Treating the kidney to cure the heart.

The incidence of chronic renal and cardiovascular diseases is increasing worldwide. Since renal disease is the strongest risk factor for cardiovascular morbidity and mortality, strategies able to reduce renal disease progression are expected to translate into a decreased incidence of cardiovascular events. To this purpose, inhibition of the renin-angiotensin system, both by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, represents the best available option.

Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy.

Background And Objectives: In idiopathic membranous nephropathy (IMN), CD(20) B-cell depletion by rituximab may induce nephrotic syndrome (NS) remission. Whether this is associated with kidney function restoration and regression of the glomerular pathology was evaluated.

Design, Setting, Participants, & Measurements: Treatment-induced morphofunctional changes were evaluated in 7 IMN patients consenting to repeat functional and morphologic evaluations after stable disease remission achieved by four weekly rituximab (375 mg/m(2)) infusions.

Role of remission clinics in the longitudinal treatment of CKD.

Heavy proteinuria is a major determinant of progression to ESRD for patients with chronic nephropathies and reducing proteinuria should be a key target for renoprotective therapy. In the Remission Clinic, we applied a multimodal intervention to target urinary proteins in 56 consecutive patients who had >3 g proteinuria/d despite angiotensin-converting enzyme inhibitor therapy. We compared the rate of GFR decline and incidence of ESRD in this cohort with 56 matched historical reference subjects who had received conventional therapy titrated to a target BP.

Intensified inhibition of renin-angiotensin system: a way to improve renal protection?

Several large, randomized, multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies have clearly demonstrated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are able to reduce urinary protein excretion and retard renal disease progression. However, the number of patients who reach end-stage renal failure is still considerable and there is a great need to identify therapies that can arrest evolution of kidney damage. Maximizing renin-angiotensin system (RAS) blockade through combined ACE inhibitor and ARB therapy has been shown to further increase antiproteinuric and nephroprotective effects of each drug class.

Latest treatment strategies for membranous nephropathy.

Thirty to forty percent of patients with idiopathic membranous nephropathy have persistent heavy proteinuria and may progress to end-stage kidney disease in 5 - 15 years. The ideal treatment for these patients is a matter of debate. Several nonspecific immunosuppressive regimens have been suggested with the aim of reducing proteinuria and to improve outcome, but all are burdened by significant toxicity.

Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury.

Background: In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg.

Methods: To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant.

Report of the first World Transplant Congress.

During the past 20 yr, new immunosuppressant medications that reduced the rate of acute rejection became available for transplantation. Long-term survival of transplanted organs, however, did not improve to the extent predicted. Chronic immunosuppression is associated with cardiovascular, metabolic, and renal toxicities that negatively affect patient and graft survival.

Rituximab for idiopathic membranous nephropathy: who can benefit?

Rituximab effectively reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to treatment may vary from patient to patient. The association between baseline clinical, laboratory, and histology covariates and proteinuria reduction was evaluated retrospectively by multiple linear regression analysis at 3 mo after rituximab therapy in 14 patients with IMN with proteinuria > 3.5 g/24 h while on angiotensin-converting enzyme inhibition for at least 6 mo and no previous remissions.

Basiliximab combined with low-dose rabbit anti-human thymocyte globulin: a possible further step toward effective and minimally toxic T cell-targeted therapy in kidney transplantation.

In high-risk kidney transplant recipients, induction therapy with rabbit anti-human thymocyte globulin (RATG) reduces the risk for acute rejection but is associated with significant toxicity, opportunistic infections, and cancer. Using reduced doses of RATG combined with anti-IL-2 antibodies may achieve the same antirejection activity of standard-dose RATG but with a better safety profile. This randomized, open-label study compared the efficacy, tolerability, and costs of low-dose RATG (0.

Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy.

Background And Objectives: Rituximab, given in four weekly doses, is a promising treatment for idiopathic membranous nephropathy and other immune-mediated diseases and lymphoproliferative disorders. This multidose regimen, however, may cause hypersensitivity reactions and is extremely expensive. This study was aimed at evaluating whether titrating rituximab to circulating CD20 B cells may improve safety and limit costs of treatment.

Kidney failure stabilizes after an increase over 2 decades.

The level of proteinuria is one of the most important predictors for progressive renal function loss in kidney disease. Reduction of urinary protein levels by renin-angiotensin-system (RAS) inhibitors limits renal function decline in patients with non-diabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been reported. The increasing use of these drugs is possibly at the basis of the stabilization of rates of new cases of kidney failure reported to the US Renal Data System after a 2-decade period of progressive increases.

Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial.

The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation.

Does remission of renal disease associated with antihypertensive treatment exist?

In diabetic and nondiabetic chronic nephropathies, high blood pressure and urinary loss of proteins represent major determinants of progressive renal function decline. Reducing blood pressure with drugs that inhibit the renin-angiotensin system also lowers glomerular hypertension and ameliorates glomerular sieving properties, thus reducing proteinuria. Reducing urinary protein levels with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists (ARA) limits renal function decline to the point that remission of disease and regression of renal lesions have been observed in experimental animals and in humans.

The Bergamo Kidney Transplant Program.

Since the beginning of transplant activities in 1989, the Kidney Transplant Center at the Ospedali Riuniti Bergamo has based its clinical program on the most recent achievements of transplant medicine, in order to optimize the outcome of kidney grafts and improve the quality of life of kidney transplant recipients. Although the transplantation community attempts to keep up with increasing demand for transplantable organs, the supply continues to fall far short of the need. This observation prompted us to focus on the expansion of the available pool of deceased donor organs.

Alterations of type IV collagen alpha chains in patients with chronic acquired glomerulopathies: mRNA levels, protein expression and urinary loss.

Background: Type IV collagen is a major structural component of the normal kidney glomerulus. However, its role in chronic acquired glomerulopathies has been only partially elucidated.

Methods: Urinary levels of col(IV)alpha1, col(IV)alpha3 and col(IV)alpha5 collagen chains were analyzed in 107 patients with chronic acquired glomerulopathies.

Regulatory T cells and T cell depletion: role of immunosuppressive drugs.

Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4(+)CD25(high) subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting.

Long-term outcome of renal transplantation from older donors.

Background: Long-term survival of kidney grafts from older donors is inferior to that of grafts from younger donors. We sought to determine whether selecting older kidneys according to their histologic characteristics before implantation would positively influence long-term outcome.

Methods: In a prospective cohort study, we assessed outcomes among 62 patients who received one or two histologically evaluated kidneys from donors older than 60 years of age.

[Hemolytic uremic syndrome].

Hemolytic uremic syndrome (HUS) is a disease characterized by non immune hemolytic anemia, low platelet count and renal impairment. In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. Coli): however, renal function recovers in up to 70% of patients.

Effect of a novel immunosuppressant, ST1959, on the immune system and renal allograft survival in rats.

Background: ST1959 is a 3,5-diaryl-s-triazole belonging to a novel class of contragestional agents with immunosuppressant activity. The aim of the present study was to investigate the effects of this drug on allogeneic immune response and on renal allograft survival in rats.

Methods: One group of naive and one group of allosensitized Lewis rats received ST1959 (0.

Cyclosporine prolongs delayed graft function in kidney transplantation: are rabbit anti-human thymocyte globulins the answer?

Background: Cyclosporine (CsA) nephrotoxicity may prolong duration of anuria in renal transplant patients with delayed graft function (DGF). Thus, many Transplant Centers tend to delay CsA treatment in order to accelerate renal function recovery.

Methods: In this single-center, retrospective analysis we compared the outcomes of 40 renal transplant patients with DGF given a CsA-based (n = 17) regimen since the day of transplant or a CsA-sparing regimen (n = 23) based on early treatment with rabbit anti-human thymocyte globulin (RATG) and delayed CsA administration.

Early proinflammatory activation of renal tubular cells by normal and pathologic IgG.

Background/aims: To verify whether human IgG induces proinflammatory activation of human proximal tubular epithelial cells (PTEC) independent of the metabolic overload of protein reabsorption.

Methods: Cultured PTEC were incubated with normal IgG, IgG from systemic lupus erythematosus (SLE) patients, albumin or transferrin. IL-6 secretion and extracellular regulated kinase (ERK) activation (dual-phosphorylated ERK) were measured by ELISA and by Western blotting of PTEC extracts, respectively; renal biopsy specimens from patients with IgG and non-IgG proteinuria were analyzed by immunohistochemistry and in situ hybridization to detect ERK-P and IL-6.

Prognostic significance of albuminuria in patients with renal cell cancer.

Purpose: A relationship between the urinary albumin excretion rate (UAE) and different types of tumors has been previously described but little is known about UAE and renal cell cancer (RCC). We evaluated the prognostic significance of UAE and its correlation with tumor clinicopathological findings in patients with RCC treated with recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha). Because rIL-2 and rIFN-alpha increase glomerular permeability, we also determined whether the first immunotherapy cycle induced a significant increase in UAE and whether it was related to tumor parameters.