Preventing Progression and Complications of Renal Disease
Authors: Sidney Kobrin, MD, and Shreeram Aradhye, MD, Hospital of the University of Pennsylvania (BUT...Altered for this venue by C. Newman)
A comprehensive, practical approach to managing renal failure and its complications, with a focus on slowing the rate of progression. [Hospital Medicine 33(11):11-12, 17-18, 20, 29-31, 35-36, 39-40, 1997. © 1997 Quadrant HealthCom, Inc.]
In this new age of managed health care, generalists have had to assume increasing responsibility for managing problems previously tackled by specialists. Although timely referral to and collaboration with a nephrologist is vital in caring for patients with renal disease, it is important for the primary care physician to be familiar with measures aimed at preventing the progression and complications of renal failure.
The number of patients with end-stage renal disease (ESRD) is rising rapidly in the United States. The cost of providing renal replacement therapy for these patients is about $12 billion per year. Early recognition of renal disease and appropriate interventions to delay its progression may decrease both human suffering and the financial costs associated with ESRD. Primary care physicians usually treat patients with diabetes and hypertension, the two leading causes of ESRD in this country. Since most patients with early renal failure are asymptomatic, awareness and vigilance on the part of the primary care physician are essential for the early diagnosis, appropriate referral, and collaborative management of these patients.
The clinical management of the patient with progressive renal failure may be divided into several components: (1) early recognition of renal failure; (2) monitoring the progression of renal failure; (3) detection and correction of reversible causes of renal failure; (4) institution of interventions to delay progression of renal failure; (5) avoidance of additional renal injury; (6) treatment of complications (ie, acid-base, mineral, and fluid-electrolyte abnormalities) of renal failure; and (7) planning ahead for renal replacement therapy (dialysis or transplantation).
Glomerular filtration rate. GFR is the standard indicator of renal function. Normal values for GFR are 130 ±15 mL/minute in males and 120 ±15 mL/minute in females. In both sexes, a GFR of 56 to 100 mL/minute constitutes mild renal failure, 25 to 55 mL/minute constitutes moderate renal failure, and 24 mL/minute or less constitutes severe renal failure. Although the GFR cannot be measured directly, it can be calculated based on the renal clearance of a marker such as inulin, which is freely filtered by the glomerulus. However, measuring the clearance of inulin or a radiolabeled marker such as iothalamate is cumbersome and expensive and is therefore not used routinely in clinical settings. Instead, GFR can be estimated by using the value for either serum creatinine concentration or 24-hour urinary creatinine clearance.
Normal values for serum creatinine concentration are <1.3 mg/dL in males and <1 mg/dL in females. Values of 1.3 to 1.9 mg/dL in males and 1 to 1.9 mg/dL in females constitute mild renal failure, values of 2 to 4 mg/dL in both sexes constitute moderate renal failure, and values >4 mg/dL in both sexes constitute severe renal failure. This measurement has limitations, however. First, although a serum creatinine level above the normal range may suggest underlying renal failure, so too may a serum creatinine value within the normal range that is higher than a patient's previous value. (Any creatinine measurement performed while the patient has been an adult is helpful; it may be necessary for the physician to perform diligent detective work to locate a prior value.) Thus, an increase in serum creatinine from 0.6 to 1.2 mg/dL represents a 50% decline in renal function, which might be missed if only the more recent value were noted, since it lies within the so-called normal range for a male. Thus, comparison with prior laboratory data is important when interpreting a serum creatinine level. In the early stages of renal failure, major decreases in GFR are often associated with what appear to be minor changes in serum creatinine.
GFR declines with age at a rate of about 10 mL/minute for each decade beyond the third: expected values (in mL/minute) are 120 for individuals in their 20s, 110 for those in their 30s, 100 for those in their 40s, 90 for those in their 50s, 80 for those in their 60s, and 70 for those in their 70s. Although this lattermost value does not constitute clinically important renal failure, it does reflect a diminished renal "reserve" that renders an older person more susceptible to renal injury.
Second, changes in serum creatinine level do not necessarily reflect changes in GFR. For example, serum creatinine levels may be elevated by (1) the use of cimetidine or trimethoprim, either of which competitively inhibits the tubular secretion of creatinine; (2) ingestion of large quantities of cooked meat; or (3) increases in muscle mass. These elevations do not reflect a decline in GFR. Conversely, severely malnourished patients lose muscle mass and may not manifest an elevation in serum creatinine, despite progression of renal disease and a decline in GFR. Serum creatinine levels correlate with GFR only in the steady state. Therefore, significant errors in the estimation of GFR may occur if the serum creatinine level is rapidly changing.
Creatinine clearance. This is usually calculated on the basis of a 24-hour urine collection. For practical purposes, this value closely correlates with the GFR in patients with mild to moderate renal failure; in those with severe renal failure, however, creatinine clearance is about 50% more than the true GFR (thus, about 35 mL/minute in these cases). When interpreting these data, you should assess the adequacy of the collection based on the expected creatinine excretion, which equals creatinine production in the steady state. Daily creatinine excretion is 20 to 25 mg/kg lean body weight in males and 15 to 20 mg/kg lean body weight in females. (Lean body weight is derived from standard height/weight tables or is represented by "ideal" weight.) Significant differences in the amount of creatinine excreted from that expected suggest the possibility of an error in urine collection. Under steady-state conditions, creatinine clearance can be estimated without a urine collection by using a formula that accounts for the influence of age and body weight on creatinine production:
Creatinine clearance = ([140 - age in years] x lean body weight [kg]) / (plasma creatinine [mg/dL] x 72)
In equating creatinine clearance with GFR, one assumes that creatinine is excreted by filtration alone. However, creatinine is also secreted by the tubules; the proportion of creatinine excreted by this process increases with worsening renal failure, leading to overestimation of GFR, especially at lower levels of renal functioning.
Practical methods. Despite all the caveats outlined above, measurements of serum creatinine and creatinine clearance are practical methods for monitoring renal failure in clinical practice. It may also be useful to follow the reciprocal of serum creatinine (1/SCr) over time. The slope of this line reflects the rate of deterioration in renal function. A sudden increase in the slope should alert the physician to additional injury. In contrast, a decrease in the slope may reflect the beneficial effects of interventions to retard progression of renal failure. Predictions regarding the timing of renal replacement therapy may be made by extrapolating the course of this line.
It is important to identify and correct reversible causes of renal failure in patients with newly diagnosed disease and in those with known renal failure in whom the rate of progression may have accelerated (Figure 1).
First, identify and treat underlying conditions (eg, urinary tract obstruction in an elderly man with symptoms of prostatism). Next, determine whether the patient is taking drugs with potentially nephrotoxic effects and stop their use if possible. Common culprits include nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycoside antibiotics, and certain antiviral agents. Finally, investigate other causes of reversible renal injury: volume depletion; atherosclerotic vascular disease causing renal ischemia; superimposed interstitial nephritis caused by drug use; and some forms of glomerular disease that may respond to therapeutic intervention.
Renal injury. Renal disease is characterized by inexorable progression despite the elimination of the original cause of injury; the rate of deterioration depends on the nature of the primary renal disease. The progressive nature of renal disease is thought to arise from "adaptive" responses of the remnant renal tissue; apparently, these responses are counterproductive and lead to progressive and irreversible renal damage.
Glomerular hyperfiltration (due to increased intraglomerular pressure) and glomerular hypertrophy are important mediators of renal injury. Glomerular hypertension is the result of dilatation of the afferent arteriole and selective constriction of the efferent arteriole (mediated by angiotensin II). The etiology of glomerular hypertrophy is unclear; it may be due to glomerular hyperfiltration or to the local release of growth factors by the remnant renal tissue. This change can contribute to injury by further increasing glomerular wall stress. It should also be noted that proteinuria is not merely a marker of glomerular injury and hyperfiltration, but also a cause of interstitial inflammation and scarring, leading to further renal injury. Furthermore, systemic hypertension, acidemia, protein intake, hyperphosphatemia, hyperlipidemia, and immune mechanisms have all been shown to contribute to renal injury.
The progression of renal disease is presumed to involve a final common pathway, which appears to be a combination of the adaptive responses (glomerular hyperfiltration, hypertension, and hypertrophy) and some of the consequences of renal disease (proteinuria, systemic hypertension, hyperlipidemia, hyperphosphatemia, and acidosis) which, in turn, aggravate injury.
Regardless of the primary etiology, interventions to delay progression aim at controlling some of these maladaptive responses, as summarized in the Table and as discussed in the following sections.
Dietary protein restriction. Dietary protein modulates renal function in healthy as well as diseased kidneys. Protein load increases GFR and protein restriction decreases basal GFR in animal and human models. The effects of protein intake on glomerular hemodynamics are mediated by decreased afferent arteriolar tone leading to enhanced renal blood flow. Since the efferent arteriole does not dilate to the same degree, glomerular capillary pressure and filtration rate are enhanced. Protein restriction has been shown to retard progression of renal disease in a variety of animal models of renal injury. This protective response is mediated by favorable effects on glomerular hyperfiltration, hypertrophy, proteinuria, and renal inflammation. Unfortunately, the leap from animal data to human application is not easy and the data in human studies remain somewhat controversial.
Several small studies have shown a benefit of protein restriction on renal disease progression in diabetic and nondiabetic renal disease.[4,5] The largest study to date was conducted by the Modification of Diet in Renal Disease (MDRD) Study Group. In this randomized, multicenter trial, the effect of dietary protein restriction and blood pressure (BP) control on the progression of renal disease was studied in 840 nondiabetics with renal failure of diverse etiology. In part A of this study, which included 585 patients with moderate renal failure (GFR, 25 to 55 mL/minute), protein intake of 0.58 g/kg/day, as compared with 1.3 g/kg/day, did not significantly slow the rate of decline in GFR at 3 years.
However, in part B of the same study, which enrolled 255 patients with more severe renal failure (GFR, 13 to 24 mL/minute), a protein intake of 0.28 g/kg/day, as compared with 0.58 g/kg/day, tended to slow the decline in renal function. Study limitations included the lack of diabetics, the presence of many patients with polycystic kidneys, and the use of ACE inhibitors as antihypertensive therapy. Secondary analysis of part B data based on protein intake achieved, as opposed to that prescribed, did show a beneficial effect of protein restriction on the progression of renal disease in patients with severe renal failure. Furthermore, when these results were combined with prior reports and subjected to a meta-analysis, a protein intake of 0.7 to 0.8 g/kg/day was found to reduce the risk of ESRD in both diabetics and nondiabetics with renal failure.
Protein restriction has several advantages in addition to the favorable effects on glomerular hemodynamics. Dietary protein is the major source of phosphate and also results in an acid load which may worsen the metabolic acidosis seen in renal failure. Protein-restricted diets may thus reduce the risk of hyperphosphatemia and secondary hyperparathyroidism. Decreased metabolic acidosis also leads to reduced protein breakdown and bone mineral loss.
The main concern with protein restriction in patients with renal failure is the risk of malnutrition. Although this concern is warranted, it is noteworthy that malnutrition was not diagnosed in any patient enrolled in the MDRD study. The World Health Organization has recommended a daily protein allowance of 0.8 g/kg for adults (daily protein requirement for the average adult, 50 to 70 g). Most American adults consume significantly greater amounts of protein than that.
Once renal failure is detected, the patient's protein intake should be limited to 0.8 g/kg/day. Patients' nutritional status should be monitored to ensure that body weight and other indicators such as serum albumin and serum transferrin remain stable. When a protein-restricted diet is implemented, the protein ingested should be of high biologic value. Adequate energy intake will guard against breakdown of endogenous muscle protein and prevent malnutrition. Unfortunately, many patients will not be able to comply with this relatively unpalatable diet. It is particularly challenging for diabetics, who may also have to restrict intake of potassium, refined carbohydrates, salt, fluids, and lipids.
In sum, patients with early renal failure should limit daily consumption of high-biologic-value protein to 0.8 g/kg. In those with a GFR <55 mL/minute but >25 mL/minute, daily protein intake should be kept between 0.7 and 0.8 g/kg, despite the fact that clinical evidence thus far is inconclusive. In patients with severe renal failure (GFR <=24 mL/minute), daily protein intake should be limited to 0.6 g/kg.
Control of systemic hypertension. Systemic hypertension is an important mediator of progressive renal injury; there is unequivocal evidence that lowering elevated BP slows the progression of renal disease, especially in patients with proteinuria. A subgroup analysis of MDRD study data showed that, in patients with urinary protein excretion >1 g/day, the rate of decline in renal function was slowest in those whose BP was maintained at 125/75 mm Hg. In patients without proteinuria there appeared to be little additional renal benefit to maintaining BP below 135/85 mm Hg.
Whereas BP control with any agent appears to slow the progression of renal disease, there is mounting evidence that ACE inhibitors are more renoprotective than other antihypertensive agents. Some calcium channel blockers (CCBs) may also have renoprotective properties. Other antihypertensive drugs should be added if monotherapy with ACE inhibitors does not lower BP adequately. Also, other agents should be used if ACE inhibitor-related adverse effects cannot be overcome. Adequate BP control, no matter how it is accomplished, is better than uncontrolled hypertension.
Use of ACE inhibitors. The renoprotective effect of ACE inhibitors appears to be independent of their antihypertensive action. These drugs decrease proteinuria and delay the progression of renal disease. Although initial data were acquired in patients with diabetic nephropathy (DN), encouraging results have also been obtained in nondiabetics with renal disease. The salutary effects of ACE inhibitors may be related to their ability to dilate efferent arterioles, thereby reducing intraglomerular pressure. The beneficial effects may also be the result of the restoration of glomerular permselectivity in proteinuric nephropathies.[11,12] This may explain why ACE inhibitors delay the progression of renal disease in normotensive diabetics with microalbuminuria.
Many studies have compared ACE inhibitors with placebo or other antihypertensive drugs at each stage of DN in patients with in-sulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Most of these studies have shown that ACE inhibitors can (1) prevent the progression of microalbuminuria to overt proteinuria; (2) reduce proteinuria in patients with overt DN; (3) slow the deterioration in GFR; and (4) delay the progression to ESRD and death.
The largest study conducted in patients with IDDM and microalbuminuria showed that captopril, relative to placebo, reduced the progression to overt proteinuria by 75%. In a landmark study of patients with IDDM, overt nephropathy, and serum creatinine values <2.5 mg/dL, captopril, relative to other antihypertensives, significantly reduced the doubling of serum creatinine values and the progression to ESRD. Based on these findings, most authorities recommend the use of ACE inhibitors in both hypertensive and normotensive patients with IDDM and any degree of DN.
Hypertensive patients with NIDDM and any degree of DN should probably be treated with ACE inhibitors. Despite evidence that ACE inhibitors slow the progression of microalbuminuria to overt proteinuria, it is debatable whether normotensive patients with NIDDM and microalbuminuria should receive ACE inhibitors; since only 10% to 20% of these patients progress to ESRD, 80% to 90% of them may be exposed to unnecessary therapy. A reasonable strategy in these patients is to monitor them closely and commence ACE inhibitor therapy if they develop hypertension or overt proteinuria. Although several small studies have suggested that ACE inhibitors retard the progression of renal disease in patients with NIDDM and overt proteinuria, no large, prospective, randomized study has been conducted. However, since histologic features appear to be identical in patients with DN secondary to IDDM or NIDDM (Figure 2), it is reasonable to assume that ACE inhibitors will have a similar effect in both patient populations.
Although not all ACE inhibitors have been tested in DN, there is no compelling evidence or physiological reason to indicate that any particular member of this class of drugs is superior to the others. Given the complicated regimens these patients follow, once-a-day agents may be preferable. Angiotensin II receptor antagonists probably have the same efficacy as ACE inhibitors and they do not cause the troubling cough that is relatively common with most ACE inhibitors (except perhaps fo-sinopril). However, the angiotensin II receptor antagonists have not yet been extensively studied in patients with DN. Currently, two studies are underway to compare angiotensin II receptor antagonists with other antihypertensives in patients with NIDDM and DN.
The ACE Inhibition in the Progression of Renal Insufficiency (AIPRI) study randomized patients with renal failure to receive benazepril or placebo after a run-in period during which strict BP control was attained. Nearly all patients in this trial were nondiabetic. During a 3-year follow-up, the risk of doubling of serum creatinine was 50% lower in the benazepril group than in the placebo group. Patients with urinary protein excretion >1 g/day and those who received therapy relatively early in the course of their renal disease appeared to derive the greatest benefit from benazepril. This advantage persisted after correction for lower mean BP in the ACE inhibitor group than in the placebo group. Patients with polycystic kidney disease did not appear to benefit from ACE inhibition, a finding previously reported in other trials.
In the Ramipril Efficacy in Ne-phropathy Trial, ramipril slowed the rate of progression of renal failure over 1 year in nondiabetics with massive proteinuria (urinary protein excretion >3 g/day); this portion of the trial was terminated prematurely because of this clear-cut benefit. The study has not been terminated for patients with urinary protein excretion between 1 and 3 g/day.
Primary care physicians often hesitate to prescribe ACE inhibitors in patients with renal failure, mainly because they fear provoking adverse reactions such as the acute worsening of renal function and hyperkalemia. However, acute renal failure occurs primarily in a subgroup of patients with bilateral renovascular disease or in those who have decreased effective circulating volume. Provided that renal function is monitored in such patients after initiation of ACE inhibitor therapy, there is no contraindication to starting therapy since the renal dysfunction is reversible. The same considerations apply to the risk of hyperkalemia. In the AIPRI study, of 300 patients given benazepril, three had a rapid increase in serum creatinine requiring drug withdrawal and five developed clinically significant hyperkalemia. Neither adverse event occurred significantly more often in the benazepril group than in the placebo group.
In sum, ACE inhibitors slow the progression of renal failure in patients with a wide variety of renal diseases and should be started early in the course. Patients with proteinuria are likely to derive the greatest benefit. The risk of adverse reactions is small but warrants close monitoring after the start of therapy. The specific agent used is not important, provided appropriate dosage adjustments for renal dysfunction are made when necessary.
Use of calcium channel blockers. Although not as well studied as the ACE inhibitors, CCBs may also have renoprotective properties. The mechanism of this protective effect may differ between the dihydropyr-idines (eg, amlodipine, nifedipine, felodipine) and other CCBs such as verapamil or diltiazem. The latter two drugs may reduce intraglo-merular pressure in a manner similar to that of ACE inhibitors; studies in patients with renal disease have shown that these drugs, as compared with the ß blocker atenolol, led to a greater reduction in proteinuria and a slower progression of renal disease. One study has demonstrated an additive reduction in proteinuria when a low-dose ACE inhibitor and verapamil were combined.
The dihydropyridines, although effective and well tolerated as antihypertensive agents, do not consistently reduce proteinuria. Never-theless, experimental and human data in nondiabetics have shown that they are as effective as ACE inhibitors in slowing the progression of renal disease. The dihydropyr-idines may mediate their beneficial effect by reducing glomerular hypertrophy rather than by reducing intraglomerular pressure. At pres-ent, ACE inhibitors should probably be the first-line agents in patients with renal failure. CCBs may be added to ACE inhibitors when BP control is suboptimal or they may be used in patients who cannot tolerate ACE inhibitors.
Phosphate restriction. Al-though a role for hyperphospha-temia in the progression of renal failure has been postulated and demonstrated in animal models, clinical data concerning the role of phosphate restriction in the prevention of the progression of renal disease in humans are scant. It should be noted that most protein-restricted diets are also low in phosphorus content. At the current time, the primary goal of phosphate restriction in these patients is to prevent secondary hyperparathyroidism and significant bone disease.
Hyperlipidemia control. There is an extensive body of literature on the role of hyperlipidemia in accelerating renal injury; this problem may be particularly relevant in patients with significant proteinuria. Proteinuria in the nephrotic syndrome has been shown to result in multiple abnormalities of lipid metabolism. Hyperlipidemia in turn aggravates the renal injury by increasing mesangial proliferation and matrix production, as well as by altering glomerular hemodynamics and increasing local inflammation. All these factors interact to increase glomerulosclerosis and hasten the progression of renal failure.
Although there is a sound biological basis for treating hyperlipidemia with a secondary aim of delaying progression of renal failure, prospective clinical data are lacking. Nevertheless, given the high rate of atherosclerotic disease in patients with renal failure, it may be wise to prescribe lipid-lowering drugs for the prevention of cardiovascular disease, with the possible simultaneous benefit of delaying the progression of renal failure.
Glycemic control in diabetics. The Diabetes Control and Complications Trial showed that stringent control of blood glucose early in the course of IDDM significantly delayed the onset of microalbuminuria. This study also showed that this intensive therapy decreased or stabilized protein excretion in patients who already had microalbuminuria. Similar reductions in the incidence of overt DN in patients with IDDM who had sustained excellent glucose control throughout their illness were obtained in a long-term study conducted in Sweden. Both of these studies aimed for a glycosylated hemoglobin value of approximately 7%. A recent Jap-anese study demonstrated benefits of similar magnitude in patients with NIDDM.
This degree of diabetic control requires multiple injections (or an insulin pump) and fingerstick glucose estimations each day. Only highly motivated and compliant patients will be able to adhere to this regimen. Unfortunately, intensive therapy may not slow the progression of renal injury following the development of overt dipstick-positive proteinuria.
Other consequences of hyperglycemia, for example, sorbitol and advanced glycosylation endproduct (AGE) accumulation, may play a role in the onset and progression of DN. Pilot studies using aldose reductase inhibitors and aminoguanidine to reduce the accumulation of sorbitol and AGEs, respectively, suggest that these agents may retard the progression of DN. The safety and efficacy of these agents, which are not yet marketed in the United States, are currently being evaluated in large clinical trials.
Smoking cessation. DN is 3 to 4 times more common in smokers than in nonsmokers; former smokers appear to have an intermediate risk. Smoking may also increase the relative risk for progression of renal disease in nondiabetics. Therefore, all patients with renal disease who smoke should be encouraged to quit the habit.
Volume depletion. When patients with any degree of renal failure present with a sudden deterioration from their baseline function, physicians should be alert to the possibility of volume depletion. Renal blood flow in these patients is reduced, triggering alterations in intrarenal hemodynamics which, in turn, decrease the GFR. Renal function is often promptly restored to baseline when the volume depletion is corrected, although some degree of transient or permanent damage may occur.
Urinary tract obstruction. Obstruction of the urinary tract should be suspected when patients experience a sudden deterioration in renal function. Common culprits include prostatic disease in elderly males and neurogenic bladder dysfunction in diabetic patients. Useful tests to determine the presence of urinary tract obstruction include palpation of the suprapubic area, assessment of postvoiding residual urine volume by catheterizing the bladder, and ultrasound scanning of the bladder and kidneys.
Iatrogenic injury. Compared with a person who has normally functioning kidneys, a patient with early renal failure is likely to suffer greater harm from additional renal insults. Certain drugs and radiocontrast media commonly aggravate renal disease.
NSAIDs. These drugs are common offenders, usually causing acute renal failure on a hemodynamic basis. If detected early, this form of renal injury is reversible. However, acute tubular necrosis may occur with prolonged ischemia. Among NSAIDs, sulindac has been shown to be relatively less nephrotoxic; regardless, caution needs to be exercised when using this drug.
Aminoglycosides. These antibiotics (eg, gentamicin, streptomycin) are obligate nephrotoxins and inevitably cause renal failure during prolonged use. Patients with preexisting renal failure are more susceptible to aminoglycoside nephrotox-icity. Dosing of aminoglycosides based on pharmacokinetic parameters does not necessarily prevent renal injury since the drug is cumulatively concentrated in the tubules. The measurement of trough serum aminoglycoside levels appears to be useful since sustained elevations correlate with renal damage. There-fore, monitoring these levels may enable physicians to discontinue or reduce the dose of the aminoglycoside prior to the development of significant additional renal failure.
It has been recommended that aminoglycosides be given on a once-daily basis; this approach has been shown to decrease the risk of nephrotoxicity in patients with normal renal function. Since the uptake of aminoglycosides by the proximal tubules is saturated, once-daily dosing, relative to multiple daily doses, causes a greater proportion of drug to be excreted and lesser amount of drug to accumulate in the cortex.[27,28] Unfortunately, this strategy has not yet been tested in patients with underlying renal failure; thus, it is probably prudent to avoid aminoglycosides in these patients when possible. If these drugs are used, the duration should be restricted and renal function should be monitored closely.
Other drugs. Antibiotics, cimetidine, anticonvulsants, and diuretics may cause acute interstitial nephritis. A high index of suspicion is necessary to make this diagnosis and a renal biopsy may be needed for confirmation. In the patient with underlying renal failure, early recognition of this condition, cessation of the offending agent, and possible therapy with corticosteroids can help avoid additional irreversible renal injury.
Radiocontrast media. Preexisting renal failure is the main risk factor for the development of radiocontrast-induced acute tubular necrosis. Although this injury is usually reversible, transient dialysis may be required; in patients with advanced renal failure, baseline renal function may not be restored. Measures to avoid radiocontrast injury include the use of imaging studies that do not involve dye and the avoidance of multiple studies performed in rapid succession. Low-osmolality contrast media may be relatively less nephrotoxic in patients with renal failure.
The best way to minimize the risk of radiocontrast nephrotoxicity is to ensure that the patient is volume replete at the time of the procedure. This is accomplished by administering normal saline at a rate of 75 to 100 mL/hour intravenously, for 8 to 10 hours before the study, and then continuing the fluids after the procedure. It is important to avoid volume depletion caused by the osmotic diuresis that the contrast material may induce.
Other measures, such as the use of diuretics, mannitol, or low-dose dopamine, are not always helpful and some have actually been shown to exacerbate the injury in patients with DN. (Theoretically, diuretics such as furosemide and mannitol might help prevent acute renal failure. Furosemide decreases oxygen consumption by the kidney, thereby protecting it from ischemic insults. Mannitol is also osmotically active and decreases cell swelling, a problem believed to contribute to the pathogenesis of acute renal failure. Both diuretics are thought to flush out cellular debris from tubules--this debris is believed to block tubules and contribute to the development of acute renal failure.)
Pregnancy. The effect of pregnancy on renal function depends upon the degree of underlying renal failure. In normotensive women with mild renal failure (serum creat-inine, 1 to 1.5 mg/dL), renal function is not likely to be compromised; nevertheless, these patients should be monitored closely for the development of hypertension or pre-eclampsia. In women who have greater renal failure, the risk of significant worsening of their renal status is high. Women who have severe proteinuria and hypertension may be at the greatest risk for pregnancy-related exacerbation of renal dysfunction.
Patients with renal failure experience myriad complications related to almost all organ systems. They are also prone to a variety of disorders of fluid, electrolyte, mineral, and acid-base balance, depending upon the degree of renal failure and the cause of renal disease. Most problems arise with a severe decline in renal function.
Most fluid and electrolyte disorders occur late in the course of renal failure, when there has been a significant decline in GFR. Impaired sodium excretion may manifest as hypertension and volume overload leading to edema. Diuretic therapy is often necessary. In contrast, excess salt wasting may occur in some patients, which predisposes them to volume depletion and which, in turn, may lead to a worsening of renal failure. Impaired tubular concentration and dilution may cause these patients to become hyponatremic with excessive intake of hypotonic fluids and hypernatremic when access to water is limited.
Potassium balance is usually maintained in early renal failure; hyperkalemia does not usually develop until renal disease is advanced, provided that potassium intake is not excessive and urine output and aldosterone secretion are adequate. However, patients with tubulointerstitial disease may become hyperkalemic with mild renal failure. Hyperkalemia commonly occurs in patients with diabetic nephropathy related to associated hyporeninemic hypoaldosteronism. Drugs such as ß blockers, NSAIDs, ACE inhibi-tors, potassium-sparing diuretics, trimethoprim, and salt substitutes may exacerbate hyperkalemia. Die-tary potassium restriction, loop diuretics, alkali therapy, and potassium exchange resins may be needed to treat it.
Net acid excretion declines with progressive renal failure despite enhanced ammonia production by the kidney. A decrease in serum bicarbonate reflective of a metabolic acidosis occurs relatively early in the course of renal failure and worsens with progression of renal disease. Decreased protein intake may improve the acidosis, but when serum bicarbonate levels fall below 16 to 17 mEq/L, it may be prudent to initiate alkali supplementation to maintain serum bicarbonate levels around 22 mEq/L. This can be done by administering either sodi-um bicarbonate or sodium citrate, at a dosage of 1 mEq/kg/day orally. Since sodium citrate markedly increases aluminum absorption, sodium bicarbonate may be preferable. Alkali supplementation may alleviate the many known ill effects of metabolic acidosis, including excessive bone loss, muscle breakdown, and tubulointerstitial inflammation.
Decreased filtered phosphate load with resultant hyperparathyroidism is seen relatively early in renal failure. Although frank hyperphosphatemia may not occur until the GFR drops below 25 to 30 mL/minute, the elevated parathyroid hormone levels seen in the earlier stages are harmful. Dietary phosphate restriction is thus important even in patients with mild renal failure.
With worsening renal failure it may become necessary to give phosphate-binding antacids to decrease the absorption of ingested phosphate. Because of the risk of hypermagnesemia and diarrhea, magnesium-containing antacids are best avoided. Aluminum-containing ant-acids should also be avoided since prolonged use may lead to aluminum intoxication. Calcium carbonate and calcium acetate are the formulations of choice. When given with meals, either compound serves as an effective phosphate binder as well as a source of alkali and calcium. Early management of abnormal phosphate and calcium metabolism can decrease the risk of bone disease and may even delay the progression of renal failure.
Anemia in renal failure may be multifactorial in origin, but the primary abnormality is diminished erythropoietin (EPO) production, which occurs with moderate to severe renal failure. Hence, significant anemia in the patient with early renal failure should prompt an evaluation for other causes. Recombinant human EPO is effective when used in the predialysis population and may improve a number of anemia-related symptoms. Furthermore, correction of anemia may reverse and prevent left ventricular hypertrophy, which may contribute to the high mortality in patients who progress to ESRD. Maintenance of adequate iron stores is important to secure optimal response to EPO.
Timely referral of the patient with renal failure to a nephrologist with a view to discuss options regarding renal replacement therapy is paramount. Outcomes are optimal when renal replacement therapy is initiated in a planned manner. Patients should be educated about the various modalities of dialysis including hemodialysis and peritoneal dialysis. When hemodialysis is planned it is important that an arteriovenous fistula be created in a timely manner. The option of transplantation should also be discussed. With adequate planning and when living donors are available and willing, it may be possible to perform a renal transplant prior to the need for dialysis.
Dr Kobrin is Associate Professor of Medicine and Dr Aradhye is Assistant Professor of Medicine, Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, Philadelphia.
|Protein restriction||Reduces glomerular hyperfiltration, hypertrophy, proteinuria, and inflammation|
|Control of systemic hypertension||Uncontrolled systemic hypertension injures glomeruli by directly transmitting high pressure to these structures|
|ACE inhibitors||Reduce intraglomerular pressure and proteinuria|
|Dihydropyridine calcium channel blockers||Reduce glomerular hypertrophy|
|Non-dihydropyridine calcium channel blockers||May reduce intraglomerular pressure and proteinuria; may also reduce glomerular hypertrophy|
|Control of hyperphosphatemia||May prevent calcium phosphate deposition in the kidney|
|Control of hyperlipidemia||Prevents hyperlipidemia-induced mesangial proliferation, matrix production, altered glomerular hemodynamics, and renal inflammation|
|Glycemic control in diabetic patients||Hyperglycemia causes mesangial expansion, glycosylation of tissue proteins, and glomerular hyperperfusion|
|Smoking cessation||Improves oxygen delivery to the already ischemic glomeruli|
|Avoiding additional "insults" such as NSAIDs, aminoglycosides, radiocontrast materials, volume depletion, and pregnancy||Patients with underlying renal failure are most susceptible to the nephrotoxicity of these insults|
Figure 1: Classification of Renal Disease
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Figure 2a: Nodular Glomerulonephritis
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Figure2b.. Diffuse Glomerulosclerosis
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Figure 2c: Exudative Glomerulonephritis
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