Ramesh Saxena

The aging kidney.

Renal aging, by itself, is associated with alterations in renal morphology and a decline in renal function, which is accelerated and/or accentuated by diseases such as diabetes mellitus and hypertension. The aging-related renal insufficiency has important implications with regards to body homeostasis, drug toxicity, and renal transplantation. An understanding of renal aging and its distinction from renal insufficiency secondary to diseases is essential for individualized care of the elderly. Toward this end, investigations are underway to elucidate the molecular mechanisms of renal aging. This review summarizes the structural and functional changes of the aging kidney and highlights the advances made in our understanding of the renal aging process.

Metabolic Disturbances Associated with Systemic Lupus Erythematosus

The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.

Lupus nephritis: current update

Lupus nephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus. The general consensus is that 60% of lupus patients will develop clinically relevant nephritis at some time in the course of their illness. Prompt recognition and treatment of renal disease is important, as early response to therapy is correlated with better outcome. The present review summarizes our current understanding of the pathogenic mechanisms underlying lupus nephritis and how the disease is currently diagnosed and treated.

Renal senescence in 2008: progress and challenges

Kidneys are significantly affected by profound anatomic and functional changes with senescence. These changes lead to decline in glomerular filtration rate, decreased urinary concentrating and diluting ability, diminished urinary acidification, and impaired potassium clearance, to list a few. Such changes make the elderly prone to drug toxicity and serious fluid and electrolyte imbalance. While the entire mystery of aging is far from being clear, the role of oxidative stress, telomere length, Klotho gene expression, and the renin angiotensin system seem to be the key mechanisms involved in aging. Aging, being a complex process, involves an array of intertwined molecular pathways. Simultaneous study of multiple molecular pathways in parallel could provide invaluable information in understanding the clinical course of kidney aging and elucidating mechanisms that play key roles in the aging process. A better understanding of these mechanisms may help to preserve renal function, improve morbidity and mortality, and hopefully reduce healthcare costs for the aging population.

Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome

Abstract. Objectives. Pulmonary renal syndrome (lung haemorrhage and glomerulonephritis) is a fulminant condition that warrants a rapid diagnosis and treatment to prevent mortality and preserve renal functions. However, the patients frequently present with non‐specific pulmonary symptoms in the early phase of the syndrome and the diagnosis is often missed. Recently, several autoantibodies have been described in association with various forms of glomerulonephritis. We evaluated the association as well as the diagnostic and the prognostic significance of these antibodies in pulmonary renal syndrome.

Urinary Angiostatin - A Novel Putative Marker of Renal Pathology Chronicity in Lupus Nephritis

There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ∼280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin.

Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis

IntroductionAlthough renal pathology is highly predictive of the disease course in lupus nephritis, it cannot be performed serially because of its invasive nature and associated morbidity. The goal of this study is to investigate whether urinary levels of CXC ligand 16 (CXCL16), monocyte chemotactic protein-1 (MCP-1) or vascular cell adhesion molecule-1 (VCAM-1) in patients with lupus nephritis are predictive of particular features of renal pathology in renal biopsies obtained on the day of urine procurement.MethodsCXCL16, MCP-1, and VCAM-1 levels were measured in urine samples from 74 lupus nephritis patients and 13 healthy volunteers. Of the patients enrolled, 24 patients had a concomitant kidney biopsy performed at the time of urine collection. In addition, patients with other renal diatheses were also included as controls.ResultsAll three molecules were elevated in the urine of systemic lupus erythematosus patients, although VCAM-1 (area under curve = 0.92) and MCP-1 (area under curve = 0.87) were best at distinguishing the systemic lupus erythematosus samples from the healthy controls, and were also most strongly associated with clinical disease severity and active renal disease. For patients in whom concurrent renal biopsies had also been performed, urine VCAM-1 exhibited the strongest association with the renal pathology activity index and glomerulonephritis class IV, although it correlated negatively with the chronicity index. Interestingly, urinary VCAM-1 was also elevated in anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis, focal segmental glomerulosclerosis and membranous nephropathy but not in minimal-change disease.ConclusionUrinary VCAM-1 emerges as a reliable indicator of the activity:chronicity ratios that mark the underlying renal pathology in lupus nephritis. Since VCAM-1 is involved in the acute phase of inflammation when leukocytic infiltration is ongoing, longitudinal studies are warranted to establish whether tracking urine VCAM-1 levels may help monitor clinical and pathological disease activity over time.

Pathogenesis and treatment of peritoneal membrane failure

Peritoneal dialysis (PD) is a viable treatment option for end stage renal disease (ESRD) patients worldwide. PD may provide a survival advantages over hemodialysis (HD) in the early years of treatment. However, the benefits of PD are short-lived, as peritoneal membrane failure ensues in many patients, owing mainly to structural and functional changes in the peritoneal membrane from the use of conventional bio-incompatible PD solutions, which are hyperosmolar, acidic, have lactate buffer and contain high concentrations of glucose and glucose degradation products (GDPs). Current data suggest that chronic exposure of the peritoneum to contemporary PD fluids provokes activation of various inflammatory, fibrogenic and angiogenic cytokines, interplay of which leads to progressive peritoneal fibrosis, vasculopathy and neoangiogenesis. There is emerging evidence that peritoneal vascular changes are mainly responsible for increased solute transport and ultrafiltration failure in long-term PD. However, the precise pathophysiologic mechanisms initiating and propagating peritoneal fibrosis and angiogenesis remain elusive. The protection of the peritoneal membrane from long-term toxic and metabolic effects of high GDP-containing, conventional, glucose-based solutions is a prime objective to improve PD outcome. Recent development of new, more biocompatible, PD solutions should help to preserve peritoneal membrane function, promote ultrafiltration, improve nutritional status and, hopefully, preserve peritoneal membrane and improve overall PD outcomes. Elucidation of molecular mechanisms involved in the cellular responses leading to peritoneal fibrosis and angiogenesis spurs new therapeutic strategies that might protect the peritoneal membrane against the consequences of longstanding PD.

Protein kinase C beta I and beta II are differentially expressed in the developing glomerulus.

In the pre‐ and postnatal period of kidney development, proliferation with subsequent functional maturation of intrinsic glomerular mesangial cells (MCs) continues within the existing framework. Recent work has suggested that PKC β isoform is responsible for the proliferation observed during maturation. We sought to ascertain whether PKC β isoform expression is altered during the development of the mesangium. MCs were subcultured from glomerular explants of Sprague‐Dawley rat kidneys, days 1, 3, 5, 8, 15 postnatally, and adult. MCs from rat kidneys postnatally days 1‐5 proliferated at a significantly greater rate than adult [> 1.169‐fold, P < 0.01] but term day 8 cells did not [> 1.34‐fold, not significant)] as assessed by [3H]thymidine incorporation. Western blot analysis using isoform specific antibodies was performed on confluent neonatal and adult MC. We observed that all neonatal and adult MC express βI PKC (n = 8 kidneys from separate primaries for each date and adult). However, unlike adult MCs, neonatal MC express βII in postnatal days 1‐5 and none thereafter. Immunofluorescent staining of postnatal kidneys confirmed that PKC βII is present in neonatal MC up to day 5. By day 8, staining of mesangium with PKC βII begins to disappear and assumes a parietal epithelial pattern. In adult kidneys, there was only PKC βII staining of the parietal epithelial cells. Our results demonstrate that differential expression of PKC βII closely parallels the proliferative behavior of the MCs of the maturing glomerulus. Therefore, PKC βII expression and activation may play a critical role in development.—Saxena, R., Saksa, B. A., Hawkins, K. S., Ganz, M. B. Protein kinase C βI and βII are differentially expressed in the developing glomerulus. FASEB J. 8: 646‐653; 1994.

Renal transplantation in the elderly

Elderly patients are increasingly being considered for kidney transplantation due to a global explosion of the aging population with end-stage renal disease (ESRD). However, mounting scarcity of available organs for transplant has led to a wider disparity between organ supply and demand. Consequently, the criteria for accepting kidneys for transplantation have been extended in an attempt to allow the use of organs from elderly donors or those with significant co-morbidities, so-called “expanded criteria donor” (ECD) kidneys. Excellent outcomes have been achieved from ECD kidneys with appropriate donor and recipient profiling and selection. With increasing recovery efforts directed at older donors, the concept of age-matching is becoming more accepted as a method of optimizing utilization of organs in elderly donors and recipients. Utilization of pulsatile perfusion has further improved ECD outcomes and helped the decision-making process for the UNOS (United Network for Organ Sharing) offer. However, age-related immune dysfunction and associated co-morbidities make the elderly transplant recipients ever more susceptible to complications associated with immunosuppressive agents. Consequently, the elderly population is at a higher risk to develop infections and malignancy in the post-transplant period notwithstanding improved transplant outcomes. Appropriate immunosuppressive agents and dosages should be selected to minimize adverse events while reducing the risk of acute rejections and maximizing patient and renal allograft survival.