Background: Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus that can be fatal if left untreated. The causes and prognostic predictors of mortality in LN have been well studied in developed countries but evidence is lacking for developing countries. The objective of this study was to investigate the causes and predictors of mortality in a cohort of Malaysian patients with biopsy-proven LN.
Methods: We retrospectively studied all patients with biopsy-proven LN treated in Sarawak General Hospital during the period of 2000-15. Demographic data, clinical features and outcomes were collected. Cox regression analysis was carried out to determine the independent predictors of mortality.
Results: There was a total of 250 patients with 259 renal biopsies available for our analysis. Our patients were of multi-ethnic origins with a female predominance (90%). Their mean ± standard deviation age was 37.7 ± 12.8 years. The patients had a mean disease duration of 135.6 ± 81.9 months. Nephrotic syndrome was the most common presentation (29.6%) and acute renal failure was evident at initial presentation in 16% of patients. Class IV LN was the predominant biopsy class within the cohort (66.8%). The majority of patients achieved remission (81.2%) and had normal renal function (83.9%) at the last follow-up. The 5-, 10-, 15- and 20-year survival rates for our cohort were 93%, 88%, 82% and 77%, respectively. There were 37 deaths (14.8%), of which the main causes were: infection and flare (52.7%), infection alone (25.0%) and other causes (22.3%). Independent predictors of mortality in our cohort of LN patients were: the presence of acute kidney injury at presentation [hazard ratio (HR) 3.41; confidence interval (CI) 1.50-7.76], failure to achieve remission at 1-year post-induction therapy (HR 2.99; CI 1.35-6.65) and non-compliance with treatment (HR 1.89; CI 1.22-2.96). Age, ethnicity, class of LN and type of immunosuppressant used were not predictive of mortality.
Conclusions: Survival and renal outcomes in our LN cohort were comparable to most LN studies reported worldwide. Both flare and infection remained the main causes of death. The presence of acute renal failure at presentation, failure to achieve remission at 1 year post-treatment and non-compliance with treatment were independent prognostic predictors of mortality in LN.
A 12-year-old Congolese girl presented with acute renal failure, edema, hypertension, hemoptysis, hematuria, and proteinuria after a history of throat infection. Renal ultrasound showed kidneys of normal size, with increased echogenicity of the cortical parenchyma and decreased corticomedullary differentiation. Other additional investigations showed pancytopenia with decreased complement (low C3 and C4). Antinuclear antibodies were strongly positive, including anti-double stranded DNA. Renal biopsy confirmed severe grade IV lupus nephritis. She was treated with high-dose steroids, mycophenolate mofetil and hydroxychloroquine, in addition to hemodialysis. After one week of intensive treatment, diuresis recovered and dialysis could be stopped after six sessions. We describe an uncommon case of severe lupus nephritis, presenting with terminal renal failure. Since the rarity of this disease presentation, other more common diagnoses have to be considered. Once the diagnosis of lupus nephritis is established, a choice has to be made between the different induction treatment protocols. The patient's ethnic background and other supportive therapies, such as the need for dialysis, can help to make this choice.
In the 12-year period between 1974 and 1985, 19 children aged between 8 and 12 years with systemic lupus erythematosus (SLE) were seen in the Department of Paediatrics, University Hospital, Kuala Lumpur. A preponderance of females (M:F = 1:2.8) and ethnic Chinese was evident. Renal biopsies revealed a wide Iange of renal morphology, including minimal change glomerulonephritis, focal proliferative glomerulonephritis, diffuse proliferative glomerulonephritis with varying degrees of severity and membranous glomerulonephritis. The majority (15) of patients had clinical SLE at the time of renal biopsy, of whom 4 were also grossly nephrotic. In the remaining 4 patients a diagnosis of SLE was made after further investigation for nephrotic syndrome (2) and acute nephritis (2). The pattern of renal pathology in childhood lupus nephritis appears not to differ significantly from adults.
Key words: Systemic lupus erythematosus, glomerulonephritis
Ki-67 expression in diffuse proliferative lupus nephritis, WHO Class IV, was compared against normal controls to establish that cellular proliferation is involved in the production of glomerular hypercellularity. Twenty-three histologically confirmed WHO Class IV lupus nephritis and 23 normal control renal tissue were immunohistochemically stained with a polyclonal antibody to Ki-67 (Dako) using the peroxidase labelled streptavidin bioitin kit (Dako). There were 20 females and 3 males, with 17 Chinese and 6 Malays in the WHO Class IV lupus nephritis group. Ages of patients ranged between 10-56 years with a mean of 31.9 years. The normal controls, 20 males and 3 females, and ethnically 9 Indians, 7 Malays, 2 Chinese, and 5 foreign nationals (4 Indonesians and 1 Bangladeshi), had an age range between 15-33 years (mean = 23.3 years). Sixteen (69.6%) WHO Class IV lupus nephritis and 8 (34.8%) normal controls demonstrated Ki-67 immunoreactivity in at least 1 glomerulus (p<0.05). Of the 256 WHO Class IV lupus nephritis non-sclerosed, glomeruli studied, 37 (14.5%) were Ki-67 immunopositive compared with normal controls where 16 (0.7%) of 2159 glomeruli demonstrated Ki-67 (p< 0.01). Cellular proliferative activity, as evidenced by Ki-67 expression, was significantly increased in WHO Class IV lupus nephritis confirming that cell proliferation contributes to glomerular hypercellularity.
OBJECTIVES: To determine the pattern of renal histology, clinical outcome of children with lupus nephritis and to identify any associated risk factors predicting renal failure in these children.
METHODS: Retrospectively, 27 children under 16 years of age with lupus nephritis who had renal biopsies done at Sultanah Aminah Hospital Johor, Malaysia from 1994 to 2002 were studied. The renal histology was graded according to WHO classification system (1982). The medical records, laboratory data and the clinical outcome of the patients were studied.
RESULTS: There were 24 cases of WHO Class IV, two cases of WHO Class II and a case of WHO Class V. Twenty children were in the good renal outcome group while six children progressed into the poor renal outcome group and required renal replacement. One child was lost to follow-up. All six children in the poor renal outcome group had WHO Class IV histology. The 5-year patient and renal survival rates were 84% and 75%, respectively. Age, sex, activity and chronicity indices in the renal histology, anaemia, elevated serum creatinine, depressed levels of C3 and C4, heavy proteinuria or presence of urinary active sediments were not associated with progression to renal failure.
CONCLUSIONS: Presently, children with lupus nephritis appeared to have better patient and renal survival rates. Assessment of renal histology in these children was important for diagnosis, treatment and probably prognosis. In this study, there was a 25% incidence of loss of renal function over 5 years in children with WHO Class IV renal histology.
Between 1980-1986, 219 renal biopsies were performed on patients with lupus nephritis (LN) presenting at the General Hospital, Kuala Lumpur. There were 172 (78.5%) females and 47 (21.5%) males. The ethnic distribution of 48.4% Malays, 46.1% Chinese and 5.5% Indians reflected their proportional composition in the general population. Peak incidence (40.6%) of cases occurred in the third decade of life (20-29 group) followed by 26.5% and 20.1% in the second and fourth decades respectively. The median age was 24 for females and 27 for males. In both sexes, nephrotic syndrome was the commonest mode of presentation (62.2%) followed by proteinuria (20.5%). Acute oliguric renal failure occurred in 11 patients (5%) and 8 of these showed crescentic glomerulonephritis with more than 50% crescents. The commonest histological picture was diffuse proliferative LN (WHO Stage IV-44.7%) which included 70% (19/27) of those with crescentic disease. This was followed by membranous LN (28.8%) of which 6 (all males) had crescentic disease. 7 (12.3%) of our patients had crescentic nephritis with a female to male distribution of 14: 13, suggesting either more aggressive disease or delayed diagnosis in males.
Key words - Renal biopsies, lupus nephritis, nephrotic syndrome, proteinuria.
Ibuprofen is a nonsteroidal anti-inflammatory drug that is used widely in treating pain, fever, and inflammation. Its side effects are mainly due to acute renal impairment and gastric discomfort. We hereby report a rare case of Henoch-Schönlein purpura nephritis secondary to ibuprofen consumption which has not been reported in literature before.
BACKGROUND: In the past, lupus nephritis was histologically classified according to the 1995 WHO Classification. With the introduction of the 2003 ISN/RPS Classification, many nephropathology services converted to this new classification. This study was undertaken to compare both classification systems in a single centre practice.
METHODS: 103 consecutive adequate renal biopsies initially reported as lupus nephritis in the Department of Pathology, Faculty of Medicine, University of Malaya were reassessed using the criteria of both the 1995 WHO Classification and the 2003 ISN/ RPS Classification.
RESULTS: The relative prevalence for each class using the WHO Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (60.2%), Class V (20.4%), Class VI (2.9%) while the prevalence using the 2003 ISN/RPS Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (61.2%), Class V (21.3%), Class VI (1%). Both classifications were essentially comparable with regards to Classes I, II and III. The differences in Classes IV, V and VI were significant in potential to alter patient management. The identification of segmental lesions (Class IV-S) over and above a global nephritis (Class IV-G) deserves more focused clinicopathological studies to gauge whether these groups have different clinical manifestations and outcomes. With regards Class V, the ISN/RPS system, by requiring that all mixed classes be stipulated in the diagnostic line, minimizes the chances of patients missing out on additional treatment. The ISN/ RPS system has stricter criteria for Class VI, which again minimizes patients missing out on therapy. On the whole, the ISN/RPS system is more user-friendly as criteria are more clearly defined which translates to more benefits to patient care.
Study site: Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
FcgammaRIIs are the most widely distributed of the Fcgamma receptor family and play an important role in the clearance of immune complexes. Evidence that the FcgammaRIIa-R131 allotype is less able to process and clear immune complexes effectively suggests that this may be a disease susceptibility factor for systemic lupus erythematosus (SLE). Data from studies published thus far do not agree on the potential role of FcgammaRIIa polymorphism in the genetics of SLE. Most studies in fact show no evidence for any correlation between polymorphism of FcgammaRIIa and risk for SLE. However, it remains to be determined whether FcgammaRIIa polymorphism may play a critical role in certain groups of patients, especially in those of differing ethnic background. Polymorphism of FcgammaRIIa may also be important in determining disease phenotype, and identification of this influence may have important implications in patient care and in identifying patients for more aggressive therapy.
In a review of 112 patients with SLE nephritis treated between 1976 and 1982, 31 were known to have died. Renal failure (32.2%) was the commonest cause of death. Gastrointestinal haemorrhage (16%), infections (12.8%) and central nervous system involvement (6.5%) were important causes of death. Thirteen out of 17 patients dying in the presence of renal failure had initially presented with renal impairment. Renal biopsies in 16 patients who have died showed diffuse proliferative glomerulonephritis in all except 1 patient, and uraemia was the commonest cause of death in these patients. Pregnancies terminating in abortions were followed by complications in 5 patients. Discontinuation of steroid therapy by patients was followed by complications, and ended in death in 6 patients.
Thirty-eight cases of lupus nephritis, all satisfying the American Rheumatism Association criteria for diagnosis of systemic lupus erythematosus (SLE), with renal involvement and biopsy were immunohistochemically studied for the expression of HLA-DR (DAKO: HLA-DR/alpha, TAL.1B5), one of the three known families belonging to the class II major histocompatibility complex (MHC), using a standard streptavidin-biotin-peroxidase method. 20 nephrectomies performed for renal trauma and tumours constituted the normal controls. Of the lupus nephritis cases, 34 were females and 4 males. Ethnically, 20 were Chinese, 13 Malay, 4 Indian and 1 of indigenous origin. Their ages ranged from 16 to 59 years (mean of 31 years). Histologically, 23 expressed World Health Organisation (WHO) class IV (diffuse proliferative), 10 WHO class V (diffuse membranous), 4 WHO class II (pure mesangiopathy) and 1 WHO class III (segmental and focal proliferative) nephritis. Activity scores ranged between 5 to 19 (mean = 8.6) and chronicity scored between 2 to 7 (mean = 3.2) on a standard scoring system. Similar to other studies, HLA-DR was expressed in the glomerular capillaries and peritubular capillaries of all and mesangium, tubules (proximal, distal and collecting), veins and arterioles of some normal controls. Interestingly, HLA-DR expression was noted in the arteries of 25% of the normal controls, a finding hitherto not reported. The frequency of lupus nephritis cases expressing HLA-DR in the various anatomical components did not differ significantly from the normal controls except that HLA-DR expression in arteries and arterioles was seen at a significantly increased frequency (p < 0.01) in lupus nephritis. This increased expression did not correlate with the WHO class, activity or chronicity scores. It therefore appears that MHC class II shows increased expression in the arterial system of lupus nephritis kidneys. The significance of this is unclear but could be related to heightened (gamma-interferon activation which may be a de novo phenomenon or result of T cell proliferation and activation in SLE.
The best therapeutic choice in the treatment of lupus nephritis remains open to debate. In addition, there have been little data on the treatment of lupus nephritis in Asian patients. The objective of this study was to look at the response rate and complications of treatment given for lupus nephritis in a group of South East Asian patients with systemic lupus erythematosus (SLE). This was a retrospective, cross-sectional study of 103 patients with lupus nephritis. Detailed analysis was done on 58 patients with Class IV disease. The median time to remission was 12.1 months for azathioprine (AZA), 15.01 months for oral cyclophosphamide (CPM) and 15.25 months for intravenous (i.v.) CPM. The percentage of patients achieving remission after the first course of treatment was 42.9% with AZA, 83.3% with oral CPM and 90.9% with i.v. CPM. Overall, 41/58 (70.7%) of patients went into remission following the first course of treatment. Seventeen (41.5%) subsequently relapsed, requiring a second course of treatment. Fifty-two (50.5%) of all patients had drug-related complications from their treatment. The most frequent complication for the group was amenorrhoea (23.3% of all patients, 40% of those who had CPM previously), which was significantly more frequent in patients given CPM. In conclusion, more patients achieve remission when treated with CPM compared with AZA alone but this is associated with a higher complication rate, especially amenorrhoea.
In view of a high prevalence of hepatitis B virus infection in the Malaysian population, indirect immunofluorescence examination for hepatitis B surface antigen (HBsAg) was routinely performed on renal biopsy specimen at the University Hospital, Kuala Lumpur, over a 3-year period. Examination of renal tissue from 259 patients, including 47 with systemic lupus erythematosus (SLE), revealed 43 cases with HBsAg in glomerular immune complexes. A significantly high proportion (30/43) of these were SLE patients. The deposits were granular in nature, situated in both the capillary walls and mesangium and associated with immunoglobulin deposition. Morphological patterns of lupus nephritis involved were focal proliferative (one case), diffuse proliferative (23 cases) and membranous (six cases). None of these patients showed clinical evidence of liver disease. The significance of these findings remains uncertain, but the possibility exists that the hepatitis B virus may have a role in the pathogenesis of SLE in the tropics where both SLE and HBs antigenaemia are common.
Tuberculosis (TB) and its association with rheumatic diseases have been widely recognised. Occurrence of multifocal skeletal involvement constitutes <5% of all skeletal TB cases. We present a Malay patient with multifocal osteoarticular TB (OATB). A 35 year-old SLE woman with background usage of corticosteroid therapy and Azathioprine presented with lupus nephritis flare. Renal biopsy revealed diffuse proliferative lupus nephritis and intravenous (IV) Cyclophosphamide 0.5 g/m2 (850 mg) was initiated. One week later, patient complained dorsum of left hand and right knee swelling. On physical examination, patient was afebrile and the left hand swelling was cystic in consistency while right knee was warm and tender. Erythrocyte Sedimentation Rate (ESR) was 50 mm/hr and C-Reactive Protein (CRP) was 9.4 mg/L. Her Mantoux test was positive with 20 mm induration. Wrist radiograph and chest radiograph was normal. Musculoskeletal ultrasound showed 4th extensor compartment tenosynovitis with Doppler signal and right knee effusion with synovial proliferation. Extensor tenosynovectomy and right knee aspiration was performed. Left hand excised tissue and right knee synovial fluid for acid-fast bacilli (AFB) stain, TB PCR, bacterial and fungal cultures were negative. Urgent histopathological examination of the excised tissue showed necrotising granulomatous inflammation. Patient was empirically started on TB treatment and subsequent mycobacterial culture confirmed the diagnosis of TB. The joints swelling resolved after one month of TB treatment. Multifocal OATB is an infrequent form of extrapulmonary TB and diagnosing OATB requires high index of suspicion particularly in SLE patient on immunosuppression. Prompt investigations are essential to the diagnosis of this rare condition for early initiation of anti-tuberculous therapy.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that is associated with lupus nephritis, initiated by the deposition of immune complexes in the kidney; subsequently, this induces the overexpression of cytokines. Lupus nephritis is known as one of the major clinical manifestations that affect the disease severity in SLE patients. An increased number of resident periglomerular and immune cells in the kidney has the potential to affect the equilibrium of different immune cell subsets, such as Th1, Th2, Th17, and Tregs, which may be central to the induction of tissue damage in kidney by exerting either proinflammatory or anti-inflammatory effects, or both. This equilibrium has yet to be confirmed, as new players such as IL-25 remain undiscovered. IL-25 is a cytokine of the IL-17 family, which stimulates Th2-mediated immune response when overly expressed. Thus, the aim of this research is to determine the plasma levels of IL-25 and Th2-associated cytokines (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) in SLE patients with (SLE-LN) and without lupus nephritis. Sixty-four (n = 64) SLE patients and fifteen (n = 15) healthy individuals were recruited. This study demonstrated that the IL-9, IL-10 and IL-25 had significantly increased expressions in SLE-LN, followed by SLE without LN, compared to healthy controls. Meanwhile, IL-5 and IL-6 had significantly reduced. No significant difference was observed with IL-13, while the level of IL-4 was undetectable. Furthermore, IL-9 and IL-10 were significantly correlated with the IL-25, and IL-25, IL-9 and IL-10 were positively correlated with the disease severity score, SLEDAI. In conclusion, IL-25 and its associated Th2 cytokines (IL-9 and IL-10) may be involved in SLE pathogenesis. These cytokines could be potential biomarkers in monitoring and predicting the disease severity during SLE pathogenesis.
Renal biopsy is essential in the management of renal parenchymal diseases. Thus far there is no publish report on the pattern of glomerulonephritis in Kelantan. We decided to establish the pattern of glomerulonephritis in Kelantan and use this information as our reference in future studies. Records of patients who had proven glomerulonephritis histologically were analysed. Their biological data, clinical presentation, etiology and clinicopathological pattern were studied. Where appropriate mean and standard deviation were calculated. A total of 74 biopsies were performed during the study period (between January 1991 and December 1993), out of which 72 biopsies (97.3%) were considered suitable for analysis. The male to female ratio was 1:1.1. Mean age at presentation was 27.6 +/- 12.2 years. Nephrotic syndrome was the commonest clinical presentation (65.3%). The main underlying cause was systemic lupus erythematosus (50%) followed by primary glomerulonephritis. Histologically, IgA nephropathy and minimal change disease were the main patterns among patients with primary glomerulonephritis while diffuse proliferative glomerulonephritis was the commonest pattern among patients with lupus nephritis. Hence the pattern of glomerulonephritis is similar to other reported series. The procedure is considered safe and has a high success rate.
OBJECTIVES: To investigate the prevalence of thickened carotid intima media thickness (CIMT) and its associated risk factors in patients with lupus nephritis (LN) who were in remission.
METHODS: This was a cross sectional study in which consecutive LN patients who were in remission and attending our Nephrology/SLE Clinic were included. Their demographic profile, traditional cardiovascular risk factors and treatment medications were evaluated by clinical interview and review of medical records. Carotid intima media thickness (CIMT) was measured using B Mode carotid ultrasonography. CIMT was considered to be abnormally thickened if it exceeded the 75th percentile matched for age-and sex-matched normal controls. The associated factors for thickened CIMT were examined.
RESULTS: A total of 39 patients with a mean remission duration of 29 ± 24.3 months and on a mean prednisolone dose of 9.10 ± 7.83 mg daily completed the study. Six patients (15.4%) had thickened CIMT. On univariate analysis, male gender, patient age, older age at diagnosis, higher serum CRP levels, greater proteinuria and higher mean cumulative azathioprine dose were associated with thickened CIMT (P<0.05). Lower mean cumulative doses of cyclosporine A (CyA) and mycophenolic acid (MPA) (P<0.05) each were associated with thickened CIMT. Using regression analysis, the associated factors of CIMT were older age at diagnosis and proteinuria.
CONCLUSIONS: Lupus factors particularly age at diagnosis and proteinuria were the associated factors of thickened CIMT. Larger prospective trials are indicated to confirm our findings.
We report a case of renal cell carcinoma diagnosed after a patient was treated successfully with intravenous cyclophosphamide for her active proliferative lupus nephritis (classes III and V). After the intravenous cyclophosphamide regimen, the patient was asymptomatic with persistent microscopic haematuria, and no proteinuria. The renal cell carcinoma was located on the left kidney; incidentally, this was where the initial renal biopsy was done to diagnose lupus nephritis.