Impact of focal segmental glomerulosclerosis over the past decade.

OBJECTIVE: This is a study on the demographics and clinical outcomes including the response to therapy of patients with focal segmental glomerulosclerosis (FSGS) over the past decade. MATERIALS AND METHODS: All histologically proven FSGS cases diagnosed between 2008 and 2018 were analyzed for their clinical, laboratory, and histological characteristics including treatment that could influence the disease progression and renal outcome of these patients. We used the Columbia Classification for FSGS for the renal biopsy. RESULTS: There were two subgroups of FSGS patients; those with nephrotic syndrome and those without nephrotic syndrome. Patients with FSGS with non-nephrotic syndrome had poorer survival rates compared to the nephrotic group. For those without nephrotic syndrome, the indices responsible for progression involved more tubular and blood vessel lesions in addition to glomerular pathology compared to those with nephrotic syndrome. Patients with FSGS with nephrotic syndrome responded to immunosuppressants more favorably compared to the non-nephrotic group, though both groups responded with decreasing proteinuria. The nephrotic group had a better 10-year long-term survival rate of 92 vs. 72% for the non-nephrotic group (log-rank 0.002). The 10-year survival for the whole group of FSGS patients was 64%. CONCLUSION: Our data suggest that in FSGS, one of the significant components of the disease is the vascular and tubular damage, apart from the underlying glomerular pathology, resulting in varying responses to therapy, and the difference is reflected in inherently poorer response to immunosuppressant therapy in those without nephrotic syndrome as opposed to those with nephrotic syndrome, who responded to immunosuppressant therapy (IST) with stabilization of renal function and had less blood vessel and tubular lesions.

Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways.

OBJECTIVE: To determine the efficacy of CXCL5 administration in lupus-prone MRL/lpr (Faslpr ) mice and elucidate its working mechanisms. METHODS: CXCL5 expression in blood (obtained from SLE patients and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real-time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. RESULTS: In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti-double-stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short-term (10 weeks) and long-term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5-mediated immunomodulation occurred by promoting energy production in renal-infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. CONCLUSION: We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.

Perivascular epithelioid cell tumour (PEComa): an unusual cause of painful defaecation.

Perivascular epithelioid cell tumours (PEComa) are rare tumours of mesenchymal origin. We report a 39-year-old patient who presented with painful defecation secondary to an anorectal mass. The diagnosis of anorectal PEComa was confirmed following excision and histopathological examination. We review the literature and discuss the management of this uncommon entity.

Native kidney biopsies in older adults: disease spectrum, long-term kidney and patient survival and safety.

PURPOSE: Patients undergoing kidney biopsy are increasingly older. We aimed to evaluate the clinical utility of kidney biopsy, long-term clinical outcomes, and safety of high-risk biopsies in older adults undergoing kidney biopsy in a multi-ethnic Southeast Asian cohort. METHODS: We performed a single-center retrospective study of older patients (age ≥ 60 years) who underwent native kidney biopsies between June 2011 and March 2015. The primary long-term outcome of interest was a composite of ESKD or death. The safety outcome of interest was post-biopsy bleeding in the high-risk subgroup, defined by serum creatinine > 150 µmol/l. RESULTS: Older adults accounted for 153 of 545 (28.1%) native renal biopsies performed. The median age of these older adults was 66.6 (IQR 63.0, 70.6) years. Kidney dysfunction was frequent and severe in this cohort, with 41.2% having eGFR < 30 ml/min/m2 and 71.2% having nephrotic-range proteinuria at presentation. A significant proportion (124 patients; 81.0%) had treatable diagnoses. Of these, 90 (72.6%) received immunosuppressive therapy. On Kaplan-Meier analysis, patients with pauci-immune glomerulonephritis (p = 0.004) and diabetic nephropathy (p = 0.005) were at a significantly increased risk of the composite outcome of ESKD or death. On multivariate analysis, older age and lower eGFR were independently associated with ESKD or death and ESKD alone. Lupus nephritis and diabetic nephropathy were independently associated with ESKD or death, while immunosuppressant therapy was associated with reduced ESKD alone. In the high-risk subgroup, post-biopsy bleeding occurred in 19 (22.8%) patients. Desmopressin use was not associated with reduced bleeding complications. CONCLUSION: Our study confirmed the utility of kidney biopsy in older adult patients for diagnosis and management, although risk counselling and close monitoring for bleeding complications is necessary.

Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN).

Multinational studies have reported monogenic etiologies in 25%-30% of children with steroid-resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi-gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one-third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1-14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8-11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co-existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent.

Breast-related extranodal Rosai-Dorfman disease presenting as subcutaneous masses with thick hyperechoic rim, with review of the literature.

Rosai-Dorfman disease (RDD) is a rare, idiopathic histiocytic proliferative disorder. We report two cases of RDD related to the breast which showed common distinctive imaging characteristics which can help facilitate accurate diagnosis and appropriate management.

Evolution of IgA nephropathy in Singapore over four decades and a comparison of two cohorts from the first and fourth decade.

OBJECTIVE: In this study, we trace the changes in the clinical and histological pattern of IgA nephritis (IgAN) in Singapore as it has evolved over 4 decades and compare the clinical, demographic, histological, and renal outcome of patients with IgAN from the 1st decade and the 4th decade. MATERIALS AND METHODS: This is a retrospective study of all histologically proven IgAN diagnosed between 1976 and 2018. Clinical, laboratory, and histological characteristics between the 1st and the 4th decade, including treatment which could influence the disease progression and renal outcome of these two groups, were compared. We used the Oxford classification to compare the renal biopsy changes for these 2 decades as we were able to retrieve 125 renal biopsy tissues for the 1st cohort of IgAN studied in the 1970s for the comparative study. RESULTS: The commonest clinical presentation throughout the first 3 decades was asymptomatic hematuria and proteinuria (63, 52, and 49%, respectively). In the 4th decade, nephrotic syndrome (31%) was the commonest followed by asymptomatic hematuria and proteinuria (30%), hypertension (21%), and chronic renal failure (11%). The data showed that treatment can modify the Oxford MEST - Crescent scores. Renin-angiotensin system (RAS) blockers modified the S scores, immunosuppressants modified the T and C scores, and combination therapy with RAS blockers and immunosuppressants modified the E, S, and T scores. CONCLUSION: The Oxford MEST classification offers a robust and expressive classification for early and late disease progression with respect to the development of end-stage renal disease (ESRD). E and S seem to be indices of continuing disease activity with progressive glomerulosclerosis, probably still amenable to therapy, but T was a predictive indicator for those destined for ESRD and no longer amenable to therapy.

The Value of Renal Biopsy in Non-Insulin-Dependent Diabetes Mellitus in Singapore over the Past Two Decades.

OBJECTIVE: This study on the prevalence of diabetic nephropathy (DN) and coexistence of non-diabetic renal disease (NDRD) in a cohort of 255 non-insulin-dependent diabetes mellitus (NIDDM) patients aims to determine the value of performing renal biopsies in these patients and elucidate the factors which could affect their progression to end-stage renal disease (ESRD). METHODS: Among 255 NIDDM patients, 93 had DN alone, 69 had NDRD alone, and the remaining 93 had DN plus NDRD (mixed group). The indications for renal biopsy were based on clinical suspicion of superimposed NDRD, including heavy or rapidly increasing proteinuria, renal impairment even though diabetes is of relatively short duration, rapidly declining renal function, and presence of hematuria with dysmorphic red blood cells suggesting presence of glomerulonephritis. RESULTS: The following were predictors of ESRD: high systolic BP at biopsy, longer duration of diabetes, heavy proteinuria, and presence of diabetic retinopathy. Comparing patients in the NDRD group with the DN group and the mixed group, the NDRD group had lower serum creatinine and higher eGFR with lower urinary proteinuria and higher serum albumin at presentation and on follow-up. Kimmelstiel-Wilson nodules were associated with a poorer prognosis leading to a higher occurrence of ESRD among patients with DN. CONCLUSION: Renal biopsy is of value in indicating the prognosis of NIDDM patients with DN based on the diabetic lesions. For NIDDM patients with atypical course and suspicion of associated NDRD, a renal biopsy would enable us to diagnose the underlying NDRD and offer appropriate therapy. Most nephrologists would consider renal biopsy for an NIDDM patient based on clinical indications like atypical clinical course and suspicion of an associated NDRD, but they would not perform a routine renal biopsy like for a CKD patient, unless it is for a research indication.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

A Global Evolutionary Trend of the Frequency of Primary Glomerulonephritis over the Past Four Decades.

OBJECTIVE: The pattern of glomerulonephritis (GN) in Singapore is compared with that of 19 other countries to review changing trends in the evolution of GN in Asian, Eastern, and Western countries. METHOD: Three thousand two hundred and eighty-nine renal biopsies in Singapore were reviewed and compared with that of 19 other countries. RESULTS: IgA nephritis is on the decline in many countries, including Singapore, though it still remains the commonest GN in Singapore. Membranous GN that if used to be more frequently present in Western countries has also declined though it continues a rising trend in countries such as Singapore and China. Worldwide, the frequency of focal sclerosing glomerulosclerosis (FSGS) continues to increase in many countries, but in some countries, the frequency is still low with mesangiocapillary GN remaining indigenous. CONCLUSION: Urbanization and socioeconomic changes and less exposure to parasitic and other infestations have transformed Singapore's pattern, which is tending toward that of more developed countries. Antigenic exposure due to lifestyle changes, environmental, and industrial pollution are significant contributory factors that affect the evolutionary trend of GN in many countries. The rising trend in the frequency of FSGS may reflect aging and obesity.