Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

Radiation nephropathy in young and adult rats.

The effects of bilateral kidney irradiation were compared in young and adult rats. During a 1 year period after a single dose of 0, 7.5, 10, 12.5, or 15 Gy on both kidneys, renal function (glomerular filtration rate and effective renal plasma flow), urine composition, and systolic blood pressure were measured periodically. The first changes after irradiation were observed in the glomerular filtration rate and urine osmolality. One month after 10, 12.5, and 15 Gy, glomerular filtration rate (GFR) and urine osmolality had declined below control values in the young rats. After this initial decline, renal function increased at control rate or even more during the third and fourth month after irradiation but decreased progressively thereafter. In the adult rats, GFR and urine osmolality started to decrease 3 months after 10, 12.5, and 15 Gy. A rise in systolic blood pressure and proteinuria started 2-3 months after 12.5 and 15 Gy in both age groups. Early changes in the glomerular filtration rate with a drop in urine osmolality in young rats, occurring during a period of rapid renal development indicated an irradiation-induced inhibition of glomerular and tubular development. Although renal function deteriorated at a later time in adult rats, dose-response relationships obtained in young and adult rats did not show significant differences.

Proteinuria is an early marker in the development of progressive renal failure in hypertensive fawn-hooded rats.

Male spontaneously hypertensive fawn-hooded (FH) rats can be divided into two classes on the basis of their proteinuria. We investigated the relationship between early proteinuria and the impairment of renal function later in life. Urinary protein excretion (UpV), systolic blood pressure (SBP) and parameters of renal function were sequentially determined in male FH rats. A significant difference in UpV was already present from the age of 10 weeks. Class I rats excreted less protein than class II animals. Initially, the glomerular filtration rate (GFR) of class II animals was somewhat higher than that of class I rats, but from week 50 onwards a decrease in GFR of class II rats was noted and from then on rats died due to uraemia. The GFR of class I animals fell from week 75. The fall in GFR was preceded by a concomitant increase in UpV and SBP. The increase occurred earlier and the rate of increase was higher in class II rats. We conclude that a number of hypertensive FH rats die prematurely from end-stage renal failure. The presence of an increased UpV at an early age is an early marker for the development of renal failure.

Prednisolone and posttransplantation hypertension in rat renal allograft recipients.

Rat recipients of renal allografts and unilaterally nephrectomized control rats were studied to evaluate the response in blood pressure to prednisolone in diverse doses, and to determine the dosage required to achieve adequate immunosuppression without undue complication of hypertension. While a continuous infusion of 2 mg/kg/day or more of prednisolone proved effective in prolonging allograft survival time, this dosage increased the blood pressure of recipients as well as unilaterally nephrectomized control rats. In contrast to control rats, the recipients remained hypertensive after the cessation of prednisolone administration. This suggests that the high blood pressure observed during prednisolone administration was due to its hypertensive action. On the other hand, the high blood pressure remaining after cessation of the prednisolone administration is likely to be caused by an incomplete prevention of rejection. If recipients had received a transfusion of donor-strain blood prior to transplantation in combination with the infusion of 2 mg/kg/day or more of prednisolone, they became normotensive when the prednisolone infusion was ceased. By reducing the prednisolone dosage to 1 mg/kg/day in combination with donor-strain blood pretreatment, hypertension could also be eliminated during the first two weeks. In conclusion, effective immuno suppression can be achieved with prednisolone in rats, without inducing hypertension, provided prednisolone is administered at a low dosage in combination with adjuvant immunosuppression--i.e., donor-strain blood pretreatment.

The influence of the recipient upon renal function after isogeneic kidney transplantation in the rat.

Little attention has been paid to the changes in renal function that occur after kidney transplantation when donor and recipient differ markedly in size. We studied this phenomenon after isogeneic kidney transplantation in rats of varying body weight (BW). Renal functional parameters, such as the glomerular filtration rate (GFR), the effective renal plasma flow (ERPF), and the plasma levels of creatinine (Pcr) and urea (Pur) were determined at regular intervals following transplantation. In the initial experimental series, juvenile (BW approximately 150 g) and adult (BW approximately 300 g) rats were used. Four groups of transplant recipients were studied. These consisted of 2 groups of adult recipients of juvenile or adult donor kidneys, and 2 groups of juvenile recipients of juvenile or adult donor kidneys. These 4 groups were compared with adult and juvenile control rats, as well as with unilaterally nephrectomized (NX) rats. A comparison between the 2 groups of juvenile recipients revealed no significant difference in the GFR, ERPF, Pcr, or Pur levels after the transplantation of adult or juvenile donor kidneys. Nor were any significant differences found when comparing the functional parameters of the 2 groups of adult recipients after transplantation of adult or juvenile donor kidneys. The transplanted kidneys generally functioned at a level amounting to 80-90% of the GFR and 90-100% of the ERPF of NX rats of comparable BW. These observations are a clear indication of functional adaptation after kidney transplantation. The compensatory functional response is augmented--in case of a young donor kidney transplanted into an adult recipient, or attenuated--in case of an adult donor kidney transplanted into a juvenile recipient. In an additional experiment, kidneys were transplanted from very young rats (BW approximately 50 g) to adult recipients. It appeared that as early as two weeks after transplantation, renal function had reached adult kidney levels, as observed in the first experimental series. In conclusion, after isogeneic kidney transplantation in rats, the transplanted kidney generally adapts rapidly to the size of the recipient and functions like an inherent part of the recipient's body.

Renal handling of technetium-99m DMSA in rats with proximal tubular dysfunction.

The renal handling of technetium-99m dimercaptosuccinic acid ([99mTc]DMSA) was studied in rats before and after treatment with Na-maleate (2 mmol/kg i.v.). In the control period, when measured 2 hr after the intravenous injection of [99mTc]DMSA, 39.9% of the injected dose was in the kidneys and 14.6% was in the bladder. After Na-maleate treatment, only 6.4% of the injected dose of [99mTc]DMSA was retained in the kidneys while 37.9% was found in the bladder. Subsequent studies revealed that Na-maleate produced a fall in the glomerular filtration rate, the effective renal plasma flow, and a generalized proximal tubular dysfunction. The latter was characterized by polyuria and an increased excretion of glucose, protein, albumin, calcium, and inorganic phosphate. It was concluded that proximal tubular dysfunction markedly alters the renal handling of [99mTc]DMSA. Whether this augmented urinary excretion is due to an inhibition of reabsorption or an enhanced cellular efflux of [99mTc]DMSA remains to be answered.

Interaction of cis-diamminedichloroplatinum and renal irradiation on renal function in the young and adult rat.

The interaction between single low doses of cis-diamminedichloroplatinum(II) (c-DDP) and renal irradiation (7.5, 10, 12.5 Gy) on renal function and systolic blood pressure (SBP) was investigated in young (3-4 weeks old, BW 45-65 g) and adult rats (over 12 weeks old, BW 230-290 g). The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), plasma creatinine, urea and SBP were measured over 24 weeks. Changes in ERPF, plasma creatinine and urea concentrations paralleled GFR changes, but tended to be less pronounced. In young rats, BW and GFR were 10-20% below control values after c-DDP administration (5 mg/kg BW). Irradiation caused a dose-dependent drop in GFR, starting 4 weeks after irradiation in young rats. When c-DDP was given immediately after irradiation to the young rats, the loss of renal function was more pronounced than after either treatment modality alone. Dose-effect curves for a greater than 25% reduction of the GFR relative to controls (ml/min) after 24 weeks gave an ED50 of 9.8 Gy for irradiation alone and 4.6 Gy for irradiation followed by c-DDP. After correction for the drug effect, dose-effect curves were similar for renal irradiation given alone or followed by c-DDP administration in young rats. In adult rats, c-DDP (2.5 mg/kg BW) or irradiation alone did not significantly alter renal function during the follow-up period. Only 12.5 Gy in combination with c-DDP, caused a significant reduction in GFR after 16 weeks in adult rats. In adult rats data were too limited for probit analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

ACE inhibition delays development of terminal renal failure in the presence of severe albuminuria.

The hypertensive fawn-hooded (FHH) rat develops progressive albuminuria (UalbV) and focal glomerulosclerosis (FGS). Early-onset angiotensin-converting enzyme inhibition (ACE-i) completely prevented the development of hypertension, UalbV, and FGS. ACE-i was still effective when the start of treatment was delayed, albeit less than early-onset treatment. In this study, we examined whether more advanced renal damage reduces the efficacy of ACE-i, and, if so, which factors dampen the efficacy. ACE-i was started in 36-week-old FHH rats, and follow-up consisted of regular assessment of systolic blood pressure (SBP) and UalbV. Untreated rats, matched for age, SBP, and UalbV, served as controls. In separate groups, untreated or treated with ACE-i from either week 7 or week 36, glomerular hemodynamics and FGS were determined at week 40. ACE-i normalized SBP and markedly reduced UalbV. The Initial UalbV response to ACE-i was inversely correlated with pretreatment UalbV, but despite control of SBP, UalbV rose again. Eventually, rats died of terminal renal failure. Life expectancy was significantly increased in treated rats. In both untreated and treated rats, there was a significant inverse correlation between baseline UalbV and survival time. However, the gain in survival time decreased when pretreatment UalbV was higher. Late-onset ACE-i reduced glomerular capillary pressure to the same extent as early-onset ACE-i. There was a significant linear correlation between FGS and UalbV. We conclude that in FHH rats with advanced renal damage, ACE-i slows down the progression to terminal renal failure. The outcome is an increased survival time that is inversely correlated with baseline UalbV.

Difference in susceptibility of developing renal damage in normotensive fawn-hooded (FHL) and August x Copenhagen Irish (ACI) rats after N(omega)-nitro-L-arginine methyl ester induced hypertension.

Previous studies using the fawn-hooded hypertensive (FHH) rat have indicated that genetic factors appear to be important in determining the susceptibility to develop renal damage. This was further investigated by comparing the effects of N(omega)-nitro-L-arginine methyl ester (L-NAME) induced hypertension on functional and structural renal damage in two normotensive strains, the resistant August x Copenhagen Irish rat (ACI) and the normotensive fawn-hooded (FHL) rat, which also appears to carry a susceptibility locus for renal failure. Male rats were studied during chronic treatment with L-NAME in either a low dose (LD, 75 to 100 mg/L drinking fluid) or a high dose (HD, 175 to 250 mg/L). Survival of FHL rats was adversely affected by L-NAME treatment. All FHL-HD and 6 of 14 FHL-LD rats died before the end of the 11 weeks of follow-up, whereas all treated ACI rats except for one ACI-HD animal survived. In both strains, L-NAME caused a dose dependent increase in systolic blood pressure (SBP). However, at similar levels of SBP, the increase in albuminuria (UaV) was significantly higher in FHL compared with ACI, as was the incidence of glomerulosclerosis (GS). Both the SBP and the blood pressure burden (SBP-Av), defined as SBP averaged over the period of follow-up, directly correlated with UaV and GS in both strains. However, the increase in the degree of renal damage per millimeter of mercury increase in SBP or SBP-Av was significantly higher in the FHL than in the ACI rats. Our findings clearly show that FHL rats are more susceptible to developing renal damage after induction of hypertension by chronic L-NAME treatment. We conclude that there is an interaction between blood pressure and the genetic susceptibility to renal disease in the FHL rat.

Genetic susceptibility of the donor kidney contributes to the development of renal damage after syngeneic transplantation.

Solitary kidneys, especially in rats, appear vulnerable to develop functional and structural damage. However, differences in susceptibility exist between strains. It is not clear whether this is intrinsic to the kidney or due to environmental factors. Therefore, the aim of the present study was to investigate possible differences in genetic susceptibility for renal damage. By transplanting different rat donor kidneys into a normotensive, histocompatible recipient, the kidneys were exposed to the same blood pressure profiles, metabolic and hormonal environment. Kidneys from young adult hypertensive fawn-hooded (FHH) rats, a strain showing early onset renal damage, normotensive, renal damage-resistant August x Copenhagen-Irish (ACI), and (ACI x FHH) F1 donors were transplanted into male F1 recipients. The native kidneys of the recipients were removed 1 week after transplantation. The results were mutually compared and to their unilaterally nephrectomized littermates. Systolic blood pressure (SBP) and albuminuria (UaV) were determined at the time of transplantation and at 8 and 16 weeks. The histomorphologic analysis included the incidence of focal glomerulosclerosis (FGS), and determination of chronic transplant dysfunction according to the BANFF criteria. A negative impact of the transplantation technique in this syngeneic situation could not be detected as F1 transplants did not differ functionally and morphologically from their UNx controls. Transplanting an ACI kidney did not result in significant changes of SBP, UaV, and incidence of FGS compared to F1 transplants and ACI-UNx. In contrast, FHH kidneys did show a progressive increase of UaV and glomerulosclerosis and a significantly higher BANFF score, whereas the SBP did not differ from F1 transplants. The moderate hypertension seen in FHH did not travel with the kidney. Compared to the FHH-UNx rats, transplantation of a FHH kidney did significantly attenuate the increase of UaV and FGS. The susceptibility of the donor kidney appears to be an important factor in the development of chronic renal damage. This may play a role in the long-term functional changes seen after clinical renal transplantation.

Hypertension after bilateral kidney irradiation in young and adult rats.

The mechanism of a rise in blood pressure after kidney irradiation is unclear but most likely of renal origin. We have investigated the role of the renin-angiotensin system and dietary salt restriction in the development of systolic hypertension after bilateral kidney irradiation in young and adult rats. Three to 12 months after a single X-ray dose of 7.5 or 12.5 Gy to both kidneys of young and adult rats, the systolic blood pressure (SBP) and plasma renin concentration (PRC) were measured regularly. A single X-ray dose of 12.5 Gy caused a moderate rise in SBP and a slight reduction in PRC in both young and adult rats. A dose of 7.5 Gy did not significantly alter the SBP or PRC during the follow-up period of 1 year. In a second experiment, the kidneys of young rats received an X-ray dose of 20 Gy. Subsequently, rats were kept on a standard diet (110 mmol sodium/kg) or a sodium-poor diet (10 mmol sodium/kg). On both diets, SBP started to rise rapidly 3 months after kidney irradiation. Sodium balance studies carried out at that time revealed an increased sodium retention in the irradiated rats compared to controls on the same diet. In rats on a low sodium intake, there was neither a delay nor an alleviation in the development of hypertension. Compared to controls, the PRC tended to be lower in irradiated rats up to 4 months after irradiation. Subsequently, malignant hypertension developed in all 20 Gy rats, resulting in pressure natriuresis, stimulating the renin-angiotensin system. Our findings indicated that hypertension after bilateral kidney irradiation was not primarily the result of an activation of the renin-angiotensin system. Although there were some indications that sodium retention played a role, dietary sodium restriction did not influence the development of hypertension.

The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

Partial ureteral obstruction: role of renal resistive index in stages of obstruction and release.

OBJECTIVES: To study the changes in renal resistive index (RI) and renal function before and after release of different grades of partial unilateral ureteral obstructions. METHODS: Ten dogs were subjected to right partial ureteral obstruction. Grade 1 (mild) obstruction was applied to 5 dogs (group A) and grade 3 (moderate and severe) obstruction was applied to the other 5 dogs (group B). Obstruction was maintained for 8 weeks, followed by release of obstruction. All dogs were subjected to excretory urography, technetium-99m mercaptoacetyltriglycine diuretic renography with calculation of half-time drainage (T1/2), and bilateral renal Doppler ultrasonography before the start of the experiment, after 8 weeks of obstruction, and every 2 weeks during the 8 weeks after release of obstruction. RESULTS: In both groups, after induction of right ureteral obstruction, there was a dramatic decrease of effective renal plasma flow (ERPF), increase of RI, and increase of T1/2 of the right kidney. Relief of obstruction was associated with normalization of T1/2, reversal of RI, and recovery of ERPF to near basal values. No correlation was found between ERPF at the end of the recovery period and the functional parameters (T1/2, RI, or ERPF) of the obstructed kidney before release of obstruction. CONCLUSIONS: (1) Unilateral partial ureteral obstruction produces an elevation of RI and T1/2 and a fall in ERPF of the corresponding kidney. (2) After relief of function is regained with associated reversal of RI. (3) Functional parameters (T1/2, RI, or ERPF) of the obstructed kidney do not predict the recovery of ERPF after release of obstruction. (4) Rapid reversal of a previously elevated RI is an early indicator of recoverability of renal function after relief of ureteral obstruction.

Renal Doppler ultrasound in children with normal upper urinary tracts: effect of fasting, hydration with normal saline, and furosemide administration.

OBJECTIVES: To study the age dependency of renal resistive index (RI) and to study the effect on the renal RI of fasting, intravenous infusion of normal saline, and administration of furosemide in children with normal upper urinary tracts. METHODS: The study included 28 nonobstructed renal units in 15 boys ranging in age from 3 to 11 years. Diuretic renography and Doppler ultrasonography were attempted in all children. Doppler ultrasonography was carried out under three different conditions: fasting state, 30 to 60 minutes after intravenous infusion of normal saline (15 mL/kg), and 10 minutes after administration of furosemide (1 mg/kg; maximum, 40 mg). RESULTS: There was an inverse correlation between age and RI of both renal units under the three conditions of Doppler studies. At fasting state mean RI was 0.70 +/- 0.04, whereas 15 of 28 renal units (54%) had an RI of 0.70 or higher. Intravenous infusion of normal saline significantly decreased the RI to 0.63 +/- 0.04 (P < 0.000001). Injection of furosemide caused a further significant decrease of RI from 0.63 +/- 0.04 to 0.60 +/- 0.04 (P < 0.002). CONCLUSIONS: The renal RI in healthy children is age dependent. In the fasting state, 54% of nonobstructed renal units in children have an RI of 0.70 or higher. Intravenous infusion of normal saline and administration of furosemide can independently cause a significant decrease of the RI in nonobstructed renal units in children.

Potentiation of cis-diamminedichloroplatinum nephrotoxicity by amikacin in rats.

The nephrotoxic interaction between cis-diamminedichloroplatinum (CDDP) and amikacin (AMI) was studied in rats. Following a single dose of CDDP (5 mg/kg i.v.), AMI (60 mg/kg s.c.) was given for 14 days. When given alone CDDP caused a 40% fall in the glomerular filtration rate (GFR), whereas AMI alone had no effect on GFR. This nonnephrotoxic course of AMI potentiated the CDDP-induced fall in GFR. Only a limited recovery of renal function was observed during a 15-week follow-up period.

The effect of prostaglandin synthesis inhibition of the acute blood pressure reduction by captopril in pentobarbital-anaesthetized rats.

Treatment of pentobarbital-anaesthetized rats with captopril (SQ 14225) caused a reduction in mean arterial blood pressure (MAP), which lasted for over 1 h when a dose of 5 mg/kg i.p was used. Pretreatment with the prostaglandin synthesis inhibitors indometacin (IND, 5 mg/kg i.p.) or acetylsalicylic acid (ASA, 100 mg/kg i.p.) did not prevent the initial decrease in MAP after captopril. However, the recovery of the MAP was much faster than after captopril alone. In rats pretreated with IND, the MAP after captopril was significantly higher than after captopril alone from 30 min onwards. With ASA pretreatment the same was observed after 45 min. These data indicate that the subacute blood pressure lowering effect of captopril in pentobarbital-anaesthetized normotensive rats may be at least partly dependent on the presence on an intact prostaglandin biosynthetic pathway. This may be due to activation of prostaglandin synthesis by the accumulation of bradykinin and angiotensin I after captopril.

Nephrotoxicity of cyclosporine A in rats with a diminished renal function.

We have studied the effect of cyclosporine A (CyA) in male Wistar rats with only one kidney, that had been subjected to 45 min of warm ischemia (IS + NX). The effects were compared with those obtained in rats with either one (NX) or two intact kidneys (2K). Vehicle treated rats that underwent the same surgical procedure served as controls. The GFR and the ERPF were determined during and after the treatment period. The CyA was administered i.m. daily for a period of 5 days a week for a period of 4 weeks. The dosages were 15, 30, or 60 mg/kg/day in the short-term study, and 15 mg/kg/day in the long-term study. With only 5 days of treatment, changes in the GFR induced by CyA were more pronounced in IS + NX rats when compared with NX rats. Furthermore, in contrast with NX rats, the GFR did not completely recover in IS + NX rats. During the 4 week treatment we found that in all 3 models the GFR was less in the CyA treated rats than in the vehicle treated rats. The degree of impairment of the GFR differed in the various models. At the end of the treatment period, the GFR of the CyA treated rats (expressed as a percentage of the vehicle treated rats) amounted to 84% in 2K rats, 64% in NX rats, and 46% in IS + NX rats. After cessation of the CyA administration, there was a complete recovery of the GFR to control levels in 2K and NX rats. In IS + NX rats, however, the GFR remained significantly below that of vehicle treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential changes in relative liver function assessed by 99mTc-HIDA scintigraphy after auxiliary heterotopic liver transplantation in dogs.

Auxiliary heterotopic liver transplantation (HLT) was used to achieve functional repair in a dog model with an inborn error of metabolism. For the interpretation of the results, information on separate liver function is essential when a normal host liver is also present. We developed a radionuclear method to quantitate the relative contribution of each liver to the total uptake of intravenously (IV) injected 99mTc-HIDA. The HLT was performed between 20 mismatched pairs of dogs from two different strains. Four surgical procedures were used. After autopsy the outcome of the premortem HIDA-scan was compared with the wet weight of the graft and the host liver. A good linear correlation was noted between the relative contribution of the uptake and weight of the graft to the total HIDA uptake and total liver weight. Therefore, the relative contribution of an auxiliary heterotopic liver graft to the total liver function can be quantitated with a 99mTc-HIDA scan. With this technique, changes in relative function after an HLT under various flow conditions can be sequentially followed.

Influence of the recipient's size upon renal function following kidney transplantation. An experimental and clinical investigation.

The influence of the size of the recipient upon posttransplantation renal function was investigated in an experimental study of inbred rats as well as in a retrospective analysis of juvenile recipients of adult donor kidneys. The experimental study revealed either augmentation of the compensatory response, in case of a juvenile donor kidney transplanted into an adult recipient, or attenuation of this response, in case of an adult donor kidney transplanted into a juvenile recipient. Various workers have reported an augmentation of renal function in humans in case of adult recipients of juvenile donor kidneys. In contrast, attenuation of renal function in case of adult donor kidneys transplanted into juvenile recipients, has not been reported. This attenuation was substantiated in our retrospective clinical study. We found that 3 weeks after transplantation, the absolute creatinine clearance (mL/min) was lower in a group of recipients under 12 years old than in a group of recipients older than 12 years. The experimental as well as the clinical investigation indicated that the size of the recipient plays an important part in the functional outcome after renal transplantation. It appeared that the transplanted kidney behaves like a single organ pertaining to the recipient.

Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog.

BACKGROUND/PURPOSE: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model. METHODS: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver. RESULTS: Metabolic correction increased in all groups after transplantation from 0.19 +/- 0.02 to 0.70 +/- 0.05 (P< .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 +/- 27 and 144 +/- 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 +/- 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 +/- 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect. CONCLUSION: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow.