Chronic Kidney Failure: Renal Replacement Therapy

Introduction

Renal replacement therapy (RRT) is a general term encompassing a range of different treatment modalities for patients with what was formally termed acute renal failure and end-stage kidney disease, which are now called acute kidney injury stage 3 (AKI-3) and chronic kidney disease stage 5 dialysis (CKD5d), respectively ( Table 3.1A and B ). RRT includes various forms of dialysis (hemodialysis, hemodiafiltration, and peritoneal dialysis), hemofiltration, and renal transplantation. Dialysis has rapidly expanded from a treatment restricted to AKI in teaching hospitals in the 1960s to what is now a routine treatment for around 3 million patients with CKD worldwide. However, all types of RRT are incomplete solutions for CKD, with a 5-year life expectancy for a dialysis patient in the United Kingdom (UK) of around 60%, somewhere between that of patients with ovarian and bowel cancer ( www.renalreg.com ).

The management of patients with CKD centers on trying to slow down the progression of underlying kidney disease and reducing cardiovascular risk factors, because many more patients will die of cardiovascular disease compared with those who progress to dialysis (CKD5d). Uncontrolled hypertension is the major risk factor for progression followed by proteinuria. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the preferred antihypertensives, aiming for blood pressure targets of 130 to 140/80 to 90 mmHg, depending on the age of the patient. In a minority of cases specific management strategies may be appropriate to halt progression, such as immunosuppression for patients with renal vasculitis or lupus nephritis. Thereafter management is directed to control the complications of progressive kidney disease, hypervolemia, anemia, acidosis, and renal bone disease. In progressive CKD patient education is vital, so that patients can make an informed decision about whether to have RRT or opt for a conservative nondialysis approach, accepting that they will die of azotemia. For those patients opting for RRT, it is important to plan ahead, asking about potential live organ donors, creating vascular access for those choosing hemodialysis, and considering the timing of inserting a peritoneal dialysis catheter.

RRT programs continue to expand ( Table 3.2 ), and, although <0.04% of the UK population has CKD requiring RRT, this consumes 2% to 3% of the overall UK health budget. The challenge for nephrologists and transplant surgeons is to provide the most appropriate RRT of the highest quality for the individual patient at the lowest possible cost. Quality standards and clinical practice guidelines have been developed by both national and international organizations (e.g., British Transplantation Society, Renal Association, European Renal Association – European Dialysis and Transplant Association, Kidney Disease Improving Global Outcomes).

Definition and Timing Referral

The estimate of glomerular filtration rate (eGFR) system ( Table 3.1A ) was introduced into the UK to alert nonrenal specialists that patients with what appeared to be high normal or mildly elevated serum creatinine had CKD, and therefore are more at risk from nephrotoxic drugs. Unfortunately, serum creatinine is not linearly associated with glomerular filtration rate and is affected by diet, exercise, and drugs (see Table 3.2 ). In the UK patients with CKD stage 3 are routinely managed by primary care physicians, unless they have rapidly progressive kidney disease, or proteinuria or hematuria, whereas those in stage 4 and 5 should be under the care of specialist nephrologists. However, there is still a relatively high number of avoidable late referrals of patients with CKD5. In some cases this situation is unavoidable—the patients may have had a truly silent illness or an acute presentation of an irreversible renal injury (e.g., myeloma, antiglomerular basement membrane disease, or renal vasculitis). The consequences for patients of late presentation are many, ranging from increased risk of infection because of the use of temporary central venous access catheters to the psychological effect of suddenly requiring dialysis, with major changes in lifestyle (dietary and fluid restriction, loss of employment). Not surprisingly, these unplanned starters have a worse prognosis, incur greater healthcare costs, and are less likely to be activated on the renal transplant waiting list.

Prevalence and Incidence

The point prevalence of CKD is unknown because most patients are asymptomatic and unaware of its presence. Referral patterns increased in the UK after the introduction of the eGFR reporting system, because of the alerts sent back from pathology laboratories to primary care physicians. Similarly, the prevalence of CKD increases as populations increase in body habitus and prevalence of diabetes. In the latest UK renal registry report the prevalence of patients receiving RRT was 913 per million population (pmp), but varies within the UK, being higher in inner-city ethnic populations and lower in predominantly affluent caucasoid suburbs, with the prevalence varying between 560 and 1680 pmp ( http://www.renalreg.org/ ).

The differences in incidence and prevalence of CKD requiring RRT ( Table 3.3 ) depend both on patient factors, such as the incidence of diabetes and hypertension in the population studied, and healthcare spending. In 2014 the highest incidence of CKD5d reported came from Taiwan, Jalisco (Mexico), United States, Thailand, and Singapore, whereas Iceland, Iran, Russia, and Bangladesh reported <80 per million ( http://www.usrds.org ). However, it must be recognized that there is a difference between the incidence of the disease and the incidence of patients starting RRT, because more affluent countries will start more elderly patients with additional comorbidities, and the incidence of CKD increases exponentially with age, whereas less affluent countries tend to restrict RRT to younger patients with fewer comorbidities. Similarly, transplantation rates also differ between countries, and although this is dependent on the provision and access to dialysis, it can also be affected by cultural and religious practices that limit cadaveric transplantation.

The numbers of patients on RRT worldwide have yet to reach a steady state, particularly in developing economies. This will only occur when the number of new patients accepted into programs is balanced by the number of deaths.

Etiology

Because RRT is an expensive supportive treatment, the key goal would be to prevent or limit the progression of CKD. Unfortunately, only a minority of conditions can be halted, and even then, only if treated early, such as withdrawal of nephrotoxic analgesics and lithium and appropriate treatment of infections, such as tuberculosis, inflammatory conditions, including sarcoid and autoimmune diseases, most commonly vasculitis and systemic lupus erythematosus, and more recently, enzyme replacement therapy for conditions such as Fabry’s disease. The incidence of diseases that cause CKD change with age, such that childhood CKD may be associated with congenital abnormalities, including urethral valves, prune-belly syndrome, vesico-ureteric reflux, whereas patients older than age 65 are more likely to have renovascular disease, hypertensive nephropathy, myeloma, and prostatic obstruction.

The prevalence of inherited diseases, such as polycystic kidney disease, appears to be similar in different ethnic populations; however, diabetic nephropathy tends to follow the rate of diabetes in the underlying population. In addition, some forms of interstitial nephritis have distinctive geographic patterns or predilection for particular ethnic groups, such as Balkan nephropathy, Chinese herbal nephropathy, associated with ingestion of Aristolochic herbs, South Asian interstitial nephropathy, Meso American nephropathy, and Sri Lankan nephropathy.

Screening programs, coupled with prompt treatment and investigation of urosepsis, have reduced the number of children with vesico-ureteric reflux progressing to CKD5d. However, these causes comprise only a minority of cases, with the vast majority of patients developing progressive CKD because of small-vessel disease in association with hypertension and diabetes. Such health screening programs have centered on the measurement of eGFR to establish an earlier diagnosis of CKD, and then active treatment of cardiovascular risk factors, because hypertension and proteinuria are the key risk factors for progression. Because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potent antihypertensive agents, and also appear to have an additional effect in terms of reducing proteinuria, these agents are preferentially prescribed. As patients develop progressive CKD, appetite declines, so patients tend to self-restrict protein, and protein-restricted diets do not appear to have any additional benefit, provided that blood pressure is adequately controlled. In addition to controlling blood pressure, prescription of sodium bicarbonate, to correct metabolic acidosis has been shown to reduce progression of CKD.

For most patients, establishing the cause of CKD can be determined by history, physical examination, simple urine dipstick testing coupled with specific biochemical and immunologic investigations, and renal imaging. Patients may have a family history of adult polycystic kidney disease, glomerulonephritis, reflux nephropathy, and hypertension. Physical examination may reveal femoral arterial bruits and signs of cholesterol embolization in renovascular disease, or skin and joint changes in vasculitis and autoimmune diseases. Patients with glomerular hematuria and proteinuria require renal biopsy because glomerulonephritis or systemic disease may be amenable to specific therapies.

Transplant surgeons prefer to know the cause of CKD in potential kidney transplant recipients, because some conditions can recur posttransplantation, including some forms of focal segmental glomerular sclerosis; hemolytic uremic syndrome and dense deposit disease, a form of membranoproliferative glomerulonephritis; and IgA nephropathy. Similarly, other renal conditions may be inherited and need to be screened in family members volunteering as living donors. In addition, patients with urogenital malformations or recurrent urosepsis may require surgical reconstruction or nephrectomy before transplantation to reduce the risk of subsequent infections.

Treatment of CKD5

Ideally patients with CKD5 should be involved in the decision to choose a form of RRT, whether conservative management or dialysis. In practice, economic and cultural pressures, the limit in kidney donor supply, and medical prejudices often dictate what treatment patients receive. This is particularly the case for patients who have had no or minimal predialysis nephrologic care, who by default typically start hemodialysis using a central venous access catheter.

Because life expectancy and quality of life are typically greater with transplantation, then transplantation should be considered for all patients with an expected 5-year survival or greater. Preemptive transplantation is an option for CKD patients attending nephrologic care if a suitable living donor is available; otherwise patients opting for dialysis should be allowed to choose between hemodialysis and peritoneal dialysis, so that vascular access can be created before initiation of hemodialysis; and for peritoneal dialysis, embedding a peritoneal dialysis catheter is also an option, but the longer the catheter remains buried the less likely it is to work when released. Home dialysis should be encouraged for patients with appropriate home circumstances, especially if patients have partners who can act as helpers, because home hemodialysis provides patients with an option for more frequent or longer overnight dialysis sessions. Although in-center hemodialysis may be the default option, ideally hemodialysis patients should dialyze close to home, in local hospital satellite or free-standing self-care centers, to minimize traveling time.

Apart from Mexico ( Table 3.4 ), and some Southeast Asian countries that have a peritoneal dialysis–first policy, hemodialysis remains the most common mode of RRT worldwide. The differences between countries are at times difficult to understand and are a result of the balance between medical and financial resources, reimbursement, and patient locality. For example, in New Zealand and Canada many patients live in rural environments distant from hospitals, and as such home-based therapies, peritoneal dialysis, and home hemodialysis are more favored. On the other hand, countries such as Japan, the United States, and Germany, which offer greater financial reimbursement for hemodialysis, typically have more center-based hemodialysis programs.