Systemic complications of chronic kidney disease
Pinpointing clinical manifestations and best management
Gregorio T. Obrador, MD, MPH; Brian J. G. Pereira, MD, MBA
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,
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.
Mild reduction in GFR (60 to 89 mL/min/1.73
Moderate reduction in GFR (30 to 59 mL/min/1.73
Severe reduction in GFR (15 to 29 mL/min/1.73
Kidney failure (GFR, <15 mL/min/1.73
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
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
Decreased hormone production
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.
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.
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).
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).
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.
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).
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).
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: email@example.com.