Targeting the sphingosine kinase/sphingosine 1-phosphate pathway to treat chronic inflammatory kidney diseases

Chronic kidney diseases including glomerulonephritis are often accompanied by acute or chronic inflammation that leads to an increase in extracellular matrix (ECM) production and subsequent glomerulosclerosis. Glomerulonephritis is one of the leading causes for end-stage renal failure with high morbidity and mortality, and there are still only a limited number of drugs for treatment available. In this MiniReview, we discuss the possibility of targeting sphingolipids, specifically the sphingosine kinase 1 (SphK1) and sphingosine 1-phosphate (S1P) pathway, as new therapeutic strategy for the treatment of glomerulonephritis, as this pathway was demonstrated to be dysregulated under disease conditions. Sphingosine 1-phosphate is a multifunctional signalling molecule, which was shown to influence several hallmarks of glomerulonephritis including mesangial cell proliferation, renal inflammation and fibrosis. Most importantly, the site of action of S1P determines the final effect on disease progression. Concerning renal fibrosis, extracellular S1P acts pro-fibrotic via activation of cell surface S1P receptors, whereas intracellular S1P was shown to attenuate the fibrotic response. Interference with S1P signalling by treatment with FTY720, an S1P receptor modulator, resulted in beneficial effects in various animal models of chronic kidney diseases. Also, sonepcizumab, a monoclonal anti-S1P antibody that neutralizes extracellular S1P, and a S1P-degrading recombinant S1P lyase are promising new strategies for the treatment of glomerulonephritis. In summary, especially due to the bifunctionality of S1P, the SphK1/S1P pathway provides multiple target sites for the treatment of chronic kidney diseases.

Impact of Baseline Renal Function on Tenofovir-containing Antiretroviral Therapy Outcomes in Zambia

Background. Although tenofovir (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. Methods. We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (eGFR 60-89 mL/min), moderate (30-59 mL/min) or severe (<30 mL/min) using the CKD-EPI formula. Differences in eGFR during ART were analyzed using linear mixed-effect models, the odds of developing moderate or severe eGFR decrease with logistic regression and mortality with competing risk regression. Results. We included 62,230 adults, of which 38,716 (62%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF compared to the non-TDF group (1.9% vs. 4.0%). Among patients with no or mild renal dysfunction, those on TDF were more likely to develop moderate (adjusted OR: 3.11; 95%CI: 2.52-3.87) or severe eGFR decrease (adjusted OR: 2.43; 95%CI: 1.80-3.28), although the incidence of such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen and mortality was similar in both treatment groups. Conclusions. TDF use did not attenuate renal function recovery or increase mortality in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort.

BACKGROUND: Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE). METHODS AND FINDINGS: PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic-demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcgammaRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model. CONCLUSIONS: Fcgamma receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.

Protein profiling of urine from dogs with renal disease using ProteinChip analysis

Measurement of total urinary proteins in individuals that tested positive by urinary dipstick is a typical method for assessing the presence of potentially serious renal disorders. In the absence of such overt proteinuria, however, measurement of specific urinary proteins may be useful in the diagnosis of nephropathies and may provide greater insight into the pathogenesis. The urine of 28 dogs (16 with renal disease and 12 healthy) was evaluated to determine whether specific low-molecular-weight proteins or the pattern of protein excretion could also be used as a marker of tubular dysfunction in dogs. Specific proteins were assessed by immunological methods, whereas protein profiles were determined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (MS). In particular, changes in the excretion of retinol-binding protein (RBP) and Tamm-Horsfall protein (THP) appear to be of clinical relevance in the diagnosis of canine kidney diseases. The pattern of urinary protein and peptides revealed specific changes in abundance in dogs with renal disease at molecular masses (kD) of 11.58, 12.41, 12.60, 14.58, 20.95 (RBP), 27.85, and 65.69 (albumin). In conclusion, comparable proteins as in humans might be used as urinary markers for proximal (RBP) and distal (THP) tubular dysfunction in dogs. Surface-enhanced laser desorption/ionization time-of-flight MS is a promising tool for the study of kidney physiology and pathophysiology and might aid in the discovery of new biomarkers of renal disease.

Chronic hepatitis B virus coinfection is associated with renal impairment among Zambian HIV-infected adults.

Among 6789 HIV-infected Zambian adults screened for hepatitis B virus (HBV) coinfection, estimated glomerular filtration rate (eGFR) was 50-90 mL/minute/1.73 m(2) in 17.6% and <50 mL/minute/1.73 m(2) in 2.5%. Human immunodeficiency virus/HBV coinfection was associated with eGFR <50 mL/minute/1.73 m(2) (adjusted odds ratio, 1.96 [95% confidence interval, 1.34-2.86]), adjusted for age, sex, CD4(+) count, and World Health Organization disease stage.

Ceramide kinase contributes to proliferation but not to prostaglandin E2 formation in renal mesangial cells and fibroblasts

Background/Aims: Ceramide kinase (CerK) catalyzes the generation of the sphingolipid ceramide-1-phosphate (C1P) which regulates various cellular functions including cell growth and death, and inflammation. Here, we used a novel catalytic inhibitor of CerK, NVP-231, and CerK knockout cells to investigate the contribution of CerK to proliferation and inflammation in renal mesangial cells and fibroblasts. Methods: Cells were treated with NVP-231 and [3H]-thymidine incorporation into DNA, [3H]-arachidonic acid release, prostaglandin E2 (PGE2) synthesis, cell cycle distribution, and apoptosis were determined. Results: Treatment of rat mesangial cells and mouse renal fibroblasts with NVP-231 decreased DNA synthesis, but not of agonist-stimulated arachidonic acid release or PGE2 synthesis. Similarly, proliferation but not arachidonic acid release or PGE2 synthesis was reduced in CERK knockout renal fibroblasts. The anti-proliferative effect of NVP-231 on mesangial cells was due to M phase arrest as determined using the mitosis markers phospho-histone H3, cdc2 and polo-like kinase-1, and induction of apoptosis. Moreover, loss of CerK sensitized cells towards stress-induced apoptosis. Conclusions: Our data demonstrate that CerK induces proliferation but not PGE2 formation of renal mesangial cells and fibroblasts, and suggest that targeted CerK inhibition has potential for treating mesangioproliferative kidney diseases.

Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts

Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.

Racial Disparities in Access to and Outcomes of Kidney Transplantation in Children, Adolescents, and Young Adults: Results From the ESPN/ERA-EDTA (European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association) Registry.

BACKGROUND Racial disparities in kidney transplantation in children have been found in the United States, but have not been studied before in Europe. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Data were derived from the ESPN/ERA-EDTA Registry, an international pediatric renal registry collecting data from 36 European countries. This analysis included 1,134 young patients (aged ≤19 years) from 8 medium- to high-income countries who initiated renal replacement therapy (RRT) in 2006 to 2012. FACTOR Racial background. OUTCOMES & MEASUREMENTS Differences between racial groups in access to kidney transplantation, transplant survival, and overall survival on RRT were examined using Cox regression analysis while adjusting for age at RRT initiation, sex, and country of residence. RESULTS 868 (76.5%) patients were white; 59 (5.2%), black; 116 (10.2%), Asian; and 91 (8.0%), from other racial groups. After a median follow-up of 2.8 (range, 0.1-3.0) years, we found that black (HR, 0.49; 95% CI, 0.34-0.72) and Asian (HR, 0.54; 95% CI, 0.41-0.71) patients were less likely to receive a kidney transplant than white patients. These disparities persisted after adjustment for primary renal disease. Transplant survival rates were similar across racial groups. Asian patients had higher overall mortality risk on RRT compared with white patients (HR, 2.50; 95% CI, 1.14-5.49). Adjustment for primary kidney disease reduced the effect of Asian background, suggesting that part of the association may be explained by differences in the underlying kidney disease between racial groups. LIMITATIONS No data for socioeconomic status, blood group, and HLA profile. CONCLUSIONS We believe this is the first study examining racial differences in access to and outcomes of kidney transplantation in a large European population. We found important differences with less favorable outcomes for black and Asian patients. Further research is required to address the barriers to optimal treatment among racial minority groups.

Sobrecarga e restrição de cloreto de sódio durante a gestação: repercussão sobre a estrutura cardíaca e renal no neonato

Introdução: Diversos estudos indicaram consequências de alterações na nutrição materna durante a gestação sobre a saúde da prole adulta, tais como: hipertensão, doenças cardiovasculares, resistência à insulina, diabete melito e doença renal. No entanto, a literatura é pobre em avaliações decorrentes de modificações nutricionais maternas sobre a prole logo após o nascimento. Métodos: Ratas Wistar durante o período gestacional foram alimentadas com dieta hipossódica (HO - 0,15% de NaCl), normossódica (NR - 1,3% de NaCl) ou hipersódica (HR - 8% de Na Cl). Após o nascimento, nas primeiras vinte e quatro horas foram coletados rins e coração dos neonatos machos e fêmeas (n=6- 8/grupo) para verificar as possíveis alterações na estrutura cardíaca e renal pelo método de estereologia. Também foi avaliada a expressão proteica e gênica dos componentes do sistema renina angiotensina (SRA) no coração e rins através do método ELISA indireto e RT-qPCR. Resultados: O peso ao nascimento foi menor em machos e fêmeas da prole de mães alimentadas com dieta hipossódica durante a gestação quando comparado NR e HR. Não houve diferença no volume renal, volume de seus compartimentos (córtex, medula e pelve) e número de glomérulos entre os grupos experimentais (HO, NR e HR). No entanto, o número de glomérulos foi maior em fêmeas comparado aos machos nos três grupos experimentais. O diâmetro transverso do núcleo dos cardiomiócitos no ventrículo esquerdo e no ventrículo direito de machos da prole HR foi maior do que na prole NR. A expressão proteica do receptor AT1 no rim de machos da prole foi menor no grupo HO do que no grupo NR e HR. A expressão proteica do receptor AT2 também foi menor em machos do grupo HO do que no grupo NR. Não houve diferença entre os grupos na expressão proteica dos receptores AT1 e AT2 no rim das fêmeas. Conclusão: O presente estudo detectou alterações na estrutura cardíaca de neonatos machos, mas não em neonatos fêmeas decorrentes de sobrecarga de sal durante a gravidez. As alterações observadas na expressão dos receptores AT1 e AT2 no rim de neonatos machos podem ser responsáveis por alterações na função renal

Principles and clinical application of assessing alterations in renal elimination pathways

Drugs and metabolites are eliminated from the body by metabolism and excretion. The kidney makes the major contribution to excretion of unchanged drug and also to excretion of metabolites. Net renal excretion is a combination of three processes - glomerular filtration, tubular secretion and tubular reabsorption. Renal function has traditionally been determined by measuring plasma creatinine and estimating creatinine clearance. However, estimated creatinine clearance measures only glomerular filtration with a small contribution from active secretion. There is accumulating evidence of poor correlation between estimated creatinine clearance and renal drug clearance in different clinical settings, challenging the 'intact nephron hypothesis' and suggesting that renal drug handling pathways may not decline in parallel. Furthermore, it is evident that renal drug handling is altered to a clinically significant extent in a number of disease states, necessitating dosage adjustment not just based on filtration. These observations suggest that a re-evaluation of markers of renal function is required. Methods that measure all renal handling pathways would allow informed dosage individualisation using an understanding of renal excretion pathways and patient characteristics. Methodologies have been described to determine individually each of the renal elimination pathways. However, their simultaneous assessment has only recently been investigated. A cocktail of markers to measure simultaneously the individual renal handling pathways have now been developed, and evaluated in healthy volunteers. This review outlines the different renal elimination pathways and the possible markers that can be used for their measurement. Diseases and other physiological conditions causing altered renal drug elimination are presented, and the potential application of a cocktail of markers for the simultaneous measurement of drug handling is evaluated. Further investigation of the effects of disease processes on renal drug handling should include people with HIV infection, transplant recipients (renal and liver) and people with rheumatoid arthritis. Furthermore, changes in renal function in the elderly, the effect of sex on renal function, assessment of living kidney donors prior to transplantation and the investigation of renal drug interactions would also be potential applications. Once renal drug handling pathways are characterised in a patient population, the implications for accurate dosage individualisation can be assessed. The simultaneous measurement of renal function elimination pathways of drugs and metabolites has the potential to assist in understanding how renal function changes with different disease states or physiological conditions. In addition, it will further our understanding of fundamental aspects of the renal elimination of drugs.

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

A single-centre experience of post-renal transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD) complicates 1 to 10% of all transplantations. Previous clinicopathological studies of PTLD have been limited by small numbers, short follow-up times, outdated data, heterogeneity of pooled solid-organ transplant results, and selective inclusion of early-onset disease. We therefore undertake here a retrospective analysis and identify all cases of PTLD that complicated renal transplantation at the Princess Alexandra Hospital between 30 June 1969 and 31 May 2001. Tumour samples were subsequently retrieved for pathological review and for Epstein-Barr virus-encoded RNA in situ hybridisation (EBER-ISH). Of 2,030 renal transplantation patients, 29 (1.4%) developed PTLD after a median period of 0.5 years (range 0.1 to 23.3 years). PTLD patients were more likely to have received cyclosporine (76% versus 62%, P