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. Exposure to ionizing radiation can cause tissue reactions depending on the absorbed dose.
Acute radiation nephropathy develops 6-12 months after irradiation, whereas chronic radiation nephropathy develops years later. Classic radiation nephropathy occurs after bilateral, local kidney irradiation and is characterized by chronic renal failure occurring months or years after renal irradiation.[1] Nearly 7 million cancer patients were treated with radiation therapy in 2012, and the number of cancer survivors is increasing each year, highlighting the importance of addressing tissue toxicity and improving quality of life after radiation therapy.[26]
Radiation nephropathy with chronic renal failure may also occur after hematopoietic stem cell transplantation (HSCT), also called bone marrow transplantation (BMT) nephropathy.[2] In addition, the use of yttrium–90–tagged (90Y-tagged) somatostatin and other radionuclides for radionuclide therapy can cause radiation nephropathy when these agents are filtered by the kidneys and reabsorbed by the renal tubule epithelium or when blood-borne exposure to the kidney cells occurs.[3] (See Etiology.)
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 radiation nephritis was commonly used in the past; however, because radiation nephropathy is not an inflammatory condition, the term nephropathy is probably more appropriate.
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 while it is still a radioemitter. This is the case for 90Y-tagged somatostatin, which has been used for the treatment of neuroendocrine malignancies, and for holmium-166–tagged (166Ho-tagged) phosphonate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP).[6, 7]
More than 70% of kidney stones in the United States are diagnosed by means of computed tomography, and many of these patients are relatively young, averaging 45 years of age at first diagnosis; 20% of patients with an acute stone episode receive a 1-year cumulative medical imaging radiation dose of greater than 50 mSv. The risk of radiation to this relatively young population is, therefore, a substantial concern.[8]
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.
Oxidative injury to 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 precise 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 to 10 weeks after the same dose, a wave of tubular epithelial cell deaths occurs. 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] With total body irradiation (TBI), chronic renal failure develops within 6-12 months after 10-Gy single-fraction 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 as nephrotoxic. This dose is given over days, not weeks, to the whole body 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 resemble 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.
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.[9]
In a United States report, 30 of 83 subjects treated with 66Ho-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.
Radiation nephropathy may progress to end-stage renal disease (ESRD). The same is true of BMT nephropathy; the occurrence of ESRD in subjects who have undergone BMT is almost 20 times higher than it is in the age-matched general population.[10] The progression to ESRD 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.[11]
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.[12]
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).
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 bone marrow transplantation (BMT),[13] 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 gastrointestinal (GI) tract, kidney injury at these doses indicates that the kidneys are quite radiosensitive.
Modern radiation therapy (RT) is sharply focused on the area to be treated; therefore, RT for uterine cervical cancer or for prostate cancer is very unlikely to result in irradiation of the kidneys. The risk of RT-induced kidney injury depends on the radiation dose and whether the partial or whole volume of one or both kidneys is exposed. Most radiation oncologists use the dose-volume histogram information to assess the organs at risk of radiation-induced injury.[27]
In patients who have undergone BMT, a history of total-body irradiation (TBI) for pre-BMT conditioning should be determined. Partial renal shielding reduces, but does not eliminate, the risk of BMT nephropathy. Retrospective evaluation of patients receiving T-cell depletion hematopoietic stem cell transplantation showed that the use of TBI predisposed patients to hypertension and chronic kidney disease.[27]
Because radiation nephropathy is a delayed injury, kidney 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 kidney 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).
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 lower levels of blood pressure elevation than would ordinarily cause such changes.[14]
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.
Basic tests in the assessment of radiation nephropathy include the following:
Urinalysis - Granular casts indicate renal parenchymal injury; red cell casts are not consistent with radiation nephropathy or bone marrow transplantation (BMT) nephropathy and instead suggest acute glomerulonephritis.
Complete blood cell count (CBC) - 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.
Kidney function studies
Lactate dehydrogenase (LDH) - The degree of LDH elevation correlates with the rapidity of renal failure in BMT nephropathy. The increased LDH level in BMT nephropathy may be transient.
Potassium - Hyperkalemia (serum potassium > 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. 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.
Proteinuria at non-nephrotic levels may be evident. It is difficult to delineate whether this is due to radiation exposure itself or a result of hypertension.
The severity of anemia is disproportionate to the degree of azotemia. This could be as a result of depletion of erythropoietin or glomerular capillary tuft damage leading to microangiopathic hemolytic anemia.[27]
Kidney function studies
Blood urea nitrogen (BUN) and serum creatinine should be measured to assess overall kidney function; the levels correlate with the glomerular filtration rate (GFR). The abbreviated Modification of Diet in Renal Disease (MDRD) formula may be used to estimate the GFR.[16] The Cockcroft-Gault formula uses patient age and weight, along with serum creatinine, to estimate the creatinine clearance, without a 24-hour urine collection. These formulas should be used only if the patient has a stable plasma creatinine level; otherwise, the Creatinine Clearance Estimate for Changing Serum Creatinine may be used. Neither the MDRD or the Cockcroft-Gault formula applies to patients with acute kidney injury.
Other laboratory studies
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
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 hypertension (blood pressure > 160/100 mm Hg).
The protein-to-creatinine ratio provides an estimate of the amount of protein in the urine over a 24-hour period. 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.[17]
Ultrasonography helps in ruling out urinary tract obstruction. A reduction in kidney size occurs over time. The finding of smaller kidneys with increased echogenicity 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.
In a case report of radiation nephropathy, fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed an increase in FDG activity in portions of the kidney that had been previously irradiated.[18]
Some studies have shown that post-radiation scintigraphy in combination with biochemical measures may allow for early identification and assessment of patients who are at higher risk for developing clinical manifestations of radiation-induced kidney injury.[27]
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.[19]
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.
View Image
Photomicrograph of a kidney-biopsy sample in a case of nephropathy associated with bone marrow transplantation (periodic acid-Schiff stain). A glomeru....
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.
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 disease, with the need for renal replacement therapy such as dialysis or kidney transplantation.[12]
The graph of 100/plasma creatinine yields a number that varies directly with the GFR and is a fair estimate of the GFR. The graph of 100/plasma creatinine over 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.
View Image
Evolution of the glomerular filtration rate (GFR) versus time in a case of nephropathy related to bone marrow transplantation (BMT). GFR may be approx....
As with chronic renal disease of any kind, the major risk with radiation nephropathy and bone marrow transplantation (BMT) nephropathy is progressive loss of renal function with evolution to end-stage renal disease. Concomitant hypertension predisposes patients to stroke and heart disease, and 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 recombinant human 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.
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (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 glomerular filtration rate (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.[20] An ARB was shown to be very effective in a single case of radiation nephropathy.[21] However, no randomized trials of ACE inhibitors or ARBs in human radiation nephropathy have been published.
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.[22] 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 these agents are started soon enough after the initial irradiation.[23] 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, compared with the placebo patients.[23]
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 hemolytic-uremic syndrome and/or a thrombotic thrombocytopenia purpura–like disorder, the use of plasma exchange may be considered. This treatment may reverse the hematologic component, but it does not improve renal function.[24]
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 the patient require an imaging study with intravenous (IV) radiocontrast, the use of IV isotonic sodium chloride solution should reduce the risk of contrast-induced nephropathy.
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 90Y-tagged somatostatin and 166Ho-tagged phosphonate.[6, 7]
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.
For patient education information, see Kidney Disease.
Technetium 99m (99mTc) mertiatide is the radiopharmaceutical of choice for the evaluation of both children and adults suspected of having renal obstruction. While the package insert suggests an administered dose range of 185 MBq (5 mCi) to 370 MBq (10 mCi) for the average adult patient who weighs 70 kg, for most 99mTc-MAG3 renal imaging examinations, administration of doses in this range fails to have a diagnostic effect and results in unnecessary radiation to the patient. Current guidelines recommend a range of 37–185 MBq be used.[25]
Control of hypertension and treatment of anemia are necessary. In bone marrow transplantation (BMT) nephropathy, the occurrence of hyperkalemia requires additional attention. For the control of hypertension, angiotensin-converting enzyme (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. Human erythropoietins are used for treatment of
Clinical Context:
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.
Clinical Context:
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.
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.
Clinical Context:
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.
Clinical Context:
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.
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.
Clinical Context:
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.
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.
Clinical Context:
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.
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.
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.
Clinical Context:
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.
Clinical Context:
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.
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.
Clinical Context:
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.
Clinical Context:
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.
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.
Jaya Kala, MD, Assistant Professor, Chair of Onco-Nephrology, Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Texas Health Science Center at Houston, McGovern Medical School; Assistant Professor, Section of Nephrology, Department of Emergency Medicine, MD Anderson Cancer Center
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: BTG international <br/>Received research grant from: National Kidney Foundation.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital
Disclosure: Nothing to disclose.
Chief Editor
Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Disclosure: Nothing to disclose.
Additional Contributors
Eric P Cohen, MD, Professor, Department of Medicine, Division of Nephrology, University of Maryland School of Medicine; Nephrology Section Chief, Baltimore Veterans Affairs Hospital
Disclosure: Nothing to disclose.
Laura Lyngby Mulloy, DO, FACP, Professor of Medicine, Chief, Section of Nephrology, Hypertension, and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia, Georgia Regents University
Kala J. Radiation-induced kidney injury. Journal of Onco-Nephrology. 2019. 3:160-167.
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.
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.
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.
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.
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