The efficacy of induction treatment in Thai patients with lupus nephritis: Observational cohort analysis.

BACKGROUND: For active proliferative lupus nephritis (LN), intravenous cyclophosphamide (IVCYC) is a standard therapy whereby mycophenolate mofetil (MMF) is less effective than IVCYC, according to the clinical trials in non-Asians. In this observational study, the clinical outcomes will be compared among Thai patients. METHODS: We had analyzed 93 adult patients who underwent a renal biopsy for active proliferative LN confirmation between January 2013 and June 2021. The assessment of the response outcomes compared the induction treatment of IVCYC versus MMF. The primary endpoint had achieved complete remission (CR) at 24 weeks, while the secondary endpoint is overall remission (OR) and urine protein creatinine ratio (UPCR) changed over time. RESULTS: 93 LN patients were separated into two groups; 40 in IVCYC and 53 in MMF. In the 24th week, based on unadjusted analysis, patient had achieved CR 20.0% of IVCYC, whereas 28.3% of MMF had achieved CR. Unadjusted CR Risk difference was -0.08 (95% CI -0.26, -0.09, p-value = 0.351) and the adjusted CR risk difference was -0.19 (95% CI -0.42, 0.04, p-value = 0.098). The unadjusted OR risk difference was -0.06 (95% CI -0.26, 0.14, p-value = 0.553) while adjusted OR risk difference was -0.24 (95% CI -0.50, 0.02, p-value = 0.067). Unadjusted UPCR mean was -0.29 (95% CI -0.77, 0.17, p-value = 0.210) and adjusted UPCR mean was -0.27 (95% CI -0.88, 0.32, p-value = 0.366). CONCLUSIONS: The induction treatment with either IVCYC or MMF had similar efficacy in Thai LN patients. The decision of treatment should be taken by applying an individualized therapeutic strategy and balancing risks, costs, and benefits.

The prevalence of normoalbuminuria and renal impairment in type 2 diabetes mellitus
.

BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) worldwide. Clinical manifestations of DKD consist of a progressive increase in albuminuria and a decline in estimated glomerular filtration rate (eGFR). Hence, the diagnosis of DKD in patients with declining renal function without albuminuria is more difficult. Although there are several reports of such patients in other geographic regions, the data in this regard are limited. OBJECTIVE: To determine the prevalence of normoalbuminuria with renal impairment and the decline in eGFR relative to their albuminuric status in type 2 diabetes mellitus (T2DM) among Thai patients. MATERIALS AND METHODS: Retrospective review was conducted on medical records of T2DM patients at a tertiary referral hospital dated from January 1, 2013, until June 30, 2016. Based on study inclusion criteria, T2DM patients with renal impairment identified by an eGFR of less than 60 mL/min/1.73m2 were eligible. Albumin excretion rate was determined by urine albumin-to-creatinine ratio from a single random urine collection. RESULTS: Of the 4,597 patients with T2DM, 16.5% had an eGFR below 60 mL/min/1.73m2. The overall prevalence rates of normoalbuminuria, moderate proteinuria, and severe proteinuria were 45.4, 30.9, and 23.7%, respectively. In the normoalbuminuria group, the incidences of chronic kidney disease at stage 3a, 3b, and 4 were 67.5, 27, and 5.5%, respectively. None of the patients with stage 5 chronic kidney disease had normoalbuminuria. The decline in eGFR with normoalbuminuria was less significant than in positive albuminuria. CONCLUSION: The association of normoalbuminuria is common in DKD. The decline of renal function is slower in normoalbuminuria; however, the risk factors, clinical progression, and renal pathology in these patients need to be further explored.

Reversibility of structural and functional damage in a model of advanced diabetic nephropathy.

The reversibility of diabetic nephropathy remains controversial. Here, we tested whether replacing leptin could reverse the advanced diabetic nephropathy modeled by the leptin-deficient BTBR ob/ob mouse. Leptin replacement, but not inhibition of the renin-angiotensin-aldosterone system (RAAS), resulted in near-complete reversal of both structural (mesangial matrix expansion, mesangiolysis, basement membrane thickening, podocyte loss) and functional (proteinuria, accumulation of reactive oxygen species) measures of advanced diabetic nephropathy. Immunohistochemical labeling with the podocyte markers Wilms tumor 1 and p57 identified parietal epithelial cells as a possible source of regenerating podocytes. Thus, the leptin-deficient BTBR ob/ob mouse provides a model of advanced but reversible diabetic nephropathy for further study. These results also suggest that restoration of lost podocytes is possible but is not induced by RAAS inhibition, possibly explaining the limited efficacy of RAAS inhibitors in promoting repair of diabetic nephropathy.

Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis.

Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-ß1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN.

BTBR Ob/Ob mutant mice model progressive diabetic nephropathy.

There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a >50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions.

Deletion of activating Fcgamma receptors does not confer protection in murine cryoglobulinemia-associated membranoproliferative glomerulonephritis.

Many types of glomerulonephritis are initiated by the deposition of immune complexes, which induce tissue injury via either engagement of Fc receptors on effector cells or via complement activation. Four murine Fcgamma receptors (FcgammaRs) have been identified at present. Ligand binding to FcgammaRI, III, and IV induces cell activation via the immunoreceptor tyrosine-based activation motif on the common gamma chain (FcRgamma). In this study, FcRgamma chain knockout (FcRgamma(-/-)) mice were crossed with thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop cryoglobulinemic membranoproliferative glomerulonephritis (MPGN). Female mice were studied at 30 and 50 days of age, when MPGN is in early and fully developed stages, respectively. Both TSLPtg and TSLPtg/FcRgamma(-/-) mice developed MPGN with massive glomerular immune deposits, mesangial cell proliferation, extensive mesangial matrix accumulation, and macrophage influx. TSLPtg/FcRgamma(-/-) mice had more glomerular immune complex deposits and higher levels of circulating cryoglobulins, IgG2a, IgG2b, and IgM, compared with TSLPtg mice. TSLPtg and TSLPtg/FcRgamma(-/-) mice developed similar levels of proteinuria. These results demonstrated that deletion of activating FcgammaRs does not confer protection in this model of immune complex-mediated MPGN. The findings contradict accepted paradigms on the role of activating FcgammaRs in promoting features of glomerulonephritis as seen in other model systems. We speculate engagement of FcgammaRs on cells such as monocytes/macrophages may be important for the clearance of deposited immune complexes and extracellular matrix proteins.

Low-dose cyclosporine for active lupus nephritis: a dose titration approach.

OBJECTIVE: Achievement of complete renal remission (CR) is an important goal in lupus nephritis (LN) treatment. The use of cyclosporine (CsA) for active LN has been challenged because of variations in CsA doses and reports of adverse reactions (AR). METHOD: A cohort of 62 patients with active LN (induction-resistant LN and flared LN) who were treated with CsA was evaluated. CsA was started at 50 mg/day and titrated up 25 mg/day every 2-4 weeks until CR was achieved or until treatment termination because of AR. RESULTS: The range of CsA dosage was 50-200 mg/day, and mean CsA dose was 102.8 ± 50.43 mg/day (1.73 ± 0.91 mg/kg/day). CsA plus mycophenolate mofetil and prednisolone was administered to 35.5% of patients, while the other 64.5% were treated with CsA and prednisolone. 90.32% had achieved CR and 4.84% had partial remission after 12 months of treatment. UPCR (urinary protein:creatinine ratio) decreased significantly in both groups (2.58 ± 3.37 to 0.36 ± 0.71 and 2.32 ± 1.45 to 0.29 ± 0.24 respectively) (P < 0.001). Non-renal activity including arthritis, alopecia, hematologic and cutaneous conditions improved in all patients. Patients whose prednisolone dose were increase received higher doses of prednisolone at baseline than patients who had stable prednisolone dose, but after 12 months the difference in dosage was insignificant (p = 0.58). CONCLUSION: Patients with active LN can be effectively treated with low dose CsA, and the dose titration approach can lead to 90.32% CR with low AR rates. No difference in clinical response was observed among patients who received CsA plus prednisolone or CsA plus MMF and prednisolone.

Efficacy of cellulose triacetate dialyzer and polysulfone synthetic hemofilter for continuous venovenous hemofiltration in acute renal failure.

OBJECTIVE: To compare the clearance performances and biocompatibility between the modified cellulose membrane and the standard synthetic membrane in continuous renal replacement therapy (CRRT). MATERIAL AND METHOD: Seventeen patients with acute renal failure (ARF) were treated with separated continuous veno venous hemofiltration (CVVH) system conducted with the pre-dilution mode. The modified cellulose used was a Sureflux150E (cellulose triacetate) and the standard synthetic membranes used was an AV-400. Blood and replacement flow rate were kept at 100 and 20 mL/min, respectively. Ultrafiltraion rate was 1,200 mL/hr. Samplings of blood and ultrafiltrate were collected at baseline, 2, 8, 16, and 24 hr. RESULTS: Patients in both methods could similarly tolerate CRRT with only minor complications. Sureflux 150E and AV-400 provided comparable values of sieving coefficients and clearances of small solutes. The albumin loss in ultrafiltrate by Sureflux 150E was greater than AV-400. The values of life span and biocompatability of both hemofilters were not different. CONCLUSION: Because of the excellent efficacy and the much cheaper cost, the modified cellulose membrane could be an appropriate alternative to standard synthetic membrane in CRRT.