2314 PART 9 Disorders of the Kidney and Urinary Tract

with muscle weakness, fibrosis of cardiac muscle, and constitutional

symptoms.

Adynamic bone disease is increasing in prevalence, especially

among diabetics and older patients. It is characterized by reduced bone

volume and mineralization and may result from excessive suppression

of PTH production, chronic inflammation, or both. Suppression of

PTH can result from the use of vitamin D preparations or from excessive calcium exposure in the form of calcium-containing phosphate

binders or high-calcium dialysis solutions.

Complications of adynamic bone disease include an increased

incidence of fracture and bone pain and an association with increased

vascular and cardiac calcification. Occasionally, the calcium will

precipitate in the soft tissues into large concretions termed tumoral

calcinosis (Fig. 311-4). Patients with adynamic bone disease often

experience the most severe symptoms of musculoskeletal pain, owing

to the inability to repair the microfractures that occur normally as

a part of healthy skeletal homeostasis with regular physical activity.

Patients with advanced CKD experience more frequent fractures than

their age-matched controls. Osteomalacia is a distinct process, consequent to reduced production and action of 1,25(OH)2

D3

, leading to

accumulation of nonmineralized osteoid.

Calcium, Phosphorus, and the Cardiovascular System There

is a strong association between hyperphosphatemia and increased cardiovascular mortality in patients with CKD. Hyperphosphatemia and

hypercalcemia are associated with increased vascular calcification, but

it is unclear whether the excessive mortality is mediated by this mechanism. Studies using computed tomography (CT) and electron-beam

CT scanning show that CKD patients have calcification in the media

of coronary arteries and even heart valves that appears to be orders

of magnitude greater than that in patients without renal disease. The

magnitude of the calcification is proportional to age and hyperphosphatemia and is also associated with low PTH levels and low bone

turnover. It is possible that in CKD patients ingested calcium cannot be

incorporated into bones with low turnover and, therefore, is deposited

at extraosseous sites, such as the vascular bed and soft tissues. There

is a similar association between osteoporosis and vascular calcification

in the general population. Finally, hyperphosphatemia can induce a

change in gene expression in vascular cells to an osteoblast-like profile,

leading to vascular calcification and even ossification.

Other Complications of Abnormal Mineral Metabolism

Calciphylaxis is a devastating condition seen almost exclusively in

patients with advanced CKD. It is heralded by painful livedo reticularis and subcutaneous nodules that advance to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts

(Fig. 311-5). Pathologically, there is evidence of vascular occlusion

in association with extensive vascular and soft tissue calcification. It

appears that this condition is increasing in incidence. Originally it was

ascribed to severe abnormalities in calcium and phosphorus control

in dialysis patients, usually associated with advanced hyperparathyroidism. However, more recently, calciphylaxis has been seen with

increasing frequency in the absence of severe hyperparathyroidism.

Warfarin is still used in some dialysis patients in whom direct oral

anticoagulants (DOACs) are contraindicated, and one of the effects of

warfarin therapy is to decrease the vitamin K–dependent activation

of matrix GLA protein. This latter protein is important in preventing

vascular calcification. Thus, warfarin treatment is considered a risk

factor for calciphylaxis, and if a patient develops this syndrome, this

medication should be discontinued and alternative means of anticoagulation should be chosen, depending on the specific underlying

indication for anticoagulation.

TREATMENT

Disorders of Calcium and Phosphate Metabolism

The optimal management of secondary hyperparathyroidism and

osteitis fibrosa is prevention. Once the parathyroid gland mass is

very large, it is difficult to control the disease. Careful attention

should be paid to the plasma phosphate concentration in CKD

patients, who should be counseled on a low-phosphate diet as well

as the appropriate use of phosphate-binding agents, which are

taken with meals and complex dietary phosphate to limit its GI

absorption. Examples of phosphate binders are calcium acetate and

calcium carbonate. A major side effect of calcium-based phosphate

binders is calcium accumulation and hypercalcemia, especially in

patients with low-turnover bone disease. Sevelamer and lanthanum

are non-calcium-containing polymers that also function as phosphate binders; they do not predispose CKD patients to hypercalcemia and may attenuate calcium deposition in the vascular bed.

Tenapanor is a sodium-proton inhibitor that decreases GI phosphate absorption and may be useful to manage hyperphosphatemia

in CKD and dialysis patients.

Calcitriol exerts a direct suppressive effect on PTH secretion and

also indirectly suppresses PTH secretion by raising the concentration of ionized calcium. However, calcitriol therapy may result in

hypercalcemia and/or hyperphosphatemia through increased GI

absorption of these minerals. Certain analogues of calcitriol are

FIGURE 311-5 Calciphylaxis. This peritoneal dialysis patient was on chronic

warfarin therapy for atrial fibrillation. She noticed a small painful nodule on

the abdomen that was followed by progressive skin necrosis and ulceration

of the anterior abdominal wall. She was treated with hyperbaric oxygen,

intravenous thiosulfate, and discontinuation of warfarin, with slow resolution

of the ulceration.

FIGURE 311-4 Tumoral calcinosis. This patient was on hemodialysis for many years

and was nonadherent to dietary phosphorus restriction or the use of phosphate

binders. He was chronically severely hyperphosphatemic. He developed an

enlarging painful mass on his arm that was extensively calcified.

2315Chronic Kidney Disease CHAPTER 311

available (e.g., paricalcitol) that suppress PTH secretion with less

attendant hypercalcemia.

Recognition of the role of the extracellular calcium-sensing

receptor has led to the development of calcimimetic agents that

enhance the sensitivity of parathyroid cells to the suppressive effect

of calcium. This class of drug, which includes cinacalcet and etelcalcetide, produces a dose-dependent reduction in PTH and plasma

calcium concentration in some patients.

Current National Kidney Foundation Kidney Disease Outcomes

Quality Initiative guidelines recommend a target PTH level between

2 and 9 times the upper limit of normal, recognizing that very low

PTH levels are associated with adynamic bone disease and possible

consequences of fracture and ectopic calcification.

■ CARDIOVASCULAR ABNORMALITIES

Cardiovascular disease is the leading cause of morbidity and mortality

in patients at every stage of CKD. The incremental risk of cardiovascular disease in those with CKD compared to the age- and sex-matched

general population ranges from 10- to 200-fold, depending on the stage

of CKD. As a result, most patients with CKD succumb to cardiovascular disease (Fig. 311-6) before ever reaching stage 5 CKD. Between 30

and 45% of those patients who do reach stage 5 CKD have advanced

significant cardiovascular complications. Thus, the focus of patient

care in earlier CKD stages should be directed to prevention of cardiovascular complications.

Vascular Disease The increased prevalence of vascular disease

in CKD patients derives from both traditional (“classic”) and nontraditional (CKD-related) risk factors. Traditional risk factors include

hypertension, diabetes mellitus, hypervolemia, dyslipidemia, sympathetic overactivity, and hyperhomocysteinemia. The CKD-related risk

factors comprise anemia, hyperphosphatemia, hyperparathyroidism,

increased FGF-23, sleep apnea, and systemic inflammation. The

inflammatory state appears to accelerate vascular occlusive disease,

and low levels of fetuin may permit more rapid vascular calcification,

especially in the face of hyperphosphatemia. Other abnormalities seen

in CKD may augment myocardial ischemia, including left ventricular

hypertrophy and microvascular disease. In addition, hemodialysis,

with its attendant episodes of hypotension and hypovolemia, may

further aggravate coronary ischemia and repeatedly stun the myocardium. Interestingly, however, the largest increment in cardiovascular

mortality rate in dialysis patients is not necessarily directly associated

with acute myocardial infarction but, instead, is the result of congestive

heart failure and sudden death. ECG monitoring studies have suggested that asystole and bradyarrhythmias are the principal causes of

sudden cardiac death in dialysis patients.

Cardiac troponin levels are frequently elevated in CKD without

evidence of acute ischemia. The elevation complicates the diagnosis of

acute myocardial infarction in this population. Serial measurements

may be needed. Therefore, the trend in levels over the hours after

presentation may be more informative than a single, elevated level.

Interestingly, consistently elevated levels are an independent prognostic factor for adverse cardiovascular events.

Heart Failure Abnormal cardiac function secondary to myocardial ischemia, left ventricular hypertrophy, diastolic dysfunction, and

frank cardiomyopathy, in combination with salt and water retention,

often results in heart failure or even pulmonary edema. Heart failure

can be a consequence of diastolic or systolic dysfunction, or both. A

form of “low-pressure” pulmonary edema can also occur in advanced

CKD, manifesting as shortness of breath and a “bat wing” distribution

of alveolar edema fluid on chest x-ray. This finding can occur even in

the absence of ECFV overload and is associated with normal or mildly

elevated pulmonary capillary wedge pressure. This process has been

ascribed to increased permeability of alveolar capillary membranes as

a manifestation of the uremic state, and it responds to dialysis. Other

CKD-related risk factors, including anemia and sleep apnea, may contribute to the risk of heart failure.

Hypertension and left ventricular hypertrophy are the most common complications of CKD. Hypertension usually develops early

during the course of CKD and is associated with adverse outcomes,

including the development of ventricular hypertrophy and a more

rapid loss of renal function. Left ventricular hypertrophy and dilated

cardiomyopathy are among the strongest risk factors for cardiovascular

morbidity and mortality in patients with CKD and are thought to be

related primarily, but not exclusively, to prolonged hypertension and

ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state

and consequent high-output heart failure.

The absence of hypertension may signify poor left ventricular

function. Indeed, in epidemiologic studies of dialysis patients, low

blood pressure actually carries a worse prognosis than does high blood

pressure. This mechanism, in part, accounts for the “reverse causation”

seen in dialysis patients, wherein the presence of traditional risk factors, such as hypertension, hyperlipidemia, and obesity, appear to

portend a better prognosis. Importantly, these observations derive

from cross-sectional studies of late-stage CKD patients and should

not be interpreted to discourage appropriate management of these

risk factors in CKD patients, especially at early stages. In contrast to

the general population, it is possible that in late-stage CKD, low blood

pressure, reduced body mass index, and hypolipidemia indicate the

presence of an advanced malnutrition-inflammation state, with the

attendant poor prognosis.

The use of exogenous ESAs can increase blood pressure and the

requirement for antihypertensive drugs. Chronic ECFV overload is

also a contributor to hypertension, and improvement in blood pressure

can often be seen with the use of dietary sodium restriction, diuretics,

and fluid removal with dialysis. Nevertheless, because of activation of

the RAS and other disturbances in the balance of vasoconstrictors and

vasodilators, some patients remain hypertensive, despite careful attention to ECFV status.

TREATMENT

Cardiovascular Abnormalities

MANAGEMENT OF HYPERTENSION

The overarching goal of hypertension therapy in CKD is to prevent

the extrarenal complications of high blood pressure, such as cardiovascular disease and stroke. Although a clear-cut generalizable

benefit in slowing progression of CKD remains as yet unproven,

the benefit for cardiac and cerebrovascular health is compelling.

In all patients with CKD, blood pressure should be controlled to

levels recommended by national guideline panels. In CKD patients

with diabetes or proteinuria >1 g per 24 h, blood pressure should

Time to event (years)

0

0.0

0.2

0.4

0.6

0.8

642 8 10 12 14

Cumulative incidence function

1.0

ESRD

CV death

Non CV death

FIGURE 311-6 The cumulative incidence of end-stage renal disease (ESRD),

cardiovascular (CV) death, and non-CV death during follow-up in cohort of 1268

participants with an estimated glomerular filtration rate (eGFR). (Reproduced with

permission from LS Dalrymple et al: Chronic kidney disease and the risk of endstage renal disease versus death. J Gen Int Med 26:379, 2010.)

2316 PART 9 Disorders of the Kidney and Urinary Tract

be reduced to <130/80 mmHg, if achievable without prohibitive

adverse effects. Salt restriction should be the first line of therapy.

When volume management alone is not sufficient, the choice of

antihypertensive agent is similar to that in the general population.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin

receptor blockers (ARBs) appear to slow the rate of decline of

kidney function in a manner that extends beyond reduction of systemic arterial pressure and that involves reduction in the intraglomerular hyperfiltration and hypertension. Occasionally, introduction

of ACE inhibitors and ARBs can actually precipitate an episode of

AKI, especially when used in combination in patients with ischemic

renovascular disease.

Slight reduction of GFR (<30% of baseline) may signify a salutary reduction in intraglomerular hypertension and hyperfiltration,

and, if stable over time, can be tolerated with continued monitoring.

Progressive decline in GFR should prompt discontinuation of these

agents. The use of ACE inhibitors and ARBs may also be complicated by the development of hyperkalemia. Often the concomitant

use of a combination of kaliuretic diuretics (e.g., furosemide with

metolazone) or a potassium-lowering GI tract binder, such as patiromer, can improve potassium excretion in addition to improving

blood pressure control. Potassium-sparing diuretics, such as amiloride and triamterene, should be avoided in most patients, and

mineralocorticoid receptor blockers should also be used with great

caution and with careful monitoring of serum potassium concentration, weighing potential cardiovascular benefits against risk for

lethal hyperkalemia.

The recent movement to even lower blood pressure targets

in the general population may not be applicable to patients with

CKD, who often lack autoregulation to maintain GFR in the face

of low perfusion pressure. If a patient experiences sudden decline

in kidney function with intensification of antihypertensive therapy,

consideration should be given to reducing therapy.

MANAGEMENT OF CARDIOVASCULAR DISEASE

There are many strategies available to treat the traditional and

nontraditional risk factors in CKD patients. Although these have

proved effective in the general population, there is little evidence

for their benefit in patients with advanced CKD, especially those on

dialysis. Certainly, hypertension and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD. Renal disease complicated by nephrotic syndrome is associated with a very

atherogenic lipid profile and hypercoagulability, which increases

the risk of occlusive vascular disease. Because diabetes mellitus and

hypertension are the two most frequent causes of advanced CKD,

it is not surprising that cardiovascular disease is the most frequent

cause of death in dialysis patients. The use of the gliflozins (SGLT2

inhibitors) in patients with diabetes mellitus has recently been

associated with kidney protection and a reduction in cardiovascular

events, including heart failure. Currently under study is the feasibility of using gliflozins in nondiabetic CKD.

The role of “inflammation” may be quantitatively more important in patients with kidney disease, and the treatment of more

traditional risk factors may result in only modest success. However,

modulation of traditional risk factors may be the only weapon in

the therapeutic armamentarium for these patients until the nature

of inflammation in CKD and its treatment are better understood.

Pericardial Disease Chest pain with respiratory accentuation,

accompanied by a friction rub, is diagnostic of pericarditis. Classic

electrocardiographic abnormalities include PR-interval depression and

diffuse ST-segment elevation. Pericarditis can be accompanied by pericardial effusion that is seen on echocardiography and can rarely lead

to tamponade. However, the pericardial effusion can be asymptomatic,

and pericarditis can be seen without significant effusion.

Pericarditis is observed in advanced uremia and, with the advent of

timely initiation of dialysis, is not as common as it once was. It is now

more often observed in underdialyzed, nonadherent patients than in

those starting dialysis.

TREATMENT

Pericardial Disease

Uremic pericarditis is an absolute indication for the urgent initiation of dialysis or for intensification of the dialysis prescription

in those already receiving dialysis. Because of the propensity to

hemorrhage in pericardial fluid, hemodialysis should be performed

without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion, especially

with echocardiographic signs of impending tamponade. Nonuremic causes of pericarditis and effusion include viral, malignant,

tuberculous, and autoimmune etiologies. It may also be seen after

myocardial infarction and as a complication of treatment with the

antihypertensive drug minoxidil. Consideration could be given

to the use of colchicine or nonsteroidal anti-inflammatory drugs,

although the latter agents could adversely affect renal function.

■ HEMATOLOGIC ABNORMALITIES

Anemia A normocytic, normochromic anemia is observed as early

as stage 3 CKD and is almost universal by stage 4. The primary cause

is insufficient production of erythropoietin (EPO) by the diseased kidneys. Additional factors are reviewed in Table 311-5.

The anemia of CKD is associated with a number of adverse pathophysiologic consequences, including decreased tissue oxygen delivery

and utilization, increased cardiac output, ventricular dilation, and

ventricular hypertrophy. Clinical manifestations include fatigue and

diminished exercise tolerance, angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection. In

addition, anemia may play a role in growth restriction in children with

CKD. Although many studies in CKD patients have found that anemia

and resistance to exogenous ESAs are associated with a poor prognosis, the relative contribution to a poor outcome of the low hematocrit

itself, versus inflammation as a cause of the anemia and ESA resistance,

remains unclear.

TREATMENT

Anemia

The availability of recombinant human ESA has been one of the

most significant advances in the care of renal patients since the

introduction of dialysis and renal transplantation. Its routine use

has obviated the need for regular blood transfusions in severely

anemic CKD patients, thus dramatically reducing the incidence of

transfusion-associated infections and iron overload.

Frequent blood transfusions in dialysis patients also lead to

the development of alloantibodies that can sensitize the patient

to donor kidney antigens and make kidney transplantation more

problematic.

Adequate bone marrow iron stores should be available before

treatment with ESA is initiated. Iron supplementation is usually

essential to ensure an optimal response to ESA in patients with

CKD because the demand for iron by the marrow frequently

TABLE 311-5 Causes of Anemia in Chronic Kidney Disease (CKD)

Relative deficiency of erythropoietin

Diminished red blood cell survival

Bleeding diathesis

Iron deficiency due to poor dietary absorption and gastrointestinal blood loss

Hyperparathyroidism/bone marrow fibrosis

Chronic inflammation

Folate or vitamin B12 deficiency

Hemoglobinopathy

Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated

disease, autoimmune disease, immunosuppressive drugs

2317Chronic Kidney Disease CHAPTER 311

exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well

as the amount in iron stores (measured by serum ferritin). For the

CKD patient not yet on dialysis or the patient treated with peritoneal dialysis, oral iron supplementation should be attempted. If

there is GI intolerance or poor GI absorption, the patient may have

to undergo IV iron infusion. For patients on hemodialysis, IV iron

can be administered during dialysis, keeping in mind that parenteral iron therapy can increase the susceptibility to bacterial infections and that the adverse effects of free serum iron are still under

investigation. In addition to iron, an adequate supply of other major

substrates and cofactors for red cell production must be ensured,

including vitamin B12 and folate. Anemia resistant to recommended

doses of ESA in the face of adequate iron stores may be due to some

combination of the following: acute or chronic inflammation, inadequate dialysis, severe hyperparathyroidism, chronic blood loss or

hemolysis, chronic infection, or malignancy.

A new class of agents to treat the anemia of CKD are the

prolyl-hydroxylase inhibitors of endogenous hypoxia-inducible factors (HIFs). This inhibition leads to an increase in both endogenous

production of EPO and an increase in GI absorption of iron. Studies

are in progress comparing the efficacy of these agents to the standard ESAs.

Randomized, controlled trials of ESA in CKD have failed to show

an improvement in cardiovascular outcomes with this therapy.

Indeed, there has been an indication that the use of ESA in CKD

may be associated with an increased risk of stroke in those with

type 2 diabetes or an increase in thromboembolic events and perhaps a faster progression of renal decline.

Therefore, any benefit in terms of improvement of anemic symptoms needs to be balanced against the potential cardiovascular risk.

Although further studies are needed, it is quite clear that normalization of the hemoglobin concentration has not been demonstrated

to be of incremental benefit to CKD patients. Current practice is to

target a hemoglobin concentration of 100–115 g/L.

Abnormal Hemostasis Patients with later stages of CKD may

have a prolonged bleeding time, decreased activity of platelet factor III,

abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased

tendency to bleeding and bruising, prolonged bleeding from surgical

incisions, menorrhagia, and GI bleeding. Interestingly, CKD patients

also have a greater susceptibility to thromboembolism, especially if

they have renal disease that includes nephrotic-range proteinuria. The

latter condition results in hypoalbuminemia and renal loss of anticoagulant factors, which can lead to a thrombophilic state.

TREATMENT

Abnormal Hemostasis

Abnormal bleeding time and coagulopathy in patients with renal

failure may be reversed temporarily with desmopressin (DDAVP),

cryoprecipitate, IV conjugated estrogens, blood transfusions, and

ESA therapy. Optimal dialysis will usually correct a prolonged

bleeding time.

Given the coexistence of bleeding disorders and a propensity

to thrombosis that is unique in the CKD patient, decisions about

anticoagulation that have a favorable risk-benefit profile in the general population may not be applicable to the patient with advanced

CKD. One example is warfarin anticoagulation for atrial fibrillation;

the decision to anticoagulate should be made on an individual basis

in the CKD patient because there appears to be a greater risk of

bleeding complications.

Certain anticoagulants, such as fractionated low-molecular-weight

heparin, may need to be avoided or dose-adjusted in these patients,

with monitoring of factor Xa activity where available. It is often

more prudent to use conventional unfractionated heparin, titrated

to the measured partial thromboplastin time, in hospitalized

patients requiring an alternative to warfarin anticoagulation. The

new classes of oral anticoagulants are all, in part, renally eliminated

and need to be avoided or dose adjusted in the face of decreased

GFR (Chap. 118).

■ NEUROMUSCULAR ABNORMALITIES

Central nervous system (CNS), peripheral, and autonomic neuropathy, as well as abnormalities in muscle structure and function, are all

well-recognized complications of CKD. Subtle clinical manifestations

of uremic neuromuscular disease usually become evident at stage 3

CKD.

Early manifestations of CNS complications include mild disturbances in memory and disturbances in concentration and sleep.

Neuromuscular irritability, including hiccups, cramps, and twitching,

becomes evident at later stages. In advanced untreated kidney failure,

asterixis, myoclonus, seizures, and coma can be seen.

Peripheral neuropathy usually becomes clinically evident after the

patient reaches stage 4 CKD, although electrophysiologic and histologic evidence occurs earlier. Initially, sensory nerves are involved

more than motor, lower extremities more than upper, and distal parts

of the extremities more than proximal. The “restless leg syndrome”

is characterized by ill-defined sensations of sometimes debilitating

discomfort in the legs and feet relieved by frequent leg movement. Evidence of peripheral neuropathy without another cause (e.g., diabetes

mellitus or iron deficiency) is an indication for starting renal replacement therapy. Many of the complications described above will resolve

with dialysis, although subtle nonspecific abnormalities may persist.

■ GASTROINTESTINAL AND

NUTRITIONAL ABNORMALITIES

Uremic fetor, a urine-like odor on the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an

unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and

mucosal ulcerations at any level of the GI tract occur in uremic patients

and can lead to abdominal pain, nausea, vomiting, and GI bleeding.

These patients are also prone to constipation, which can be worsened

by the administration of calcium and iron supplements. The retention

of uremic toxins also leads to anorexia, nausea, and vomiting.

Protein restriction may be useful to decrease nausea and vomiting;

however, it may put the patient at risk for malnutrition and should

be carried out, if possible, in consultation with a registered dietitian

specializing in the management of CKD patients. Weight loss and

protein-energy malnutrition, consequences of low protein and caloric

intake, are common in advanced CKD and are often an indication for

initiation of renal replacement therapy. Metabolic acidosis and the

activation of inflammatory cytokines can promote protein catabolism.

A number of indices are useful in nutritional assessment and include

dietary history, including food diary, and subjective global assessment;

edema-free body weight; and measurement of urinary protein nitrogen

appearance. Dual-energy x-ray absorptiometry bioimpedance analysis

is now widely used to estimate lean body mass versus fluid weight.

Nutritional guidelines for patients with CKD are summarized in the

“Treatment” section.

■ ENDOCRINE-METABOLIC DISTURBANCES

Glucose metabolism is impaired in CKD. However, fasting blood

glucose is usually normal or only slightly elevated, and mild glucose

intolerance does not require specific therapy. Because the kidney

contributes to insulin removal from the circulation, plasma levels of

insulin are slightly to moderately elevated in most uremic patients,

both in the fasting and postprandial states. Because of this diminished

renal degradation of insulin, patients on insulin therapy may need

progressive reduction in dose as their renal function worsens. Many

anti-hyperglycemic agents, including the gliptins, require dose reduction in renal failure, and some, such as metformin and sulfonylureas,

are contraindicated when the GFR is less than half of normal. The gliflozins, discussed above, that inhibit sodium-glucose transport in the

proximal tubule result in glucose lowering, accompanied by striking

reductions in kidney function decline and in cardiovascular events.

2318 PART 9 Disorders of the Kidney and Urinary Tract

The stabilization of GFR in many patients with this therapeutic intervention represents a major, important added beneficial effect of these

drugs. Their long-term stabilizing effect on GFR and urine albumin

excretion appears to result from correction of hyperfiltration early in

type 2 diabetes mellitus via reactivation of the tubuloglomerular feedback loop. This represents a fortunate convergence of pathophysiology

of glomerular hyperfiltration in diabetes with drug discovery. A similar

effect on hyperfiltration by residual nephrons in certain nondiabetic

forms of CKD may explain the salutary role of this class of medications

more broadly in CKD. Other studies have also pointed to a more direct

effect on proximal tubule metabolic pathways that alleviate cell injury.

In women with CKD, estrogen levels are low, and menstrual abnormalities, infertility, and inability to carry pregnancies to term are

common. When the GFR has declined to ~40 mL/min, pregnancy is

associated with a high rate of spontaneous abortion, with only ~20%

of pregnancies leading to live births, and pregnancy may hasten the

progression of the kidney disease itself. Women with CKD who are

contemplating pregnancy should consult first with a nephrologist in

conjunction with an obstetrician specializing in high-risk pregnancy.

Men with CKD have reduced plasma testosterone levels, and sexual

dysfunction and oligospermia may supervene. Sexual maturation may

be delayed or impaired in adolescent children with CKD, even among

those treated with dialysis. Many of these abnormalities improve or

reverse with intensive dialysis or with successful renal transplantation.

■ DERMATOLOGIC ABNORMALITIES

Abnormalities of the skin are prevalent in progressive CKD. Pruritus

is quite common and one of the most vexing manifestations of the

uremic state. In advanced CKD, even on dialysis, patients may become

more pigmented, and this is felt to reflect the deposition of retained

pigmented metabolites, or urochromes. Although many of the cutaneous abnormalities improve with dialysis, pruritus is often tenacious.

The first lines of management are to rule out unrelated skin disorders,

such as scabies, and to treat hyperphosphatemia, which can cause itch.

Local moisturizers, mild topical glucocorticoids, oral antihistamines,

and ultraviolet radiation have been reported to be helpful. Recently,

agonists of kappa opioid receptors have shown promise in reducing

pruritis in hemodialysis patients.

A skin condition unique to CKD patients called nephrogenic

fibrosing dermopathy consists of progressive subcutaneous induration,

especially on the arms and legs. The condition is seen very rarely in

patients with CKD who have been exposed to the magnetic resonance

contrast agent gadolinium. Current recommendations are that patients

with CKD stage 3 (GFR 30–59 mL/min) should minimize exposure to

gadolinium and those with CKD stages 4–5 (GFR <30 mL/min) should

avoid the use of gadolinium agents unless it is medically necessary.

However, no patient should be denied an imaging investigation that is

critical to management, and under such circumstances, rapid removal

of gadolinium by hemodialysis (even in patients not yet receiving renal

replacement therapy) shortly after the procedure may mitigate this

sometimes devastating complication.

EVALUATION AND MANAGEMENT OF

PATIENTS WITH CKD

■ INITIAL APPROACH

History and Physical Examination Symptoms and overt signs

of kidney disease are often subtle or absent until renal failure supervenes. Thus, the diagnosis of kidney disease often surprises patients

and may be a cause of skepticism and denial. Particular aspects of the

history that are germane to renal disease include a history of hypertension (which can cause CKD or more commonly be a consequence

of CKD), diabetes mellitus, abnormal urinalyses, and problems with

pregnancy such as preeclampsia or early pregnancy loss. A careful

drug history should be elicited. Drugs to consider include nonsteroidal anti-inflammatory agents, cyclooxygenase-2 (COX-2) inhibitors,

antimicrobials, chemotherapeutic agents, antiretroviral agents, proton

pump inhibitors, phosphate-containing bowel cathartics, and lithium.

In evaluating the uremic syndrome, questions about appetite, weight

loss, nausea, hiccups, peripheral edema, muscle cramps, pruritus, and

restless legs are especially helpful. A family history of kidney disease,

together with assessment of manifestations in other organ systems

such as auditory, visual, and integumentary, may lead to the diagnosis

of a heritable form of CKD (e.g., Alport’s or Fabry’s disease, cystinosis)

or shared environmental exposure to nephrotoxic agents (e.g., heavy

metals, aristolochic acid). It should be noted that clustering of CKD,

sometimes of different etiologies, is often observed within families.

The physical examination should focus on blood pressure and target

organ damage from hypertension. Thus, funduscopy and precordial

examination should be carried out. Funduscopy is especially important in the diabetic patient, because it may show evidence of diabetic

retinopathy, which is associated with diabetic nephropathy. Other

physical examination manifestations of CKD include edema and sensory polyneuropathy. The finding of asterixis or a pericardial friction

rub not attributable to other causes usually signifies the presence of the

uremic syndrome.

Laboratory Investigation Laboratory studies should focus on a

search for clues to an underlying causative or aggravating disease process and on the degree of renal damage and its consequences. Serum

and urine protein electrophoresis, looking for multiple myeloma,

should be obtained in all patients >35 years old with unexplained

CKD, especially if there is associated anemia and elevated, or even

inappropriately normal, serum calcium concentration in the face of

renal insufficiency. In the presence of glomerulonephritis, autoimmune

diseases such as lupus and underlying infectious etiologies such as

hepatitis B and C and HIV should be tested. Serial measurements of

renal function should be obtained to determine the pace of renal deterioration and ensure that the disease is truly chronic rather than acute

or subacute and hence potentially reversible. Serum concentrations of

calcium, phosphorus, vitamin D, and PTH should be measured to evaluate metabolic bone disease. Hemoglobin concentration, iron, vitamin

B12, and folate should also be evaluated. A 24-h urine collection may

be helpful, because protein excretion >300 mg may be an indication

for therapy with ACE inhibitors or ARBs and also is associated with a

higher risk of progression.

Imaging Studies The most useful imaging study is a renal ultrasound, which can verify the presence of two kidneys, determine if they

are symmetric, provide an estimate of kidney size, and rule out renal

masses and evidence of obstruction. Because it takes time for kidneys

to shrink as a result of chronic disease, the finding of bilaterally small

kidneys supports the diagnosis of CKD of long-standing duration. If

the kidney size is normal, it is possible that the kidney disease is acute

or subacute. The exceptions are diabetic nephropathy (where kidney

size is increased at the onset of diabetic nephropathy before CKD

supervenes), amyloidosis, and HIV nephropathy, where kidney size

may be normal in the face of CKD. Polycystic kidney disease that has

reached some degree of renal failure will almost always present with

enlarged kidneys with multiple cysts (Chap. 315). A discrepancy >1 cm

in kidney length suggests either a unilateral developmental abnormality

or a disease process or renovascular disease with arterial insufficiency

affecting one kidney more than the other. The diagnosis of renovascular disease can be undertaken with different techniques, including

Doppler sonography, nuclear medicine studies, or CT or magnetic

resonance imaging (MRI) studies. If there is a suspicion of reflux

nephropathy (recurrent childhood urinary tract infection, asymmetric

renal size with scars on the renal poles), a voiding cystogram may be

indicated. However, in most cases, by the time the patient has CKD, the

reflux has resolved, and even if still present, repair does not improve

renal function. Radiographic contrast imaging studies are not particularly helpful in the investigation of CKD. Intravenous or intraarterial

dye should be avoided where possible in the CKD patient, especially

with diabetic nephropathy, because of the risk of radiographic contrast

dye–induced renal failure. When unavoidable, appropriate precautionary measures include avoidance of hypovolemia at the time of contrast

exposure, minimization of the dye load, and choice of radiographic

contrast preparations with the least nephrotoxic potential. Additional

measures thought to attenuate contrast-induced worsening of renal

2319Chronic Kidney Disease CHAPTER 311

function include judicious administration of sodium bicarbonate–

containing solutions and N-acetylcysteine, although these agents may

not be as effective as previously thought.

Kidney Biopsy In the patient with bilaterally small kidneys,

renal biopsy is not advised because (1) it is technically difficult and

has a greater likelihood of causing bleeding and other adverse consequences, (2) there is usually so much scarring that the underlying

disease may not be apparent, and (3) the window of opportunity to

render disease-specific therapy has passed. Other contraindications to

renal biopsy include uncontrolled hypertension, active urinary tract

infection, bleeding diathesis (including ongoing anticoagulation), and

severe obesity. Ultrasound-guided percutaneous biopsy is the favored

approach, but a surgical or laparoscopic approach can be considered,

especially in the patient with a single kidney where direct visualization

and control of bleeding are crucial. In the CKD patient in whom a

kidney biopsy is indicated (e.g., suspicion of a concomitant or superimposed active process such as interstitial nephritis or in the face of

accelerated loss of GFR), the bleeding time should be measured, and

if increased, desmopressin should be administered immediately prior

to the procedure.

A brief run of hemodialysis (without heparin) may also be considered prior to renal biopsy to normalize the bleeding time.

■ ESTABLISHING THE DIAGNOSIS AND

ETIOLOGY OF CKD

The most important initial diagnostic step is to distinguish newly

diagnosed CKD from acute or subacute renal failure, because the latter

two conditions may respond to targeted therapy. Previous measurements of serum creatinine concentration are particularly helpful in

this regard. Normal values from recent months or even years suggest

that the current extent of renal dysfunction could be more acute, and

hence reversible, than might otherwise be appreciated. In contrast,

elevated serum creatinine concentration in the past suggests that the

renal disease represents a chronic process. Even if there is evidence

of chronicity, there is the possibility of a superimposed acute process

(e.g., ECFV depletion, urinary infection or obstruction, or nephrotoxin

exposure) supervening on the chronic condition. If the history suggests

multiple systemic manifestations of recent onset (e.g., fever, polyarthritis, rash), it should be assumed that renal insufficiency is part of an

acute systemic illness.

Although kidney biopsy can usually be performed in early CKD

(stages 1–3), it is not always indicated. For example, in a patient with

a history of type 1 diabetes mellitus for 15–20 years with retinopathy,

nephrotic-range proteinuria, and absence of hematuria, the diagnosis of diabetic nephropathy is very likely and biopsy is usually not

necessary. However, if there is another finding not typical of diabetic

nephropathy, such as hematuria or white blood cell casts, or absence of

diabetic retinopathy, some other disease may be present and a biopsy

may be indicated.

In the absence of a clinical diagnosis, kidney biopsy may be the

only recourse to establish an etiology in early-stage CKD. However,

as noted above, once the CKD is advanced and the kidneys are small

and scarred, there is little utility and significant risk in attempting to

arrive at a specific diagnosis. Genetic testing using a combination of

chromosomal microarray and whole exome sequencing is increasingly

entering the repertoire of diagnostic tests since the patterns of injury

and kidney morphologic abnormalities often reflect overlapping causal

mechanisms, whose origins can sometimes be attributed to a genetic

predisposition or cause (Table 311-2).

TREATMENT

Chronic Kidney Disease

Treatments aimed at specific causes of CKD are discussed elsewhere. Two recent developments in the etiology-directed therapy

of CKD include the now-proven role of gliflozins in diabetic kidney

disease and the emergence of genome-specific therapies now established for certain patients with ADPKD (Chap. 315), which are

at the clinical trial stage for APOL1-mediated kidney disease and

certain forms of hyperoxaluria. The optimal timing of both specific

and nonspecific therapy is usually well before there has been a measurable decline in GFR and certainly before CKD is established. It is

helpful to measure sequentially and plot the rate of decline of GFR

in all patients. Any acceleration in the rate of decline should prompt

a search for superimposed acute or subacute processes that may be

reversible. These include ECFV depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to

nephrotoxic agents (such as nonsteroidal anti-inflammatory drugs

[NSAIDs] or radiographic dye), and reactivation or flare of the

original disease, such as lupus or vasculitis.

SLOWING THE PROGRESSION OF CKD

There is variation in the rate of decline of GFR among patients with

CKD. However, the following interventions should be considered in

an effort to stabilize or slow the decline of renal function.

Reducing Intraglomerular Hypertension and Proteinuria Increased

intraglomerular filtration pressures and glomerular hypertrophy

develop as a response to loss of nephron number. This response

is maladaptive as it promotes the ongoing decline of kidney function even if the inciting process has been treated or spontaneously

resolved. Control of glomerular hypertension is important in

slowing the progression of CKD. Moreover, elevated blood pressure

increases proteinuria by increasing its flux across the glomerular

capillaries. Conversely, the renoprotective effect of antihypertensive medications is gauged through the consequent reduction of

proteinuria. Thus, the more effective a given treatment is in lowering protein excretion, the greater is the subsequent impact on

protection from decline in GFR. This observation is the basis for

the treatment guideline establishing 130/80 mmHg as a target blood

pressure in proteinuric CKD patients.

Several controlled studies have shown that ACE inhibitors and

ARBs are effective in slowing the progression of renal failure in

patients with advanced stages of both diabetic and nondiabetic

CKD, in large part through effects on efferent vasodilatation

and the subsequent decline in glomerular hypertension. In the

absence of an anti-proteinuric response with either agent alone,

combined treatment with both ACE inhibitors and ARBs has

been considered. The combination is associated with a greater

reduction in proteinuria compared to either agent alone. Insofar

as reduction in proteinuria is a surrogate for improved renal

outcome, the combination would appear to be advantageous.

However, there is a greater incidence of AKI and adverse cardiac

events from such combination therapy. On balance, therefore,

ACE inhibitor plus ARB therapy should be avoided. A progressive increase in serum creatinine concentration with these agents

may suggest the presence of renovascular disease within the large

or small arteries.

Among the calcium channel blockers, diltiazem and verapamil

may exhibit superior antiproteinuric and renoprotective effects

compared to the dihydropyridines. At least two different categories

of response can be considered: one in which progression is strongly

associated with systemic and intraglomerular hypertension and

proteinuria (e.g., diabetic nephropathy, glomerular diseases) and

in which ACE inhibitors and ARBs are recommended choices,

and another in which proteinuria is mild or absent initially (e.g.,

ADPKD and other tubulointerstitial diseases), where the contribution of intraglomerular hypertension is less prominent and

other antihypertensive agents can be useful for control of systemic

hypertension.

MANAGING OTHER COMPLICATIONS OF CKD

Medication Dose Adjustment Although the loading dose of most

drugs is not affected by CKD because renal elimination is not

used in the calculation, the maintenance doses of many drugs will

need to be adjusted. For those agents in which >70% excretion is

by a nonrenal route, such as hepatic elimination, dose adjustment

may not be needed. Some drugs that should be avoided include

2320 PART 9 Disorders of the Kidney and Urinary Tract

metformin, meperidine, and oral anti-hyperglycemics that are

eliminated by the kidney. NSAIDs should be avoided because of

the risk of further worsening of kidney function. Many antibiotics,

antihypertensives, and antiarrhythmics may require a reduction in

dosage or change in the dose interval. Several online Web-based

databases for dose adjustment of medications according to stage

of CKD or estimated GFR are available (e.g., http://www.globalrph

.com/index_renal.htm). Nephrotoxic radiocontrast agents and gadolinium should be avoided or used according to strict guidelines

when medically necessary, as discussed above.

PREPARATION FOR RENAL REPLACEMENT THERAPY

(See also Chap. 313) Temporary relief of symptoms and signs of

impending uremia, such as anorexia, nausea, vomiting, lassitude,

and pruritus, may sometimes be achieved with dietary protein

restriction. However, this diet carries a risk of malnutrition; thus,

plans for more long-term management should be in place.

Maintenance dialysis and kidney transplantation have extended

the lives of hundreds of thousands of patients with CKD worldwide. Clear indications for initiation of renal replacement therapy

for patients with CKD include anorexia and nausea not attributable to reversible causes such as peptic ulcer disease, evidence of

malnutrition, and fluid and electrolyte abnormalities, principally

hyperkalemia or ECFV overload, that are refractory to other measures. Encephalopathy and pericarditis are very late complications,

so it is now rare that they serve as indications for initiation of renal

replacement therapy.

Recommendations for the Optimal Time for Initiation of Renal

Replacement Therapy Because of the individual variability in the

severity of uremic symptoms and renal function, it is ill-advised

to assign an arbitrary urea nitrogen or creatinine level to the need

to start dialysis. Moreover, patients may become accustomed to

chronic uremia and deny symptoms, only to find that they feel

better with dialysis and realize in retrospect how poorly they were

feeling before its initiation.

Previous studies suggested that starting dialysis before the onset

of severe symptoms and signs of uremia was associated with prolongation of survival. This led to the concept of “healthy” start and

is congruent with the philosophy that it is better to keep patients

feeling well rather than allowing them to become ill with uremia

and then attempting to return them to better health with dialysis

or transplantation. Although recent studies have not confirmed an

association of early-start dialysis with improved patient survival,

there may be merit in this approach for some patients. On a practical level, advanced preparation may help to avoid problems with the

dialysis process itself (e.g., a poorly functioning fistula for hemodialysis or malfunctioning peritoneal dialysis catheter) and, thus,

preempt the morbidity associated with resorting to the insertion

of temporary hemodialysis access with its attendant risks of sepsis,

bleeding, thrombosis, and association with accelerated mortality.

Patient Education Social, psychological, and physical preparation

for the transition to renal replacement therapy and the choice of

the optimal initial modality are best accomplished with a gradual

approach involving a multidisciplinary team. Along with conservative measures discussed in the sections above, it is important to

prepare patients with an intensive educational program, explaining the likelihood and timing of initiation of renal replacement

therapy and the various forms of therapy available and the option

of nondialytic conservative care. The more knowledgeable that

patients are about hemodialysis (both in-center and home-based),

peritoneal dialysis, and kidney transplantation, the easier and more

appropriate will be their decisions. Patients who are provided with

education are more likely to choose home-based dialysis therapy.

This approach is of societal benefit because home-based therapy is

less expensive to most jurisdictions and is associated with improved

quality of life. The educational programs should be commenced no

later than stage 4 CKD so that the patient has sufficient time and

cognitive function to learn the important concepts, make informed

Dialysis may be required for the treatment of either acute or chronic

kidney disease (CKD). The use of continuous renal replacement therapies (CRRTs) and prolonged intermittent renal replacement therapy

(PIRRT)/slow low-efficiency dialysis (SLED) is specific to the management of acute renal failure and is discussed in Chap. 310. These modalities are performed continuously (CRRT) or over 6–12 h per session

312 Dialysis in the Treatment

of Kidney Failure

Kathleen D. Liu, Glenn M. Chertow

choices, and implement preparatory measures for renal replacement therapy.

Exploration of social support is also important. Early education

of family members for selection and preparation of a home dialysis helper or a biologically or emotionally related potential living

kidney donor should occur long before the onset of symptomatic

renal failure.

Kidney transplantation (Chap. 313) offers the best potential

for complete rehabilitation because dialysis replaces only a small

fraction of the kidneys’ filtration function and none of the other

renal functions, including endocrine and anti-inflammatory effects.

Generally, kidney transplantation follows a period of dialysis treatment, although preemptive kidney transplantation (usually from a

living donor) can be carried out if it is certain that the renal failure

is irreversible.

■ IMPLICATIONS FOR GLOBAL HEALTH

In contrast to the natural decline and successful eradication of many

devastating infectious diseases, there is rapid growth in the prevalence

of metabolic and vascular disease in developing countries. Diabetes

mellitus is becoming increasingly prevalent in these countries, perhaps

due in part to change in dietary habits, diminished physical activity,

and weight gain. Therefore, it follows that there will be a proportionate

increase in vascular and renal disease. Health care agencies must plan

for improved screening of high-risk individuals for early detection,

prevention, and treatment plans in these nations and must start considering options for improved availability of renal replacement therapies.

There is also increasing recognition of endemic nephropathies in

developing countries that particularly target young males working in

agriculture. The extent of morbidity and mortality associated with

these nephropathies is only starting to be appreciated. It is unclear

what the cause is, but population genetic risk, endemic nephrotoxins,

exposure to pesticides, NSAID use, and chronic volume depletion have

all been suggested to contribute.

■ FURTHER READING

Carney EF: The impact of chronic kidney disease on global health. Nat

Rev Nephrol 16:251, 2020.

Heerspink HJL et al: Dapagliflozin in patients with chronic kidney

disease. N Engl J Med 383:1436, 2020.

Pollak MR, Friedman DJ: The genetic architecture of kidney diseases. Clin J Am Soc Nephrol 15:268, 2020.

Sato Y, Yanagita M: Immune cells and inflammation in AKI to CKD

progression. Am J Physiol Renal Physiol 315:F1501, 2018.

Tangri N et al: Multinational assessment of accuracy of equations for

predicting risk of kidney failure: A meta-analysis. JAMA 315:164,

2016.

Zelniker TA et al: SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A

systematic review and meta-analysis of cardiovascular outcome trials.

Lancet 393:31, 2019.

2321 Dialysis in the Treatment of Kidney Failure CHAPTER 312

HEMODIALYSIS

Hemodialysis relies on the principles of solute diffusion across a

semipermeable membrane. Movement of metabolic waste products

takes place down a concentration gradient from the circulation into

the dialysate. The rate of diffusive transport increases in response to

several factors, including the magnitude of the concentration gradient,

the membrane surface area, and the mass transfer coefficient of the

membrane. The latter is a function of the porosity and thickness of the

membrane, the size of the solute molecule, and the conditions of flow

on the two sides of the membrane. According to laws of diffusion, the

larger the molecule, the slower its rate of transfer across the membrane.

A small molecule, such as urea (60 Da), undergoes substantial clearance, whereas a larger molecule, such as creatinine (113 Da), is cleared

less efficiently. In addition to diffusive clearance, movement of waste

products from the circulation into the dialysate may occur as a result

of ultrafiltration. Convective clearance occurs because of solvent drag,

with solutes being swept along with water across the semipermeable

dialysis membrane.

■ THE DIALYZER

There are three essential components to hemodialysis: the dialyzer,

the composition and delivery of the dialysate, and the blood delivery

system (Fig. 312-1). The dialyzer is a plastic chamber with the ability

to perfuse blood and dialysate compartments simultaneously at very

high flow rates. The hollow-fiber dialyzer is the most common in use in

the United States. These dialyzers are composed of bundles of capillary

tubes through which blood circulates while dialysate travels on the outside of the fiber bundle. Virtually all dialyzers now manufactured in the

United States are “biocompatible” synthetic membranes derived from

polysulfone or related compounds (vs older cellulose “bioincompatible”

membranes that activated the complement cascade). The frequency of

reprocessing and reuse of hemodialyzers and blood lines varies across

the world. In general, as the cost of disposable supplies has decreased,

their use has increased. In the United States, reprocessing of dialyzers is

now extremely rare. Formaldehyde, peracetic acid–hydrogen peroxide,

glutaraldehyde, and bleach have all been used as reprocessing agents.

■ DIALYSATE

The potassium concentration of dialysate may be varied from

0–4 mmol/L depending on the predialysis serum potassium concentration. The use of 0- or 1-mmol/L potassium dialysate is becoming

less common owing to data suggesting that patients who undergo

treatments with very low potassium dialysate have an increased risk of

sudden death, perhaps due to arrhythmias in the setting of potassium

shifts. The usual dialysate calcium concentration is 1.25 mmol/L (2.5

mEq/L), although modification may be required in selected settings

(e.g., higher dialysate calcium concentrations may be used in patients

with hypocalcemia associated with secondary hyperparathyroidism

or with “hungry bone syndrome” following parathyroidectomy). The

usual dialysate sodium concentration is 136–140 mmol/L. In patients

who frequently develop hypotension during their dialysis run, “sodium

modeling” to counterbalance urea-related osmolar gradients may be

employed. With sodium modeling, the dialysate sodium concentration

is gradually lowered from the range of 145–155 mmol/L to isotonic

concentrations (136–140 mmol/L) near the end of the dialysis treatment, typically declining either in steps or in a linear or exponential

fashion. However, higher dialysate sodium concentrations and sodium

modeling may predispose patients to positive sodium balance and

increased thirst; thus, these strategies to ameliorate intradialytic

hypotension may be undesirable in patients with hypertension or in

patients with large interdialytic weight gains. Because patients are

exposed to ~120 L of water during each dialysis treatment, water used

for the dialysate is subjected to filtration, softening, deionization, and,

ultimately, reverse osmosis to remove microbiologic contaminants and

dissolved ions.

■ BLOOD DELIVERY SYSTEM

The blood delivery system is composed of the extracorporeal circuit

and the dialysis access. The dialysis machine consists of a blood pump,

(PIRRT/SLED), in contrast to the 3–4 h of an intermittent hemodialysis

session. Advantages and disadvantages of CRRT and PIRRT/SLED are

discussed in Chap. 310.

Peritoneal dialysis is rarely used in developed countries for the treatment of acute renal failure because of the increased risk of infection

and (as will be discussed in more detail below) less efficient clearance

per unit of time. The focus of this chapter will be on the use of peritoneal and hemodialysis for end-stage kidney disease (ESKD).

With the widespread availability of dialysis, the lives of hundreds

of thousands of patients with ESKD have been prolonged. In the

United States alone, there are now ~750,000 patients with treated

ESKD (kidney failure requiring dialysis or transplantation), the vast

majority of whom require dialysis. Since 2000, the prevalence of treated

ESKD has increased 65%, which reflects both a small increase in the

incidence rate and marginally enhanced survival of patients receiving

dialysis. The crude incidence rate for treated ESKD in the United States

is 370 cases per million population per year; ESKD is disproportionately higher in African Americans as compared with white Americans.

In the United States, the leading cause of ESKD is diabetes mellitus,

currently accounting for approximately 45% of newly diagnosed cases

of ESKD. Approximately 30% of patients have ESKD that has been

attributed to hypertension, although it is unclear whether in these

cases hypertension is the cause or a consequence of vascular disease

or other unknown causes of kidney failure. Other prevalent causes

of ESKD include glomerulonephritis, polycystic kidney disease, and

obstructive uropathy. A fraction of the excess incidence of ESKD in

African Americans is likely related to transmission of high-risk alleles

for the APOL1 gene.

Globally, mortality rates for patients with ESKD are lowest in Europe

and Japan but very high in the developing world because of the limited

availability of dialysis. In the United States, the mortality rate of patients

on dialysis has decreased somewhat, but remains extremely high, with

a mortality rate of 167 per 1000 patient-years for patients receiving

hemodialysis and 156 per patient-years for patients receiving peritoneal

dialysis. Deaths are due mainly to cardiovascular diseases and infections. Older age, male sex, nonblack race, diabetes mellitus, malnutrition, and underlying heart disease are important predictors of death.

TREATMENT OPTIONS FOR PATIENTS

WITH ESKD

Commonly accepted criteria for initiating patients on maintenance

dialysis include the presence of uremic symptoms, the presence of

hyperkalemia unresponsive to conservative measures, persistent extracellular volume expansion despite diuretic therapy, acidosis refractory

to medical therapy, a bleeding diathesis, and a creatinine clearance or

estimated glomerular filtration rate (GFR) <10 mL/min per 1.73 m2

(see Chap. 311 for estimating equations). Timely referral to a nephrologist for advanced planning and creation of a dialysis access, education

about ESKD treatment options, and management of the complications

of advanced CKD, including hypertension, anemia, acidosis, and secondary hyperparathyroidism, is advisable. Recent data have suggested

that a sizable fraction of ESKD cases result following episodes of acute

kidney injury, particularly among persons with underlying CKD.

Furthermore, there is no benefit to initiating dialysis preemptively at a

GFR of 10–14 mL/min per 1.73 m2

 compared to initiating dialysis for

symptoms of uremia.

In ESKD, treatment options include hemodialysis (in-center or at

home); peritoneal dialysis, as either continuous ambulatory peritoneal

dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD); or

transplantation (Chap. 313). Although there are significant geographic

variations and differences in practice patterns, in-center hemodialysis

remains the most common therapeutic modality for ESKD (>85% of

patients) in the United States. In contrast to hemodialysis, peritoneal

dialysis is continuous, but much less efficient in terms of solute clearance. While no large-scale clinical trials have been completed comparing outcomes among patients randomized to either hemodialysis or

peritoneal dialysis, outcomes associated with both therapies are similar

in most reports, and the decision of which modality to select is often

based on personal preferences and quality-of-life considerations.

2322 PART 9 Disorders of the Kidney and Urinary Tract

dialysis solution delivery system, and various safety monitors. The

blood pump moves blood from the access site, through the dialyzer,

and back to the patient. The blood flow rate typically ranges from

250–450 mL/min, depending on the type and integrity of the vascular access. Negative hydrostatic pressure on the dialysate side can

be manipulated to achieve desirable fluid removal or ultrafiltration.

Dialysis membranes have different ultrafiltration coefficients (i.e., mL

removed/min per mmHg) so that along with hydrostatic changes, fluid

removal can be varied. The dialysis solution delivery system dilutes

the concentrated dialysate with water and monitors the temperature,

conductivity, and flow of dialysate.

■ DIALYSIS ACCESS

The fistula, graft, or catheter through which blood is obtained for

hemodialysis is often referred to as a hemodialysis (or vascular) access.

A native fistula created by the anastomosis of an artery to a vein (e.g.,

the Brescia-Cimino fistula, in which the cephalic vein is anastomosed

end-to-side to the radial artery) results in arterialization of the vein.

This facilitates its subsequent use in the placement of large needles

(typically 15 gauge) to access the circulation. Fistulas have the highest

long-term patency rate of all hemodialysis access options. For patients

in whom fistulas fail to mature, or in patients whose vasculature does

not allow creation of a successful fistula (i.e., poor arterial inflow or

recipient veins of inadequate caliber), patients undergo placement of

an arteriovenous graft (i.e., the interposition of prosthetic material,

usually polytetrafluoroethylene, between an artery and a vein) or a

tunneled hemodialysis catheter. In recent years, nephrologists, vascular surgeons, and health care policy makers in the United States

have encouraged creation of arteriovenous fistulas in a larger fraction

of patients (the “fistula first” initiative). Unfortunately, even when

created, arteriovenous fistulas may not mature sufficiently to provide

reliable access to the circulation, or they may thrombose early in their

development.

The most important complication of arteriovenous grafts is thrombosis of the graft and graft failure, due principally to intimal hyperplasia at the anastomosis between the graft and recipient vein. When

grafts (or fistulas) fail, catheter-guided angioplasty can be used to dilate

stenoses; monitoring of venous pressures on dialysis and of access flow,

although not universally performed, may assist in the early recognition

of impending vascular access failure. In addition to increased rates of

access failure, grafts and (in particular) catheters are associated with

much higher rates of infection than fistulas.

Intravenous large-bore catheters are often used in patients with

acute renal failure and CKD. For persons on maintenance hemodialysis, tunneled catheters (either two separate catheters or a single catheter

with two lumens) are often used when arteriovenous fistulas and grafts

have failed or are not feasible due to anatomic considerations. These

catheters are tunneled under the skin; the tunnel reduces bacterial

translocation from the skin, resulting in a lower infection rate than

with nontunneled temporary catheters. Most tunneled catheters are

placed in the internal jugular veins; the external jugular, femoral, and

subclavian veins may also be used. Infection, venous thrombosis, and

venous stenosis resulting in swelling of the extremity or superior vena

cava syndrome are complications best avoided by limiting the time

during which catheters are employed.

Nephrologists, interventional radiologists, and vascular surgeons

generally prefer to avoid placement of catheters into the subclavian

veins; while flow rates are usually excellent, subclavian stenosis is a frequent complication and, if present, will likely prohibit permanent vascular access (i.e., a fistula or graft) in the ipsilateral extremity. Infection

rates may be higher with femoral catheters. For patients with multiple

vascular access complications and no other options for permanent

vascular access, tunneled catheters may be the last “lifeline” for hemodialysis. Translumbar or transhepatic approaches into the inferior vena

cava may be required if the superior vena cava or other central veins

draining the upper extremities are stenosed or thrombosed.

■ GOALS OF DIALYSIS

The hemodialysis procedure consists of pumping heparinized blood

through the dialyzer at a flow rate of 250–450 mL/min, while dialysate

flows in an opposite counter-current direction at 500–800 mL/min. The

efficiency of dialysis is determined by blood and dialysate flow through

the dialyzer as well as dialyzer characteristics (i.e., its efficiency in

removing solute). The dose of dialysis, which is currently defined as a

Venous

Arterial

Dialysate

Dialysate

Dialysate drain “Delivery” system

Hollow fiber

dialyzer

Arterial line

Venous line

V

Arteriovenous

fistula

Na+ Cl–

K+ Acetate–

Ca2+ Mg2+

Water treatment

(deionization

and reverse

osmosis)

Acid

concentrate

NaBicarb

NaCl

Arterial pressure

Venous pressure

Blood flow rate

Air (leak) detection

Dialysate

flow rate

Dialysate

pressure

Dialysate

conductivity

Blood (leak)

detection

A

FIGURE 312-1 Schema for hemodialysis.

2323 Dialysis in the Treatment of Kidney Failure CHAPTER 312

derivation of the fractional urea clearance during a single treatment,

is further governed by patient size, residual kidney function, dietary

protein intake, the degree of anabolism or catabolism, and the presence

of comorbid conditions.

Since the landmark studies of Sargent and Gotch relating the measurement of the dose of dialysis using urea concentrations with morbidity in the National Cooperative Dialysis Study, the delivered dose

of dialysis has been measured and considered as a quality assurance

and improvement tool. While the fractional removal of urea nitrogen

and derivations thereof are considered to be the standard methods

by which “adequacy of dialysis” is measured, a large multicenter randomized clinical trial (the HEMO Study) failed to show a difference

in mortality associated with a large difference in per-session urea

clearance. Current targets include a urea reduction ratio (the fractional reduction in blood urea nitrogen per hemodialysis session) of

>65–70% and a body water–indexed clearance × time product (Kt/V)

>1.2 or 1.05, depending on whether urea concentrations are “equilibrated.” For the majority of patients with ESKD, 9–12 h of dialysis are

required each week, usually divided into three equal sessions. Several

studies have suggested that longer hemodialysis session lengths may

be beneficial (independent of urea clearance), although these studies

are confounded by a variety of patient characteristics, including body

size and nutritional status. Hemodialysis “dose” should be individualized, and factors other than the urea nitrogen should be considered,

including the adequacy of ultrafiltration or fluid removal and control

of hyperkalemia, hyperphosphatemia, and metabolic acidosis. A randomized clinical trial comparing 6 versus 3 times per week hemodialysis (the Frequent Hemodialysis Network Daily Trial) demonstrated

improved control of hypertension and hyperphosphatemia, reduced

left ventricular mass, and improved self-reported physical health with

more frequent hemodialysis. Secondary analyses also demonstrated

improvements in other metrics of health-related quality of life, including improved self-reported general health and a reduced “time to

recovery” (time until usual activities can be resumed) among patients

randomized to more frequent hemodialysis. A companion trial in

which frequent nocturnal hemodialysis was compared to conventional

hemodialysis at home showed no significant effect on left ventricular

mass or self-reported physical health. Finally, an evaluation of the U.S.

Renal Data System registry showed a significant increase in mortality

and hospitalization for heart failure after the longer interdialytic interval that occurs over the dialysis “weekend.”

■ COMPLICATIONS DURING HEMODIALYSIS

Hypotension is the most common acute complication of hemodialysis, particularly among patients with diabetes mellitus. Numerous

factors appear to increase the risk of hypotension, including excessive

ultrafiltration with inadequate compensatory vascular filling, impaired

vasoactive or autonomic responses, osmolar shifts, overzealous use of

antihypertensive agents, and reduced cardiac reserve. Patients with arteriovenous fistulas and grafts may develop high-output cardiac failure

due to shunting of blood through the dialysis access; on rare occasions,

this may necessitate ligation of the fistula or graft. The management of

hypotension during dialysis consists of discontinuing ultrafiltration, the

administration of 100–250 mL of isotonic saline, or administration of

salt-poor albumin, although the latter is generally unavailable in outpatient settings. Hypotension during dialysis can frequently be prevented

by careful evaluation of the dry weight and by ultrafiltration modeling,

such that more fluid is removed at the beginning rather than the end of

the dialysis procedure. Excessively rapid fluid removal (>13 mL/kg per h)

should be avoided, as rapid fluid removal has been associated with

adverse outcomes, including cardiovascular deaths. Additional maneuvers to prevent intradialytic hypotension include the performance of

sequential ultrafiltration followed by dialysis, cooling of the dialysate

during dialysis treatment, and avoiding heavy meals during dialysis.

Midodrine, an oral selective α1 adrenergic agent, has been advocated by

some practitioners, although there is insufficient evidence of its safety

and efficacy to support its routine use.

Muscle cramps during dialysis are also a common complication.

The etiology of dialysis-associated cramps remains obscure. Changes

in muscle perfusion because of excessively rapid volume removal or

targeted removal below the patient’s estimated dry weight often precipitate dialysis-associated cramps. Strategies that may be used to prevent

cramps include reducing volume removal during dialysis, ultrafiltration profiling, and the use of sodium modeling (see above).

Anaphylactoid reactions to the dialyzer, particularly on its first

use, have been reported most frequently with the bioincompatible

cellulosic-containing membranes. Dialyzer reactions can be divided

into two types, A and B. Type A reactions are attributed to an IgEmediated intermediate hypersensitivity reaction to ethylene oxide used

in the sterilization of new dialyzers. This reaction typically occurs soon

after the initiation of a treatment (within the first few minutes) and

can progress to full-blown anaphylaxis if the therapy is not promptly

discontinued. Treatment with steroids or epinephrine may be needed if

symptoms are severe. The type B reaction consists of a symptom complex of nonspecific chest and back pain, which appears to result from

complement activation and cytokine release. These symptoms typically

occur several minutes into the dialysis run and typically resolve over

time with continued dialysis.

PERITONEAL DIALYSIS

In peritoneal dialysis, 1.5–3 L of a dextrose-containing solution is

infused into the peritoneal cavity and allowed to dwell for a set period

of time, usually 2–4 h. As with hemodialysis, metabolic by-products

are removed through a combination of convective clearance generated

through ultrafiltration and diffusive clearance down a concentration

gradient. The clearance of solutes and water during a peritoneal dialysis

exchange depends on the balance between the movement of solute and

water into the peritoneal cavity versus absorption from the peritoneal

cavity. The rate of diffusion diminishes with time and eventually stops

when equilibration between plasma and dialysate is reached. Absorption of solutes and water from the peritoneal cavity occurs across the

peritoneal membrane into the peritoneal capillary circulation and via

peritoneal lymphatics into the lymphatic circulation. The rate of peritoneal solute transport varies from patient to patient and may be altered

by the presence of infection (peritonitis), drugs, and physical factors

such as position and exercise.

■ FORMS OF PERITONEAL DIALYSIS

Peritoneal dialysis may be carried out as CAPD, CCPD, or a combination of both. In CAPD, dialysate is manually infused into the peritoneal

cavity and exchanged three to five times during the day. A nighttime

dwell is frequently instilled at bedtime and remains in the peritoneal

cavity through the night. In CCPD, exchanges are performed in an

automated fashion, usually at night; the patient is connected to an automated cycler that performs a series of exchange cycles while the patient

sleeps. The number of exchange cycles required to optimize peritoneal

solute clearance varies by the peritoneal membrane characteristics; as

with hemodialysis, solute clearance should be tracked to ensure dialysis

“adequacy.”

Peritoneal dialysis solutions are available in volumes typically ranging from 1.5–3 L. The major difference between the dialysate used for

peritoneal rather than hemodialysis is that the hypertonicity of peritoneal dialysis solutions drives solute and fluid removal, whereas solute

removal in hemodialysis depends on concentration gradients, and fluid

removal requires transmembrane pressure. Typically, dextrose at varying concentrations contributes to the hypertonicity of peritoneal dialysate. Icodextrin is a nonabsorbable carbohydrate that can be used in

place of dextrose. Studies have demonstrated more efficient ultrafiltration with icodextrin than with dextrose-containing solutions. Icodextrin

is typically used as the “last fill” for patients on CCPD or for the longest

dwell in patients on CAPD. The most common additives to peritoneal

dialysis solutions are heparin to prevent obstruction of the dialysis

catheter lumen with fibrin and antibiotics during an episode of acute

peritonitis. Insulin may also be added in patients with diabetes mellitus.

■ ACCESS TO THE PERITONEAL CAVITY

Access to the peritoneal cavity is obtained through a peritoneal catheter. Catheters used for maintenance peritoneal dialysis are flexible,

2324 PART 9 Disorders of the Kidney and Urinary Tract

being made of silicone rubber with numerous side holes at the distal

end. These catheters usually have two Dacron cuffs. The scarring that

occurs around the cuffs anchors the catheter and seals it from bacteria

tracking from the skin surface into the peritoneal cavity; it also prevents the external leakage of fluid from the peritoneal cavity. The cuffs

are placed in the preperitoneal plane and ~2 cm from the skin surface.

The peritoneal equilibrium test is a formal evaluation of peritoneal

membrane characteristics that measures the transfer rates of creatinine

and glucose across the peritoneal membrane. Patients are classified as

low, low–average, high–average, and high transporters. Patients with

rapid equilibration (i.e., high transporters) tend to absorb more glucose

and lose efficiency of ultrafiltration with long daytime dwells. High

transporters also tend to lose larger quantities of albumin and other

proteins across the peritoneal membrane. In general, patients with

rapid transporting characteristics require more frequent, shorter dwelltime exchanges, nearly always obligating use of a cycler. Slower (low

and low–average) transporters tend to do well with fewer exchanges.

The efficiency of solute clearance also depends on the volume of dialysate infused. Larger volumes allow for greater solute clearance, particularly with CAPD in patients with low and low–average transport

characteristics.

As with hemodialysis, the optimal dose of peritoneal dialysis is

unknown. Several observational studies have suggested that higher

rates of urea and creatinine clearance (the latter generally measured

in L/week) are associated with lower mortality rates and fewer uremic

complications. However, a randomized clinical trial (Adequacy of

Peritoneal Dialysis in Mexico [ADEMEX]) failed to show a significant

reduction in mortality or complications with a relatively large increment in urea clearance. In general, patients on peritoneal dialysis do

well when they retain residual kidney function. Rates of technique failure increase with years on dialysis and have been correlated with loss of

residual function to a greater extent than loss of peritoneal membrane

capacity. For some patients in whom CCPD does not provide sufficient solute clearance, a hybrid approach can be adopted where one or

more daytime exchanges are added to the CCPD regimen. While this

approach can enhance solute clearance and prolong a patient’s capacity

to remain on peritoneal dialysis, the burden of the hybrid approach can

be overwhelming.

■ COMPLICATIONS DURING PERITONEAL DIALYSIS

The major complications of peritoneal dialysis are peritonitis,

catheter-associated nonperitonitis infections, weight gain and other

metabolic disturbances, and residual uremia (especially among patients

with little or no residual kidney function).

Peritonitis typically develops when there has been a break in sterile

technique during one or more of the exchange procedures. Peritonitis

is usually defined by an elevated peritoneal fluid leukocyte count (100/

mm3

, of which at least 50% are polymorphonuclear neutrophils); these

cutoffs are lower than in spontaneous bacterial peritonitis because

of the presence of dextrose in peritoneal dialysis solutions and rapid

bacterial proliferation in this environment without antibiotic therapy. The clinical presentation typically consists of pain and cloudy

dialysate, often with fever and other constitutional symptoms. The

most common culprit organisms are gram-positive cocci, including

Staphylococcus, reflecting the origin from the skin. Gram-negative rod

infections are less common; fungal and mycobacterial infections can

be seen in selected patients, particularly after antibacterial therapy.

Most cases of peritonitis can be managed either with intraperitoneal

or oral antibiotics, depending on the organism; many patients with

peritonitis do not require hospitalization. In cases where peritonitis is

due to hydrophilic gram-negative rods (e.g., Pseudomonas sp.) or yeast,

antimicrobial therapy is usually not sufficient, and catheter removal is

required to ensure complete eradication of infection. Nonperitonitis

catheter-associated infections (often termed tunnel infections) vary

widely in severity. Some cases can be managed with local antibiotic or

silver nitrate administration, while others are severe enough to require

parenteral antibiotic therapy and catheter removal.

Peritoneal dialysis is associated with a variety of metabolic complications. Albumin and other proteins can be lost across the peritoneal

membrane in concert with the loss of metabolic wastes. Hypoproteinemia obligates a higher dietary protein intake in order to maintain

nitrogen balance. Hyperglycemia and weight gain are also common

complications of peritoneal dialysis. Several hundred calories in the

form of dextrose are absorbed each day, depending on the concentration of dextrose employed. Patients receiving peritoneal dialysis,

particularly those with diabetes mellitus, are prone to other complications of insulin resistance, including hypertriglyceridemia. On the

positive side, the continuous nature of peritoneal dialysis usually allows

for a more liberal diet due to continuous removal of potassium and

phosphorus—two major dietary components whose accumulation can

be hazardous in ESKD.

LONG-TERM OUTCOMES IN ESKD

Cardiovascular disease constitutes the major cause of death in patients

with ESKD. Cardiovascular mortality and event rates are higher

in patients receiving dialysis than in patients posttransplantation,

although rates are extraordinarily high in both populations. The

underlying cause of cardiovascular disease is unclear but may be

related to shared risk factors (e.g., diabetes mellitus, hypertension,

atherosclerotic and arteriosclerotic vascular disease), chronic inflammation, massive changes in extracellular volume (especially with high

interdialytic weight gains), inadequate treatment of hypertension,

dyslipidemia, anemia, dystrophic (vascular) calcification, and, perhaps,

alterations in cardiovascular dynamics during the dialysis treatment.

Few studies have targeted cardiovascular risk reduction in patients

with ESKD; none has demonstrated consistent benefit. Two clinical

trials of statin agents in ESKD demonstrated significant reductions

in low-density lipoprotein (LDL) cholesterol concentrations but no

significant reductions in death or cardiovascular events (Die Deutsche

Diabetes Dialyse Studie [4D] and AURORA studies). The Study of

Heart and Renal Protection (SHARP), which included patients on

dialysis and others with non-dialysis-requiring CKD, showed a 17%

reduction in the rate of major cardiovascular events or cardiovascular

death with simvastatin-ezetimibe treatment. Most experts recommend

conventional cardioprotective strategies (e.g., lipid-lowering agents,

aspirin, inhibitors of the renin-angiotensin-aldosterone system, and

β-adrenergic antagonists) in patients receiving dialysis based on the

patients’ cardiovascular risk profile, which appears to be increased by

more than an order of magnitude relative to persons unaffected by kidney disease. Other complications of ESKD include a high incidence of

infection, progressive debility and frailty, protein-energy malnutrition,

and impaired cognitive function.

GLOBAL PERSPECTIVE

The incidence of ESKD is increasing worldwide with longer life

expectancies and improved care of infectious and cardiovascular diseases. The management of ESKD varies widely by country and within

country by region, and it is influenced by economic and other major

factors. In general, peritoneal dialysis is more commonly performed

in poorer countries owing to its lower expense and the high cost of

establishing in-center hemodialysis units.

■ FURTHER READING

Cooper BA et al: A randomized, controlled trial of early versus late

initiation of dialysis. N Engl J Med 363:609, 2010.

Correa-Rotter R et al: Peritoneal dialysis, in Brenner and Rector’s

The Kidney, 9th ed, MW Taal et al (eds). Philadelphia, Elsevier, 2011.

Fellstrom BC et al: Rosuvastatin and cardiovascular events in

patients undergoing hemodialysis. N Engl J Med 360:1395, 2009.

Flythe JE et al: Rapid fluid removal during dialysis is associated with

cardiovascular morbidity and mortality. Kidney Int 79:250, 2011.

Foley RN et al: Long interdialytic interval and mortality among

patients receiving hemodialysis. N Engl J Med 365:1099, 2011.

Frequent Hemodialysis Network Trial Group: In-center hemodialysis six times per week versus three times per week. N Engl J Med

363:2287, 2010.