Systemic complications of chronic kidney

disease
Pinpointing clinical manifestations and best management
Gregorio T. Obrador, MD, MPH; Brian J. G. Pereira, MD, MBA
VOL 111 / NO 2 / FEBRUARY 2002 / POSTGRADUATE MEDICINE

Kidneys play an essential role in the maintenance of normal homeostasis. A variety of

diseases may affect the kidneys and lead to progressive nephron loss. As kidney function
deteriorates, loss of excretory, regulatory, and endocrine function takes place, and
complications develop in virtually every organ system. Despite the diversity of causes,
the pathophysiology and clinical manifestations of progressive kidney disease are quite
similar across the spectrum.

Stages of kidney disease

Glomerular filtration rate (GFR) is accepted as the best index of overall kidney function
in health and disease. Several stages of CKD, defined as structural abnormalities of the
kidney that can lead to decreased GFR, are recognized.
Kidney damage
This stage is defined as the presence of structural or functional abnormalities of the
kidney, initially without decreased GFR, which over time can lead to decreased GFR.
Mild reduction in GFR (60 to 89 mL/min/1.73 m )
At this stage, patients usually have hypertension and may have laboratory abnormalities
indicative of dysfunction in other organ systems, but most are asymptomatic. If the serum
creatinine level is elevated, it may be no more than borderline and of equivocal
significance.
2

Moderate reduction in GFR (30 to 59 mL/min/1.73 m )

This stage is characterized primarily by the presence of azotemia, defined as the
accumulation of the end products of nitrogen metabolism in the blood and expressed by
an elevation in serum creatinine and serum urea nitrogen (SUN) concentrations.
Erythropoietin production decreases, and laboratory abnormalities reflecting dysfunction
in other organ systems are usually present. Although patients may have symptoms, they
often remain remarkably asymptomatic even though their kidney function may be
reduced by as much as 70%.
2

Severe reduction in GFR (15 to 29 mL/min/1.73 m )

In this extremely tenuous stage of CKD, the worsening of azotemia, anemia, and other
2

laboratory abnormalities reflect dysfunction in several organ systems. However, patients

usually have mild symptoms.
Kidney failure (GFR, <15 mL/min/1.73 m )
In most cases, this level of kidney function is accompanied by a constellation of
symptoms and laboratory abnormalities in several organ systems, which are collectively
referred to as uremia. Initiation of kidney replacement therapy (dialysis or
transplantation) is typically required for treatment of comorbid conditions or
complications of decreased GFR, which would otherwise increase the risk of morbidity
and mortality.
2

Pathophysiology of uremia
Although the pathogenesis of the different uremic symptoms is not completely
understood, three major mechanisms are involved: diminished excretion of electrolytes
and water, reduced excretion of organic solutes, and decreased hormone production (1,2).
Diminished excretion of electrolytes and water
An important function of the healthy kidney is to excrete the electrolytes and water
generated from dietary intake in order to maintain a steady state in which intake and
urinary excretion are roughly equal. The conditions that cause loss of kidney function
induce adaptive mechanisms that attempt to preserve the homeostatic state of electrolyte
and water balance. If, for example, three quarters of nephrons have been lost, then each
remaining nephron must excrete four times the amount of electrolytes and water to
maintain the excretion at the same level of dietary intake.
However, all these compensatory mechanisms eventually fail, at which stage the
continual loss of function results in the kidney's inability to maintain balance. At this
point, patients are said to have end-stage renal disease (ESRD). The number of
functioning nephrons at this time is so small that urinary excretion cannot achieve a level
equal to intake. Clinical manifestations include edema and hypertension (caused by
sodium retention), hyponatremia (resulting from free water retention), hyperkalemia,
metabolic acidosis, hyperuricemia, and hyperphosphatemia.
Reduced excretion of organic solutes
The kidneys excrete a variety of organic solutes, the most commonly measured ones
being urea and creatinine. Unlike the excretion of electrolytes and water, the excretion of
urea and creatinine is not actively regulated. Thus the plasma level of these solutes begins
to rise with the initial decline in GFR and increases progressively as kidney function
deteriorates. Once the GFR falls below 15 mL/min/1.73m , patients begin to complain of
many of the manifestations listed in table 1. It is thought that many of these symptoms
are mediated by an accumulation of uremic toxins. However, it is not yet possible to
identify the toxins responsible for most uremic symptoms (3). Although it has been
postulated that urea may be an important toxin, symptoms of uremia correlate only
inconsistently with the level of urea.
2

Table 1. Clinical manifestations of kidney failure

System
Clinical manifestations
Electrolytes

Edema, hyponatremia, hyperkalemia, metabolic acidosis, hyperuricemia,

hyperphosphatemia, hypocalcemia

Gastrointestinal Anorexia, nausea, vomiting, malnutrition

Cardiovascular Accelerated atherosclerosis, systemic hypertension, pericarditis
Hematologic

Anemia, immune dysfunction, platelet dysfunction

Musculoskeletal Renal osteodystrophy, muscle weakness, growth retardation in children,

amyloid arthropathy caused by beta -microglobulin deposition
2

Neurologic

Encephalopathy, seizures, peripheral neuropathy

Endocrine

Hyperlipidemia, glucose intolerance caused by insulin resistance,

amenorrhea and infertility in women, impotence

Skin

Pruritus

Decreased hormone production

The kidneys normally produce several hormones, including erythropoietin and calcitriol
(1,25-dihydroxycholecalciferol), the active form of vitamin D. The decreased production
of these two hormones plays an important role in the development of anemia and bone
disease, respectively.

Systemic complications and their treatment

Uremic syndrome consists of an array of complex symptoms and signs that occur when
advanced kidney failure prompts the malfunction of virtually every organ system.
However, the onset of uremia is slow and insidious, beginning with rather nonspecific
symptoms such as malaise, weakness, insomnia, and a general feeling of being unwell.
Patients may lose their appetite and complain of morning nausea and vomiting.
Eventually, signs and symptoms of multisystem failure are evident. Table 1 lists major
complications of kidney failure.
Electrolyte disturbances
CKD prompts a variety of disturbances in electrolytes and fluid balance.
Sodium balance: Sodium balance remains virtually normal until very late in the course
of CKD, because the kidney can markedly increase the amount of sodium excreted per

nephron by reducing tubular sodium reabsorption. Although sodium balance is

maintained, the kidney loses its ability to adapt to large variations in salt intake. Indeed,
intake of large amounts of sodium can easily overwhelm the excretory capacity of the
failing kidney and result in fluid retention, edema, and hypertension. Likewise, if
diuretics are used overzealously, the patient may become volume-depleted, with further
aggravation of the kidney failure. Wasting of sodium by the chronically diseased kidney-so-called sodium-wasting nephropathies--is rare.
Clinically evident edema is uncommon until the GFR falls to less than 15
mL/min/1.73m . However, edema can occur at higher GFR levels in patients with
glomerular disease and significant proteinuria (ie, nephrotic syndrome) and in those with
heart failure. The cornerstone of treatment of edema (and hypertension) is restriction of
dietary sodium to a level lower than that recommended for uncomplicated hypertension
(<100 mEq/day; 2.3 g of sodium or 6 g of salt) (4).
2

If sodium restriction is not effective or not achieved, diuretics should be used (5).
Thiazide diuretics are usually ineffective if the serum creatinine level is greater than 3
mg/dL (>265 micromole/L). Thus, more potent loop diuretics are the agents of choice in
patients with CKD. The initial aim is to determine the threshold dose that is effective.
Patients with advanced CKD may require doses of furosemide (Lasix) as high as 400 mg
per day. Lack of response to high doses of loop diuretics often is due to noncompliance
with dietary sodium restriction. In such cases, a combination of a thiazide diuretic or
metolazone (Mykrox, Zaroxolyn) given before the loop diuretic may induce diuresis. For
maximum efficacy, the thiazide diuretic should be given 30 minutes before the loop
diuretic. Potassium-sparing diuretics (eg, spironolactone [Aldactone]) are contraindicated
because of the risk of inducing hyperkalemia.
Potassium balance: Potassium balance and plasma potassium level are also maintained
until very late in CKD, mainly because of an increase in renal excretion of potassium per
functioning nephron and an increase in potassium output in the stool (6). Hyperkalemia
may develop earlier in the course of CKD in patients with hyporeninemic
hypoaldosteronism, a complication usually seen in patients with diabetic nephropathy or
tubulointerstitial disease.
Hyperkalemia may occur in association with dietary indiscretion (eg, excessive
consumption of chocolate, dried fruits, or bananas), use of potassium-containing salt
substitutes, increased catabolism (as with severe intercurrent illness), or metabolic
acidosis. It may also be seen with the use of potassium-sparing diuretics, angiotensinconverting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs
(NSAIDs). Hypokalemia may occasionally occur in patients with CKD, and it is usually
due to gastrointestinal losses or excessive use of the cation exchange resin sodium
polystyrene sulfonate (Kayexalate, SPS).
Mild hyperkalemia in the range of 5 to 5.5 mEq/L is a common feature in patients with
CKD and requires dietary potassium restriction to 2 to 3 g (50 to 75 mEq) per day as well
as discontinuation of any offending drug. Patients with a serum potassium concentration

below 6 mEq/L usually respond to a combination of a loop diuretic and a low-potassium

diet. Asymptomatic patients with a serum potassium level above 6 to 6.5 mEq/L can be
treated with sodium polystyrene sulfonate, given orally or by colonic enema at a dose of
15 to 30 g every 6 hours with sorbitol.
More marked or symptomatic hyperkalemia, particularly in the presence of
electrocardiographic changes, is treated with combinations of intravenous calcium
gluconate (for urgent situations) and infusions of glucose and insulin with or without
bicarbonate. This therapy transiently drives potassium into the cells until excess
potassium can be removed from the body. The latter can be achieved with sodium
polystyrene sulfonate or diuretics at high doses. In patients with kidney failure, dialysis
may be required.
Water balance: The ability to concentrate or dilute urine is impaired in patients with
CKD, which makes them more susceptible to hypernatremia and hyponatremia.
Hypernatremia may occur if water consumption is not sufficient to replace fluid loss.
More commonly, hyponatremia develops in patients with CKD because they either drink
water or are given hypotonic fluids in excess of their ability to excrete water. To prevent
hyponatremia, most patients are permitted a modest fluid intake of 1.5 L per day. Also,
intravenous administration of hypotonic solutions should be avoided.
Metabolic acidosis: Most patients with CKD develop metabolic acidosis because of their
reduced ability to excrete the hydrogen ions generated mainly from the metabolism of
sulfur-containing amino acids (7,8). As a patient's condition approaches ESRD, serum
bicarbonate concentration often falls to between 12 and 20 mEq/L and the anion gap
increases. A level below 10 mEq/L is unusual, because buffering of the retained hydrogen
ions by intracellular buffers prevents a progressive fall in the concentration of serum
bicarbonate.
Treatment of metabolic acidosis appears to be justified because chronic acidemia has
been associated with worsening of hyperparathyroid-induced kidney bone disease and
negative calcium balance, enhanced skeletal muscle breakdown and catabolism, growth
retardation in children, and probably faster progression of GFR loss (9). The goal is to
maintain the serum bicarbonate level above 20 mEq/L. Sodium bicarbonate in a dose
equivalent to the daily production of acid (0.5 to 1 mEq/kg body weight per day) is
generally recommended. Because of the concomitant sodium load, diuretic therapy may
be necessary to avoid edema and hypertension.
Sodium citrate is better tolerated than sodium bicarbonate because it does not produce
carbon dioxide gas in the stomach. However, sodium citrate should not be used in
patients taking aluminum-containing phosphate binders, because it markedly increases
aluminum absorption and increases the risk of aluminum intoxication. Calcium
carbonate, which is often used as a phosphate binder, can help control acidemia as well.
Gastrointestinal complications
Anorexia, nausea, and vomiting are common in advanced kidney failure (10). These

symptoms are usually corrected by dialysis. However, malnutrition is a common problem

in CKD patients, and nutritional support coordinated with an experienced renal dietitian
is an important component of management of these patients (11).
Cardiovascular complications
The most common cause of death in patients with ESRD is cardiovascular disease. Thus,
reduction of both traditional and CKD-related cardiovascular risk factors is of utmost
importance to reduce morbidity and mortality from cardiovascular disease. (The next
article in this series discusses the effects of CKD on the cardiovascular system in greater
detail.)
Hypertension almost invariably develops in patients with CKD and is usually volumedependent. Less often, high levels of renin and angiotensin are important contributory
factors (12,13). Aggressive management of blood pressure can, in addition to controlling
a modifiable cardiovascular risk factor, slow the progression of kidney disease; the goal
is to achieve a blood pressure of less than 130/85 mm Hg. Treatment of hypertension
includes restriction of dietary sodium and use of diuretics. (See information on sodium
balance earlier in this article.)
ACE inhibitors are the antihypertensive agents of choice because they offer the advantage
of slowing the progression of GFR decline by an additional effect that is above and
beyond their ability to lower blood pressure (14,15). The protective effect of ACE
inhibitors is more pronounced in patients with a higher degree of proteinuria (16). While
a patient is taking ACE inhibitors, serum potassium and serum creatinine levels should be
checked often.
Pericarditis was once a common finding but is seen much less often today because
dialysis is usually started before it appears. Treatment of this condition includes intensive
dialysis and the use of NSAIDs (17).
Hematologic complications
A normochromic and normocytic anemia, defined as hemoglobin levels lower than
physiologic norms, starts to develop in most patients when the GFR falls below 60
mL/min/1.73 m . It occurs mainly as a result of erythropoietin deficiency and, to a lesser
degree, from hemolysis, presence of uremic inhibitors, blood loss (either occult or overt),
and deficiency in iron, folate, or vitamin B .
2

12

The availability of recombinant human erythropoietin has revolutionized the management

of anemia in CKD (table 2), although it is expensive. Correction of anemia with
erythropoietin results in improved cardiac function, exercise tolerance, central nervous
system symptoms, appetite, and sexual function (18,19).
Table 2. Erythropoietin therapy for anemia of chronic kidney disease:
administration, side effects, causes of resistance
Before starting therapy
Exclude other treatable causes of anemia (iron, folic acid, or vitamin B deficiency)
12

Achieve adequate blood pressure control

Check that iron stores are adequate (ferritin, >100 ng/mL; iron saturation, >20%)
Dosage
Dispense initial dose of 50-100 U/kg SQ once or twice per week
Increase dose to achieve target hematocrit level between 33% and 36%
Monitor hematocrit and hemoglobin levels every 1 to 2 weeks initially and after a major
change in dose
As follow-up, monitor hematocrit and hemoglobin levels every 4 to 12 weeks or when
indicated clinically
Monitor iron stores and provide adequate amounts of iron
Side effects (% of patients)*
Hypertension (17% to 65%)
Headache (15%)
Influenzalike syndrome (5%)
Causes of resistance
Iron deficiency (most common)
Chronic inflammation
Occult malignancy
Aluminum toxicity
Severe hyperparathyroidism
Malnutrition

*Side effects of erythropoietin are unlikely to hasten progression of decline in glomerular

filtration rate if blood pressure control is adequate.

Although white blood cell count is usually within normal range when CKD is present, the
function of these cells may be defective, leading to an increased susceptibility to
infections (20). Other common effects include an increased capillary fragility and
bleeding tendency resulting from defective platelet function.
Bone disease
Metabolism of calcium and phosphorus is abnormal in patients with CKD and is
associated with the development of bone disease. Phosphate retention occurs as GFR
declines. Both hyperphosphatemia and, more important, reduction in the active form of
vitamin D (1,25-dihydroxycholecalciferol) lead to hypocalcemia. (The active form of
vitamin D is normally produced by the kidney and increases calcium absorption in the
intestine.) As attempts are made to normalize the serum calcium level, secondary
hyperparathyroidism can develop, causing significant bone damage (figure 1) to occur
(21,22).

The spectrum of bone disease, also known as renal osteodystrophy, includes osteitis
fibrosa, osteomalacia, and adynamic bone disease. The most common form is osteitis
fibrosa caused by secondary hyperparathyroidism. Although initially asymptomatic,
osteitis fibrosa can produce bone pain, pathologic fractures, and metastatic calcifications
in its more advanced stages. The complications associated with hyperparathyroidism can
be prevented or minimized by controlling hyperphosphatemia and by lowering the
parathyroid hormone level (table 3) (23).
Table 3. Treatment of abnormal calcium and phosphorus balance in chronic kidney
disease
General goals
Treatment is directed first at control of hyperphosphatemia and thereafter at control of
PTH secretion.
Hyperphosphatemia
The goal is to maintain serum phosphate levels in the upper range of normal (4.5-5.5
mg/dL [1.5-1.8 mmol/L]).
A low-phosphorus diet (<800 g/day) should be attempted first but is difficult to attain.
Phosphate binders are used as follows:
Aluminum hydroxide and magnesium-containing antacids should not be used because of
the risk of aluminum toxicity and hypermagnesemia.

Calcium carbonate and calcium acetate are the binders of choice because they are
effective phosphate binders and also correct hypocalcemia.

Start with 1 to 2 tablets three times per day with meals and increase dose until
serum phosphorus level falls to <5.5 mg/dL (<1.8 mmol/L).
Daily dose ranges from 2 to 10 g of binder.
Monitor serum calcium level because of the risk of hypercalcemia.

Sevelamer HCl (Renagel) can also be considered because it is a cationic polymer that
binds phosphate through ion exchange. It is as effective as calcium acetate and does not
cause hypercalcemia, but it is considerably more expensive.
PTH suppression
The goal is to achieve a PTH level 2 to 3 times normal (130-195 pg/mL [13.7-20.5
pmol/L]).
Calcitriol (1,25-dihydroxycholecalciferol) (Calcijex, Rocaltrol) is used as follows:

Treatment should be started in patients with a PTH level of >200 pg/mL (>21
pmol/L) only after the phosphate level has been controlled (<6.5 mg/dL [2.1
mmol/L]).
Low-dose therapy (0.25 mg/day) may be as effective as pulse therapy (2 to 3 times
per week).
Complications of therapy include adynamic bone disease resulting from excessive
PTH suppression and hypercalcemia.

PTH, parathyroid hormone.

Neurologic complications
Cerebrovascular accidents of all types are common in CKD. Uremic encephalopathy is
often seen in advanced kidney failure and is characterized by insomnia, impairment of
concentration, alterations in usual sleep rhythms, lability of emotion, anxiety, and
depression. Dialysis produces rapid clearing of the mental state and correction of
abnormal electroencephalographic findings. Generalized motor seizures may also occur
in patients with advanced kidney failure.
A symmetrical polyneuropathy of a mixed sensory-motor type is commonly seen.
Sensory symptoms present first (eg, cramps, paresthesias, restless legs). Disturbances in
autonomic function may cause postural hypotension and impotence (24).

Summary and conclusion

The kidney plays a critical role in the maintenance of homeostasis. As kidney function
diminishes, excretory, regulatory, and endocrine function is lost, and complications
develop in essentially every organ system. Kidney failure is the last stage in the
continuum of progressive CKD. Management of the complications associated with CKD
mainly includes dietary counseling, adequate control of volume and blood pressure, and
use of phosphate binders, calcitriol (Calcijex, Rocaltrol), and erythropoietin. Many of
these complications can be prevented or attenuated with optimal CKD care, which
involves early detection of progressive kidney disease, interventions to retard its
progression, prevention of uremic complications, attenuation of comorbid conditions,
adequate preparation for kidney replacement therapy, and timely initiation of dialysis
(figure 2). Closer attention to CKD care is likely to be the key to improved outcomes
among patients with kidney failure (25,26).

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Dr Obrador is staff physician, division of nephrology, New England Medical Center,
Boston; assistant professor of medicine, Tufts University School of Medicine, Boston;
and associate dean for academic affairs, Universidad Panamericana School of Medicine,
Mexico City. Dr Pereira is senior vice president, division of nephrology, New England
Medical Center, and professor of medicine, Tufts University School of Medicine.
Correspondence: Brian J. G. Pereira, MD, MBA, Division of Nephrology, New England
Medical Center, 750 Washington St, Box 5224, Boston, MA 02111. E-mail:
bpereira@lifespan.org.