Radiation Nephropathy 

Updated: Dec 01, 2015
Author: Eric P Cohen, MD; Chief Editor: Vecihi Batuman, MD, FASN 

Overview

Background

Radiation nephropathy is kidney injury and impairment of function caused by ionizing radiation. It may occur after irradiation of one or both kidneys, and it may result in kidney failure.

Classic radiation nephropathy occurs after bilateral, local kidney irradiation. It is a syndrome of chronic renal failure, occurring months or years after renal irradiation.[1] Acute radiation nephropathy develops 6-12 months after irradiation, whereas chronic radiation nephropathy develops years later. Radiation nephropathy has also been discovered to cause chronic renal failure after hematopoietic stem cell transplantation (HSCT), also called bone marrow transplantation (BMT).[2] In addition, the use of yttrium–90–tagged (90 Y-tagged) somatostatin and other radionuclides for radionuclide therapy cause radiation nephropathy when they are filtered by the kidneys and reabsorbed by the renal tubule epithelium or when blood-borne exposure to the kidney cells occurs. (See Etiology, Prognosis.)[3]

An excess occurrence of chronic kidney disease is reported in long-term survivors of the atomic bomb explosions at Hiroshima and Nagasaki.[4] Total or partial body radiation exposures as might occur in an accident or a belligerent exposure may also cause renal injury.

The term nephritis was commonly used in the past; however, because radiation nephropathy is not an inflammatory condition, the term nephropathy is probably more appropriate.

Etiology

Radiation nephropathy is due to cellular injury caused by ionizing radiation. All components of the kidney are affected, including the glomeruli, blood vessels, tubular epithelium, and interstitium.[5]

In the case of local kidney irradiation or total-body irradiation, the injury is direct. In the case of injury by radionuclide therapy, a radioisotope can injure the kidneys if its pharmacokinetics cause it to lodge in the kidney during a time when it is still a radioemitter. This is the case for the90 Y-tagged somatostatin, which has been used for the treatment of neuroendocrine malignancies, and for holmium-166–tagged (166 Ho-tagged) phosphonate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP).[6, 7]

Not all patients exposed to sufficient renal irradiation develop renal injury. The reason for this clinical variability is unknown. Indeed, the heterogeneity of response of healthy tissue to ionizing radiation is poorly understood. No reliable clinical predictors are available for the development of radiation nephropathy. Some individuals may develop radiation nephropathy at a dose of radiation that has no clinical effect on others.

Pathophysiology

Oxidative injury to the deoxyribonucleic acid (DNA) initiates injury to healthy tissue by ionizing radiation. This is a genotoxic injury. A cell with sufficient DNA injury eventually dies after several divisions. The delay in cell death may partially explain why radiation injury to healthy tissue is a delayed reaction.

The detailed mechanism whereby the kidney cells and tissues malfunction after this injury remains poorly understood. In experimental models, ultrastructural damage to the glomerular endothelium is observed 3 weeks after a 10 Gy (1000 rad) dose of local kidney irradiation, and neutrophil adherence to the endothelium occurs.[5] By 6 to10 weeks after the same dose, a wave of tubular epithelial cell deaths occur. This is followed by interstitial scarring. The scarring tends to be most severe in the outer cortex, and it proceeds inward. The progression of these events is accelerated with higher doses of radiation.

The earliest functional evidence of experimental radiation nephropathy is proteinuria, which is evident by 6 weeks in a radiation nephropathy model with 17-Gy multifraction total-body irradiation. Azotemia and hypertension are present by 12-15 weeks in the same model. The origin of the hypertension probably is similar to that of most experimental hypertension, although pressure-natriuresis curves have not been studied. Renin levels in systemic blood are normal or low, and blood and intrarenal angiotensin II levels are within the reference range (ie, not elevated).

In clinical experience, radiation nephropathy does not occur until months after the kidneys are exposed to sufficient ionizing radiation. Early data suggested that a dose of 20 Gy (2000 rads) given in multiple fractions over several weeks can cause radiation nephropathy.[1] Ten-Gy single-fraction total body irradiation (TBI) causes chronic renal failure after irradiation within 6-12 months after TBI. The long-term Hiroshima-Nagasaki data suggest that a single fraction dose as low as 1 Gy is associated with an elevated risk of chronic kidney disease over many years of follow-up.

Radiation nephropathy after BMT (BMT nephropathy) occurs following a lower dose of radiation than had been traditionally accepted. This dose is given over days, not weeks, to the whole body (total-body irradiation) and is accompanied by chemotherapy, which may account for the unexpectedly dramatic effect on the kidneys. Proteinuria is usual, although generally not in the nephrotic range. Azotemia and hypertension also develop. Anemia out of proportion to the degree of azotemia is a characteristic finding.

Severe cases of radiation nephropathy after BMT may be associated with a picture that appears similar to the hemolytic uremic syndrome (HUS), with thrombocytopenia, microangiopathic hemolytic anemia, and a high blood level of lactate dehydrogenase (LDH). This last syndrome may be the result of severe endothelial injury.

In the case of unilateral renal irradiation, progressive scarring of the irradiated kidney may occur, with severe hypertension related to renin release by the single irradiated kidney.

Epidemiology

Clinical radiation nephropathy, and its congener, the BMT nephropathy syndrome, have been reported worldwide.

Radiation nephropathy does not occur in all irradiated patients. In the large British series of classic radiation nephropathy described by Luxton, only 20% of subjects developed radiation nephropathy, although each received more than 2500 rads to the kidneys.[1] The form of radiation nephropathy in patients who receive BMT occurs in 10-20% of these patients.

In a report from Seattle, Wash, 30 of 83 subjects treated with 166 Ho tagged DOTMP developed some kidney injury; 7 subjects had thrombotic microangiopathy (ie, hemolytic-uremic syndrome [HUS]).[7]

No confirmed sex-based differences in radiation nephropathy have been reported. At the BMT unit of the Medical College of Wisconsin, BMT nephropathy has affected more women than men, but other centers have not had this experience. No age-based differences in susceptibility to classic radiation nephropathy have been confirmed. However, in the case of BMT nephropathy, children appear to be more likely to develop this syndrome than adults.

No racial or ethnic predisposition to radiation nephropathy has been identified.

Prognosis

Radiation nephropathy may progress to end-stage renal failure. The same is true of BMT nephropathy; the occurrence of end-stage renal failure in subjects who have undergone BMT is almost 20 times higher than it is in the age-matched general population.[8] The progression to end-stage renal failure has also occurred after internal radioisotope radiotherapy. Complete renal failure may evolve in weeks in severe cases, and after years in less severe cases. One can predict when a patient will need dialysis by making a graph of 100/plasma creatinine versus time. At the point where the 100/plasma creatinine value is equal to 10, the estimated renal function is approximately 10% of normal, revealing that dialysis may be needed soon after that. (See Rate of Kidney Function Loss.)

Patients with BMT nephropathy whose renal function declines to the point of their needing chronic dialysis have a poor prognosis compared with that of age-matched control subjects receiving dialysis. This probably is related to the burden of immunosuppression and past illness associated with BMT. Individuals with BMT nephropathy may also have accelerated atherosclerosis, which may be related to total-body irradiation and chemotherapy.[9]

Mortality/morbidity

As with other causes of chronic renal failure, radiation nephropathy may be asymptomatic. When it sufficiently reduces kidney function, symptoms and signs of renal failure occur. End-stage renal disease and the need for dialysis or transplantation may develop. In patients with BMT nephropathy who are receiving dialysis, the survival rate is less than that of age-matched control subjects.[10]

Proteinuria occurs, but it is usually not a striking feature in patients with radiation nephropathy. Reports of classic radiation nephropathy generally describe non–nephrotic-range proteinuria (< 3 g/d). In BMT nephropathy, the average urinary protein level has been reported at 2.5 g/d. Fluid overload, edema, pulmonary edema, and hyperkalemia are additional complications that can occur in these patients.

In classic radiation nephropathy, malignant hypertension may affect as many as 30% of patients and can occur as late as 11 years after irradiation. In BMT nephropathy, hypertension is a cardinal feature and observed along with azotemia. Were it not for antihypertensive agents, malignant hypertension would probably be a major feature of BMT nephropathy.

On hematologic analysis, accompanying anemia is present in radiation nephropathy and BMT nephropathy and is more severe than that expected for the degree of azotemia. In severe cases of BMT nephropathy, hemolytic anemia, a high blood LDH level, and a decreased platelet count may be present. This syndrome may be mistaken for HUS or thrombotic thrombocytopenic purpura (TTP).

 

Presentation

History

Previous exposure to a sufficient dose of ionizing radiation is a necessary element in the patient's history. External-beam irradiation is usually a clear-cut feature in the history, and it should have encompassed the kidney areas. Use of a radioactive isotope in therapeutic doses may not be obvious. Classically, exposure of the kidneys to x-rays or gamma rays in a dose higher than 2000 cGy (rads) is required to cause radiation nephropathy. However, a 10-Gy single-fraction dose is sufficient to cause chronic renal failure after BMT,[11] and with many years of follow-up, a 1-Gy single-fraction dose is associated with development of chronic kidney disease.[4] While these effects are not immediate, as is the case for radiation injury to the bone marrow or GI tract, kidney injury at these doses indicates that the kidneys are quite radiosensitive.

Modern radiation therapy is sharply focused on the area to be treated; therefore, it is very unlikely that the kidneys would be irradiated in a case of irradiation for uterine cervical cancer or for prostate cancer.

In patients who have undergone BMT, a history of total-body irradiation for pre-BMT conditioning should be determined. Partial renal shielding reduces, but does not eliminate, the risk of BMT nephropathy.

Because radiation nephropathy is a delayed injury, renal disease that quickly follows kidney irradiation (ie, within hours or days) is usually caused by some other factor. Classic acute radiation nephropathy occurs 6-12 months after irradiation, and chronic radiation nephropathy may not develop for years. Similarly, proteinuria or hypertension ascribed to radiation nephropathy does not develop for months or years.

Expected symptoms of radiation nephropathy and BMT nephropathy are the same as those observed in patients with chronic renal disease. Nocturia may develop due to the loss of urine concentrating ability. Retention of salt and water may lead to edema and an increase in blood pressure. Anemia may occur, with fatigue, dyspnea, and loss of endurance. Loss of appetite, nausea, and weight loss may occur when there is a severe reduction in renal function. Itching may occur with advanced renal failure, that is, stage V chronic kidney disease (see Staging).

Physical Examination

Hypertension, often severe, is a major feature of radiation nephropathy. It may be the only clinical feature. When this blood pressure elevation is associated with end-organ damage, such as eyeground changes or encephalopathy, it is termed malignant. Malignant hypertension has been reported in radiation nephropathy. Eyeground abnormalities, such as cotton-wool spots, retinal hemorrhage, and even optic disc edema, may occur at levels of blood pressure elevation that ordinarily would not cause such eyeground changes.[12]

Long-standing hypertension may result in left ventricular enlargement or hypertrophy, which may be detectable on examination. Findings on physical examination are not specific for radiation nephropathy or BMT nephropathy.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of radiation nephropathy, along with those in the next section, include the following:

  • Cyclosporine or tacrolimus toxicity

  • Pamidronate-induced focal glomerulosclerosis

  • Nephrotic syndrome associated with graft versus host disease

  • Polyoma virus nephropathy

These diagnoses must all be considered in the 15% of bone marrow transplantation (hematopoietic stem cell transplantation) survivors who develop chronic kidney disease.[13]

Differential Diagnoses

 

Workup

Approach Considerations

Various laboratory studies may be useful in the differential diagnosis of renal failure with nephrotic-range proteinuria and should be ordered according to the clinical presentation. These studies include the following:

  • Serum complement testing

  • Antinuclear antibody measurement

  • Antineutrophil cytoplasmic antibody measurement

  • Hepatitis panel

  • Protein electrophoreses

Urinalysis

Urinalysis results may show renal parenchymal injury by showing granular casts. The presence of red cell casts is not consistent with radiation nephropathy or BMT nephropathy and instead suggests acute glomerulonephritis.

CBC count

A complete blood count (CBC) helps to evaluate the degree of anemia and/or thrombocytopenia. In BMT nephropathy, lower platelet counts correlate with a more rapid decline in renal function. In less severe cases, the drop in the platelet count is transient.

Plasma LDH level

This level has been correlated with the rapidity of renal failure in BMT nephropathy. The increased LDH level in BMT nephropathy may be transient.

Plasma potassium level

Hyperkalemia (serum [K] >5.5 mmol/L) may occur in BMT nephropathy, even in subjects not taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), or cyclosporine A. Further studies may show that the fractional excretion of potassium is lower than expected for the degree of azotemia. In addition, the plasma aldosterone level may be low.

Kidney biopsy

Although not necessary in every case, kidney biopsy allows histologic confirmation of the diagnosis. Biopsy can be performed percutaneously or transvenously; it may be associated with bleeding complications in cases of thrombocytopenia (platelet count < 100,000/µL) or if blood pressure is high (>160/100 mm Hg).

BUN and Serum Creatinine Levels

Blood urea nitrogen (BUN) and serum creatinine tests help in assessing overall kidney function and are correlated with the glomerular filtration rate (GFR). The abbreviated Modification of Diet in Renal Disease (MDRD) formula may be used to estimate the GFR.[14]

By using patient age and weight, the Cockcroft-Gault formula enables calculation of the creatinine clearance from the plasma creatinine, without a 24-hour urine collection. These formulas should be used only if the patient has a stable plasma creatinine level. Neither formula applies to patients with acute renal failure.

Urine Protein Level

The protein-to-creatinine ratio provides an estimate of the amount of protein in the urine over a 24-hour period. The values help in assessing the degree of proteinuria. A 24-hour urine protein value higher than 3 g or more than 2 g per gram of urinary creatinine is in the nephrotic range.

Nephrotic-range proteinuria may suggest a diagnosis other than radiation nephropathy or BMT nephropathy. For instance, focal glomerulosclerosis can occur in subjects who have undergone BMT and then treatment with pamidronate. In these cases, the urine protein excretion may be high, even as high as 10 g/d.[15]

Imaging Studies

Ultrasonography helps in ruling out urinary tract obstruction. A reduction in kidney size occurs over time. Images show smaller kidneys with increased echogenicity, and that is consistent with chronic radiation nephropathy, although it could be seen in many chronic progressive kidney diseases.

Long-standing or severe hypertension may cause cardiac enlargement with left ventricular hypertrophy, which can be seen on chest radiographs. With advanced renal failure and fluid retention, pleural effusions and/or interstitial edema may be present, which can also be seen on radiographs.

One case using FDG PET/CT showed an increase in FDG activity in portions of the kidney that had been previously irradiated.[16]

Histologic Findings

In classic radiation nephropathy, arterial and arteriolar thickening is present, and arteriolar fibrinoid necrosis and ischemic and sclerotic glomerular changes are possible. Interstitial fibrosis is also present. Early descriptions of radiation nephropathy note glomerular hypocellularity and cellular degeneration. Electron microscopy shows endothelial degeneration and subendothelial expansion by electron-lucent material.[17]

In BMT nephropathy (see the image below), glomerular mesangiolysis, or loss of mesangial cells and rarefaction of the mesangial matrix, develops. Tubular atrophy and interstitial fibrosis may be present. Arteriolar fibrinoid necrosis has been described. As in classic radiation nephropathy, electron microscopy shows subendothelial expansion by electron-lucent material and endothelial degeneration. A similar appearance is described in cases of renal failure that occur after radioisotope internal radiotherapy.

Photomicrograph of a kidney-biopsy sample in a cas Photomicrograph of a kidney-biopsy sample in a case of nephropathy associated with bone marrow transplantation (periodic acid-Schiff stain). A glomerulus is in the center and is relatively hypocellular. Increased mesangial matrix is present. The glomerular basement membranes are not thickened; in some places, however, they are separated from the capillary lumens by a low-density, matrixlike material. Interstitial fibrosis separates the tubules from each other. Arteriolar thickening and arteriolar hyalin are present.

Proliferative crescentic glomerulonephritis has been reported as a rare, late complication of BMT. Kidney biopsy shows glomerular hypercellularity with crescent formation. This type of nephritis does not appear to be caused by irradiation.

Rate of Kidney Function Loss

An estimate of the rate of kidney function loss can be made by graphing the reciprocal of the plasma creatinine versus time. The X intercept on the graph is a guide to when the patient will have reached end-stage renal failure, with the need for renal replacement therapy, such as dialysis or kidney transplantation.[10]

The graph of 100/plasma creatinine yields a number that varies directly with the GFR and that is a fair estimate of the GFR. The graph of 100/plasma creatinine versus time in BMT nephropathy may be biphasic (as seen in the graph below), with a rapid phase followed by a slower phase. Such graphs can be made by using spreadsheet programs, such as Microsoft Excel. Some clinical laboratories may report results on computer programs that allow easy portrayal of the laboratory data as a graph.

Evolution of the glomerular filtration rate (GFR) Evolution of the glomerular filtration rate (GFR) versus time in a case of nephropathy related to bone marrow transplantation (BMT). GFR may be approximated as 100/plasma creatinine on the Y axis and graphed versus time on the X axis. As is true in many cases of BMT nephropathy, the evolution appears to be biphasic, with an initial rapid decline in GFR, then a slower plateau phase. The patient whose data are shown here ultimately underwent kidney transplantation.

Staging

In terms of kidney function, the stages of radiation nephropathy are the same as those of all chronic kidney diseases. These stages are as follows:

  • Stage I - GFR 90 mL/min or better, but injury present

  • Stage II - GFR 60-89 mL/min

  • Stage III - GFR 30-59 mL/min

  • Stage IV - GFR 15-29 mL/min

  • Stage V - GFR < 15 mL/min or dialysis needed

 

Treatment

Approach Considerations

As with chronic renal disease of any kind, the major risk with radiation nephropathy and BMT nephropathy is progressive loss of renal function with evolution to end-stage renal failure. Concomitant hypertension predisposes patients to stroke and heart disease. Uncontrolled hypertension may accelerate the loss of renal function. To slow the progression of renal disease, good control of blood pressure must be maintained; this is also true for radiation nephropathy and BMT nephropathy. (Monitoring blood pressure for 24 hours [ambulatory blood pressure monitoring] may help to differentiate true hypertension from white-coat hypertension.)

Antihypertensive agents are an important part of clinical management of radiation nephropathy or BMT nephropathy. The goal of therapy is to keep blood pressure at less than 130/85 mm Hg or 125/75 mm Hg if the patient has proteinuria of greater than 1000 mg/d.

Other drugs used in renal disease treatment include the following:

  • Diuretics - Treat fluid overload and enhance potassium excretion

  • Sodium polystyrene sulfonate- Treats hyperkalemia

  • Fludrocortisone - Treats aldosterone deficiency and hyperkalemia

Patients with radiation nephropathy or BMT nephropathy may be more anemic than expected for their level of renal function. Anemia may be treated with subcutaneous injections of erythropoietin.

Dietary salt restriction probably helps to control hypertension in cases of radiation nephropathy or BMT nephropathy. Patients must avoid instant, processed, or snack foods, and they must not use salt in cooking or at the dining table. No specific activity restrictions are necessary.

No specific consultations are necessary other than those that may arise from intercurrent illness. A patient who has undergone BMT may have other medical problems, such as hypothyroidism, cataracts, or bone avascular necrosis. Secondary cancers are a substantial risk, so ongoing oncologic follow-up is essential. Patient transfer or referral may be necessary in the event of complications or management difficulty.

Antihypertensive Agents

ACE inhibitors, ARBs, and/or calcium channel blockers control blood pressure. Improved blood pressure control helps to slow the progression of renal failure. In patients with chronic kidney disease, especially when the serum creatinine level is elevated or the GFR is reduced, more than 1 antihypertensive drug is typically needed to control blood pressure.

No proof suggests that one type of antihypertensive agent is superior to another in radiation nephropathy and BMT nephropathy. Nonetheless, ACE inhibitors are favored because of their known benefit in other progressive kidney diseases.[18] An angiotensin II blocker (ARB) was shown to be very effective in a single case of radiation nephropathy.[19] There are no randomized trials of ACE inhibitors or ARBs in human radiation nephropathy. ACE inhibitors or ARBs may be the best medicines to use, but definitive proof is lacking.

In experimental studies of radiation nephropathy, ACE inhibitors and ARBs have been particularly effective in the treatment and prevention of histologic injury and renal function loss.[20] Conversely, angiotensin II infusion in experimental radiation nephropathy models has had distinct adverse effects. The use of ACE inhibitors (eg, captopril) may mitigate, or even entirely prevent, radiation nephropathy if patients are started soon enough after the initial irradiation.[21] This effect has been demonstrated in experimental animals.

In a clinical study of the use of captopril versus a placebo in patients who underwent radiation-based hematopoietic stem cell transplantation, a lower serum creatinine level and a higher GFR were found after 1 year in the captopril patients, in comparison with the placebo patients.[21]

Inpatient Care

In-hospital care may be needed for complications, such as fluid overload or hyperkalemia. With any patient with chronic renal disease, intercurrent illness may precipitate hospitalization.

In the case of acute BMT nephropathy associated with an HUS- and/or a TTP-like disorder, the use of plasma exchange may be considered. This treatment may reverse the hematologic component, but it does not improve renal function.[22] Most patients with renal insufficiency require a dose adjustment for many medications. One should avoid the use of any nephrotoxic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs). Should it become necessary to use intravenous (IV) radiocontrast, the use of IV isotonic sodium chloride solution should reduce the risk of contrast nephrotoxicity.

Long-Term Monitoring

Outpatient care of any patient with chronic renal failure requires sufficient frequency of doctor visits, attention to blood pressure control, and assessment of the rate at which renal function is lost. These principles are valid for radiation nephropathy and BMT nephropathy. Monthly or weekly outpatient visits may be needed for patients whose blood pressure remains uncontrolled or who have fluid overload requiring an adjustment of diuretic doses.

The rate of loss of kidney function is adequately assessed by construction of a graph of 100/plasma creatinine versus time. Such a graph should be updated after each visit. Such a graph may permit prediction of future decline in renal function and its timing. (See Rate of Kidney Function Loss.)

Follow-up of patients who have received therapeutic irradiation must address not only the cancer for which they were irradiated but also the possible injury to healthy tissue. For this reason, patients who have undergone BMT must have periodic medical visits.

In addition, the use of new therapies involving radiation, such as radioisotope therapies, requires careful monitoring for unexpected injuries to healthy tissue. These injuries have occurred with the use of 90 Y-tagged somatostatin and 166 Ho-tagged phosphonate.[6, 7]

Patient Education

Any patient with chronic renal disease must comply with outpatient follow-up and blood pressure control. This compliance helps to slow the decline in renal function; the same is true for patients with radiation nephropathy or BMT nephropathy.

Patients must be aware of their maintenance medications and dosages. They must avoid nephrotoxins, such as over-the-counter nonsteroidal arthritis medicines, including ibuprofen.

 

Medication

Medication Summary

Control of hypertension and treatment of anemia are necessary. In BMT nephropathy, the occurrence of hyperkalemia requires additional attention. For the control of hypertension, ACE inhibitors are preferred, but they may raise the serum potassium level and should be avoided if the patient is hyperkalemic. Other antihypertensives, such as calcium channel blockers and diuretics, may be used to control blood pressure. Experience at the author’s center is that 75% of patients with radiation nephropathy require diuretics for control of their blood pressure.

ACE inhibitors

Class Summary

These agents reduce the systemic arterial blood pressure, reducing injury caused by elevated blood pressure. They may not only reduce cardiovascular risk but also slow progression of renal failure. ACE inhibitors may also slow progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

A dry cough can occur in about 5% of subjects taking ACE inhibitors. If the cough occurs with one ACE inhibitor, it is likely to occur with another. If a cough develops, a reasonable substitute for an ACE inhibitor is an ARB, such as losartan, valsartan, or candesartan.

Captopril

Captopril, a competitive ACE inhibitor, prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, increasing levels of plasma renin and reducing angiotensin II levels and aldosterone secretion. It has been clinically used for more than 30 years and is effective in experimental radiation nephropathy. Captopril may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

Enalapril (Vasotec)

This competitive ACE inhibitor also reduces angiotensin II levels, decreasing aldosterone secretion. The drug lowers systemic arterial blood pressure, reducing injury caused by elevated blood pressure. It may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms. Enalapril may be used every day or twice per day, which may improve compliance in comparison with a 3-time-per-day medication, such as captopril.

Angiotensin II receptor antagonists

Class Summary

ARBs antagonize the action of angiotensin II at its type 1 receptor, reducing systemic arterial blood pressure and blunting the intrarenal effect of angiotensin II. If ACE inhibitors cause cough, ARBs may be substituted.

Losartan (Cozaar)

Losartan is the prototype ARB. It is specific for the type 1, as opposed to type 2, angiotensin receptor. It may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. Losartan does not appear to affect bradykinin and is less likely to cause a cough or angioedema. One can use it in patients who do not tolerate ACE inhibitors.

Valsartan (Diovan)

Valsartan also directly antagonizes angiotensin II receptors. Like losartan, it displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Valsartan may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. It does not affect bradykinin and is unlikely likely to cause a cough or angioedema. Valsartan can be used in patients who do not tolerate ACE inhibitors.

Calcium channel blockers

Class Summary

Antihypertensive agents other than or in addition to ACE inhibitors and ARBs may be needed for blood pressure control in many subjects with hypertension and chronic renal failure. The same is true for subjects with radiation nephropathy. No evidence indicates that one type of calcium channel blocker is preferred over another for radiation nephropathy. However, one should avoid verapamil, because the use of this drug in a subject with hyperkalemia may cause atrial arrest.

Nifedipine (Procardia, Adalat, Nifedical XL)

Like other calcium channel blockers, nifedipine causes peripheral arterial vasodilation by inhibiting calcium influx across vascular smooth-muscle cell membranes. Long-acting formulations are used for control of blood pressure.

Cation exchange resins

Class Summary

Hyperkalemia may occur in patients with BMT nephropathy, whether or not they are simultaneously taking ACE inhibitors or ARBs. For life-threatening hyperkalemia (plasma K >6 mmol/L and/or electrocardiographic changes), emergency measures, such as IV glucose and insulin, are needed. For persistent, lesser degrees of hyperkalemia, a cation exchange resin may be needed to remove potassium by means of the gut.

Sodium polystyrene sulfonate (Kayexalate, Klonex, Kalexate)

Sodium polystyrene sulfonate is given by mouth or retention enema. It exchanges approximately 2 sodium atoms for 1 potassium atom; the potassium is then lost in the feces.

Mineralocorticoids

Class Summary

Impaired potassium excretion in BMT nephropathy may be associated with low blood levels of aldosterone. In other causes of chronic renal failure with such aberrant potassium metabolism, use of a synthetic mineralocorticoid has been helpful.

Fludrocortisone

Fludrocortisone mimics the action of aldosterone, promoting sodium retention and potassium excretion.

Erythropoietins

Class Summary

Anemia may occur in radiation nephropathy and BMT nephropathy, which has been associated with low blood levels of endogenous erythropoietin. Treatment of anemia with exogenous erythropoietin may relieve symptoms of anemia.

Epoetin (Epogen, Procrit)

This glycoprotein is a recombinant human erythropoietin (glycoprotein with 165 amino acids). It stimulates bone marrow red blood cell (RBC) production. It is widely used in subjects who require chronic dialysis for end-stage renal disease. Epoetin is given intravenously or by subcutaneous (SC) injection.

Darbepoetin alfa (Aranesp)

This is an erythropoiesis-stimulating protein that is closely related to erythropoietin. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase RBC production. Darbepoetin alfa differs from epoetin alfa (recombinant human erythropoietin) in that it contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. Darbepoetin also has a longer half-life than epoetin alfa; it may be administered weekly or biweekly.

Diuretics

Class Summary

Control of hypertension in radiation nephropathy and most chronic renal diseases requires the use of a diuretic. This is the clinical correlate of impaired natriuresis that exists in most forms of experimental hypertension. Additionally, diuretics facilitate potassium excretion.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide (HCTZ) acts on the distal nephron to impair sodium and chloride reabsorption, thus enhancing sodium excretion. It has been in use for more than 40 years and is an important agent for the treatment of essential hypertension.

Furosemide (Lasix)

Furosemide acts on the thick ascending limb of loop of Henle to enhance sodium, potassium, and chloride and water excretion. It is more potent than HCTZ and may be required for the control of fluid retention in subjects with impaired renal function.