Unilateral radiation nephropathy—the long-term significance

??Original Contribution

UNILATERAL

RADIATION ‘TAIK

H. AND

McGill

University

Department

KIM,

NEPIIROPATHY-THE

M.D., PETERJ.

CAROLYN

R.

LONG-TERM

SOMERVILLE,

FREEMAN,

M.B.,

B.S.,

SIGNIFICANCE

MB., F.R.C.P.(C)* F.R.C.P.(C)

of Radiation Oncology and the Division of Nephrology*, l650 Cedar Ave., Montreal. Quebec. Canada H3G IA4

The Montreal

General

Hospital.

Eighteen patients with gastrointestinsl and retroperitoneal non-flodgkin’s lymphoma received abdominal radiotherapy as their primary treatment. Each patient received a total tumor dose of 2200 to 4500 cGy in 5 to 9 weeks to the whole or half of one kidney. Nine patients developed unilateral radiation nephropathy demonstrable on post-treatment evaluation with 99m Tc glucoheptonate blood flow, delayed static scan, and an I-131 radiohippurate renal perfusion study. The tests were periodically repeated over periods ranging from 5 to 8 years. Six patients with nephropathy and 4 patients without nephropathy were followed 5 years or longer. The minimum nephropathogenic irradiation dose was 2200 cCy delivered in 59 days. The incidence of nephropathy is higher with increase in the total dose. Short term recovery in function was observed in 3 patients and long-term complete recovery was observed in one patient. Atrophic renal change was irreversible and progressive in 3 patients over a 6 to 7 year follow-up period. In this group of patients, an abnormal creatinine clearance and serum beta-2 microglobulin level was indicative of vascular damage. Elevated arterial blood pressure was seen in 5 patients. All were controlled medically, without nephrectomy. There was no other clinically significant problem resulting from the unilateral Radiation

nephrnpathy

complications,

in this group of patients.

Nephropathy.

INTRODUCI’ION

In modern radiotherapy practice, bilateral radiation nephropathy is a rare occurrence due to improved understanding of renal radiation tolerance and efficient protection of the kidneys. ‘” However, partial or unilateral renal irradiation beyond the tolerance dose is often delivered in order to adequately treat the tumor in the vicinity of the kidney. 4~“*‘8Most studies suggest a subclinical or mild clinical course,4.‘5.‘* and even those patients with a clinical syndrome, usually hypertension, are easily controlled by simple nephrectomy,‘.“’ although some authors have suggested detrimental long-term effects.27 In a previous report,‘5 we indicated that unilateral radiation nephropathy is a tolerable clinical syndrome if the patients are carefully monitored. Clinically symptomatic cases were relatively infrequent and nephrectomy could be avoided in all cases on short term follow-up. All seven patients have now been followed for between 5 and 8 years. The purpose of this paper is to report the long-term clinical evolution and functional changes in these patients. In addition, we attempted to evaluate these Presented at the ASTR’s 25th Annual Meeting at Los Angeles, California, Ott 3-7. 1983. Reprint requests to: Dr. Taik H. Kim, Department of Radiation Oncology, Vassar Brothers Hospital, Reade Place. Poughkeepsie, NY I260 I.

patients by studying serum and urine beta 2 microglobulin levels, creatinine clearance, and performed some tubular function tests. We also followed and reported on those patients who did not develop nephropathy.

METHODS

AND

MATERIALS

Over 30 patients with GI or retroperitoneal non-Hodgkin’s lymphoma were treated with radiotherapy from 1975 to 198 1 at McGill University hospitals. All patients were treated with a megavoltage unit (Co-60 or a 4 MeV linear accelerator). Typically, the dose to the whole abdomen was 3000 cGy in 6 weeks, at 100 cGy per fraction. Most patients received an additional boost dose of IOOO-I400 cGy in I to 1’12weeks with 200 cGy per fraction given to the major tumor-bearing area. In 18 of these patients, the left kidney or half of the left kidney received at least 2200 cGy. The dose to the right kidney was kept below 1500 cGy over the same period, except for two patients whose right renal doses were 1850 cGy and 2 100 cGy, respectively. Neither of these patients developed any

Acknowledgments-The

authors wish to thank MN. Janet Strycek and Ms. Joanne Sears for secretarial assistance and Betsy Barber for the measurement of urine samples. Accepted for publication 6 June 1984.

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Table

1. The profile of patients with unilateral

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nephropathy

II

and the results of renal studies

I Pt. no.

(days)

Time after treatment in months

Scan

l8F

3 I50/4400 (55)

40 91

Atrophy Unchanged

4YM

3300/4500

16 21

Atrophy Unchanged

36 47 85

Atrophy Progressed Progressed

Mod. reduced Further reduced Further reduced

16 33 85 13 41 81

Normal Normal

Reduced Normal Reduced Normal Normal Normal Mildly reduced

Mod. delayed Further delayed Very faint perfusion Delayed Normal Delayed Delayed Normal Normal Mildly delayed

Mildly reduced Further reduced Normal Mod. reduced Further reduced Reduced Some improvement Mildly reduced

Mildly delayed Further delayed Mildly delayed Mod. delayed Further delayed Delayed Some improvement Mildly delayed

Some improvement

Some improvement

Age/

Dose cGy’

Sex

(31)

3

65M

3060 (47)

4

52M

3050 (61)

4YF

3000/3400 (56)

49F

70M

2850-3 100

21

(59)

34 81 4 16 77 7

2800 (60)

54F

2350/4OGO

78F

(45) 2200 (59)

2 numbers

??

1;12microglobulin rn strum rgm/l

Normal Normal

60

1575

Red uccd

Dclaycd

-

Unchanged

Unchanged

Blood flow

Progressed

19 17 22

Atrophy Same dose of the kidney

due to different

change in the right kidney, systemic symptoms, or signs of renal failure. Pretreatment renal assessment with 99m Tc glucoheptonate renal blood flow and delayed imaging was performed on all patients. This study also served to localize the kidneys for appropriate shielding. In eight patients, I- 13 1 radiohippurate perfusion studies were obtained. All renal function tests including I- 13 1 radiohippurate perfusion studies were repeated at least once during the follow-up period in all patients. Subsequent studies were obtained fo’rthe five patients who developed demonstrable changes and who have been followed for 5 years or more. In the remaining patients with nephropathy, two followup studies were obtained. Three patients had impaired parenchymal renal function on pretreatment work-up. Following the course of treatment, renal function tests continued to show the abnormality, but since no unilateral manifestation of the nephropathy was observed, these patients were not considered to have unilateral radiation nephropathy. Eight patients who deveioped unilateral nephropathy as determined by radio-isotope techniques were evaluated with creatinine clearance, protein excretion, and beta 2 microglobulin excretion in 24-hour urine specimens.

??

Perfusion

Normal Normal

Atrophy Normal Normal Normal Atrophy Progressed Normal Atrophy Progressed Atrophy Same

designate different

Creatinine clearance ml/min

Radioisotopic study

Pharmacia Diagnostics AB. Uppsala, Sweden,

Clinical status of patient Alive and well 96 months Died of pancreatic Ca-39 months Alive and well 91 months

75

2940

54

3192

Alive and well 85 months

65

2100

Alive and well 81 months

25

3138

Alive and well 81 months

34

7140

Alive and well 83 months

61

2436

38

6216

Alive and well 24 months Alive and well 22 months

shielding.

Urine pH, quantitative white cell excretion, and urine osmolality were measured on a fasting morning specimen. These measurements were taken using standard biochemical methods. Creatinine clearance was measured using SMAC auto analyzer technology, urine osmolality found by measuring freezing point depression, and white cell excretion rate was determined according to the protocol of Gyory et al. I2 Beta 2 microglobulin excretion was measured in serum and urine using a commercially available kit* and the urine was collected in containers containing 5 ml of ION NaOH to prevent enzymatic breakdown of the protein. These series of renal function tests were carried out to determine first, whether any abnormality in renal function could be detected when only one kidney was involved in the process and second, whether there was any evidence of tubulointerstitial disease. A similar group of tests was carried out in the seven normal volunteers, age range 31 to 66 years. Other routine follow-up examinations included arterial blood pressure, serum biochemistry, and hemogram. The patients who developed a change in the kidney were carefully observed for signs of renal failure or other nephropathy. The results are reported as means rtr standard deviation from the mean, and Student’s t-test was used to

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treatment in one patient (No. 7). Among those patients without unilateral renal change, six had follow-up studies within one year. Repeat studies in four patients from 6 months to 4 years after treatment remained negative for unilateral renal change. It seems reasonable to assume that the latent period occurs within one year of the treatment, probably within the first 6 months. Eight patients were found to have developed atrophic changes in the left kidney as demonstrated on 2-hour delayed glucoheptonate renal scan. Once established, atrophic change is irreversible. Of five patients with demonstrable atrophic change followed for more than 5 years, progressive atrophy was seen in three. The most striking change was observed in a patient (No. 3) whose left kidney became rudimentary with almost no uptake 7 years after treatment. The right kidney which was hypertrophic on the first follow-up study, 3 years after treatment, remained hypertrophied (Fig. 2). I- 13 1 perfusion study was impaired in those patients who had atrophic change. In two patients (Nos. 4, 5) however, the first follow-up studies, 13 and 16 months after treatment, revealed only perfusion delay without atrophic change. Subsequent follow-up studies, 2 and 5 years later in one patient, showed the reversal of this abnormality. In the other patient, the repeat study, 17 months later (33 months after treatment), demonstrated recovery of renal perfusion, However, a further 4 years later (7 years after treatment) we then found an impaired

determine whether statistically significant differences between patients and controls were present.

RESULTS Nine of 18 patients were found to have a demonstrable change in the left kidney which had not been present on the evaluation prior to radiotherapy. Seven of these were described in the previous report. I5 Two more patients who developed nephropathy were added to the study. Table 1 illustrates the patient characteristics, individual radiation dose to the kidney and the follow-up renal studies for these nine patients. Figure I graphs the nephropathy cases according to the time-dose relation. The minimum dose to produce nephropathy is 2200 cGy in 59 days (603 ret). Between 2 100 and 3000 cGy, two of nine kidneys (including one right kidney) developed nephropathy. In the 3000-4000 cGy range, there were four nephropathies out of seven irradiated kidneys. Three kidneys which received over 4000 cGy developed nephropathy. Since the initial follow-up renal study was not obtained at a uniform interval after treatment, with the result that some of the studies were obtained quite late, the latent period may not have been determined in this series of patients. However, the initial follow-up studies were obtained within 1.5 years in six patients (Nos. 2, 4, 5, 7, 8, 9) and demonstrable changes were evident by this time. Changes were detected 4 months after the

5000 CGY

4000

0

0

A

0

?? 0

3000

0 0

0 0

0

0

0

0

.

2000

30

40

50

70dWS

60

Fig. I. Total absorbed dose to each left kidney plotted against total treatment

days.

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the patients (2.46 ? 6. I6), and that of the controls (0.83 + 0.36 mg). Thus, these basic estimations oftubular function did not reveal any abnormalities in the patient group. It should be pointed out that the high S.D. of the mean urine beta 2 microglobulin levels in the patient group was due entirely to one value of 18.02 mg. This patient may have had bilateral renal disease in addition to unilateral radiation damage. In contrast, the creatinine clearance of 52 + 16 ml/min and serum beta 2 microglobulin level of 3.67 4 1.86 mg/L were significantly different from the controls p -=z0.001 and p < 0.05 respectively. The mean serum beta 2 microglobulin in the controls was 1.9 f 0.46 mg/L, and the creatinine clearance in this group of controls was 93 t 9 ml/min. These latter findings would indicate that the renal effect of the radiation was to cause chronic endothelial damage either at the arteriolar or the glomerular capillary level rather than causing an interstitial inflammation with consequent tubular damage. Five patients were found to have a moderate elevation of systemic and/or diastolic arterial blood pressure (BP) (Table 2). Three patients required treatment with antihypertensive medication. Malignant hypertension was not observed in any of these patients. In three patients, the BP has been followed for over 6 years. There was no further elevation of BP and it in fact decreased to normal in one patient. Cerebrovascular accidents or other hypertension related problems have not been seen. Apart from hypertension, none of the patients developed clinically overt symptoms or signs related to unilateral or bilateral nephropathy. Three patients died after surviving 3.5 to 6 years. The causes of death were recurrent lymphoma, pancreatic carcinoma and bone marrow failure of undetermined etiology, respectively. The remaining patients are alive and well with a minimum follow-up of 2 1 months and maximum follow-up of 8 years. Only one living patient with initial retroperitoneal presentation has recurrent disease outside the abdomen. DISCUSSION Fig. 2. 99; Tc gluconate delayed renal scan obtained (a) 36 months and (b) 85 months after the treatment (Patient No. 3). The latter scan shows further atrophic change.

perfusion study and atrophic renal changes (Fig. 3). Two more recent patients (Nos. 8 and 9) with follow-up periods of 18 to 20 months also revealed some recovery of the perfusion function (Table 1). In the eight patient group who carried out the urine collections, the mean urine pH after overnight fasting was 5.3 + 0.33, the osmolality on the same specimen was 806 + 67 mOSm/Kg, and the quantitative white cell excretion was 10.626 f 4.16 1 cells/min. None of these values differed significantly from those of the control group 5.85 + 0.6, 918 + 133, and 3,542 + 2,369 respectively. In addition, no significant difference was found between the mean 24-hour urine beta 2 microglobulin excretion of

The dose dependency of radiation nephropathy is well documented in clinical experiences’s.‘7.‘9 and animal experiments.“.‘j.20.2’ While Luxton and Kunkler considered renal tolerance to be 2300 cGy delivered in 5 weeks,‘5.‘9 radiation nephropathy with a lower dose has been reported. 6.27One of our patients developed clearly demonstrable renal atrophy and impairment of perfusion and blood flow when given 2200 cGy delivered over a period of 8V2weeks. Animal experiments suggest that even lower doses (as low as 1500 cGy) produce morphological change in the kidney,“*20*23although their studies used a single exposure instead of multiple fractionation as in the clinical situation. Dose dependency is well demonstrated in our series. Although the number is small, the total absorbed dose appears more important than the treatment duration in the pathogenesis of nephropathy. In most patients, radiation nephropathy is either pro-

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C

Fig. 3. I-l 31 radiohippurate renal perfusion study of patient No. 5 obtained 13 months (A), 25 months (B), and 85 months (C) after the treatment. The left renal function became worse in the last study following some recovery in the second study. Atrophic change is also observed in the last study.

gressive or becomes stabilized after an acute episode,2.‘4.‘7 although Kunkler et al.” reported some clinical improvement in their original series. Since most of our patients were asymptomatic or minimally symptomatic and no histological specimen was obtained, renal function tests have been the sole method. of evaluation. Four patients demonstrated some improvement in renal function. It is Table

Pt no.

2 3 6 I 9

2. The blood pressure changes in patients who develooed hvoertension

Pretreatment 140- 1so/90

140-160/80-96 130/80-96 140/70-80 120-150/60-80

At diagnosis of nephropathy

After 5 years or longer

200/100 180-190/100-110 lSO/lOO-II0 140-150/100-l 10 i40-150/100-i 10 210/100 140-170/70-90 160-210/90-110

particularly interesting that a period of 3 years, or even longer, elapsed in one patient before atrophic change developed. After initial functional impairment and subsequent improvement, one patient with only a perfusion deficit recovered completely and remained well over 6.5 years. The renal function in the remaining patients is either stable or progressively deteriorating. Eight patients were also subjected to detailed renal function studies a variable period after radiotherapy had been completed. In these studies, we looked for abnormalities in glomerular filtration rate using 24-hour creatinine clearances and serum beta 2 microglobulin levels. This latter measurement has been shown to be a more sensitive test than serum creatinine for determining glomerular filtration rate (GFR)25 however, it has its limitations. As far as we are aware, none of these patients had a recurrence of the original lymphoma at the time of study. This factor is relevant when measuring beta 2

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microglobulin levels in serum, as certain neoplastic diseases have shown to elevate the level of this protein independent of changes in GFR.2h Definite abnormalities in both these measurements were present, indicating that the radiation had produced glomerular capillary damage and possibly a reduction in glomerular blood flow by affecting larger vessels. These changes have been well described pathologically.’ Only the left kidney showed changes on renal scanning, and only this side received a dose of radiation greater than 2200 cGy. The right side did in fact receive some radiation, calculated to be less than 1500 cGy in most patients. Thus, we are not able to state categorically that the diminished creatinine clearance in these patients was due to unilateral radiation damage. However, previous studies would suggest that total dose of less than 2000 cGy would be unlikely to reduce GFR.3 Glomerular capillary thickening and changes to the mesangium are the main features of chronic radiation nephritis and clinically likely to be the most important. However, tubular damage also occurs.‘4 Thus we sought for evidence of abnormalities in tubular function by several screening tests. The urine beta 2 microglobulin excretion, a test for disordered proximal tubule function,22 was not different from our control group. When we examined a morning urine specimen after an overnight fast, we found the mean pH of the group was 5.3 +: 0.36 and the osmolality was 806 + 180 mOSm/Kg, suggesting that there would be little likelihood of finding an important distal tubular disorder on more detailed tubular function testing. Furthermore, the fact that these screening tests were carried out several years (range 3 to 8 years, six patients) after completion of radiotherapy suggests that future deterioration would be unlikely. The white cell excretion rate is probably a less useful test, nevertheless, we again did not find any difference between the control and the patient groups, although one patient (No. 7) was excluded because of an active lower urinary tract infection at the time of the investigation. Therefore, we conclude

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that these tests of glomerular and tubular function showed that minor abnormalities in glomerular filtration rate can be demonstrated when only one, or part of one, kidney receives full dose radiotherapy. This seems to be of little clinical consequence apart from an effect on blood pressure. Hypertension remains one of the most notable clinical problems resulting from unilateral radiation nephropathy.5.7.X.Y.‘6.‘ Malignant 4 hypertension which may require nephrectomy has been reported.‘.’ Although blood pressure change was observed in over half of our patients with renal function alteration, this was either medically controlled or no treatment was necessary throughout the entire follow-up period, as the BP either became stable or fell. Nephrectomy was not necessary in any patient. As we reported previously,‘” most of the patients (four of five) had a past history of hypertension even prior to the radiotherapy. We suspect that preexisting hypertension predisposes the patient to nephropathy and that further elevation of blood pressure may be caused by a change in the renal microvasculature. The absolute tolerance dose of renal irradiation is still unclear. When the literature was reviewed, some morphological change could be observed after a quite low dose level. Perhaps there is no absolutely tolerable radiation dose. However the clinical significance can only be determined by observation of patients who develop changes after irradiation. Our experience, based on reasonably long-term follow-up, indicates that the well-being of the patients who developed unilateral radiation nephropathy is not compromised in spite of the mild loss of renal function. Unilateral or partial irradiation of the kidney appears to be justified, especially when the abdominal lymphoma is seen to be controlled in a high percentage of patients over a long period of time. However, exhaustive work-up, careful shielding of the other kidney, and judicious follow-up after the treatment cannot be overstressed.

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Alfrey. A.C.: The renal response to vascular injury. In The Brenner B.M.. and Rector F.C. (Eds.). NY, W.B. Saunders and Co. 1981, pp. 1706-1718. Kidney,

2. Arruda, J.A.L.: Radiation nephritis. Conremporary Issues in Nephrology. Vol. 10. Tubulointersririal Nephropathies,

In Cotran R.S., Brenner B.M., Stein J.H. (Eds.). New York, Edinburgh, London, Melbourne, Churchill Livingstone. 1983, pp. 275-285. 3. Avioli, L.V., Lazor, M.Z., Cotlove, E., Brace, K.C., Andrew% J.R.: Early effects of radiation on renal function in man. Am. J. Med. 34: 329. 1963. 4. Birkhead, B.M., Dobbs, C.E., Beard, M.F., Tyson, J.W.. Fuller. E.A.: Assessment of renal function following irradiation of the intact spleen for Hodgkin’s disease. Radiology 103: 473-47s. 1979. 5. Bloomfield, D.K., Schneider, D.H., Vertes, V.: Renin and angiotension II studies in malignant hypertension after x-

irradiation for seminoma. Ann. Intern. Med. 68: l46- I5 I, 1968. 6. Cogan, M.G., Arieff, A.E.: Radiation nephritis an intravascular coagulation. Clin. Nephrology 10: 74-78, 1978. 7. Cogan, S.R., Ritter, 1.: Radiation nephritis, clinicopathologic correlation of 3 surviving cases. Am. J. Med. 24: 530-534, 1958. 8. Crummy, A.B., Jr., Hellman, S., Stansel, H.C., Hukill, P.B.:

Renal hypertension secondary to unilateral radiation damage relieved by nephrectomy. Radiology 84: lO8- 1 I I, 1965. 9. Dhaliwal, R.S., Adelman, R.D., Turner, E., Ruddo. J.C.. Ruebner, B.: Radiation nephritis with hypertension and hyperreninemia following chemotherapy; cure by nephrectomy. J. Pedial. 96: 68-70, 1980. IO. Fajardo, L.E.: Pathology of Radialion Injury. Urinary System. NY, Masson. 1982, pp. 97-107. l I. Fajardo, L.E., Brown, J.M., Glatstein, E.: Glomerular and

?05V

Radiation nephropathy 0 T. t-1.KIM (‘I(11. juxtaglbmerular lesions in radiation nephropathy. Radiur. Res. 68: 177-183, 1976. 12. Gyory,A.Z., Edwards, K.D.G., Stewart, J.H., Whyte, H.M.: Comprehensive one day renal function testing in man. J. C/in. Palh. 27: 382-391,

1974.

13. Jordan, SW., Yuhas, J.M., Keg, C.R.: Late effects of unilateral radiation on the mouse kidney. Radial. Res. 76: 429-435,

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14. Keane, W.F., Crosson, J.F., Staley, N.A., Anderson, W.R., Shapiro, F.L.: Radiation-induced renal disease. A clinicopathologic study. Am. J. Med. 60: 127-l 37, 1976. 15. Kim, T.H., Freeman, C.R., Webster, J.H.: The significance of unilateral radiation nephropathy. In;. J. Radial. Oncol. Biol. Phys. 6: 1567-1571,

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16. Kosters, S., Birzele, H., Hienz, H.A., Baumbusch, F.: Kidney damages by ionizing radiation. Eur. J. Vrol. 7: 11% 117, 1981. 17. Kunkler, P.B., Farr, R.F., Luxton, R.W.: The limit of renal tolerance to X-rays. Br. J. Radiol. 25: 190-201, 1952. 18. LeBourgeois, J.P., Meignan, M., Parmentier, C., Tubiana, M.: Renal consequence of irradiation of the spleen in lymphoma patients. Br. J. Radiol. 52: 56-60, 1979. 19. Luxton, R.W., Kunkler, P.B.: Radiation nephritis. Acta. Radiol. 2: 169-178,

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20. Madrazo, A.A., Churg, J.: Radiation nephritis. Chronic changes following moderate dose of radiation. Lab. Invexf. 34: 283-290, 1976. 21. Madrazo, A.A., Suzuki, Y., Churg, J.: Radiation nephritis II. Chronic changes after high doses of radiation. Am. J. Pathol. 61: 37-44,

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22. Peterson, P.A., Ervin, P.E., Berggard, I.: Differentiation of glomerular, tubular and normal proteinuria: determinations of urinary excretion of 2 microglobulin, albumin and total protein. J. C/in. Invest. 48: I 189-l 198. 1969. 23. Phillips, T.L., Ross, G.: A quantitative technique for measuring renal damage after irradiation. Radiology 109: 457462, 1973.

24. Shapiro, H.P., Cavallo, T., Cooper, W., Lapenas, D.. Bron, K., Berg, G.: Hypertension in radiation nephritis. Arch. Intern. Med. 137: 848-851, 1977. 25. Shea, P.H., Maher, J.F., Horak, E.: Prediction of glomerular filtration rate by serum creatinine and 2 microglobulins. Nephron. 29: 30-35, 1981. 26. Shuster, J., Gold, T., Poulik, M.D.: Beta 2 microglobulin levels in cancerous and other diseases stated. Clinica. Chim. Acfa 67: 307-313, 1976. 27. Thompson, P.K., MacKay, I.R., Robsen, C.S.M., Wall, A.J.: Later radiation nephritis after gastric x-irradiation for peptic ulcer. Quarl. J. Med. 40: 145- 155, I97 1.