinine 1.14 ± 0.2mg/dL, 24h proteinuria 0.3 ± 0.3g). While in group 2, 13 patients showed improvement. Two patients were in complete remission, seven in partial remission, one patient died and four patients had mild renal failure at last follow up of 40.2 ± 10.4 months (serum creatinine 1.81 ± 0.74, 24h proteinuria 2.19 ± 2.54g). the side effects of therapy included infection, transient leucopenia and vomiting. We conclude that intravenous (I.V) cyclophosphamide is an effective therapy in severe lupus nephntis with renal impairment.     

Role of RAS inhibitor in the treatment of lupus nephritis with thrombotic microangiopathy

Objective To investigate whether RAS inhibitors can improve renal function in the treatment of lupus nephritis (LN) with thrombotic microangiopathy (TMA). Methods A total of 15 LN patients with TMA proven by renal pathology, from January 2000 to December 2013 in PUMCH, were included. The serum creatinine (Scr) and blood pressure (BP) before and after using RAS inhibitors were analyzed. Results (1)Male/female ratio was 1∶14. All of the patients had renal dysfunction, and median peak value of Scr was 396 μmol/L (160～643 μmol/L). 5 cases (33.3%) required acute dialysis during hospitalization. Hypertension occurred in 15 patients, while 6 cases (40.0%) were diagnosed malignant hypertension. (2) Anemia and thrombocytopenia occurred in 15 and 14 cases, respectively. Three cases (20.0%) were diagnosed MAHA definitely and 5 cases (33.3%) were diagnosed MAHA probably. (3) Renal biopsy showed class Ⅱ in 1 case, Ⅲ in 4 cases, Ⅳ-(G) in 2 cases, IV(S) in 5 cases and IV+V in 3 cases. Active lesions were predominant in both glomeruli and renal vasculopathy. (4) All the patients received steroid and immunosuppressive therapy, of whom 9 cases were given steroid pulse therapy. Thirteen cases received cyclophosphamide, and the rest 2 cases received cyclophosphamide and mycophenolate. After steroid pulse therapy, there were only 5 patients (55.6%) who got decreased Scr. In 13 patients (86.7%), hypertension was ameliorated and Scr decreased within one week after implementing RAS inhibitors, which fell medianly 15.8% and 17.0%, respectively. (5) Eleven of the 15 patients were followed from 8 to 135 months (median 32 months), and the other 4 patients were lost. Five cases who was on dialysis during hospitalization became independent of renal replacement therapy, while the other cases also got improved renal function. Conclusions Patients of LN with TMA who develop AKI and refractory hypertension should be treated with RAS inhibitors. Improved renal survival and successful discontinuation of dialysis are possible benefits when RAS inhibitors are used to treat LN with TMA.     

Lupus nephritis in childhood: a review of 53 patients followed at a single center

We retrospectively evaluated the clinical and histopathological features, treatment modalities, and outcome of 53 children and adolescents with biopsy-proven lupus nephritis (LN), followed between September 1983 and September 2001. The mean age (±SD) at the time of diagnosis of systemic lupus erythematosus (SLE) was 12.9±2.6 years and the mean follow-up from the time of biopsy was 4.8±3.4 years. At the time of biopsy, all 53 patients had proteinuria, 21 (40%) had nephrotic syndrome, and 14 (26%) had impaired renal function. Class IV nephritis, observed in 34 (64%) patients, was the most frequent histopathology on initial renal biopsy. The patients with class IV LN had a significant tendency to develop hypertension (P=0.04) and nephrotic syndrome (P=0.027), and a lower mean glomerular filtration rate (P=0.000). Based on the renal histopathology and clinical presentation, patients were treated with corticosteroids alone or combined with azathioprine or with intravenous cyclophosphamide. Plasmapheresis or cyclosporine was used in 4 and 1 patient, respectively. Follow-up biopsies, performed in 13 patients, showed no change in 6 patients, were progressive in 4, and regressive in 3. On final clinical evaluation, renal disease was in complete or partial remission in 42 of 53 patients (80%), 4 had clinically active disease but with normal renal function, and 7 (13%), all with WHO class IV LN, were classified as having an adverse outcome, i.e., either preterminal (2) or terminal (4) renal failure or death (1). Five-year kidney and patient survival rates from the time of biopsy to the endpoints of terminal renal failure or death were 88.6% and 98.1%, respectively, in the whole group, and 82.4% and 97.1%, respectively, in the WHO class IV group. Nephrotic syndrome and class IV nephritis at initial biopsy were the only parameters significantly associated with adverse outcome in our study group. There was no association with gender, age, hypertension, impaired renal function, anemia, increased morphological index scores, and treatment modalities. We conclude that clinical and histopathological features of LN and treatment regimens in our study do not differ markedly from those in most pediatric series. However, the 5-year kidney and patient survival rates are among the best reported in recent pediatric series. The prognosis of LN is primarily dependent on the histopathological lesions.In memory of Professor Miodrag Sindji (1927–2000), nephropathologist, our teacher and friend     

Apoptosis and proliferating cell nuclear antigen in lupus nephritis (class IV) and membranoproliferative glomerulonephritis

BACKGROUND: The role of apoptosis in the pathogenesis of renal diseases has not been clearly established. Proliferating cell nuclear antigen (PCNA) is also a proliferation marker. In this study, we investigated the relationship between clinical course and PCNA apoptosis on baseline renal biopsy in patients with Lupus nephritis (LN) and membranoproliferative glomerulonephritis (MPGN). METHODS: Thirty-nine patients with proliferative glomerulonephritis [lupus nephritis (LN)[21] and MPGN[18]] were included in this study. PCNA and apoptosis on renal biopsies were detected by immunohistochemical and terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) methods, respectively. We calculated the ratios of intraglomerular apoptotic cells and PCNA positive cells per glomeruli, and total numbers of apoptotic tubular cells and PCNA positive tubular cells among the 100 tubular cells, and PCNA positive cell and apoptotic cell on two different tubulointerstitial areas (40 x 10). RESULTS: In LN: Apoptotic indexes of glomerulus and tubulus were 1.08+/-0.49 and 3.71+/-1.38, respectively. PCNA positivities were found at 16.76+/-11.34%, 46.57+/-22.54%, and 40.28+/-23.14% on glomerulus, tubulus, and interstitium, respectively. The activity index was 11.23+/-3.41, and the chronicity index was 3.81+/-1.99. In MPGN: Apoptotic indexes were found at 0.83+/-0.25 and 3.55+/-1.75 on glomerulus and tubulus, respectively. PCNA positivities were found at 21.33+/-18.42%, 35.5+/-25.99%, and 34.66+/-26.84% on glomerulus, tubulus, and interstitium, respectively. In controls, apoptosis was not found. In LN: PCNA positivity on tubulus and interstitium were correlated with the activity index (r = 0.768, p < 0.001, r = 0.721, and p < 0.001, respectively). Glomerular PCNA and apoptosis on interstitium and glomerulus were not correlated with the activity index. The activity index also was not correlated with creatinine clearance and daily proteinuria (p = 0.35 for both). At the end of the first year, patients with recovered or stabilized renal function had higher interstitial and tubular PCNA than others in G1 and G2. CONCLUSION: It can be said that expression of PCNA on renal biopsy was correlated with activity indexes in LN. PCNA may be a prognostic indicator in MPGN and LN. However, apoptosis does not have a predictive value for MPGN and LN.     

Mycoplasma pneumoniae-associated nephritis in children

 Mycoplasma pneumoniae infection is a rare cause of acute nephritis. Six children (2 girls) aged 5–10 years, admitted for nephritis, had serological tests showing recent Mycoplasma pneumoniae infection. The diagnosis of Mycoplasma pneumoniae infection was based on the presence of serum IgM, detected either by immunofluorescence (IF) (n=1) or enzyme-linked immunosorbent assay (n=5). Four children had a renal biospy, with analysis of parenchymal Mycoplasma pneumoniae components by indirect IF and polymerase chain reaction. Extrarenal symptoms were: respiratory (n=3), ear, nose, and throat (n=2), gastrointestinal (n=3), hepatic (n=1), neurological (n=1), articular (n=1), and hematological (n=3). The patients presented with acute nephritis (1 had a nephrotic syndrome) or with acute renal failure and proteinuria. Pathological findings included type 1 membranoproliferative glomerulonephritis (MPGN, n=1), proliferative endocapillary glomerulonephritis (n=2), and minimal change disease (n=1). The patient with type 1 MPGN progressed rapidly towards end-stage renal failure because of a congenital solitary kidney. Among the patients with endocapillary glomerulonephritis, 1 relapsed 6 months later and remained proteinuric, while the other recovered, as did the child with minimal change disease. The search for Mycoplasma pneumoniae antigens and nucleic acids in renal tissue was negative. However, the absence of the microorganism in the kidney is a common feature of post-streptococcal glomerulonephritis. We conclude that Mycoplasma pneumoniae is a rare yet potential cause of acute glomerulonephritis. Received: 13 September 1996 / Revised: 16 June 1998 / Accepted: 18 June 1998     

Clinicopathology of childhood-onset renal systemic lupus erythematosus

AIMS: To determine the clinicolaboratory renal manifestations; glomerular, extra-glomerular histopathologic lesions; renal tubular dysfunction (RTD) frequency and outcome of a short-term renal follow up in Nigerian children with systemic lupus erythematosus (SLE). METHODS: A non-randomized prospective study of consecutive cases of childhood-onset SLE with nephropathy was conducted. Baseline/follow-up clinicolaboratory data were collected. Each patient was followed up for 12 months. RESULTS: Seven of the 11 children studied were girls. The median age at diagnosis was 11.0 years. Median diagnosis time interval (1.9 years) and median time of renal disease onset (1.0 year) were similar. Hypertension, nephrotic syndrome and acute renal failure (ARF) occurred in 45.5%, 54.5% and 63.7% of the patients, respectively. The glomerular lesions were non-proliferative lupus nephritis (LN) in 9.0% (class II LN); focal (class III LN) and diffuse (class IV LN) proliferative LN (PLN) in 27.0% and 64.0%, respectively. Tubulointerstitial nephritis (TIN, 91.0%) and RTD (64.0%) were common. ARF (P = 0.033) and RTD (P = 0.015) were significantly associated with severe TIN. Complete renal remission rate at end-point was 71.4%. Relapse and renal survival rates were 14.3% and 86.0%, respectively. RTD was persistent in 43.0%. CONCLUSION: Renal function disorders, diffuse PLN and extra-glomerular lesions were frequent. Significant association of ARF and RTD with severe TIN in this series suggests the need for early renal tubular function (RTF) assessment in our SLE patients. Deranged RTF may be marker of severe TIN in SLE warranting early confirmatory renal biopsy and aggressive interventional treatment.