Differentiation of cell-mediated and humoral rejection by orthoiodohippurate kinetics.

The differentiation of two types of renal graft rejection may be made early in incipient stages by means of a comprehensive renal function study. In the acute cell-mediated form, prolongation of orthoiodohippurate renal transit time as reflected in a diminished excretory index (El) is first observed, followed by a diminution in the effective renal plasma flow (ERPF). On reversal of the process, El precedes ERPF in returning to normal. In chronic humoral rejection, the principle feature is simple reduction of ERPF; transit time within the kidney appears normal. No reversal processes have been observed, although the process may be decelerated. At approximately 100 ml/min ERPF, these kidneys may undergo an acceleration of the clinical failure with rapid deterioration in El and in ERPF. At this point, surgical removal of the kidney has been carried out.

On the mechanism by which chloride corrects metabolic alkalosis in man.

To determine whether administration of chloride corrects chloride-depletion metabolic alkalosis (CDA) by correction of plasma volume contraction and restoration of glomerular filtration rate or by an independent effect of chloride repletion, CDA was produced in normal men by the administration of furosemide and maintained by restriction of dietary sodium chloride intake. Negative sodium balance (-112 +/- 16 meq) and reduced plasma volume (2.53 versus 2.93 liters, p less than 0.05) developed. The cumulative chloride deficit of 271 +/- 16 meq was then repleted by oral potassium chloride (267 +/- 19 meq) over 36 hours with continued serial measurements of glomerular filtration rate, effective renal plasma flow, plasma volume, body weight, and plasma renin and aldosterone levels. CDA was corrected, even though body weight, plasma volume, glomerular filtration rate, and renal plasma flow all remained reduced and plasma aldosterone was elevated; urinary bicarbonate excretion increased during correction. Administration of an identical potassium chloride load to similarly sodium-depleted but not chloride-depleted normal subjects produced no change in acid-base status. It is concluded that chloride repletion can correct CDA by a renal mechanism without restoring plasma volume or glomerular filtration rate or by altering sodium avidity.

Comparison of single-injection multisample renal clearance methods with and without urine collection.

UNLABELLED: Single-injection renal clearance methods based on plasma clearance alone, without urine collection, are sometimes met with skepticism. They require data extrapolation to infinite time, which is hard to justify a priori. It has been asserted that they are less accurate for rapidly cleared tubular agents than for slowly cleared glomerular filtration rate agents. In this study, we compare urine-based and urine-free methods for the tubular agents 99mTc-MAG3 and 131I-OIH. METHODS: In 18 patients, dual-tracer plasma data were obtained from 4 to 90 min after injection (nine samples). Urine was also collected for 90 min (in two voidings). The urine counts wre corrected for residual bladder activity by pre- and postvoid dual-channel gamma camera images. RESULTS: When comparing the two methods of clearance calculations, the difference between urine-based and urine-free measurements 1 +/- 5 ml/min for 99mTc-MAG3 and 23 +/- 8 for 131I-OIH (mean +/- s.e. of the mean). For 99mTc-MAG3, the regression line did not differ significantly from the line of identity. The correlation coefficient was 0.94 for both agents. CONCLUSION: Urine collection is not necessary to measure renal clearance, even for the rapidly cleared tubular agents, except at low clearance levels (when the small absolute error corresponds to a large percentage error).

Reproducibility of single-sample clearance of 99mTc-mercaptoacetyltriglycine and 131I-orthoiodohippurate.

UNLABELLED: Recent literature has questioned whether 99mTc-mercaptoacetyltriglycine (MAG3) clearance measurements are reproducible enough for routine clinical monitoring of renal function. For many years, we have routinely followed the renal function of patients with spinal cord injuries using a combination of radionuclide imaging and clearance measurement. METHODS: In this study, we retrospectively review 1626 effective renal plasma flow (ERPF) measurements in 197 patients with paraplegia or quadriplegia performed over a 21-y period, using 131I-orthoiodohippurate (OIH) through 1990 and MAG3 since 1991. MAG3 clearance was divided by 0.53 to convert it to ERPF. Reproducibility was measured as pooled SD from the single-patient linear regression lines of ERPF versus time. RESULTS AND CONCLUSION: There was no significant difference between MAG3 (SD = 46 mL/min, n = 907) and OIH (SD = 52 mL/min, n = 719). The data were therefore combined to obtain the SD for a single ERPF measurement, which was 49 mL/min. The corresponding coefficient of variation was 8.5% of the mean value of 581 mL/min. In our experience, this is adequate for monitoring the renal function of these patients.

Measurement of renal function with radionuclides.

For the nuclear physician who wants to measure renal function, the biggest problem may be having to choose among the dozens of methods that have been proposed. An overview will be presented here. The final selection must depend upon the needs of each clinic as well as its technical and financial resources. Except at very low levels of renal function, almost any of these methods can be more reliable than creatinine clearance.

Quantitation of renal parenchymal retention of technetium-99m-MAG3 in renal transplants.

UNLABELLED: When imaging renal transplants with tubular agents, such as mercaptoacetyltriglycine, marked parenchymal retention is a hallmark of acute rejection (AR) or acute tubular necrosis (ATN). (AR can be distinguished from ATN by the time course on serial studies.) The quantitative relationship of retention to uptake can be measured by dividing the background-corrected renal activity at 20 min by that at 3 min. METHODS: The diagnostic value of this ratio (R20/3) was tested in a series of 555 renograms. Because patients with mild disease have minimal abnormalities, the patients were ranked by their estimated severity of disease (1-4 for abnormal and 0 for normal). RESULTS: R20/3 was found to correlate strongly with severity of ATN (Spearman's rho = 0.879, p < 0.001, n = 168) and also with severity of AR (rho = 0.888, p < 0.001, n = 267). There were two (3%) false-positive results in 64 normal patients. CONCLUSION: If 0.8 is taken as the upper limit of normal for R20/3, then among patients with disease severity 3 or 4, there were no false-negative findings in 104 patients with ATN or in 203 patients with AR. R20/3, despite its simplicity, is an effective diagnostic parameter.

Simplified methods for renal clearance in children: scaling for patient size.

Development and validation of simplified renal clearance methods has required a research data base of multiple blood samples drawn over a substantial time interval, which is difficult to obtain for children. While the medical risks entailed in drawing multiple samples may be negligible, the problems of parental and institutional consent make such studies more difficult in the pediatric population. Scaling for patient size permits combining data from patients of different age and limits the number of studies required. A scaling technique is presented and evaluated here. With scaling, adult data can be used successfully to predict pediatric responses and to develop pediatric methods based on adult data alone. Inclusion of pediatric data improves the fit and permits development of generic methods that work with both adults and children.

Renal transplant hypertension caused by iliac artery stenosis.

A captopril renal study performed with both radiohippuran and 99mTc-MAG3 demonstrated the typical changes of a hemodynamically significant renal artery stenosis in a hypertensive renal allograft recipient. Arteriography demonstrated high grade stenosis not of the renal artery but of the iliac artery. After successful angioplasty, the patient's hypertension resolved.

Measurement of renal function with technetium-99m-MAG3 in children and adults.

UNLABELLED: A single-injection, single-sample procedure for measuring 99mTc-MAG3 clearance is presented that incorporates scaling for patient size and is valid for both children and adults. METHODS: The procedure is based on an empirical formula in which all measurements are expressed in dimensionless combinations. The formula was obtained by fitting data collected from 122 adults and 80 children at several centers. RESULTS: All results were scaled to standard adult surface area and are presented in units of ml/min/1.73 m2. For adult subjects, the residual standard deviation (r.s.d.) calculated from a single sample at 45 min was found to be 23, using the plasma clearance calculated from a multi-sample clearance curve as a reference. This did not differ significantly from the value of 22 obtained with our previous formula, which was valid for adults only. For pediatric subjects, an r.s.d. of 24 was calculated by the new formula from a single sample at 35 min; a comparable value of 33 was found using a pediatric formula previously published. CONCLUSION: The new clearance formula is recommended as a replacement for the formula we previously published, since it is based on a larger and more diverse subject population, and since it now holds for children as well, with no loss of accuracy for adult subjects.

Prediction of urinary excretion of technetium-99m-MAG3.

UNLABELLED: The urinary excretion of 99mTc-mercaptotriacetylglycine (MAG3), like that of 131I-orthoiodohippurate (OIH), can be used to identify acute renal transplant rejection and measure its severity. This parameter is often quantitated as the excretory index (observed excretion/predicted excretion). A new method for predicting the urinary excretion of 99mTc-MAG3 is presented. METHODS: The expected excretion was calculated from multisample plasma time-activity curves in 122 subjects, with correction for the first pass of the initial bolus. The resulting formula was tested prospectively against actual urine measurements in an additional 466 subjects. RESULTS: Least-squares fitting led to the following equation: Predicted excretion = 0.79(1-exp(-0.0066CMAG3), with residual s.d. 0.06, where CMAG3 is MAG3 clearance in ml/min and the predicted excretion is expressed as a fraction of the administered dose. Tested prospectively in the additional 466 subjects, the s.d. was 0.09. CONCLUSION: A new formula to predict the urinary excretion of 99mTc-MAG3 has been developed and prospectively validated. Based on our data, the normal range for the excretory index using MAG3 is the same as that of 131I-OIH, 0.8-1.2.

Estimation of extracellular fluid volume from plasma clearance on technetium-99m DTPA by a single-injection, two-sample method.

A simple method is presented for estimating extracellular fluid volume from the plasma clearance of [99mTc])DTPA or [169Yb]DTPA. Two plasma samples are required, at 1 and 3 hr, following a single intravenous injection. (The same plasma samples can be used for measurement of glomerular filtration rate.) Using the complete plasma clearance curve as a reference (eight samples at 10 to 240 min), the error of the two-sample method in 40 patients was 1.5 I for [99mTc]DTPA, 2.1 I for [169Yb]DTPA (residual standard deviation).

Quantitation of renal function with technetium-99m MAG3.

The technetium-labeled hippuran analog [99mTc]MAG3 was compared with [131I]hippuran in 50 patients using a quantitative renal function protocol that includes: (a) estimation of effective renal plasma flow by a single-injection, single-sample plasma clearance method, (b) determination of relative function of right and left kidney from the initial count rate over each kidney, and (c) comparison of recovered urine activity with plasma disappearance. This protocol is suitable for routine clinical use, and, in fact, has been used heavily at our clinic for a number of years. By slight modification of the formulas, the results obtained with [99mTc]MAG3 agreed well with those using [131I]hippuran. We conclude that [99mTc]MAG3 can be substituted for [131I]hippuran in the quantitative protocol, with the better image quality and lower radiation dose (in abnormals) of a technetium-labeled agent.

Abnormal captopril renogram with a technetium-99m-labeled hippuran analog.

A case of renovascular hypertension is presented in which the [131I]hippuran renogram was initially normal, but became strikingly abnormal upon administration of the angiotensin converting enzyme (ACE) inhibitor captopril. The patient presented with fibromuscular dysplasia of the renal arteries, which was shown by hippuran renography to be functionally significant on the right side. She became normotensive after angioplasty of the right renal artery. Hypertension recurred a year later, at which time the renogram was normal without captopril, but showed functionally significant left renal artery stenosis with captopril challenge. Both the conventional agent, [131I]hippuran, and an experimental new 99mTc-labeled hippuran analog, [99mTc]MAG3, were used. Angiography confirmed progression of disease on the left side, which was successfully treated by angioplasty. Functionally significant unilateral renal artery stenosis was thus demonstrated first on the right side and then, 1 yr later, on the left side, using hippuran and [99mTc]MAG3. Anatomic progression of disease was documented by angiography.

Comparison of technetium-99m MAG3 with iodine-131 hippuran by a simultaneous dual channel technique.

Technetium-99m MAG3, a technetium-labeled analog of hippuran, was compared with [131I] hippuran using a simultaneous dual isotope study in 20 patients. The plasma clearance for MAG3 was lower than that of hippuran, but its plasma concentration was higher, resulting in similar rates of excretion and similar renal time-activity curves. Apart from better statistics with the technetium-labeled agent, there were no clinically significant differences in this group of patients.

Value of gallium-67 citrate scanning in Crohn's disease: concise communication.

A frequent problem in Crohn's disease is the distinction between exacerbated inflammation of the bowel, which can be treated medically, and intra-abdominal abscess, a common complication that requires surgical management. We present evidence that the gallium scan is of value in making this distinction. From a series of 11 studies, negative gallium scans correctly excluded abscess in over half. All patients were symptomatic at the time of the scan. Most patients with active Crohn's disease do not have abnormal gallium uptake and in these patients the gallium scan is useful to exclude the possibility of abscess.

Comprehensive evaluation of renal function in the transplanted kidney.

By means of a comprehensive renal function test based on the analysis of orthoidohippurate kinetics carried out 223 times in 86 renal transplatn patients, we have been able to separate clearly five clinical entities: normally functioning transplanted kidneys, acute tubular necrosis, cell-mediated rejection, humoral (chromin) rejection, and postrenal obstruction. Accurate prediction of the fate of the rejecting kidney can be made while still subclinical as much as a week before manifestations by other techniques are evident. Data on 22 donors studied 44 times are also presented. The comprehensive test consists of measurements of effective renal plasma flow (ERPF), sequential scintigraphy, calculations of excretory index (EI) (percent dose actually found in bladder and voided urine as a fraction of the percent dose expected at a given time after injection at the patient's specific ERPF), and residual urine volume. Formulas and regression equations for the calculation of ERPF, EI, residual urine, etc., are presented.

Prediction of renal transplant survival from early postoperative radioisotope studies.

UNLABELLED: It has been routine at the University of Alabama Medical Center to obtain a radionuclide renal function study immediately after transplantation (usually within 3 d) that includes estimation of effective renal plasma flow (ERPF) from a single plasma sample in addition to imaging. We present here the correlation between baseline measurements and the 1-y graft survival. METHODS: Two cohort years were reviewed: 1988, when 131I-orthoiodohippurate (OIH) was used; and 1995, when 99mTc-mercaptoacetyltriglycine (MAG3) was used. ERPF was measured concurrently with gamma-camera imaging by previously published single-injection, single-sample methods (converting MAG3 clearance to ERPF by means of a correction factor). RESULTS: Graft survival during the first postoperative year improved significantly in the interval between cohort years, from 74% of 147 cadaver (CD) grafts in 1988 to 91% of 200 CD grafts in 1995 (log rank test, P < 0.05). In contrast, for living related donor (LRD) grafts there was no significant change, from 91% of 66 in 1988 to 91% of 83 in 1995. The baseline ERPF was a significant predictor of graft survival in both 1988 and 1995 (Wilcoxon test, P > 0.05). For LRD grafts the association was not significant in either year. Using MAG3 (1995), the peak time and the ratio of counting rate (R) at 20 min to that at 3 min (R20:3) were also significant predictors for CD graft survival. Using OIH (1988 cohort), the correlation with peak time did not reach significance, and the R20:3 measurement was not available. Although multivariate combinations (Cox proportional hazards model) did not have significantly more predictive value at the 95% confidence level than ERPF or R20:3 alone, some statisticians suggest a 75% confidence level for adding an additional covariate to a multivariate model. Use of this level led to a model including both ERPF and R20:3. CONCLUSION: Single-sample ERPF measured in the immediate post-transplant period, whether from OIH clearance or MAG3 clearance, was a statistical predictor of graft survival for CD transplants. For MAG3, the peak time and R20:3 were also significant predictors. These associations held only for CD transplants and not for LRD transplants.

Quality control of Tc-99m DTPA for measurement of glomerular filtration: concise communication.

When technetium-99m DTPA is used to measure glomerular filtration rate (GFR), the accuracy depends on the supplier of the radiopharmaceutical. The error in GFR is due to protein binding, as we have shown by direct measurement. In 19 patients, GFR measured with Tc-DTPA and corrected for protein binding agreed with that measured simultaneously using Yb-169 DTPA (correlation coefficient 0.991). Without correction, Tc-DTPA gave falsely low values in patients having good renal function, in whom unbound activity cleared rapidly while bound activity remained in the circulation. When Tc-DTPA is used to measure GFR, the in vivo protein binding should be measured and used to correct the data.

Measurement of glomerular filtration rate: single injection plasma clearance method without urine collection.

Glomerular filtration rate (GFR) can be calculated from the plasma clearance of any of several radiopharmaceuticals that are excreted by glomerular filtration. Simplified methods have been proposed that require only one or two plasma samples in lieu of a more complete clearance curve. We examined the error introduced by this simplification. Forty patients were studied using a dual-isotope technique employing [99mTc]DTPA and [169Yb]DTPA, obtaining eight plasma samples for each clearance curve at intervals from 10 to 240 min after injection. Data were fit to several empirical or semiempirical formulae and also to a two-compartment computer model that permitted GFR estimation from only one or two data points. The computer model gave good fit, but so did several simpler methods. The error that results from replacing the complete clearance curve by a single 3-hr sample was about 8 ml/min (residual s.d.). By using two samples (at 1 and 3 hr), the error could be reduced to 4 ml/min. Recommended one- and two-sample methods are presented.

Radionuclide evaluation of renal transplants.

In this review article, the following topics are treated: the radiopharmaceuticals 99mTc-diethylenetriaminepentaacetic acid (DTPA), 131I-orthoiodohippurate (OIH), 99mTc-mercaptoacetyltriglycine (MAG3), 67Ga-citrate, radioiodinated fibrinogen, 99mTc-sulfur colloid, 111In-labelled white cells and platelets; gamma camera methods based on images, on first pass and on tubular transit; blood clearance methods; and the diagnosis of surgical complications, acute rejection (AR), acute tubular necrosis (ATN), chronic rejection (CR), and cyclosporine-A (CYA) toxicity.