Split renal function of the primarily irradiated kidney and creatinine clearance were found to significantly decrease over time following abdominal chemoradiation. Progressive decline in relative renal function and biochemical endpoints were seen as early as 6 months following completion of radiation. V25 and V40 were shown to correlate with ≥5 % decrease in relative renal function of the primary irradiated kidney at 6-12 months post-radiation.
Figure 2 Representative three-dimensional conformal radiation treatment plan for a patient with locally advanced pancreatic cancer showing the anterior radiation treatment field (A) and isodose distributions (B). The right kidney (in orange) is in close proximity (more ...)
The literature available on progressive change in renal function following abdominal chemoradiotherapy in the treatment of gastrointestinal malignancies is limited. Renal effects of radiation are dose and volume dependent (4)
. Renal tolerances per Emami et al predict the likelihood of normal tissue complications based on volume of tissue irradiated to specific doses (14)
. Current dose tolerance limits do not specifically consider the relative function of each kidney and its contribution to global renal function (14)
Pathophysiologic mechanisms for radiation induced renal injury include glomerular and tubular damage and disruption of renal microvasculature (4)
. Subclinical evidence of renal injury can be observed within 6-12 months following radiation (1)
. A longer latency period is needed for development of symptomatic nephropathy (2)
. Renal toxicity can be detected by functional and biochemical endpoints in advance of presentation of clinical symptoms (5)
Biochemical endpoints such as serum creatinine and creatinine clearance are reflective of global renal function. Serum creatinine is the most commonly used biochemical measure of renal function in clinical practice; however significant decline in glomerular filtration rate can occur prior to rise in creatinine (17)
. Creatinine clearance is an estimate of glomerular filtration rate and a more sensitive measurement of renal function than creatinine (19)
. Creatinine clearance is measured by 24 hour urine collection. An estimated creatinine clearance can be calculated by various formulas including the Cockcroft-Gault equation (15)
. While estimated creatinine clearance is not fully concordant with measured creatinine clearance, such formulas are frequently used in clinical practice as the clinical and laboratory data points needed for calculation are readily available on most patients (20)
Nuclear renography can provide additional clinically relevant information on renal function and can be used to determine glomerular filtration rate and differential renal function (18)
. Renal clearance by scintigraphy is an accurate estimate of glomerular filtration rate and correlates well with creatinine clearance measured by 24 hour urine collection (24)
Assessment of each kidney’s relative contribution to global renal function can be done by both scintigraphy and biochemical endpoints. Techniques for measurement of unilateral creatinine clearance are available but are invasive and not practical for routine use. Correlation between split renal function as determined by renogram and lateralized creatinine clearance has been shown (26)
. Renal scintigraphy can provide accurate quantitative determination of relative renal function less invasively (22)
. The normal range for symmetric split function of each kidney is between 45-55% and changes of ≥5% are considered significant (28)
Renal scintigraphy can detect post radiotherapy renal damage prior to creatinine elevation (17)
. LeBourgeois and colleagues reported their findings on the renal effects of splenic irradiation in lymphoma patients using 197Hg neohydrin scintigrams (33)
. Reduced uptake of radioisotope in the irradiated kidney was detected by the eighth month following radiation, with stabilization after the twentieth month, but not recovery.
Radiation induced injury to the kidney was prospectively studied by Dewit et al using scintigraphic and biochemical endpoints (6)
. Significant progressive renal toxicity was seen following abdominal radiation. In patients who received the highest doses to the entire left kidney, renal function assessed by scintigraphy decreased by 60-70% after 3-5 years whereas creatinine clearance decreased by 20%. In patients in who part of the kidney was shielded, relative renal function decreased by 20-25% at 5 years.
In a prospective analysis of relative renal function and late toxicity in patients with gastric cancer who received postoperative chemoradiation, dose volume parameters for the left kidney were predictive of worse subsequent decline in split renal function (11)
. Jansen et al observed a progressive decline in left renal function with 11% decrease at 6 months and 52% decline at 18 months post-radiation.
In patients with non primary gastrointestinal malignancies treated with chemoradiation, Kost and colleagues prospectively investigated the dose effect on renal damage using functional and biochemical endpoints (9)
. Decline in renal function on static scintigraphy was seen in 23% of patients. The extent of scintigraphic change was related to dose and volume irradiated and changes were observed even at relatively low doses (<10Gy). Decline of the relative contribution of the irradiated kidney to overall renal function was detected at one year post-radiation and progressively decreased to 35-40% at 3 years. The influence of chemotherapy on renal toxicity was not specifically analyzed given small patient numbers and the variety of chemotherapeutic regimens included.
Use of nephrotoxic chemotherapeutic agents such as cisplatin with abdominal radiation has been shown to reduce renal tolerance and potentiate renal toxicity (34)
. All patients in our study received concurrent chemotherapy and most received additional systemic therapy following radiation. As only 10% patients received cisplatin containing regimens, we did not analyze the use of cisplatin as a predictor for subsequent renal dysfunction. Nor did we analyze the influence of other chemotherapeutic agents specifically given the variability of regimens used.
We further evaluated patients who had at least one renogram obtained 6-12 months post-radiation, biochemical data, and dose volume parameters available for factors associated with subsequent decline in split renal function of the primarily irradiated kidney. Of patients identified, three patients demonstrated increases greater than 5% in relative renal function of the primarily irradiated kidney from baseline renogram. This observation is unexpected following radiation and the explanation for increase in split renal function is likely multifactorial. These patients were not included in the subsequent analysis.
In patients with < 5% increase, stable, or decreased split renal function following radiation, no patient related factors were found to be associated with decrease in relative renal function of the primarily irradiated kidney. Treatment related factors significantly associated with decrease of ≥5% relative renal function on univariate analysis included V25 and V40. The mean kidney dose of the primarily irradiated kidney trended toward significance. Although our study was not able to identify other factors associated with decrease in relative renal function following abdominal radiation, it is likely that additional dose volume parameters are involved as they are interrelated. The limited sample size of patients with postradiation renograms available for analysis likely precluded our ability to detect these differences.
Our study is consistent with others in showing progressive decline in renal function as measured by functional scintigraphic imaging and biochemical endpoints (6)
. In contrast to Kost et al who noted decline after one year, we observed decreases in relative renal function and biochemical endpoints as early as 6 months post-radiation.
We observed significant decline in both relative renal function of the primarily irradiated kidney detected on scintigraphy and global renal function as measured by creatinine clearance following abdominal chemoradiation. Post-radiation renography in combination with biochemical measures may allow for early identification and assessment of patients at greater risk for developing clinical manifestations of radiation nephropathy. As radiation induced renal injury is progressive, it is likely that the functional impairments observed in this study will increase over time. With longer follow up, further correlation between changes detected on renal scintigraphy, biochemical endpoints, and radiation dose volume parameters may be observed.