Norberto Perico

Cyclosporine/tacrolimus (FK-506)

The search for effective and safe methods of blocking the immune response has continued over the last four decades and has in fact permitted many advances in clinical organ transplantation. In the mid-1970s Borel et al.[1] discovered the immunosuppressive properties of a new agent, cyclosporine (CsA), that, unlike azathioprine and adrenal corticosteroids, selectively inhibits the adaptive immune response. This was the basis for its widespread clinical use during the 1980s and it had a major impact on the management of graft rejection in organ transplantation.

Do attributes of persons with chronic kidney disease differ in low-income and middle-income countries compared with high-income countries? Evidence from population-based data in six countries

Kidney biopsies to elucidate the cause of chronic kidney disease (CKD) are performed in a minority of persons with CKD living in high-income countries, since associated conditions—that is, diabetes mellitus, vascular disease or obesity with pre-diabetes, prehypertension or dyslipidaemia—can inform management targeted at slowing CKD progression in a majority. However, attributes of CKD may differ substantially among persons living in low-income and middle-income countries (LMICs). We used data from population or community-based studies from five LMICs (China, urban India, Moldova, Nepal and Nigeria) to determine what proportion of persons with CKD living in diverse regions fit one of the three major clinical profiles, with data from the US National Health Nutrition and Examination Survey as reference. In the USA, urban India and Moldova, 79.0%–83.9%; in China and Nepal, 62.4%–66.7% and in Nigeria, 51.6% persons with CKD fit one of three established risk profiles. Diabetes was most common in urban India and vascular disease in Moldova (50.7% and 33.2% of persons with CKD in urban India and Moldova, respectively). In Nigeria, 17.8% of persons with CKD without established risk factors had albuminuria ≥300u2009mg/g, the highest proportion in any country. While the majority of persons with CKD in LMICs fit into one of three established risk profiles, the proportion of persons who have CKD without established risk factors is higher than in the USA. These findings can inform tailored CKD detection and management systems and highlight the importance of studying potential causes and outcomes of CKD without established risk factors in LMICs.

Pathogenesis of Preeclampsia

Preeclampsia commonly occurs in primiparas [1], the usual clinical manifestations being hypertension, proteinuria, and edema. Even after a severe preeclampsia in the first pregnancy, however, these women may have no more trouble in subsequent pregnancies [2], Preeclampsia, in fact, is rare in multiparas unless there are some predisposing factors, such as conditions associated with increased placental mass (hydatiform mole, Rh incompatibility, twin pregnancies) or previous maternal vascular diseases, such as essential hypertension, hypertensive nephropathies, or autoimmune disorders with vascular damage (scleroderma, systemic lupus erythematosus). Placental tissue, but not fetus, is required for development of preeclampsia, as in pregnancy complicated by hydatiform mole.

Prevention of Chronic Renal Diseases in the Elderly

Chronic kidney disease is a major public health problem worldwide, as Chapter 23 discusses further. In the United States, the number of persons treated with end-stage renal disease (ESRD) has increased substantially over the past 20 years [1]. This growth has occurred primarily in individuals older than 65 years of age [1] (see Chapter 23). The incidence of renal replacement therapy (RRT) for ESRD continues to increase also in other geographical areas of the world, but at rates that vary considerably among countries. Over the last decade, RRT registries have reported average annual increases of 11% in Japan [2], 9% in Australia and 6.5% in New Zealand [3], and 6.1% in Canada [4]. In the same period, data from national and regional registries and from repeated cross-sectional surveys in Western Europe have shown increases in rates ranging from 2 to 4.3% per year in Germany [5], Spain [6], the UK [7], and France [8]. A more recent analysis from nine countries participating in the new European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) registry [9] reported that the adjusted (for age and gender) incidence rate of RRT increased from 79.4 per million population (pmp) in 1990–1991 to 117.1 pmp in 1998–1999, i.e., a 4.8% increase each year. This increase did not flatten out at the end of decade except in the Netherlands and was greater in men than women, 5.2 versus 4.0% per year. In most countries, the incidence rate remained stable for those younger than 45 years; it rose by 2.2% per year on average in those between 45 and 64 years old and by 7.0% among those aged 65–74 years; it tripled over the decade in those 75 years or older, and by 1998–1999, it ranged from 140.9 to 540.4 pmp, depending on the country. In the same countries, the incidence of ESRD due to diabetes, hypertension, and renal vascular disease nearly doubled over 10 years; in 1998–1999, it varied among countries from 10.2 to 39.3 pmp for diabetes, from 5.8 to 21.0 for hypertension, and from 1.0 to 15.5 for renal vascular disease [9]. Thus, RRT incidence continues to rise at various rates throughout the world, with the gap between countries resulting from enlarging differences in incidence

Acute Renal Failure in Kidney Transplant Recipients

Abstract Delayed graft function (DGF) is a form of acute renal failure of kidney transplantation resulting in post-transplant oliguria, increased allograft immunogenicity and risk of acute rejection. Rarely, the graft never functions this leading to primary non-function. Experimental studies have shown that both ischemia and reinstitution of blood flow in ischemically damaged kidneys after hypothermic preservation activate a complex sequence of events that sustain renal injury and play a pivotal role in the development of DGF (1). Quality of donor grafts, organ preservation technique, and choice of early immunosppression are key determinants of DGF that will be discussed herein.

Pharmacological Induction of Kidney Regeneration

The incidence of kidney disease is increasing worldwide, becoming one of the major public health problems. Until recently, the kidney was considered an organ with a limited capacity for repair and the progression to end-stage renal disease has generally been considered inexorable. Technological advances in the field of three-dimensional visualization of organ ultrastructure made in recent decades, together with the identification of renal progenitor cells lining the Bowman’s capsule of adult rat and human kidneys, have allowed to prove that tissue repair in the adult kidney is possible, even in mammals. Experimental and clinical studies that aim to identify drugs capable to influence renal progenitors fate and/or interfere with the pathogenetic pathways underlying renal disease progression have great potential for future kidney regeneration.

Molecular Medicine in Organ Transplantation: How and When?

Short-term graft survival has been remarkably improved in the past two decades thanks to increased skill coupled with new immunosuppressants. Although 1 year graft survival is now close to 85–90%, at least for cadaver kidney transplant, long-term results are less impresssive [1] despite recent data open new hopes. Data from the UNOS registry in more than 93,000 patients who had a renal transplant between the years 1988–1996 showed a projected graft half-life of 21.6 years living and 13.8 years for cadaver donors, respectively [S. Hariharan, personal communication]. The remark-able success is mostly related to the ability of new anti-rejection drugs to limit acute rejections within the first year post surgery. Whether these important findings can be extended also to other transplants is unknown at the present, so that up to now the half-life for most organs other than kidney is only 9.9 years, with no substantial improvement over the past 20 years. Medications moreover have to be given long-life, which invariably impairs systemic immunity translating in more risk of infections and cancers. Tumors of viral origin, including non-Hodgkin’s lymphoma, squamous cell-carcinoma of the skin, and Kaposi’s sarcoma are 6.5 times more common in transplant recipients than in the general population [2], and their frequency is estimated to increase with time.

Pharmacologic Monitoring of Immunosuppressive Drugs

Organ transplantation as a treatment modality for patients with end-stage organ diseases of kidney, heart, liver, and pancreas has achieved impressive results in the past 2 decades thanks to better understanding of basic immunobiology and more advanced measures for medical and surgical management. Although immunosuppressive therapies to overcome host reaction to allografts have been employed since the early days of clinical transplantation, immunosuppressive agents and treatment protocols are constantly evolving. Since the 1978 introduction of cyclosporine (CsA) [1] there has been some doubt about its value as the single most important agent in the armamentarium of maintenance immunosuppression for organ transplantation. Triple-drug therapy with CsA, corticosteroid and azathioprine is now the most frequently used regimen for cadaver kidney recipients. However, the continuing search for more selective and specific agents has become, in the past decade, one of the priorities for transplant medicine. Some of these compounds are now entering routine clinical practice: among them are tacrolimus, mycophenolate mofetil (MMF) and sirolimus.

Mechanisms and Mediators of Cyclosporine-Induced Renal Vascular Changes

Cyclosporines are a family of structurally related endecapeptides isolated as metabolites during fermentation of the soil fungi Trichoderma polysporum Rifae and Cylindrocarpon lucidum Booth [1]. Cyclosporin A (CyA), the clinically active compound, is a hydrophobic cyclic peptide containing a unique, nine-carbon amino acid bearing an ethylene band, which is essential for its biological activity. In contrast with the conventional immunosuppressive drugs, azathioprine and adrenal corticosteroids, CyA selectively inhibits adaptive immune responses, primarily through the inhibition of interleukin-2 gene translocation to mRNA and reduction of interleukin-2 production at T-cell level, while other events of T-cell activation continue unabated [2]. By virtue of its peculiar and selective activity on the immune system, CyA has improved the management of patients with organ transplantation by increasing graft and patient survival rates [3,4]. Moreover, the use of CyA has recently been advocated for the prevention of graft-versus-host disease in bone marrow transplantation [5] and for the treatment of autoimmune diseases such as uveitis [6], systemic lupus erythematosus [7], rheumatoid arthritis [8], and various forms of glomerulonephritis [9]. However, the major concern regarding CyA therapy has focused upon its association with an array of side-effects, the most serious of which is nephrotoxicity [10,11]. Thus, acute reversible dose-related decreases in renal function have been observed in over 50% of cases in some series [12]. Persistent increase in serum creatinine has prompted discontinuation or reduction of the CyA dose in a large number of patients, with subsequent improvement in renal function [13].

Models of human renal disease

During the last few years exciting new insights into the mechanisms underlying the development of human renal diseases have been obtained from animal experiments. For the interpretation of the pathogenesis of membranous glomerulonephritis in man, important knowledge has been gained from the Heymann glomerulonephritis model in rats. Experimental studies enabled us to establish that interaction of antibodies with cell surface antigen results in antigen redistribution, immune complex aggregation and shedding, which are influenced by physiological forces of flow, filtration, and diffusion [1, 2]. Experimental models of chronic renal failure, particularly the renal mass ablation model in rats, provided a tool for understanding the characteristics of the deleterious intrarenal processes responsible for the progression of several human renal diseases to glomerulosclerosis and renal failure [3]. Several factors such as glomerular capillary hypertension and hyperperfusion, coagulation abnormalities, and alterations of lipid metabolism have been proposed as accounting for progressive glomerulosclerosis after nephrectomy [4–6]. The availability of experimental models of renal disease which closely mimic the human condition has greatly helped in defining therapeutic strategies such as dietary or pharmacological manipulations aimed at preventing or retarding the progression of kidney disease.