Kidney transplantation,bioengineering and regeneration: an originally immunology-based discipline destined to transition towards ad hoc organ manufacturing and repair

Kidney transplantation (KT), as a modality of renal replacement therapy (RRT), has been shown to be both economically and functionally superior to dialysis for the treatment of end-stage renal disease (ESRD). Progress in KT is limited by two major barriers: a) a chronic and burgeoning shortage of transplantable organs and b) the need for chronic immunosuppression following transplantation. Although ground-breaking advances in transplant immunology have improved patient survival and graft durability, a new pathway of innovation is needed in order to overcome current obstacles. Regenerative medicine (RM) holds the potential to shift the paradigm in RRT, through organ bioengineering. Manufactured organs represent a potentially inexhaustible source of transplantable grafts that would bypass the need for immunosuppressive drugs by using autologous cells to repopulate extracellular matrix (ECM) scaffolds. This overview discusses the current status of renal transplantation while reviewing the most promising innovations in RM therapy as applied to RRT.     

Pathophysiologie und Therapie von Lipidstoffwechselstörungen bei Nierenerkrankungen

Summary Nephrotic syndrome, uremia, hemodialysis, peritoneal dialysis, and renal transplantation are accompanied by alterations in lipoprotein metabolism (Table 1). In nephrotic patients, total cholesterol, LDL, VLDL and triglycerides are elevated, while HDL may be increased, normal, or decreased. The pathophysiology includes increased hepatic synthesis of VLDL and cholesterol, decreased activity of lipoprotein lipase, and increased urinary excretion of HDL (Fig. 1). The risk of coronary heart disease (CHD) is increased in nephrotic patients, and elevated LDL-cholesterol may contribute to this risk. Cholesterol lowering diet and drugs are indicated. Presently, Lovastatin and Simvastatin are the most potent cholesterol lowering drugs in nephrotic patients with good evidence of long-term safety. Most patients with impaired renal function or on hemodialysis have moderate hypertriglyceridemia due to decreased lipoprotein lipase activity (Fig. 2). HDL may be slightly decreased. Although the risk of CHD is increased in these patients, triglyceride lowering drugs are not indicated, since no benefit can be expected. Peritoneal dialysis is accompanied by elevated VLDL in addition to hypertriglyceridemia. Reabsorption of large amounts of glucose from peritoneal dialysis fluid increases the carbohydrate load and stimulates hepatic VLDL synthesis. Cholesterol lowering therapy may be advantageous, but the experience is very limited. Side effects of lipid lowering drugs may be aggravated in renal failure. Total cholesterol, LDL, VLDL, and triglycerides are elevated in 50% of patients following renal transplantation. Corticosteroides and cyclosporin are major causes of hyperlipidemia. Cholesterol lowering therapy is indicated since the incidence of CHD is increased. Lipid lowering diet, triple immunosuppression with low dose cyclosporin, azathioprim, and prednisone, or conversion from cyclosporin to azathioprim are valuable measures to reduce cholesterol. Low-dose lovastatin (20 mg/24 h) seems to be an effective and safe cholesterol lowering drug in renal transplantation, while higher doses may induce rhabdomyolysis.

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Abkürzungsverzeichnis NS Nephrotisches Syndrom - LDL Low Density Lipoprotein Cholesterin - VLDL Very Low Density Lipoprotein Cholesterin - HDL High Density Lipoprotein Cholesterin - KHK Koronare Herzerkrankung - HMG-CoA 3-Hydroxy-3-Methylglutaryl-Coenzym A - NIH National Institute of Health - GFR Glomeruläre Filtrationsrate     

Current trends in renal transplant immunosuppression

Several new immunosuppressives have been introduced in renal transplantation during the past decade. Mycophenolate mofetil, tacrolimus, cyclosporine microemulsion, sirolimus, monoclonal and polyclonal antibodies have all contributed to decreasing the rate of acute rejection. However, a more intense immnuosuppression has resulted in an increased incidence of opportunistic infections and malignant diseases. The main cause of death in renal transplant recipients are cardiovascular diseases, and the majority of patients die with a functioning graft. Renal transplant recipients are at an increased risk of the development of cardiovascular diseases due to prolonged uremia and dialysis itself, combined with the proatherogenic effect of immunosuppressive drugs. Corticosteroids and calcineurin inhibitors are the main groups of drugs associated with an increased risk of atherosclerosis. The main challenge in the present and future treatment of transplanted patients is the establishment of an immunosuppressive protocol that will minimize or completely avoid proatherogenic immunosuppressives while preserving the low incidence of acute rejection.     

Laboratory tests in acute renal failure]

This review is focused on the roles of laboratory test in acute renal failure (ARF). The roles of the laboratory test changes along with the alterations in clinical features and with the advances of treatment. Recent acute renal failure is characterized by the following three features: most of the ARF develops in hospitals, the frequency of nonoliguric ARF is increasing, and the association of other organ failure such as heart failure, liver failure or respiratory failure, increases the mortality rate. Hemodialysis is instituted in the early phase of ARF to enable the supply of enough nutriments and drugs. These features of recent ARF increases the importance of the frequent analysis of plasma creatinine in patients, who are at risk for ARF, to diagnose ARF at the onset. After the development of ARF, laboratory tests for the evaluation of other organ function is repeated. The development of new drugs increases the incidence of interstitial nephritis, and the advances in the therapeutic approach on systemic diseases (such as SLE or PN), which frequently develop ARF, alter the prognosis of these diseases. Since the early diagnosis of these diseases is important, it is necessary to develop noninvasive and reliable tests for the diagnosis of these diseases.     

Use of HMG-CoA Reductase Inhibitors after Kidney and Heart Transplantation

Hypercholesterolaemia is common in patients treated with cyclosporin after kidney and heart transplantation; coronary vasculopathy, graft atherosclerosis or cardiovascular complications are the most frequent causes of mortality. Coronary heart disease has been attributed to hypercholesterolaemia and has been identified as a major risk factor of long term graft outcome in patients after kidney transplantation. HMG-CoA reductase inhibitors have been proven to be effective in lowering serum cholesterol concentrations in kidney and heart graft recipients receiving long term cyclosporin immunosuppression, and are therefore the drugs of choice in patients requiring treatment for hypercholesterolaemia after organ transplantation. The hydrophilic HMG-CoA reductase inhibitors, such as pravastatin and fluvastatin, should be distinguished from the lipophilic agents, lovastatin and simvastatin, with regard to toxicity and accumulation. Maximal doses of drugs in the latter group should be avoided, whereas the former have been administered at high dosages over prolonged periods of time without adverse effects. Recent preliminary data indicate that treatment with pravastatin not only decreases serum cholesterol but may have beneficial effects on the incidence, recurrence and severity of rejection episodes after kidney and heart transplantation.     

Glycosylated haemoglobin in chronic renal failure and after renal transplantation.

Haemoglobin A1 (HbA1) was determined by ion-exchange chromatography in 37 normoglycaemic patients with chronic renal failure (CRF) and 26 with successful renal transplants. Blood glucose concentrations in patients with CRF were similar to those in controls, and there was a significant correlation between fasting blood glucose concentration and HbA1 in these groups. HbA1 in patients with CRF was, however, significantly lower than that in control subjects. Concentrations of HbA1 in patients on haemodialysis, peritoneal dialysis, and those with steady state CRF prior to dialysis were not significantly different from each other. Whereas patients with successful renal transplants of greater than 3 months' duration had HbA1 concentrations indistinguishable from controls, HbA1 in patients with transplants of shorter duration were significantly lower. These observations are suggestive of a shortened erythrocyte survival in CRF per se. Furthermore, these results indicate: (a) the inadequacy of HbA1 in monitoring the quality of diabetic control in patients with CRF, and (b) the absence of a specific effect of dialysis on HbA1, and the restoration to normal HbA1 after successful renal transplantation.     

Biologics in the prevention and treatment of graft rejection

Biologics are used in solid organ allografting and hematopoietic stem cell transplantation (HSCT) for the induction and maintenance of immunosuppression. In solid organ transplantation, antibodies targeting T cells are part of induction protocols administered for initiation of immunosuppression during organ transfer and during sustained post transplant periods for prevention of graft rejection. Several clinical trials in renal allografting provide data for the efficacy and safety of biologics in this clinical setting. Application of biologics also allows the reduction of calcineurin inhibitors, thereby reducing toxicity and improving long-term graft function. In acute rejection periods, anti T cell antibodies are established in steroid-resistant cases. Strategies interfering with the activity of soluble cytokines are less frequently applied for solid organ transplantation. In HSCT, T cell directed antibodies as part of conditioning protocols improve engraftment and reduce the incidence of detrimental graft vs host disease (GvHD). In acute GvHD, both antibodies targeting T cells and cytokines like TNF-α are established therapeutics for remission induction.     

Role of anti-interleukin-2 receptor antibodies in kidney transplantation

From the early 1960s, the mainstay of immunosuppression for kidney transplantation has been corticosteroids. Since then, many new drugs have been developed to maintain the renal allograft. Current maintenance immunosuppression commonly consists of corticosteroids, antiproliferative agents and calcineurin inhibitors (e.g. cyclosporin). More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction at the time of transplantation or to treat rejection. With the advances in molecular technology, a new class of antihuman antibodies [the anti—interleukin-2 receptor (IL-2R) antibodies] has emerged that incorporate a murine antigen-binding site on to a human immunoglobulin backbone. Such methodology creates antihuman antibodies with high affinity for the epitope and with prolonged serum antibody half-lives. Interleukin-2 and its receptor are central to lymphocyte activation and are the main targets of calcineurin inhibitors. In addition, the anti—IL-2R antibodies inhibit a key target in immune activation. Daclizumab and basiliximab have been shown to significantly reduce the incidence of acute rejection in kidney transplantation. Since these anti—IL-2R antibodies are well tolerated and since calcineurin inhibitors are intrinsically nephrotoxic, anti—IL-2R antibodies have been used in an attempt to avoid cyclosporin after transplantation. Data from clinical trials seem to indicate that the addition of an anti-IL-2R antibody is not sufficient to warrant complete withdrawal of calcineurin inhibitors for more than a very short period after transplantation. A more promising role for anti—IL-2R antibodies may be in renal transplant recipients with delayed graft function (DGF). Recent data on the use of either low-dose calcineurin inhibitors or sirolimus (rapamycin) in conjunction with the anti-IL-2R antibodies for patients with DGF showed no increased risk of acute rejection. Long-term graft survival with use of these low-dose calcineurin inhibitor protocols has yet to be established.     

Cutaneous responses to histamine, compound 48/80, and codeine in patients with chronic renal failure

Pruritus is a common symptom associated with chronic renal failure (CRF). But increased plasma histamine levels and skin mast cell proliferation previously reported in these patients did not correlate with the intensity of the pruritus. Since increased mast cell releasability was described in chronic idiopathic urticaria, we attempted to examine whether this mechanism could explain pruritus in patients with CRF. Twenty-five patients with end stage renal failure were skin tested with histamine, codeine, and compound 48/80. There were nine patients on continuous ambulatory peritoneal dialysis, eight patients on hemodialysis, (tested both before and after dialysis) and eight patients with advanced CRF. Wheal area after intradermal injection of three concentrations of the above substances was measured. In general, the wheal areas in all patients with CRF were either similar to or smaller than those of the control group who were without renal impairment. In conclusion, patients with CRF with or without dialysis therapy demonstrated unchanged or decreased skin test responses to histamine, codeine, and compound 48/80. Increased mast cell releasability cannot explain the pruritus in patients with CRF.     

Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant

BACKGROUND AND METHODS: The extent to which renal allotransplantation - as compared with long-term dialysis - improves survival among patients with end-stage renal disease is controversial, because those selected for transplantation may have a lower base-line risk of death. In an attempt to distinguish the effects of patient selection from those of transplantation itself, we conducted a longitudinal study of mortality in 228,552 patients who were receiving long-term dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a waiting list for transplantation, 23,275 of whom received a first cadaveric transplant between 1991 and 1997. The relative risk of death and survival were assessed with time-dependent nonproportional-hazards analysis, with adjustment for age, race, sex, cause of end-stage renal disease, geographic region, time from first treatment for end-stage renal disease to placement on the waiting list, and year of initial placement on the list. RESULTS: Among the various subgroups, the standardized mortality ratio for the patients on dialysis who were awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to 58 percent lower than that for all patients on dialysis (annual death rate, 16.1 per 100 patient-years). The relative risk of death during the first 2 weeks after transplantation was 2.8 times as high as that for patients on dialysis who had equal lengths of follow-up since placement on the waiting list, but at 18 months the risk was much lower (relative risk, 0.32; 95 percent confidence interval, 0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups within 5 to 673 days after transplantation in all the subgroups of patients we examined. The long-term mortality rate was 48 to 82 percent lower among transplant recipients (annual death rate, 3.8 per 100 patient-years) than patients on the waiting list, with relatively larger benefits among patients who were 20 to 39 years old, white patients, and younger patients with diabetes. CONCLUSIONS: Among patients with end-stage renal disease, healthier patients are placed on the waiting list for transplantation, and long-term survival is better among those on the waiting list who eventually undergo transplantation.     

Multi organ transplantation: a review of the Irish experience

As the criteria for organ transplantation have broadened, multi organ transplantation has become more common. Calcineurin inhibitor induced end stage renal failure is a common indication for kidney transplantation. We present our experience of 12 kidney transplants, in 11 patients, over a period of 9 years all in the setting of multi-organ transplantation. Kaplan-Meier survival estimates were applied. Estimated patient survival at 1, 3 and 5 years post transplant was 100%, 83% and 66% respectively. Estimated graft survival at 1, 3 and 5 years was 90%, 79% and 63% respectively. The estimated median renal graft survival was 6.2 years. Calcineurin inhibitor toxicity was the most common cause of end stage renal failure in this series of patients. There is a very fine balance between ideal immunosuppression for kidney and other organ transplants. Patients who avoid morbidity such as sepsis or graft rejection enjoy good graft function at 5 years post transplant.     

Hepatitis C therapy with long term remission after renal transplantation

Hepatitis C virus infection (HCV) is common in patients with end-stage renal disease (ESRD) and long observation periods have shown the detrimental effect of HCV infection on patient and graft survival after renal transplantation. At present, interferon is the most important agent for the treatment of hepatitis C in ESRD; however, limited information exists concerning the long-term response of patients who undergo renal transplantation after successful antiviral therapy. We describe the evolution of HCV infection in a dialysis patient with hepatitis C who was successfully treated with interferon alpha and then underwent renal transplantation. He received aggressive immunosuppression during the induction phase and for allograft rejection; however, regular screening showed complete absence of biochemical and virological relapse of HCV over a 6-year post-transplantation period. We conclude that interferon can offer excellent response in selected dialysis patients with hepatitis C. Alternative strategies with newer antiviral agents are currently under active investigation.     

Long-term outcome of kidney transplantation in adult recipients with focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is an important cause of nephrotic syndrome and end-stage renal disease. FSGS recurrence after renal transplantation has a potentially detrimental course leading to the loss of renal function. In order to establish FSGS recurrence rates and evaluate the course of the disease on living-related-donor renal transplantation in ethnic Korean adults (> or = 18 years), we reviewed our experiences of 27 kidney transplantations with FSGS over the last 15 years. Of the 27 renal allografts, 13 were found to have recurrent FSGS by graft biopsy. In comparison with background data upon patients with and without recurrence of FSGS, the donor age of patients with recurrent FSGS was significantly higher than that of those without recurrence (median, 39 years vs 26, p < 0.05). In terms of, age at transplantation, length of dialysis period, and mode of dialysis no differences were found between recurrent and nonrecurrent cases. The graft survival rate of recipients from a kidney donor of age less than 40 years was significantly higher than that of recipients from a kidney donor of age more than 40 years, at 5 and 10 years, respectively (87% vs 33%, 41% vs 0%, p < 0.05). The association between clinical variables and recurrence was assessed by multiple logistic regression analysis, and donor age was found to be a risk factor of FSGS recurrence (p<0.05). Variables such as HLA-mismatch numbers and immunosuppression were not found to be associated. In conclusion, the recurrence rate of FSGS in adult recipients with FSGS was 48% and patients that received kidney from an older donor appear to be at higher risk of developing recurrence. The use of a renal graft from a younger donor is considered advisable for adult recipients with FSGS.     

Hyperparathyroidism and bone disease after renal transplantation

Metabolic bone disease is one of the most frequent complications of chronic renal failure. Numerous disorders leading to the metabolic bone disease can be reversed by successful renal transplantation. However, in some patients, in spite of satisfactory renal function, some disorders may persist for months after successful transplantation, e.g. increased parathyroid hormone secretion. Besides, drugs used in immunossuppressive therapy may cause metabolic bone disease or reduction of of bone mass. Therefore, significant loss of mass takes place in the majority of patients during the first six months. Among drugs used in the prevention of bone disease after transplantation of solid organs the most important role have biphosphonates and vitamin D, i.e. calcitriol.     

颅内出血心脑死亡器官捐献供体的安全性评估

随着器官移植技术的发展,肾移植成为治疗终末期肾病的最有效方法,与透析相比,肾移植受者预期寿命得到延长,生活质量显著提高,总的治疗费用基本持平。然而,器官供应短缺是肾移植的主要障碍,等待移植的患者以及等待中死亡的患者人数却逐年增加,当今心脑死亡供体的器官捐献是我国肾移植的主要来源,扩大标准供体的使用已被提上日程以扩大供体池。实践中,颅内出血导致患者心、脑死亡所占比例大,成为供体器官最重要来源。但是,颅内出血病因众多,因供体评估时间、评估手段、评估经验欠缺等原因,存在供体既存的其他病理性因素未被发现或者认识不足,例如供肾质量差,隐匿的肿瘤性病变等情况。一旦将此类供肾移植给受着,则会带来肿瘤的复发、移植肾功能丧失、甚至危及受体生命的严重后果。反之因过度担心术后并发症,可能将符合标准的移植物弃用,而导致器官的浪费现象。因此通过文献回顾,总结国内外有颅内出血病史供体器官的使用经验和原则。     

Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: The importance of durable chimerism

Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system in order to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for anti-rejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for anti-rejection drugs. Establishment of durable hematopoietic chimerism through hematopoietic stem cell transplantation (HSCT) has been shown in preclinical models and patients to lead to donor specific tolerance. However, the application HSCT is limited by the potential toxicity of conditioning regimens, the risk of graft versus host disease (GVHD) and the challenge of HLA mismatching. In this review we describe the clinical outcomes and science behind a CD8⁺/TCR^? facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to mismatched renal allografts while minimizing the risk of graft-versus-host GVHD and achieving avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients.     

Elevation of pro-inflammatory cytokines, C-reactive protein and cardiac troponin T in chronic renal failure patients on dialysis

Chronic renal failure (CRF) patients suffer from a chronic inflammation. They are at increased risk of cardiovascular disease. In order to investigate this inflammatory process and cardiovascular risk factors associated with haemodialysis (HD) and peritoneal dialysis (PD), we compared serum/plasma pro-inflammatory cytokines, C-reactive protein (CRP), and cardiac troponin T (cTnT) of 146 CRF patients treated or not treated with PD or HD. Serum cytokines and CRP as well as plasma cTnT were measured by enzyme-linked immunosorbent assay, chemiluminescence immunoassay, and electrochemiluminescence immunoassay, respectively. Results indicated that serum interleukin (IL)-18 concentrations were significantly higher in PD and low creatinine clearance pre-dialysis CRF (LCC) patients than HD patients (both p < 0.05). IL-6 and tumour necrosis factor (TNF)-alpha concentrations were significantly higher in PD patients than LCC patients (both p < 0.01). Serum hsCRP and plasma cTnT in HD were significantly higher than LCC (both p < 0.01). The elevation of pro-inflammatory cytokines should play an important role in the chronic inflammation and increased cardiovascular risk of CRF patients on dialysis. We are evaluating further the diagnostic and prognostic applications of pro-inflammatory cytokines and biochemical inflammatory markers for these patients.     

Arterial hypertension in renal transplant recipients

Arterial hypertension develops in up to 80% of renal transplant recipients. Uncontrolled hypertension induces left ventricular hypertrophy, heart failure and death, but also promotes deterioration of allograft function. Cadaveric transplantation, delayed graft function, renal artery stenosis, presence of native kidneys, increased body weight and therapy with calcineurin inhibitors and steroids have been associated with an increased incidence of hypertension after kidney transplantation. Cyclosporine increases both systemic and renal vascular resistance, enhances sympathetic activation, endothelin production and, possibly, decreases vascular relaxation by decreasing the generation of nitric oxide. Tacrolimus has less pronounced prohypertensive role after renal transplantation. Corticosteroids contribute to the development of hypertension, since their withdrawal results in a significant decrease of blood pressure in the majority of patients. Renal artery stenosis occurs in almost 12% of hypertensive renal transplant recipients. It is a correctable cause of hypertension, and for this reason should be investigated in all suspected patients. Doppler ultrasonography is used as the screening method that is highly sensitive and specific in the hands of a well-experienced investigator. However, dependence of the method on the experience of the investigator is its major drawback. Magnetic resonance angiography and spinal computed tomography angiography are useful noninvasive methods, but arteriography remains a method for establishing the definitive diagnosis. Percutaneous balloon angioplasty, with or without placement of the stent, is successful in the majority of patients, but with a high incidence of restenoses (20%). Surgery is indicated for stenoses that cannot be treated with angioplasty or that recur. Auto-transplantation of the kidney with complex stenoses of graft arteries is useful in selected cases. Posttransplant hypertension should be aggressively treated to prevent the development of end-organ damage. Every effort should be invested in reducing immunosuppression when appropriate, together with salt restriction and weight reduction. Calcium channel blockers have good antihypertensive properties accompanied with minimization of cyclosporine-induced renal vasoconstriction. Angiotensin-converting enzyme inhibitors (ACEi) should be used in patients with proteinuria. Renal function should be carefully monitored after their introduction since they may cause transitory deterioration of glomerular filtration and/or hyperkaliemia. ACEi can induce anemia in renal transplant recipients, side effect that is often used in the treatment of posttransplant erythrocytosis. All other antihypertensive drugs could be used, with minoxidil being the most potent one. Patients with resistant hypertension should be investigated for the presence of renal artery stenosis. After exclusion of rejection, renal artery stenosis and recurrent disease, in cases of severe hypertension, native kidneys laparoscopic nephrectomy should be considered.     

Problems and solutions for artificial kidney.

The uremic syndrome is the prototype of a slowly progressive endogenous intoxication, when a detoxifying organ (in this case the kidney) fails. It is characterized by the gradual retention of a host of metabolites, which is in part corrected by dialysis, allowing survival with an acceptable quality of life. This paper reviews the main problems of hemodialysis today, and possible solutions. Adequacy of dialysis is estimated currently from the concentration of urea, which is used as a marker molecule. The problem is that urea is not really toxic by itself. Other markers with known toxicity, such as middle molecules (300-12,000 D) and protein bound compounds should be considered. The question then arises whether the classical dialytic concept based on diffusion should be modified. Adsorptive systems may be strong binders of protein bound solutes. Other concepts that are now arising, and that may add to toxin removal, are slow and daily dialysis. Another question that could be raised is whether it would not be possible to support toxin removal, by administering peroral sorbants. Dialysis patients are prone to vascular disease and die early from cardio-vascular complications. One of the solutions for this problem could be to bring the blood of dialyzed patients into contact with antioxidants (e.g. vitamin C or E). The risk for perdialytic hemodynamic instability is increased in many dialysis patients. The ideal solution would be to develop an "intelligent" dialysis system, whereby blood volume and plasma osmolality are sensed continuously, and ultrafiltration and dialysate sodium concentration are adapted in function of this evolution. An adequate vascular access is indispensable to perform adequate dialysis, but thrombotic/stenotic complications are frequent. This could be prevented by molecular biological modification of vascular grafts, whereby genetic information is entered into the cells, blocking the natural chain of events that otherwise unavoidably leads to neointimal hyperplasia and atherosclerosis. Another old dream is to develop a wearable artificial kidney, whereby patients can move around, and be treated 24 hours per 24 hours, in stead of being treated intermittently at a specific location by the dialysis machine. According to some authors, part of the natural renal function could be replaced by cultured renal tubular cells, which are brought in contact with the blood of the patients. It is concluded that thrilling improvements lie ahead in the future, but the following questions arise: 1) What is the cost of all these improvements? 2) Will it remain possible to reimburse all this? 3) What is going to happen in transplantation, mainly regarding improvements in immunosuppression and the development of xenotransplantation?