The survival advantage observed among peritoneal dialysis patients early on after dialysis initiation has been largely attributed to residual renal function (RRF) preservation due to higher baseline ...residual function and fewer comorbidities. We hypothesize that a rapid decline in RRF is associated with higher risk of anuria and mortality. In a retrospective cohort study of 581 subjects on peritoneal dialysis with longitudinal prevalent data, we assessed whether RRF change over time, in addition to baseline RRF, increased risk of mortality and anuria using Kaplan-Meier analysis and Cox proportional hazard analysis to control for known risk factors. Rapid RRF decline (≥ 0.09 decline) over a 12-month period was associated with a 2.6-fold increase in the risk of death (hazard ratio HR 2.60, 95% confidence interval CI 1.66 – 4.07, compared with < 0.09 decline) and a 2-fold increase in anuria (HR 2.06, 95% CI 1.24 – 3.42). Each quartile of increasing severity of RRF decline over a 12-month period increased risk incrementally for death (2nd quartile: HR 3.04, CI 1.26 – 7.34; 3rd quartile: HR 4.01, CI 1.71 – 9.83; 4th quartile HR 5.78, CI 2.10 – 15.9) and generally for anuria (quartiles with HR 5.72 – 7.21). The escalating risk of mortality and anuria was greater for those with diabetes mellitus. In conclusion, rapid decline in RRF over a 12-month period increased the risk of mortality and likewise anuria, beyond previously established risk factors for mortality and anuria. The impact on mortality and RRF preservation was particularly severe for those with diabetes mellitus.
Tripterygium wilfordii Hook F. (TwHF) is a traditional Chinese herb and has a broad spectrum of biological functions including immunosuppression and anti-inflammatory effects. When used in ...combination with other standard of care medications, such as glucocorticoids and calcineurin inhibitors like cyclosporine A, for treating glomerular diseases, TwHF demonstrates a remarkable dose-sparing effect, the molecular mechanism for which remains largely unknown. In an
model of podocytopathy elicited by a diabetic milieu, triptolide, the major active component of TwHF, at low doses, potentiated the beneficial effect of cyclosporine A, and protected podocytes against diabetic milieu-elicited injury, mitigated cytoskeleton derangement, and preserved podocyte filtration barrier function, entailing a synergistic cytoskeleton-preserving and podocyte protective effect of triptolide and cyclosporine A. Mechanistically, inhibitory phosphorylation of GSK3β, a key molecule recently implicated as a convergence point of podocytopathic pathways, is likely required for the synergistic effect of triptolide and cyclosporine A on podocyte protection, because the synergistic effect was largely blunted in cells expressing the constitutively active GSK3β. Ergo, a synergistic podocyte cytoskeleton-stabilizing mechanism seems to underlie the cyclosporine A-sparing effect of triptolide in glomerulopathies. Combined triptolide and cyclosporine A therapy at reduced doses may be an invaluable regimen for treating diabetic nephropathy.
Background: Organ transplantation is considered the ultimate therapy for end-stage organ disease. While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the ...survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes. Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression. Summary: Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice. The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation. Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance. Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance-inducing features of Tregs. A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance. In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections. Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status. Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant. Key Messages: Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients.
Background
The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease.
...Methods and results
We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type‐2 diabetes (BARI‐2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin–creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow‐up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all‐cause mortality. Additionally, nonwhites with type‐II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all‐cause mortality, and two times for (P = 0.015) MI during follow‐up.
Conclusions
Mildly increased albuminuria is a significant predictor of all‐cause mortality in those with type‐II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.
Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well ...understood. Methods and Results Patients enrolled in the medical therapy-only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy-only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 1.11-2.85; P=0.02), age (odds ratio, 1.04 1.00-1.07; P<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine eGFR (odds ratio, 1.86 1.15-3.0; P=0.01) were associated with an early RD. Despite continued medical therapy only, the RD group had an improvement in eGFR at 1 year (6.9%; P=0.04). The RD and nondecline groups were not significantly different for clinical events and all-cause mortality (P=0.78 and P=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the RD patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in eGFR at 1 year in the RD group was estimated at 5.8±7.1%. Conclusions Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.
Hepatocyte growth factor (HGF) has been shown to reduce renal injury in a variety of animal models of chronic renal disease. Suggested mechanisms to explain this action include prevention of tubular ...cell apoptosis, blocking epithelial-to-mesenchymal transition, and promotion of extracellular matrix degradation. Inflammation is another common finding in kidneys that progress to end-stage renal failure; however, the effect of HGF on inflammation has hardly been investigated. For examining this issue, beginning 2 wk after subtotal nephrectomy, rats received a continuous infusion of recombinant HGF, neutralization of endogenous HGF by daily injection of an anti-HGF antibody, or preimmune IgG for an additional 2 wk. HGF infusion halted the progression of proteinuria and decreased renal collagen accumulation. Renal inflammation in both glomeruli and tubulointerstitium was significantly attenuated, associated with reductions in the tubular expression of the chemokines macrophage chemoattractant protein-1 (MCP-1) and RANTES (regulated upon expression normal T cell expressed and secreted). In contrast, HGF neutralization worsened renal fibrosis, aggravated renal inflammation, and enhanced tubular expression of MCP-1 and RANTES. In vitro, HGF suppressed basal and TNF-alpha-induced expression of these chemokines at both the mRNA and protein levels in a time- and dose-dependent manner in proximal tubular epithelial cells. HGF also blunted TNF-alpha-induced nuclear translocation and activation of NF-kappaB, a pivotal transcription factor that regulates chemokine expression. Immunohistochemistry showed that activated NF-kappaB was evident in tubules in remnant kidneys and increased remarkably with anti-HGF treatment. HGF infusion markedly suppressed expression of activated NF-kappaB in remnant kidneys. These findings suggest that the beneficial effect of HGF in chronic renal disease is attributable, at least in part, to a direct anti-inflammatory action, likely via NF-kappaB, on tubular epithelial cells.
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