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Radiation-Associated Kidney Injury

      The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy-associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients.

      1. Clinical Significance

      The kidneys are the dose-limiting organs for radiotherapy (RT) to gastrointestinal cancers, gynecologic cancers, lymphomas, and sarcomas of the upper abdomen and during total body irradiation (TBI). The kidneys are vitally important, responsible for filtering waste metabolites and electrolytes from the blood, producing erythropoietin to stimulate red blood cell production, and modulating blood pressure by fluid/electrolyte balance. The incidence of RT-associated kidney injury is likely underreported owing to its long latency and because dysfunction is likely often attributed to more common causes.

      2. Endpoints

      The findings associated with RT-induced kidney injury can be segregated into subclinical and clinical (Table 1). After TBI, RT-induced kidney injury often includes features of hemolytic-uremic syndrome (e.g., microangiopathic hemolytic anemia, and thrombocytopenia) (
      • Cruz D.N.
      • Perazella M.A.
      • Mahnensmith R.L.
      Bone marrow transplant nephropathy: A case report and review of the literature.
      ).
      Table 1Radiation-associated kidney toxicity endpoints
      CategoryPhysiologicBiochemicalImaging
      SubclinicalElevated blood pressure

      Increased weight
      Elevated serum β2-microglobulin

      Elevated urine beta2 microglobulin

      Elevated serum blood urea nitrogen

      Elevated serum creatinine

      Elevated serum renin

      Reduced glomerular filtration rate

      Decreased creatinine clearance
      Often used to estimate GFR.


      Proteinuria

      Urine casts

      Hematuria

      Anemia
      Reduced glomerular function, GFR

      99mTc-DTPA renography

      Reduced tubular function

      99mTc-DMSA scintigraphy

      Perfusion deficits on scintigraphy

      131Iodine radiohippurate

      Asymmetric uptake of intraenous contrast on computed tomography

      Kidney atrophy
      ClinicalMalignant hypertension

      Headache, Edema, Dyspnea

      Fatigue, Nausea, Vomiting

      Confusion, Coma, Death
      Abbreviations:99mTc-DTPA = 99mTechnetium-diethylene-triamine-penta-acetic acid; GFR = glomerular filtration rate; 99mTc-DMSA = 99mTechnetium-dimercaptosuccinyl acid.
      Often used to estimate GFR.
      Acute (within 3 months) RT-induced kidney injury is generally subclinical. The signs and symptoms (e.g., decreased glomerular filtration rate [GFR], increased serum β2-microglobulin) usually develop during the subacute period (3–18 months). Chronic injury (>18 months) is characterized by benign or malignant hypertension, elevated creatinine levels, anemia, and renal failure (
      • Rubin P.
      • Casarett G.
      ,
      • Verheij M.
      • Dewit L.G.
      • Valdes Olmos R.A.
      • et al.
      Evidence for a renovascular component in hypertensive patients with late radiation nephropathy.
      ). If no changes in renal blood perfusion or GFR are observed within 2 years after RT, subsequent chronic injury is unlikely (
      • Cohen E.P.
      • Robbins M.E.
      Radiation nephropathy.
      ). RT-induced kidney injury can also reduce a patient's reserve against future renal insults.
      The long latency for clinical kidney toxicity was highlighted in a study of 67 patients with peptic ulcer disease, without pre-existing hypertension, who were treated with ∼20 Gy within 3 weeks (encompassing the left kidney) (
      • Thompson P.L.
      • Mackay I.R.
      • Robson G.S.
      • et al.
      Late radiation nephritis after gastric x-irradiation for peptic ulcer.
      ). Of the 67 patients, 31 (46%) developed kidney toxicity within 8–19 years after RT, including 7 patients with fatal uremia (n = 5) or malignant hypertension (n = 2). At autopsy, atrophy of the left kidney with degenerative changes of the small and medium arteries were observed. The long latency for RT-induced kidney injury and the high prevalence of confounding non–RT-related factors (see the section “Patient- and Treatment-Related Factors”) that can injury the kidneys have hindered our ability to understand the effects of partial kidney RT.

      3. Defining the Kidneys

      The kidneys are relatively easy to identify on the planning computed tomography (CT) scan, even without intravenous contrast. Typically, the doses delivered to each kidney alone and combined should be evaluated. Ideally, the kidney parenchyma should be segmented, because this is the “functional” component. The magnitude of errors introduced by including the collecting system in the “kidney volume” is unclear.
      The existing published data were largely derived from patients treated without computed tomography-based planning, and with delivery techniques associated with substantial dosimetric uncertainty (e.g., the moving strip technique). Even with modern planning, kidney breathing motion or shifts in kidney position are not usually accounted for, introducing uncertainty in the delivered vs. the planned kidney doses (
      • Ahmad N.R.
      • Huq M.S.
      • Corn B.W.
      Respiration-induced motion of the kidneys in whole abdominal radiotherapy: Implications for treatment planning and late toxicity.
      ). The kidneys move inferiorly (by ≤7 cm) and change shape in the upright vs. supine position (
      • Reiff J.E.
      • Werner-Wasik M.
      • Valicenti R.K.
      • et al.
      Changes in the size and location of kidneys from the supine to standing positions and the implications for block placement during total body irradiation.
      ); thus, if kidney blocks were designed using supine CT scans for patients treated in the upright position (e.g., with TBI), the actual kidney doses would be far greater than planned.

      4. Review of Dose–Volume Data

      The risk of RT-induced kidney injury largely depends on the use of whole-volume or partial-volume RT to one or both kidneys. In the present report, whole kidney tolerance refers to bilateral, uniform kidney RT, segregated by the use of TBI or not, and partial kidney tolerance includes any partial-volume RT experience, including uniform RT to one kidney.

       Whole kidney tolerance

      The dose–response data for whole kidney irradiation in patients undergoing TBI is summarized in Table 2 and Fig. 1. Patients undergoing TBI typically have substantial co-morbidities and also receive potentially nephrotoxic chemotherapy. Cheng et al.(
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ) conducted a comprehensive review of 12 studies reporting kidney toxicity (increased creatinine or hemolytic uremic syndrome) after TBI (Table 2 and Fig. 1). On multivariate analysis, for those reports describing adult-only experience (n = 479 patients), the dose was the only significant factor associated with increased kidney toxicity. Neither the dose rate nor the number of fractions were significant in their model. For the studies that included adult and pediatric populations (n = 437 patients), significant factors included the dose, dose rate (≤6 vs. 6.1–9.9 vs. ≥10 cGy/min) and the use of fludarabine. Considering all the studies, except for those with pediatric populations only (n = 916 patients), the number of fractions became a significant factor, in addition to the total dose and dose rate. The dose associated with a 5% risk of kidney toxicity, without nephrotoxic drugs, was 9.8 Gy, regardless of the fractionation scheme used (median dose, 12 Gy; range, 7.5–14; median fractions, 6; range 1–11, delivered once or twice daily).
      Table 2Selected studies of bilateral whole kidney toxicity after TBI and transplantation
      Authors
      All references in first column are included within the review by Cheng et al.(8).
      Patients (n)PopulationTotal kidney dose (Gy)Fractions (n)Fractions/d (n)Dose rate (cGy/min)Renal toxicity (%)Chemotherapy regimen
      Chemotherapy regimens: 1, teniposide, daunorubicin, vincristine, cyclophosphamide, and cytarabine; 2, cytarabine and cyclophosphamide; 3, cyclophosphamide with or without cytarabine; 4, cyclophosphamide with or without thiotepa, daunorubicin, busulfan, or cytarabine; 5, cyclophosphamide, cytarabine, methotrexate, and etoposide; 6, cyclophosphamide with or without melphalan, busulphan, or etoposide; 7, cyclophosphamide or etoposide; 8, cyclophosphamide, teniposide, and cytarabine; 9, neuroblastoma—teniposide, cyclophosphamide, cisplatin, and melphalan with or without methotrexate; 10, cyclophosphamide and cytarabine or cyclophosphamide and busulfan; 11, cyclophosphamide and fludarabine with or without alemtuzumab; 12, cyclophosphamide with or without alemtuzumab, or melphalan, or etoposide; 13, cyclophosphamide with or without alemtuzumab; 14, vincristine, adriamycin, and melphalan; 15, Cyclosporin A and/or amphoterecin B.
      Frisk 200222P7.5111527.31
      Lawton 199772A14931418.12
      68A11.99311.910.32
      17A9.8939.802
      Rabinowe 1991112A12627.59.83
      Miralbell 199624P/A1062164.24
      32P/A12621628.14
      23P/A13.5621634.84
      Chou 199658P1262153.45
      Borg 200247P/A12627.52.16
      Bradley 199831A12621212.97
      36P13.21131207
      10P13.59212307
      Tarbell 199012P14821033.38
      15P12621046.78, 9
      Igaki 200570P/A1262102010
      39A10628.5010
      Delgado 200665P/A7.511139.211
      46P/A7.511132.212
      84P/A126261.212
      26P/A14.48263.811
      20P/A14.4826013
      Moreau 2005140A841NA3.614
      Van Why 199139P13.2821423.115
      Abbreviations: P = pediatric; A = adult; P/A = mixed; NA = not available.
      Modified, with permission, from Cheng et al.
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      .
      ^ All references in first column are included within the review by Cheng et al.
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      .
      Chemotherapy regimens: 1, teniposide, daunorubicin, vincristine, cyclophosphamide, and cytarabine; 2, cytarabine and cyclophosphamide; 3, cyclophosphamide with or without cytarabine; 4, cyclophosphamide with or without thiotepa, daunorubicin, busulfan, or cytarabine; 5, cyclophosphamide, cytarabine, methotrexate, and etoposide; 6, cyclophosphamide with or without melphalan, busulphan, or etoposide; 7, cyclophosphamide or etoposide; 8, cyclophosphamide, teniposide, and cytarabine; 9, neuroblastoma—teniposide, cyclophosphamide, cisplatin, and melphalan with or without methotrexate; 10, cyclophosphamide and cytarabine or cyclophosphamide and busulfan; 11, cyclophosphamide and fludarabine with or without alemtuzumab; 12, cyclophosphamide with or without alemtuzumab, or melphalan, or etoposide; 13, cyclophosphamide with or without alemtuzumab; 14, vincristine, adriamycin, and melphalan; 15, Cyclosporin A and/or amphoterecin B.
      Figure thumbnail gr1
      Fig. 1Dose–response curve for increased creatinine or hemolytic uremic syndrome after total body irradiation (TBI). Open diamonds represent fitted data for studies that included adults alone or adult/pediatric mixed populations (with or without nephrotoxic drugs). Solid squares represent fitted data for same population excluding those treated without nephrotoxic (NT) drugs, cyclosporine, teniposide, or fludarabine. Fractionation schemes (listed in ) were converted to “equivalent” doses delivered in six fractions at 10-cGy/min dose rate. Modified, with permission, from Cheng et al.
      (
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      )
      .
      The whole kidney dose–response data, excluding TBI, is summarized in Table 3 and Fig. 2, Fig. 3. The dose–response data are consistent with previous reviews (e.g., Emami et al.[
      • Emami B.
      • Lyman J.
      • Brown A.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ] in 1991 and Cassady [
      • Cassady J.R.
      Clinical radiation nephropathy.
      ] in 1995; Fig. 1) that suggested a total dose associated with a 5% and 50% risk of injury at 5 years of 18–23 Gy and 28 Gy, in 0.5–1.25 Gy/fraction, respectively. Increases in creatinine clearance have been observed after 10–20 Gy to both kidneys, at 0.8–1.25 Gy/fraction (
      • Schneider D.P.
      • Marti H.P.
      • Von Briel C.
      • et al.
      Long-term evolution of renal function in patients with ovarian cancer after whole abdominal irradiation with or without preceding cisplatin.
      ).
      Table 3Selected studies of bilateral whole kidney irradiation (non-TBI)
      InvestigatorPatients (n)DiseaseChemotherapyDose (Gy)Dose/fraction (Gy)Incidence of injuryEndpoint
      Kunkler 1952
      • Kunkler P.B.
      • Farr R.W.
      • Luxton R.W.
      The Limit of Renal Tolerance to X Rays.
      55SeminomaNone
      23 or 280.9–1.1222/55 (40%)

      7/55
      RF (sBP >160 mm Hg + albuminuria)

      Death
      230.922/18 (11%)
      Denominator estimated from text.
      RF (sBP >160 mm Hg + albuminuria)
      281.1218/25 (51%)
      Denominator estimated from text.
      RF (sBP >160 mm Hg + albuminuria)
      Avioli 1963
      • Avioli L.V.
      • Lazor M.Z.
      • Cotlove E.
      • et al.
      Early effects of radiation on renal function in man.
      10None
      Gynecologic cancer (n = 8), Sarcoma (n = 1), Seminoma (n = 1)7.5–16.5; 20–240.5–1.1; 1.0–1.20/5; 4/5No change in GFR; no HTN or RF; Reduced GFR (75-83%), no HTN or RF
      Keane 1976
      • Keane W.F.
      • Crosson J.T.
      • Staley N.A.
      • et al.
      Radiation-induced renal disease. A clinicopathologic study.
      2Ovarian cancerNone25, 272/2Reduced CrCl (30 mL/min), ESRD
      Churchill 1978
      • Churchill D.N.
      • Hong K.
      • Gault M.H.
      Radiation nephritis following combined abdominal radiation and chemotherapy (bleomycin vinblastine).
      1SeminomaBleomycine and vinblastin26–38
      Two-thirds of kidneys received 38 Gy.
      1.61/1ARF at 5 wk
      Irwin 1996
      • Irwin C.
      • Fyles A.
      • Wong C.S.
      • et al.
      Late renal function following whole abdominal irradiation.
      60Ovarian cancer, NHL, carcinoidNone7–231–1.255/60New HTN,

      No change in CrCl
      Schneider 1999
      • Schneider D.P.
      • Marti H.P.
      • Von Briel C.
      • et al.
      Long-term evolution of renal function in patients with ovarian cancer after whole abdominal irradiation with or without preceding cisplatin.
      56Ovarian cancerCisplatin (n = 25)5–170.65–1.1571–76%Reduced CrCl by >2 mL/min,

      Reduced CrCl (84–66 mL/min)
      Abbreviations: RF = renal failure; sBP = systolic blood pressure; GFR = glomerular filtration rate; HTN = hypertension; CrCl = creatinine clearance; ESRD = end-stage renal disease; ARF = acute (<1 y) RF; NHL = non-Hodgkin's lymphoma.
      Denominator estimated from text.
      Two-thirds of kidneys received 38 Gy.
      Figure thumbnail gr2
      Fig. 2Dose–response curve for symptomatic kidney injury after non–total body irradiation of bilateral kidneys. Note, y axis is different from than that in . Data from review from Cassady et al.
      (
      • Cassady J.R.
      Clinical radiation nephropathy.
      )
      .
      Figure thumbnail gr3
      Fig. 3Composite schematic of combined kidney dose–volume histogram of data from Table 4, Table 5, represented as regions associated with minimal (<5%), low (∼5%), moderate-to-high (∼5–30%), high (≥30%), or undocumented estimated toxicity risks. Clinical experience that yielded risk estimates for each region also indicated. Actual risks associated with using each region on its own or regions in combination are plan-specific and associated with substantial uncertainty.

       Partial kidney tolerance

      Nephrectomy is more often associated with subclinical elevations in creatinine and late chronic kidney injury than is “nephron-sparing” partial nephrectomy (
      • McKiernan J.
      • Simmons R.
      • Katz J.
      • et al.
      Natural history of chronic renal insufficiency after partial and radical nephrectomy.
      ). Thus, the global function/reserve appears related to the nephron volume, and tolerance to RT is likely reduced in patients with one (vs. two) kidneys.
      Table 4 summarizes the key studies describing partial kidney tolerance to RT. Unilateral kidney RT is not risk free, as shown by Thompson et al.(
      • Thompson P.L.
      • Mackay I.R.
      • Robson G.S.
      • et al.
      Late radiation nephritis after gastric x-irradiation for peptic ulcer.
      ), who observed a dose response for kidney atrophy and clinical kidney toxicity many years after unilateral kidney RT (
      • Welz S.
      • Hehr T.
      • Kollmannsberger C.
      • et al.
      Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer.
      ). Willett et al.(
      • Willett C.G.
      • Tepper J.E.
      • Orlow E.L.
      • et al.
      Renal complications secondary to radiation treatment of upper abdominal malignancies.
      ) found a volume-dependent decrease in creatinine clearance after ≥26 Gy to ≥50% of one kidney. In gastric cancer patients treated primarily using anteroposterior beams with little dose to the right kidney, a progressive decrease in left (vs. right) renal function, as assessed by renography, was seen 12–18 months after chemoradiotherapy, with an associated increase in serum creatinine (
      • Jansen E.P.
      • Saunders M.P.
      • Boot H.
      • et al.
      Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer.
      ). The volume of the left kidney receiving >20 Gy and the mean left kidney dose were associated with increased risk of renal injury. Regional kidney injury has been detected using scintigraphy after low doses; 5% of the irradiated kidneys developed abnormalities after 3–6 Gy, in 15–30 fractions, independent of the irradiated volume. These findings improved with time, likely due to the reserve capacity of the spared kidney tissue (
      • Kost S.
      • Dorr W.
      • Keinert K.
      • et al.
      Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy.
      ).
      Table 4Selected studies addressing partial kidney irradiation
      InvestigatorPatients (n)DiseaseChemotherapyDose/fraction (Gy)Dose/volumeIncidenceEndpoint
      Kunkler 1952
      • Kunkler P.B.
      • Farr R.W.
      • Luxton R.W.
      The Limit of Renal Tolerance to X Rays.
      60SeminomaNone0.9–1.12D33% < 18 Gy (18–29 Gy to kidneys)0/60No RF (sBP >160 mm Hg + albuminuria
      Thompson 1971
      • Thompson P.L.
      • Mackay I.R.
      • Robson G.S.
      • et al.
      Late radiation nephritis after gastric x-irradiation for peptic ulcer.
      67Peptic ulcerNone1.0–1.3D50% = 15–35 Gy31/67RF or HTN (8–19 y)
      D50% = 15 Gy0/2Kidney atrophy (I/S)
      D50% = 20 Gy6/6Kidney atrophy (I/S)
      D50% = 30–35 Gy2/2Marked kidney atrophy (I/S)
      2/2Malignant HTN
      Le Bourgeois 1978
      • LeBourgeois J.
      • Meignan M.
      • Parmentier C.
      • et al.
      Renal consequences of irradiation of the spleen in lymphoma patients.
      74Hodgkin's diseaseNone1D15–40% = 20 Gy74/7470% Focal decrease in glomerular fn
      3/74Proteinuria, no change in CrCl
      Birkhead 1979
      • Birkhead B.M.
      • Dobbs C.E.
      • Beard M.F.
      • et al.
      Assessment of renal function following irradiation of the intact spleen for Hodgkin disease.
      23Hodgkin's disease1 Patient2D16% = 40 Gy6/16Focal scintigraphy changes; no RF
      Kim 1980
      • Kim T.H.
      • Freeman C.R.
      • Webster J.H.
      The significance of unilateral radiation nephropathy.
      18NHLNone1D25–50% = 25–44 Gy3/18Decreased CrCl
      5/18HTN
      Kim 1984
      • Kim T.H.
      • Somerville P.J.
      • Freeman C.R.
      Unilateral radiation nephropathy--the long-term significance.
      18NHLNone1D25–50% = 21– 33 Gy2/9Reduced blood flow or perfusion
      D25–50% = 30–40 Gy4/7Reduced blood flow or perfusion
      D25–50% > 40 Gy3/3Atrophy
      Willett 1986
      • Willett C.G.
      • Tepper J.E.
      • Orlow E.L.
      • et al.
      Renal complications secondary to radiation treatment of upper abdominal malignancies.
      86MixedNot stated1.5–1.8V26Gy = 50%10% Decrease in CrCl
      V26Gy > 90%24% Decrease in CrCl
      All patients2/73

      4/13
      New HTN

      Increase in HTN medications
      Flentje 1993
      • Flentje M.
      • Hensley F.
      • Gademann G.
      • et al.
      Renal tolerance to nonhomogenous irradiation: comparison of observed effects to predictions of normal tissue complication probability from different biophysical models.
      142SeminomaNone0.7–1D50% < 18 Gy0/100RF or HTN
      D50% > 18–32 Gy7/42
      Dewitt 1993
      • Dewit L.
      • Verheij M.
      • Valdes Olmos R.A.
      • et al.
      Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney.
      7SeminomaNone2V25–35Gy = 20–30%0/7CrCl or SC
      Dewitt 1993
      • Dewit L.
      • Verheij M.
      • Valdes Olmos R.A.
      • et al.
      Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney.
      7NHLNoneV40Gy = 50%

      V12–13Gy = 100%
      25% Decrease in glomerular fn Sc

      31% Decrease in tubular fn Sc
      Kost 2002
      • Kost S.
      • Dorr W.
      • Keinert K.
      • et al.
      Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy.
      91Seminoma (n = 45),

      NHL (n = 42), RCC (n = 6),

      Sarcoma (n = 1)
      1.8–2.0V3–6Gy > 10%

      V27Gy = 10%

      V7.6Gy = 100%
      5%

      50%

      50%
      Decrease in fn Sc

      Decrease in fn Sc

      Decrease in renal flow; no RF
      Nevinny-Stickel 2007
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
      19Cervical cancer0.4–1.8V28Gy < 25%

      V23Gy < 33%
      3/19Decrease in renal flow; no RF
      Jansen 2007
      • Jansen E.P.
      • Saunders M.P.
      • Boot H.
      • et al.
      Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer.
      44Gastric cancerCapecitabine or cisplatin (n = 21)0.4–1.8V20Gy (1 kidney) >64% vs. <64%1/15
      Among patients with follow-up ≥18 months.
      66% vs. 34% decrease in fn (I/S)

      HTN
      Welz 2007
      • Welz S.
      • Hehr T.
      • Kollmannsberger C.
      • et al.
      Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer.
      27Gastric cancer5-FU, cisplatin, paclitaxel0.4–1.8V12Gy < 62.5% functional kidneysTrend toward increase Cr; no HTN
      Abbreviations: Dy% = dose to y% of volume; I/S = irradiated vs. spared; fn = function; RCC = renal cell cancer; 5-FU = 5-fluoruracil; Sc = scintigraphy; Vx Gy = volume receiving >x Gy; NHL = non-Hodgkin's lymphoma; other abbreviations as in Table 1.
      Among patients with follow-up ≥18 months.

       Pediatric kidney tolerance

      Neonates appear to have an increased sensitivity to RT. Doses of 12–14 Gy at 1.25–1.5 Gy/fraction to an entire neonate kidney have been associated with a decreased GFR (
      • Peschel R.E.
      • Chen M.
      • Seashore J.
      The treatment of massive hepatomegaly in stage IV-S neuroblastoma.
      ) and subsequent abnormalities on bone scan and intravenous pyelography. Age less than 5 years was associated with increased risk of acute renal dysfunction post TBI in one study (new reference ‘A’) For older children, no convincing evidence has shown that the kidney tolerance is different from that of adults. A study of 108 children who underwent nephrectomy predominantly for Wilms tumor and RT to the contralateral remaining entire or partial kidney showed that abnormal creatinine clearance was dose dependent (
      • Esiashvili N.
      • Chiang K.Y.
      • Hasselle M.D.
      • Bryant C.
      • Riffenburgh R.H.
      • Paulino A.C.
      Renal toxicity in children undergoing total body irradiation for bone marrow transplant.
      ). Abnormal creatinine clearance, defined as <63 mL/min/m2, was found in 29 (41%) of 70 children receiving <12 Gy, 15 (56%) of 27 children receiving 12–24 Gy, and 10 (91%) of 11 children receiving >24 Gy to the remaining kidney (p < .05). All 5 patients with clearance <24 mL/min/m2 had hypertension and elevated blood urea nitrogen, and 4 died of kidney failure. In a different Wilms tumor study, nephropathy was seen in 0 of 17 children receiving 11–14 Gy to the remaining kidney and 1 (25%) of 4 receiving 14–15 Gy (fraction size not reported) (
      • Cassady J.R.
      Clinical radiation nephropathy.
      ). In another study, 1 of 38 children with bilateral Wilms tumors developed kidney failure after 27 Gy in 21 fractions to the lower half and 12 Gy in 11 fractions to the upper half of the remaining kidney (
      • Mitus A.
      • Tefft M.
      • Fellers F.X.
      Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease.
      ). No kidney failure occurred in children receiving bilateral kidney doses of 10–12 Gy, in 1.5–2 Gy/fraction. In the National Wilms Tumor Study experience, kidney failure was more common in children with bilateral than unilateral Wilms tumor (
      • Paulino A.C.
      • Wilimas J.
      • Marina N.
      • et al.
      Local control in synchronous bilateral Wilms tumor.
      ). For the 3 patients with unilateral tumors who developed kidney failure, the dose to the remaining kidney was 15, 18, and 20 Gy in 1.5–2 Gy/fraction.
      In the review by Cheng et al.(
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ) of kidney toxicity after TBI, for pediatric patients (n = 192), the use of cyclosporine and teniposide was associated with an increased risk of kidney toxicity. When these drugs were excluded, no dose response was found, and, at doses ≤13 Gy, the incidence of kidney toxicity was <8% (
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ). Data on the pediatric kidney partial volume tolerance are not available.

       RT-induced reduction in compensatory response

      After injury to one kidney, a compensatory increase in kidney function of the spared kidney often occurs. Low-dose RT to the “spared” kidney can blunt this compensation. At 6–9 years after 40 Gy in 1.5-Gy fractions to the left kidney and 12–13 Gy in 1-Gy fractions to the right kidney, the left kidney glomerular and tubular function, as assessed by scintigraphy, had decreased to 21% and 31% of baseline, respectively, with an associated decline in creatinine clearance. The compensatory response was reduced compared with that in patients with complete sparing of ≥70% of one kidney (
      • Ritchey M.L.
      • Green D.M.
      • Thomas P.R.
      • et al.
      Renal failure in Wilms tumor patients: A report from the National Wilms Tumor Study Group.
      ).

      5. Patient- and Treatment-Related Factors

      Chemotherapy can enhance RT-associated kidney injury in adults and pediatric populations treated with and without TBI (
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ,
      • Dewit L.
      • Verheij M.
      • Valdes Olmos R.A.
      • et al.
      Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney.
      ) (Fig. 1). The review by Cheng et al.(
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ) found that after TBI, the use of fludarabine, cyclosporine, or teniposide increased the risk of renal injury (odds ratio, 6.2, 5.9, and 10.5, respectively). A TBI dose rate of ≤6 cGy/min and 6.1–9.9 cGy/min was associated with an odds ratio of 0.0046 and 0.083, respectively, compared with ≥10 cGy/min (
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ). Underlying renal insufficiency, diabetes, hypertension, liver disease, heart disease, and smoking can also reduce the kidney's tolerance to RT; however, the magnitude of these effects is unclear. Animal models have suggested that angiotensin-converting enzyme inhibitors, dexamethasone, and acetylsalicylic acid can prevent and treat RT-induced kidney injury (
      • Donaldson S.S.
      • Moskowitz P.S.
      • Canty E.L.
      • et al.
      Combination radiation-adriamycin therapy: Renoprival growth, functional and structural effects in the immature mouse.
      ,
      • Moulder J.E.
      • Fish B.L.
      • Cohen E.P.
      Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists.
      ,
      • Cohen E.P.
      • Fish B.L.
      • Sharma M.
      • et al.
      Role of the angiotensin II type-2 receptor in radiation nephropathy.
      ). Angiotensin-converting enzyme inhibitors improve non–RT-associated kidney failure (
      • Verheij M.
      • Stewart F.A.
      • Oussoren Y.
      • et al.
      Amelioration of radiation nephropathy by acetylsalicylic acid.
      ) and, recently, were suggested in a randomized trial to reduce the incidence of nephropathy or hemolytic uremic syndrome (3.7% vs. 15%, p = .1) after TBI (
      • Cohen E.P.
      • Hussain S.
      • Moulder J.E.
      Successful treatment of radiation nephropathy with angiotensin II blockade.
      ).

      6. Predictive Models

      The Lyman-Burman-Kutcher normal tissue complication probability model parameters (median toxic dose, 28 Gy, n = 0.70, m = 0.10) (
      • Cohen E.P.
      • Irving A.A.
      • Drobyski W.R.
      • et al.
      Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: A randomized controlled trial.
      ) have been used to describe the tolerance estimates reported by Emami et al.(
      • Emami B.
      • Lyman J.
      • Brown A.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ). Cassady (
      • Cassady J.R.
      Clinical radiation nephropathy.
      ) pooled the data on bilateral whole kidney RT tolerance and confirmed a threshold dose for RT injury of 15 Gy with a 5% and 50% risk of injury at 5 years for whole-kidney RT of 18 Gy and 28 Gy, respectively, within 5 weeks (Fig. 2). It has been demonstrated that greater doses can be safely delivered to partial kidney volumes (
      • Emami B.
      • Lyman J.
      • Brown A.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ,
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
      ). Quantitative data to support more refined models are not available.
      Cheng et al.(
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
      ) found a less steep dose response (m = 0.26) after TBI (median dose, 12 Gy in six fractions twice daily). The dose associated with a 5% risk of kidney toxicity was 9.8 Gy. The addition of nephrotoxic drugs made the dose–response curve steeper (Fig. 1).

      7. Special Situations

      The response of the kidney is highly dependent on the fraction size; therefore, extrapolation of previous experience to different fraction sizes can be problematic (
      • Nevinny-Stickel M.
      • Poljanc K.
      • Forthuber B.C.
      • et al.
      Optimized conformal paraaortic lymph node irradiation is not associated with enhanced renal toxicity.
      ,
      • Svedman C.
      • Sandstrom P.
      • Pisa P.
      • et al.
      A prospective phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma.
      ,
      • Wersall P.J.
      • Blomgren H.
      • Lax I.
      • et al.
      Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma.
      ,
      • Beitler J.J.
      • Makara D.
      • Silverman P.
      • et al.
      Definitive, high-dose-per-fraction, conformal, stereotactic external radiation for renal cell carcinoma.
      ). One hypothesis is that nearly complete sparing of a substantial volume of the kidney should be associated with compensatory effects and preservation of renal function, despite the delivery of focal high doses. Symptomatic kidney injury has not been reported after potent doses of stereotactic body radiotherapy; however, elevations in creatinine have been observed 52 months after renal stereotactic body radiotherapy (SBRT) (
      • Teh B.
      • Bloch C.
      • Galli-Guevara M.
      • et al.
      The treatment of primary and metastatic renal cell carcinoma (RCC) with image guided stereotactic body radiation therapy (SBRT).
      ). Follow-up of long-term survivors from these series is required to determine the kidney's and collecting system's tolerance to SBRT.
      Few of the published reports on kidney tolerance have focused on intensity-modulated RT (IMRT), and the effects of different spatial dose distributions are not well established. IMRT often leads to a low dose delivered to a larger volume compared with simpler plans, which might reduce the possibility of a compensatory increase in kidney function.

      8. Dose–Volume Recommendations

      All dose–volume recommendations are associated with substantial uncertainty, because few studies are available of patients who have been followed for ≥10 years. However, some broad guidelines can be useful and will hopefully be tested in future studies (Table 5 and Fig. 3).
      Table 5Suggested dose–volume constraints for estimated risk of <5%
      VariableDose–volume metricInvestigator
      Bilateral kidney irradiation
       TBIMean kidney dose <10 GyCheng et al.
      • Cheng J.
      • Schultheiss T.
      • Wong J.
      Impact of drug therapy, radiation dose and dose rate on renal toxicity following bone marrow transplantation.
       Non-TBIMean kidney dose <18 GyCassady
      • Cassady J.R.
      Clinical radiation nephropathy.
      Partial kidney irradiation
       Bilateral kidneysMean kidney dose <18 GyNevinny-Stickel et al.
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
       Bilateral kidneysV28Gy < 20%Nevinny-Stickel et al.
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
       Bilateral kidneysV23Gy < 30%Nevinny-Stickel et al.
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
       Bilateral kidneysV20Gy < 32%Jansen et al.
      • Jansen E.P.
      • Saunders M.P.
      • Boot H.
      • et al.
      Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer.
       Bilateral kidneysV12Gy < 55%Welz et al.
      • Welz S.
      • Hehr T.
      • Kollmannsberger C.
      • et al.
      Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer.
      Estimated from Welz et al.(13); 62.5% reduced to 55% because 62.5% was functional volume.
       If mean kidney dose to 1 kidney >18 GyV6Gy (remaining kidney) <30%
      Abbreviations: Vx Gy = volume of bilateral kidneys receiving >x Gy; TBI = total body irradiation.
      Estimated from Welz et al.
      • Welz S.
      • Hehr T.
      • Kollmannsberger C.
      • et al.
      Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer.
      ; 62.5% reduced to 55% because 62.5% was functional volume.

      9. Areas for Future Study

      The kidney partial tolerance to RT is largely unknown and deserves more study. Collaborative prospective studies are needed, with collection of dose–volume histogram and spatial dose data, along with serial long-term objective outcome assessments. The baseline clinical kidney function and co-morbidities need to be documented, along with the use of nephrotoxic or antihypertensive medications. Differences in the dose per fraction should also be accounted for. Proposed research topics of importance include the following:
      • –Pathophysiology of RT-induced kidney injury
      • –Interaction between clinical factors and kidney tolerance to RT
      • –Mitigating factors and radioprotectors
      • –Renal compensatory effects and how low-dose RT alters the compensatory capacity
      • –Spatial variation in radiation sensitivity (e.g. with functional imaging)
      • –Surrogates for risk of clinical toxicity (e.g., cytokines, proteonomics)

      10. Scoring Toxicity

      Studies of RT-induced kidney injury have been confounded by the use of variable, most often asymptomatic, endpoints, largely because the symptoms usually occur many years after RT. Because early changes in renal flow and GFR correlate with an increased risk of subsequent symptomatic toxicity, these endpoints should be considered in future studies. The severity of injury should be graded according to the GFR, as has been recommended for all chronic kidney disease (Table 6) (
      • Svedman C.
      • Karlsson K.
      • Rutkowska E.
      • Sandstrom P.
      • Blomgren H.
      • Lax I.
      • Wersall P.
      • et al.
      Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with only one functioning kidney.
      ). Serial urine protein, serum blood urea nitrogen, creatinine clearance, blood pressure measurements, and symptoms of renal failure can also been used to grade the severity of RT-induced injury (
      • Levey A.S.
      • Eckardt K.U.
      • Tsukamoto Y.
      • et al.
      Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
      ).
      Table 6K/DOQI stages of chronic kidney disease (kidney disease occurring for > 3 mo)
      StageDescriptionGFR (mL/min/1.73 m2)
      1Kidney damage with normal or GFR≥90
      2Kidney damage with mildly decreased GFR60–89
      3Moderately decreased GFR30–59
      4Severely decreased GFR15–29
      5Kidney failure<15 (or dialysis)
      Abbreviations: K/DOQI = Kidney/Dialysis Outcomes Quality Initiative; GFR = glomerular filtration rate.
      Kidney damage defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
      Data from National Kidney Foundation (available from: www.kidney.org).

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