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 ).

Table 3.1A

Staging for Chronic Kidney Disease ^a

CKD Stage	eGFR (mL/min/1.73 m ²)
Stage 1	>90
Stage 2	60–90
Stage 3a	45–60
Stage 3b	30–44
Stage 4	15–29
Stage 5	<15 mL/min
Stage 5d	Dialysis

a Staging for chronic kidney disease (CKD), based on an estimate of glomerular filtration rate (eGFR) after the modification of diet in renal disease (MDRD) 4 value equation. The suffix (p) can be used to denote the presence of proteinuria as defined by a spot urinary albumin:creatinine ratio of ≥30 mg/mmol, which is approximately equivalent to a protein:creatinine ratio of ≥50 mg/mmol (≥0.5 g/24 h).

Table 3.1B

Staging for Acute Kidney Injury ^a

Stage	Serum Creatinine Criteria	Urine Criteria
1	↑ SCreat ≥0.3 mg/dL or 27 μmol/L above baseline within 48 h or ↑ SCreat ≥1.5–1.9× above baseline within 7 days	<0.5 mL/kg/h for >6 h
2	↑ SCreat 2.0–2.9× above baseline within 7 days	<0.5 mL/kg/h for >2 h
3	SCreat 3× above baseline or SCreat ≥4.0 mg/dL (350 μmol/L) or RRT within 7 days	<0.3 mL/kg/h for 24 h or anuria for 12 h

a The baseline serum creatinine (SCreat) measurement should be the admission serum creatinine after resuscitation, or a recent clinic value. The change in serum creatinine should occur within 7 days. All patients who are treated by renal replacement therapy are staged as stage 3.

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).

Table 3.2

Examples of Nonrenal Factors That Affect Serum Creatinine Measurements, Without Changing Renal Function

Factor		Effect on Serum Creatinine
General factors	Age	Decreased
	Female sex	Decreased
Ethnicity compared with Caucasoids	Black Asian	Increased Decreased
Body habitus	Muscular	Increased
	Obese	Decreased
Chronic illness	Cirrhosis	Reduced
	Cancer	Reduced
	Heart failure	Reduced
Endocrine diseases	Hypothyroidism	Increased
Diet	Vegetarian	Reduced
	Meat stews	Increased
Drugs	Antibiotics	Trimethoprim
	Gastroprotection	Cimetidine
	Diuretics	Amiloride
		Spironolactone

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.

Table 3.3

Incidence and Prevalence of Chronic Kidney Disease Treated by Dialysis, and Transplantation Prevalence of Functioning Grafts and Transplant Rate (Rates Expressed per Million Population)

	Dialysis	Dialysis	Dialysis	Dialysis	Transplant	Transplant
Year	2010	2012	2014	2014	2014	2014
Country	Incidence	Incidence	Incidence	Prevalence	Prevalence	Rate
Argentina	152	156	155	856	191	29.8
Australia	106	114	111	944	431	40.4
Austria	140	143	122	1062	549	46.8
Bangladesh	23	45	49	113		0.6
Belgium	200	191	175	1242	515	36.0
Brazil	147	172	180	773	224	27.8
Canada	178	182	193	1291	534	41.5
Chile	156	170	157	1301	207	16.7
Denmark	198		191	906	449	43.9
France	153	155	161	1203	540	49.1
Iceland	107	62	58	675	452	24.4
Iran	74	74	78	617	294	29.7
Israel	186	183	203	1169	405	31
Japan	291	285	285	2505	65	12.6
Mexico Jalisco	404	467	421	1568	590	60.3
Netherlands	118	121	115	967	583	59.2
New Zealand	118	189	122	962	364	31.7
Philippines	104	127	161	289	4	4.0
Qatar	133	99	116	689	358	21.9
Russia	45	53	60	283	51	5.7
Saudi Arabia	100	100	104	771	258	21.0
Singapore	243	285	294	1891	33	15.0
Spain	121	120	132	1168	605	56.8
Taiwan	439	446	455	3219	126
Thailand	146	221	299	1203	106	8.5
Turkey	223	139	147	918	143	37.6
UK (England and Wales)	108	111	118	932	494	48.5
USA	367	360	370	2076	630	56.2
Uruguay	153	150	151	1122	366	39.9

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.

Table 3.4

Proportion (%) of Chronic Kidney Disease Patients Treated by Different Dialysis Modalities in 2014

Modality	Center Hemodialysis	Home Hemodialysis	Peritoneal Dialysis
Argentina	94.2	0	5.8
Australia	70.2	9.4	20.4
Austria	90.9	0.1	9.0
Bangladesh	93.6	0	6.4
Belgium	90.9	1.3	7.8
Brazil	92.7	0.1	7.2
Canada	75.1	4.8	19.1
Chile	94.2	0	5.8
Denmark	78.7	0	21.3
France	92.6	0.6	6.8
Iceland	78.0		21.9
Iran	94.1	0	5.9
Israel	89.0	0	11.0
Japan	96.9	0.2	2.9
Mexico (Jalisco)	52.3	0.8	46.9
Netherlands	82.7	3.8	13.5
New Zealand	51.1	18.3	30.6
Philippines	95.2	0	4.8
Qatar	73.3	0	26.7
Russia	93.6	0	6.4
Saudi Arabia	88.3		11.6
Singapore	93.5	0.1	6.4
Spain	88.3	0.3	11.4
Taiwan	69.6		30.4
Thailand	69.6	0	30.4
Turkey	72.3	0.3	7.4
UK (England and Wales)	82.1	4.4	13.5
USA	88.6	1.8	9.6
Uruguay	91.0	0	9