Renal Replacement Therapy - The good and the bad

Transcription

1 Renal Replacement Therapy - The good and the bad Introduction Prevalence of Chronic kidney disease in Asia is rising as screening becomes more widespread. Glomerulonephritis as a cause of CKD is more common in Asia than in the Western world, perhaps because of infections and overcrowding. It is estimated that over 90% of patients with ESRD in South Asia die within months of diagnosis because they cannot afford treatment.the age-adjusted incidence of ESRD of India is estimated at 229 per million. Renal replacement therapy, which is the treatment of ESRD, constitutes Hemodialysis, Peritoneal dialysis and renal transplantation. Hemodialysis is the most common form of RRT in Asia, followed by peritoneal dialysis and renal transplantation. Ideally, when patients begin renal replacement therapy (RRT), they should meet the following conditions: firstly, they should not require hospitalization for the management of untreated acute or chronic complications of uremia; secondly, they should have a thorough understanding of the different treatment options; and thirdly, they should have a functioning, permanent access for the dialysis therapy of their choice.

2 Hemodialysis vs Peritoneal dialysis Dialysis modalities include hemodialysis, either in a dialysis center or at home, or peritoneal dialysis, including chronic ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). The percentage of patients undergoing hemodialysis far surpasses that being maintained on peritoneal dialysis. Based on the 2009 United States Renal Data System (USRDS) report, 94 and 6 percent began hemodialysis and peritoneal dialysis in the United States, respectively. Approximately 11 percent of dialysis patients worldwide are treated with peritoneal dialysis, with the relative proportion increasing in developing, but not developed countries Approximately 2.5 percent of patients with end-stage renal disease (ESRD) received a renal transplant as the initial treatment for their ESRD. Hemodialysis is generally more expensive than peritoneal dialysis. In 2006, Medicare expenditures for hemodialysis were $71,889 per patient per year, compared with $53,327 for those on peritoneal dialysis The selection of dialysis modality is influenced by a number of considerations such as availability and convenience, comorbid conditions, socioeconomic and dialysis-center factors, the patient's home situation, the method of physician reimbursement, and the ability to tolerate volume shifts. Patients generally like to have a choice of modalities. As an example, in the Netherlands study cited above, in which, among 738 eligible patients, only 38 agreed to be randomly assigned to a specific therapy, 50 percent of patients chose peritoneal dialysis Among some patients, it may be optimal to utilize both hemodialysis and peritoneal dialysis in a way that provides the advantages of each modality, but without the disadvantages. An optimal strategy, for example, may be an integrated-care approach in which incident dialysis patients initially undergo peritoneal dialysis, with transfer to hemodialysis once complications ensue with peritoneal dialysis. This is based in part on the hypothesis that, principally via its ability to preserve residual renal function, peritoneal dialysis provides significant benefits as an initial modality. Other benefits may include preservation of vascular access and perhaps better survival during the first few years of dialysis A large number of studies, practically all retrospective and observational, have been performed concerning the relative effect upon mortality of peritoneal dialysis versus incenter hemodialysis. The results have been conflicting, with hemodialysis reportedly having no difference, a relative benefit, or a relative adverse effect upon survival, compared with peritoneal dialysis. Reasons for these variable results include selection bias, flawed study design, differences in mortality effects with time from initiation of dialysis, differences in comorbid diseases, and other factors. Multiple studies have found that peritoneal dialysis may provide relative short-term survival benefits, but comparable or decreased survival after one to two years. Analysis of data provided by the United States Renal Data Systems (USRDS) also suggested a survival benefit associated with peritoneal dialysis during the first few years on dialysis, but which was lost over time. Patients on peritoneal dialysis had a slight overall survival

3 advantage, compared with those on hemodialysis during the first three years of therapy, but, at five years, survival was equal at 34 percent. The time after dialysis initiation at which the relative survival benefit associated with peritoneal dialysis is lost and survival comparisons start to favor hemodialysis depends on multiple variables, including the cause of ESRD, vintage (ie, the year patient started renal replacement therapy), gender, country of treatment, and presence or absence of comorbidities. As an example, the survival advantage conferred by peritoneal dialysis is not as robust if the primary case of ESRD is diabetes, the patient is older, or the patient has comorbidities. The presence of heart failure may also attenuate the early survival benefit associated with peritoneal dialysis. Although one study found one- and two-year survivals of 90 and 64 percent among peritoneal dialysis patients with severe systolic dysfunction, a subsequent study found poorer survival among new dialysis patients with heart failure who were initially treated with peritoneal dialysis, compared with hemodialysis. ACUTE COMPLICATIONS DURING HEMODIALYSIS: 1. Hypotension 25 to 55 percent of treatments 2. Cramps 5 to 20 percent

4 3. Nausea and vomiting 5 to 15 percent 4. Headache 5 percent 5. Chest pain 2 to 5 percent 6. Back pain 2 to 5 percent 7. Itching 5 percent 8. Fever and chills <1 percent 9. Hemolysis 10. Arrhythmias 11. Air embolism 12. Access issues Renal replacement therapy in acute kidney injury : Recovery of renal function and effect of hemodialysis membrane Dialysis may be required in patients with severe acute renal failure. Mortality in such patients is often associated with infection or bleeding. Since these problems can be exacerbated by uremia, it has been suggested that dialysis begun before evidence of overt uremia may lead to improved survival. This issue is complicated by evidence that dialysis may delay the recovery of renal function. Before discussing dialysis in acute renal failure, an overview of general issues in non-dialytic management of patients with established acute renal failure is indicated. The basic goals for the management of established acute renal failure are the maintenance of fluid and electrolyte balance, avoidance of nephrotoxic medications, adequate nutrition, treatment of infections, correction of reversible prerenal (eg, hypovolemia) and postrenal factors, close monitoring, and proper dosing of medications. There is a theoretical concern that dialysis might have detrimental effects on renal function. Three factors that may be important in this regard include a reduction in urine output; induction of hypotension; and complement activation resulting from a blood-dialysis membrane interaction. A reduction or cessation of the urine output results in both removal of excess volume and of urea. Urea may be a surrogate marker of other substances that are removed by dialysis which stimulate urine output. Hypotension is a common complication of hemodialysis. This may be a particular problem in recovery of renal function in a patient who has acute tubular necrosis (ATN). Whereas normal kidneys vasodilate in the presence of ischemia as part of the autoregulatory response to maintain renal blood flow and glomerular filtration rate near the baseline level, autoregulation is impaired in ATN, resulting in recurrent ischemic tubular injury, thereby delaying the restoration of function. Complement activation during the blood-dialyzer interaction with cuprophane membranes, but not more compatible membranes, can lead to neutrophilic infiltration into the kidney (and other tissues) and prolonged acute kidney injury. We favor the routine use of biocompatible dialysis membranes among patients with acute kidney injury. Membranes can be of low or high flux. High flux membranes can enhance removal of putative toxins and improve outcome, but may also allow the back transport (from dialysate to blood) of potentially harmful water-borne molecules.

5 Having the purest dialysate water possible should be a goal when using these more porous membranes to utilize their positive attributes and to minimize their potential risks. If the water used is high quality, we suggest that high flux biocompatible dialysis membranes be used in patients with acute kidney injury. If the water system is not of high quality, low flux biocompatible dialysis membranes should be used. Continuous renal replacement therapies Continuous renal replacement therapies (CRRTs) involve either dialysis (diffusion-based solute removal) or filtration (convection-based solute and water removal) treatments that operate in a continuous mode. Variations of CRRT might run 12 to 14 hours, especially during daytime periods of full staffing. This regimen has become more prevalent in Europe and has been called "go slow dialysis." Other variations of this technique are discussed below and probably should be called hybrid therapies because they are a merging of intermittent and continuous duration. The longer duration of CRRT makes it quite different from conventional intermittent hemodialysis (HD), in which each treatment lasts four to six hours or less. The major advantage of continuous therapy is the slower rate of solute or fluid removal per unit of time. Thus, CRRT is generally better tolerated than conventional therapy since many of the complications of intermittent HD are related to the rapid rate of solute and fluid loss. Artificial kidneys If an implantable device was to mimic the function of a native kidney it would need to operate continuously to remove solutes. The device would not necessarily need to be functionally flexible; that is, its capacity to remove water and solutes would not need to be able to adapt to day-to-day variations (as a native kidney can). Regular dialysis techniques are effective despite not having this adaptive capacity. The device would need to be wearable or implantable, lightweight, safe, and reliable. Nanotechnology, the science of developing functional machine systems on the scale of nanometers, could help in the design of membranes that are more selective than polymer membranes; that is, a membrane could be designed that filters in a manner analogous to that of the glomerulus. Other filters placed in series with this membrane could separate waste compounds from substances to be retained and returned to the circulation.

6 Tissue engineering and stem-cell techniques The aim of tissue engineering is to repair dysfunctional organs by using human tissue. Approaches to the repair and (re)construction of kidneys include the integration of new nephrons into native kidneys or into other sites in the organism,the repair of kidneys in situ with the use of stem cells, and the generation of histocompatible tissues with the use of nuclear transplantation. This new field combines principles of cell transplantation, materials science and engineering to construct biological substitutes that will restore the function of diseased and injured tissues This technology has great potential for use in renal replacement, but there are several safety issues common to the options. First, transformation of stem cells into cells with oncogenic potential can occur; harnessing stemcell proliferative potential could help to optimize the amount of tissue that is repaired, but proliferation could become neoplastic.25 Maintaining the functionality and viability of cells that are either injected or implanted into tissue-engineered devices, and the immunological issues associated with the use of nonautologous cells, are further obstacles. Delivering cells to the correct anatomical location and preventing them from migrating thereafter is also challenging.

7 Peritoneal dialysis Peritoneal dialysis now the most commonly practiced form of home dialysis is used to treat an estimated 250,000 individuals worldwide.1 Use of the therapy has always been strongly influenced by extrinsic factors such as government policy and clinician reimbursement. Although increasing overall, particularly in emerging economies, use of peritoneal dialysis is stable or decreasing in countries where more money is spent on health care but where different pressures apply. Changes in health-care trends present both opportunities and challenges to peritoneal dialysis. Growth is good for business, so a guaranteed increase in the use of the

8 therapy will ensure continued industrial and clinical investment and innovation. Peritoneal dialysis is the most common method of home dialysis and its relative simplicity is attractive in many settings; for example, use of the therapy enables and encourages patient autonomy and control, which is in keeping with the aspirations of self care in chronic disease management and translates into greater reported treatment satisfaction. Evidence also exists that in many health-care systems, peritoneal dialysis is less costly than in-centre haemodialysis. A recent cost benefit analysis of peritoneal dialysis in the UK by the National Institute of Clinical Excellence estimated that the country s National Health Service could make significant savings if the proportion of patients who commence renal replacement treatment with peritoneal dialysis was increased. This finding undoubtedly also applies to many other countries that do not currently take sufficient advantage of the therapy, such as the USA, where recent changes to the dialysis reimbursement system have been designed to encourage greater usage of home dialysis. In some countries, notably Hong Kong, Mexico and Thailand, high use of peritoneal dialysis in the context of a peritoneal dialysis-first policy has largely been a result of health economic arguments. However, these arguments are not universally applicable; in countries like India that have to import dialysis fluid and/or in those with very low labour costs, peritoneal dialysis may be more expensive than haemodialysis. Challenges of peritoneal dialysis Along with its own set of advantages as RRT, peritoneal dialysis has been ridden with several challenges. For example, given the high and increasing prevalence of obesity and metabolic syndrome in patients with CKD, a treatment that relies on regular intraperitoneal infusions of glucose (potentially resulting in hyperglycaemia and weight gain) must be viewed with caution. Increasing evidence indicates that diabetic patients with poor metabolic control who receive peritoneal dialysis have poorer survival than patients without diabetes who receive the therapy. Transient hyperglycaemia and progressive worsening of atherogenic lipid profiles has been shown to occur in nondiabetic patients on peritoneal dialysis and although increased BMI has been reported to have a protective effect in patients on haemodialysis, this is not the case in patients on peritoneal dialysis where increased BMI may be associated with worse outcomes. In addition, reports from Europe and the USA consistently suggest that older women, but not older men, with diabetes survive less well on peritoneal dialysis than on haemodialysis. Further research is required to understand the reason for this reduced survival (which might not be directly related to metabolic control) and for the sex-related difference. Possible explanations include underestimation of associated comorbidity, such as diastolic heart failure (which is poorly recognized in women) and/or insufficient social support for older women with diabetes. Another major challenge for increasing the utilization of peritoneal dialysis in an ageing and increasingly multimorbid population, is overcoming the accompanying barriers to independent self care. As discussed in detail below, these barriers are often multiple and complex and are as dependent on social and cultural factors as on clinical constraints. Little doubt exists, however, that these barriers are surmountable in many situations. The proportion of patients treated with home therapies varies considerably; in some Swedish dialysis units

9 approximately 40% of patients are treated at home (B. Rippe, personal communication) whereas in many dialysis units worldwide only in-centre treatment is available. The place of peritoneal dialysis in the environmental agenda has not yet been properly quantified. As mentioned earlier, this treatment modality is associated with a high use of consumables as well as with the manufacture and disposal of dialysate fluid and plastic containers. The industry has made efforts to improve the constituents of the containers (for example plasticizers) in order to improve drug stability and reduce wastage but heat sterilization and incineration generates greenhouse gases. Set against these disadvantages is the advantage of reduced travel for patients receiving dialysis at home, although this benefit will be ameliorated if these patients require outside assistance with their treatment Patient survival on peritoneal dialysis Over the past two decades, the survival of patients treated with peritoneal dialysis has steadily improved, both in absolute terms and in comparison to that of patients receiving haemodialysis. A randomized trial of peritoneal dialysis versus haemodialysis that is currently recruiting in China will add value to our understanding but is unlikely to influence the overall picture of survival on dialysis, which can be summarized as follows: firstly, the improvement in survival of patients on peritoneal dialysis over the past 20 years has occurred at a consistent rate in North America and Europe, and has out-stripped the improvement in survival seen in patients on haemodialysis and secondly, overall medium-term survival (3 5 years in most analyses) is now equivalent for peritoneal dialysis and haemodialysis. A couple of exceptions to these findings exist; for example, the Choices for Healthy Outcomes in Caring for End-stage Renal Disease (CHOICE) study reported survival patterns, such as better survival in patients with diabetes on peritoneal dialysis than on haemodialysis, that are wholly at odds with data from other studies. In addition, an analysis of data from the Australia and New

10 Zealand Dialysis and Transplant Registry (ANZDATA) found that overall patient survival was worse on peritoneal dialysis than on haemodialysis in a pattern not dissimilar to the findings of earlier analyses undertaken in the USA and in The Netherlands. Disproportionality of the peritoneal dialysis and haemodialysis survival curves has been described repeatedly, and as discussed above, tends to favour longer-term survival of older, female patients with diabetes who are on haemodialysis, although in the case of the ANZDATA registry study there was also an interaction with obesity, again favouring haemodialysis. Finally, the early survival benefit reported with peritoneal dialysis is most evident in those patients with the least comorbidity, and in at least one analysis could be attributed to increased mortality associated with the use of temporary lines in haemodialysis patients, which itself may be a surrogate for the quality of predialysis management and planning.

11 Renal transplantation Kidney transplantation an experimental, risky and very limited treatment option 50 years ago is now routine clinical practice in more than 80 countries. What was once limited to a few individuals in a small number of academic centers is routinely transforming lives in most high-income and medium-income countries. The largest numbers of kidney transplantations are performed in the USA, China, Brazil and India, whereas the greatest population-adjusted access to kidney transplantation occurs in Croatia, Portugal, Spain, Austria, the USA and Norway.1 Almost all countries, however, have rising waiting lists and donor organ availability meets only 10% of global needs. Barriers to the broader application of kidney transplantation include economic limitations, but the major restrictions on kidney transplantation rates are the shortage of donated organs and the number of trained medical workforces with the required expertise. The first successful kidney transplantation was carried out between identical twins in Between 1965 and 1980 patient survival after kidney transplantation

12 progressively increased towards 90% and graft survival rose to at least 60%. 30 years on, unsensitized recipients of first deceased or living donor kidney transplants can expect 1-year patient survival rates of 95% and transplant survival of at least 90%.2 Recent developments have also led to excellent results in ABO-incompatible recipients with low-titer ABO antibodies, and desensitization protocols and paired kidney exchange programs now afford real opportunities for individuals who have high titers of donor-specific anti-hla antibodies and were previously deemed unsuitable for transplantation. Kidney transplantation improves life expectancy and quality of life compared with maintenance dialysis. Transplantation, especially when it pre-empts dialysis, provides a mechanism both to expand access and reduce costs for the successful treatment of end-stage renal disease (ESRD). Developing countries have poor transplantation rates because of a combination of factors: low infrastructure levels; insufficient training; lack of legal frameworks to govern brain death; religious, cultural and social constraints; patient apprehension; physician bias; commercial incentives that favor dialysis, and geographical remoteness. Poor access to transplantation is therefore almost inevitable for most of the world s population Renal transplantation vs Dialysis: Kidney transplantation was associated with reduced risk of mortality and cardiovascular events as well as better quality of life than treatment with chronic dialysis. This is true for different dialysis modalities, for transplantation from both deceased and living donors and across countries with differing health care systems. It can be said kidney transplantation is the preferred modality of treatment for chronic kidney failure, and justifies current attempts to increase the number of patients worldwide who benefit from kidney transplantation by increasing rates of deceased and living kidney donation, expanding the pool of potential donors and recipients and reducing the likelihood that potentially viable organs are discarded. Immunosuppressive medications used in transplant recipients may cause anemia, hypertension, glucose intolerance and dyslipidemia. Despite this, transplantation was associated with significantly lower risk of cardiovascular events compared to treatment with dialysis. Although this finding might be partially because of selection of healthier patients for transplantation, results were similar in analyses restricted to dialysis patients who were active on the transplant waiting list which should minimize the effect of such bias. Although immunosuppressive medications can predispose to infection, transplantation is associated with reduced risk of hospitalization for infection emphasizing the high risk of sepsis associated with vascular and peritoneal access required to perform dialysis.

13 Pre-emptive kidney transplantation Pre-emptive kidney transplantation (PKT), which is carried out before starting either hemodialysis or chronic peritoneal dialysis, has been demonstrated to be the optimal treatment strategy for patients with advanced chronic kidney disease (CKD). PKT improves short-term and long-term patient survival and quality of life (including a shortening of the time taken to return to work) and reduces total medical and social costs. Moreover, use of PKT avoids most of the usual complications caused by renal replacement therapy, such as permanent vascular access for hemodialysis, peritoneal infections associated with chronic peritoneal dialysis and cardiovascular complications, such as sudden cardiac death and coronary lesions. However, although PKT is an ideal procedure for patients with CKD, its widespread use is thwarted by a shortage of living and deceased donors. The availability of donors also varies with a country s rules about organ retrieval and allocation, the difficulties in many countries of encouraging people to be living donors and the huge discrepancy between the size of waiting lists and the number of organs harvested from deceased donors. These problems can mean that patients spend long periods of time on transplantation waiting lists and are likely to receive a transplant from an extended- criteria donor. In PKT, living donor transplantation is easier than cadaveric transplantation, as the timing of surgery for a deceased donor transplantation depends on the rules for organ allocation in a particular transplantation network program. Although PKT is widely accepted as superior to other renal replacement therapies, no optimal time during the course of CKD has been recommended for this procedure. If a transplantation is carried out too early (that is, before the optimal time for renal replacement, which depends on various factors, including the cause of nephropathy and good control of blood pressure), it can induce premature loss of any remnant renal function, thereby decreasing the overall time until dialysis is required and increasing the complications caused by immunosuppression. However, early PKT does prevent CKD-associated cardiovascular morbidity and mortality. Conversely, transplantation carried out too late exposes recipients to the severe complications of end-stage CKD that are sometimes life-threatening, such as fluid overload, hyperkalemia and emergency hemodialysis by catheter before surgery. Thus, PKT seems to be an ideal procedure, but the optimal timing of the procedure and its effects on patient and graft survival remain undetermined.