TOC   |     

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

Preview: Kidneys bear a huge responsibility in the survival of the human body. They keep our internal environment in balance and play an essential role in the maintenance of normal homeostasis. It therefore comes as no surprise that chronic kidney disease (CKD)--and the resultant decline in kidney function--can seriously affect essentially every organ system. In this article, Drs Obrador and Pereira review the most frequent systemic complications of CKD and offer recommendations for their management.

Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival; but should the kidney fail . . . neither bone, muscle, gland nor brain could carry on.

Homer W. Smith,
From Fish to Philosopher

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 m²)
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.

Moderate reduction in GFR (30 to 59 mL/min/1.73 m²)
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%.

Severe reduction in GFR (15 to 29 mL/min/1.73 m²)
In this extremely tenuous stage of CKD, the worsening of azotemia, anemia, and other laboratory abnormalities reflect dysfunction in several organ systems. However, patients usually have mild symptoms.

Kidney failure (GFR, <15 mL/min/1.73 m²)
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.

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/1.73m², 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.

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 beta2-microglobulin deposition
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/1.73m². 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).

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, angiotensin-converting 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 volume-dependent. 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 m². 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 B₁₂.

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 B12 deficiency) 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).

References

1. Rose BD, Rennke HG. Signs and symptoms of chronic renal failure. Renal pathophysiology--the essentials. Baltimore: Williams & Wilkins, 1994;276-300

2. Bailey JL, Mitch WE. Pathophysiology of uremia. In: Brenner BM, ed. Brenner & Rector's the kidney. Vol 2. 6th ed. Philadelphia: WB Saunders, 2000;2059-78

3. Ringoir S. An update on uremic toxins. Kidney Int 1997;52(Suppl 62):S2-4

4. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda: National Institutes of Health, National Heart, Lung, and Blood Institute, 1997

5. Suki WN. Use of diuretics in chronic renal failure. Kidney Int 1997;51(Suppl 59):S33-5

6. Allon M. Hyperkalemia in end-stage renal disease: mechanisms and management. J Am Soc Nephrol 1995;6(4):1134-42

7. Warnock DG. Uremic acidosis. Kidney Int 1998;34(2):278-87

8. Santella RN. Chronic renal insufficiency. In: Gennari FJ, ed. Medical management of kidney and electrolyte disorders. New York: Marcel Dekker, 2001;269-92

9. Alpern RJ, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. Am J Kidney Dis 1997;29(2):291-302

10. Etemad B. Gastrointestinal complications of renal failure. Gastroenterol Clin North Am 1998;27(4):875-92

11. Ikizler TA, Hakim RM. Nutrition in end-stage renal disease. Kidney Int 1996;50(2):343-57

12. Buckalew VM Jr, Berg RL, Wang S-R, et al. Prevalence of hypertension in 1,795 subjects with chronic renal disease: the modification of diet in renal disease study baseline cohort. Modification of Diet in Renal Disease Study Group. Am J Kidney Dis 1996;28(6):811-21

13. Preston RA, Singer I, Epstein M. Renal parenchymal hypertension: current concepts of pathogenesis and management. Arch Intern Med 1996;156(6):602-11

14. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456-62

15. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997;127(5):337-45

16. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: Is this a cause for concern? Arch Intern Med 2000;160(5):685-93

17. Rutsky EA, Rostand SG. Treatment of uremic pericarditis and pericardial effusion. Am J Kidney Dis 1987;10(1):2-8

18. Erslev AJ, Besarab A. Erythropoietin in the pathogenesis and treatment of the anemia of chronic renal failure. Kidney Int 1997;51(3):622-30

19. Kausz AT, Obrador GT, Pereira BJ. Anemia management in patients with chronic renal insufficiency. Am J Kidney Dis 2000;36(6 Suppl 3):S39-51

20. Cohen G, Haag-Weber M, Hörl WH. Immune dysfunction in uremia. Kidney Int 1997;52 (Suppl 62):S79-82

21. Hruska KA, Teitelbaum SL. Renal osteodystrophy. N Engl J Med 1995;333(3):166-74

22. Martinez I, Saracho R, Montenegro J, et al. The importance of dietary calcium and phosphorus in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 1997;29(4):496-502

23. Coburn JW, Elangovan L. Prevention of metabolic bone disease in the pre-end-stage renal disease setting. J Am Soc Nephrol 1998;9(12 Suppl):S71-7

24. Fraser CL, Arieff AI. Nervous system complications in uremia. Ann Intern Med 1988;109(2):143-53

25. Obrador GT, Arora P, Kausz AT, et al. Pre-end-stage renal disease care in the United States: a state of disrepair. J Am Soc Nephrol 1998;9(12 Suppl):S44-54

26. Pereira BJ. Optimization of pre-ESRD care: the key to improved dialysis outcomes. Kidney Int 2000;57(1):351-65

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.