Tacrolimus decreases tubular phosphate wasting in renal allograft recipients

The aim of the study was to elucidate whether cyclosporine- and tacrolimus-based immunosuppression impairs tubular reabsorption of phosphate after kidney transplantation. Sixty cadaveric allograft recipients were included in the study. Forty patients receiving triple immunosupression with cyclosporine, azathioprine, and prednisone were studied for 1, 6, 12 months (groups A1 and A2, 20 patients) and for 24, 30, and 36 months (groups B1 and B2, 20 patients) after transplantation. Twenty patients who received tacrolimus with steroid withdrawal after 3 months were included in the study (group C). Recipients from groups A2 and B2 were treated additionally with vitamin D and calcium carbonate. Serum iPTH, 25-OHD, 1.25(OH)(2)D concentrations were determined, and TRP (mmol/L) and TmP/GFR (mmol/L) were calculated using Walton-Bijvoet nomogram. Higher values of total calcium serum concentration in group A were detected. Lower inorganic phosphate serum concentrations were detected in groups A and C, in contrast to group B where they remained within normal values. TmP/GFR values were significantly higher in group C in the first and third examination in comparison with patients of group A. Moreover, TRP index values were significantly higher than analogous values of groups A and B. Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared to cyclosporine-treated recipients. No correlation between iPTH, 25-OHD, 1,25(OH)(2)D concentration, and tubular dysfunction parameters was observed. Amelioration of phosphate handling, in spite of hyperparathyroidism intensity, can follow early steroid avoidance.     

Conversion from sirolimus to everolimus in maintenance renal transplant recipients within a calcineurin inhibitor-free regimen: results of a 6-month pilot study

AIM: To provide data on conversion of kidney transplant patients from sirolimus to everolimus. MATERIALS AND METHODS: In this 6-month prospective, open-label pilot study, maintenance renal transplant patients receiving sirolimus, mycophenolic acid and corticosteroids without concomitant calcineurin inhibitor (CNI) therapy were converted to everolimus 8 mg/day (8 - 15 ng/ml), and followed for 6 months. Mycophenolic acid and corticosteroid therapy were continued unchanged. Patients with acute rejection within the previous 3 months were excluded. RESULTS: 11 patients were recruited and completed the study (mean 5.1 +/- 1.8 years post transplant). Mean everolimus trough level remained within target throughout the study. Mean GFR remained stable (Day 0, 48.4 +/- 8.4 ml/min/1.73 m2, Month 6, 49.5 +/- 17.3 ml/ min/1.73 m2 (p = 0.966), as did mean renal phosphate threshold (TmPO4/GFR) (Day 0, 0.41 +/- 0.15 mmol/l, Month 6, 0.40 +/- 0.17 mmol/l (p = 0.966)). Serum phosphates increased significantly from 0.71 to 0.77 mmol/l (p = 0.01), but tubular reabsorption of phosphates and 24-h phosphaturia remained unchanged and mean PTH concentration tended to decrease. No patient died, lost their graft or experienced biopsy-proven acute rejection after conversion. There were no cases of CMV infection. Tolerability remained similar post conversion. Hematological and lipid parameters remained stable. Liver enzymes and sex hormones remained within normal ranges. CONCLUSION: This pilot study suggests that converting kidney transplant patients receiving CNI-free maintenance immunosuppression from sirolimus to everolimus, at relatively high exposure levels, is safe and easily manageable. There was no consistent evidence for a change in GFR or proximal tubular function.     

Why do preemptive kidney transplant recipients have an allograft survival advantage?

BACKGROUND: Preemptive kidney transplantation is associated with an allograft survival advantage and is promoted in part because of this association. The basis for the allograft survival advantage in preemptive recipients is unclear. Possibilities include a lead time bias due to the earlier transplantation of patients with preserved native kidney function, less rapid loss of kidney function after transplantation, or the longer patient survival of preemptive recipients. METHODS: We compared the glomerular filtration rate (GFR) six months after transplantation and the subsequent rate of loss of kidney function as defined by the annualized change in GFR (mL/min/1.73 m2/year) in 5,966 preemptive and 34,997 non-preemptive recipients. Linear regression methods were applied to serial GFR estimates after transplantation to determine the annualized change in GFR. Multiple regression was used to determine the independent effect of preemptive transplantation upon the annualized change in GFR. RESULTS: The mean GFR six months after transplantation was similar among preemptive (49.5+/-15.7 mL/min/1.73 m2) and non-preemptive (49.2+/-14.7 mL/min/1.73 m2) recipients (P=0.37). In multivariate analysis, preemptive recipients had a slower decline in GFR (0.28 mL/min/year/1.73 m2; 95% confidence interval 0.11, 0.46; P=0.002). However, this difference was of modest clinical significance and would not explain the allograft survival advantage of preemptive transplantation. CONCLUSIONS: Neither the preservation of native kidney function nor differences in the rate of loss of kidney function explain the superior allograft survival of preemptive recipients. By exclusion, the allograft survival advantage associated with preemptive transplantation may be due to the longer survival of preemptive recipients.     

Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression.

BACKGROUND: Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients. METHODS: Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B). RESULTS: Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls. CONCLUSION: These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation.     

Assessment of glomerular and tubular functions in renal transplant patients receiving cyclosporine A in combination with either sirolimus or everolimus

AIMS: The aim of this study was to examine the glomerular filtration rate (GFR) and tubular function at three months after renal transplantation in two groups of patients receiving cyclosporine A associated with either sirolimus (SRL) (n = 18) or everolimus (RAD) (n = 12), two structurally similar immunosuppressant drugs. RESULTS: Donors' and recipients' characteristics and mean cyclosporine A trough levels were similar in the two groups. The mean sirolimus trough level was 12.01 +/- 1.6 ng/ml whereas the mean everolimus trough level was 4.23 +/- 0.36 ng/ml. GFR, equated by the clearance of inulin, was higher in RAD patients (64 +/- 4 ml. min- 1.1.73 m(-2)) than in SRL patients (49 +/- 4 ml.min(-1) .1.73 m(-2)) (p < 0.05). The significant difference in GFR between the groups was not affected by differences in mean arterial blood pressures, or by differences in daily prednisone dosages, cyclosporine trough levels, or SRL and RAD trough levels. Phosphatemia, renal phosphate threshold (TmPO4/ GFR ratio) and uric acid clearance were significantly lower in the SRL than in the RAD group, despite similar levels of parathyroid hormone. Finally, urinary acid excretion was significantly lower in the RAD group. CONCLUSION: In conclusion, regarding nephrotoxicity, our preliminary data suggest that it seems to be preferable to combine cyclosporine with RAD rather than with sirolimus in renal transplant patients. However, long-term renal effects of this combination are still to be determined in a larger cohort.     

Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

BACKGROUND: Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. METHODS: CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. RESULTS: In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. CONCLUSIONS: Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.     

Serum TGF-beta1 correlates with chronic histopathological lesions in protocol biopsies of kidney allograft recipients

INTRODUCTION: Transforming growth factor-beta (TGF-beta) is a well-known profibrotic factor playing a role in chronic kidney allograft nephropathy. Cyclosporine (CsA)-sparing immunosuppressive regimens may improve long-term graft function. Our aim was to study the influence of immunosuppressive treatment with versus without calcineurin inhibitors on serum TGF-beta levels and histological changes in protocol biopsies of kidney allograft recipients. PATIENTS AND METHODS: In this prospective, randomized study of 42 low-rejection risk patients we randomized two groups: group A: mycophenolate mofetil (MMF), prednisone, daclizumab, and reduced CsA dose for 7 months (5 mg per kg per day) followed by complete withdrawal (n = 21); and group B: normal CsA dose (10 mg per kg per day adjusted according to C2 levels), MMF, prednisone, and no daclizumab (n = 21). METHODS: In both groups we performed histological assessments (Banff 97) and measured serum TFG-beta levels before as well as, at 3 and 12 months after transplantation. RESULTS: We found a relationship between immunosuppressive regimen and the TGF-beta concentration over 1 year of observation. Before transplant the TGF-beta1 levels did not differ between the groups (P = .29); at 3 months they were 33 +/- 9 vs 49 +/- 15 pg per mL, respectively, in groups A and B (P = .08), and at 12 months they were 39.5 +/- 4 versus 55.5 +/- 11 pg per mL, respectively, in groups A and B (P = .03). Protocol biopsies at 12 months in group B showed chronic tubular lesions more pronounced than in group A. TGF-beta1 concentrations were significantly higher among group B than A. We conclude that TGF-beta1 concentration may predict the development of kidney graft fibrosis; early CsA withdrawal may achieve a reduction in chronic tubular and interstitial injury of cadaveric kidney allografts.     

Long-Term Consequences of Live Kidney Donation Follow-Up in 93% of Living Kidney Donors in a Single Transplant Center

Live kidney donation is increasing rapidly. Increases of blood pressure and proteinuria but no accelerated loss of renal function in kidney donors have been described. The credibility of this research is hampered by retrieval rates of only 50-70% of donors. We studied renal function, blood pressure, proteinuria, parathyroid hormone, 1,25(OH)2 cholecalciferol and calcium and phosphate excretion in a live kidney donor cohort with a 93% retrieval rate. A comprehensive physical and laboratory examination including 24-h urine collection was conducted. None of the 152 donors had renal failure. Mean time after uninephrectomy was 11 +/- 7 (range: 1-28) years. GFR had declined by 25%. Blood pressure had increased from 125 +/- 15/79 +/- 11 to 134 +/- 19/81 +/- 9 mmHg (p < 0.01) but remained significantly below normal. Fifty six percent of donors developed proteinuria (>150 mg/day), but only 10% had albuminuria. Nineteen percent had increased PTH, 30% had a decreased tubular reabsorption rate of phosphate. Regarding risk factors for a higher loss of GFR, greater increases in blood pressure or proteinuria no consistent picture emerged. Because of the high incidence of proteinuria and possible changes in bone metabolism inclusion of kidney donors in registries appears worthwhile.     

Gender differences in renal growth and function after uninephrectomy in adult rats.

BACKGROUND: It is known that compensatory renal growth (CRG) following unilateral nephrectomy (UNX) increases both the size of the kidney and its functional capacity; however, few studies have investigated whether differences in CRG exist between the sexes. Our study examined the sex-related differences in remnant kidney growth and function two months following UNX. METHODS: Adult male and female Wistar rats underwent either left UNX or sham operation and recovered for 8 to 10 weeks. Another group of female rats underwent ovariectomy (Ox), with vehicle, estrogen, or testosterone replacement: two-weeks postsurgery animals underwent UNX and recovered for 8 to 10 weeks. Metabolic studies, acute renal function studies [response to acute saline volume expansion (2 to 4% of body wt) or phosphate (Pi) infusions in thyroparathyroidectomized rats (to determine the transport maximum (TmPi)], and renal morphology were assessed at the end of the experimental period. RESULTS: Two months post-UNX, male remnant kidneys grew 114+/-7% of their excised kidney weight (KW), whereas female remnant kidneys grew only 57+/-4% (P<0.05). There was a significant increase in the glomerular volume of male remnant kidneys (126.2+/-13.4%, P<0.001) compared with control kidney volume, whereas there was no change in glomerular volume in female remnant kidneys (20.2+/-16.1%, P = NS). There was also glomerular and tubular damage in the male remnant kidneys, whereas female remnant kidneys were intact. Studies in Ox female rats supplemented with gonadal steroids determined that testosterone is the driving force for the enhanced remnant kidney growth and glomerular hypertrophy. Renal function studies determined that UNX males had significantly higher glomerular filtration rates (GFRs) than UNX females, although the GFR/single KW was not different between the sexes, indicating a proportional increase in GFR. Basal urinary sodium excretion and urine flow rates were significantly higher in anesthetized UNX rats than their sham-operated controls, and urinary sodium excretion and urine flow rates in UNX males were significantly higher than in UNX females. Both male and female UNX rats responded to volume expansion with an exaggerated initial sodium and urine excretion compared with their controls. Phosphate handling was not altered in UNX male rats; however, UNX female rats had increases in fractional Pi excretion that were associated with significant reductions in the maximum capacity for Pi reabsorption (2.10+/-0.07 vs. 3.43+/-0.24 micromol/ml GFR in female controls, P<0.0001). This difference was also observed in Ox rats treated with estrogen and testosterone (2.31+/-0.07 vs. 3.12+/-0.11 micromol/ml GFR, P<0.0007). CONCLUSIONS: These findings indicate that sexual dimorphism exists in remnant kidney growth and function two months following UNX. Indeed, morphological abnormalities and impairment in renal phosphate handling are affected by gonadal steroids by two-months post-UNX. The fact that renal Pi transport was reduced in female but not male UNX rats may also have important implications during periods of high metabolic demand for phosphate in the female.     

Renal reabsorption of phosphate in children with sickle cell anemia

It has previously been reported that in adult patients with sickle-cell anemia the serum phosphate value and the maximum tubular reabsorption of phosphate per liter of glomerular filtrate (TmP/GFR) were significantly higher than in normal controls. This does not appear to have been studied in children with sickle cell anemia (young sicklers) and this prompted us to assess renal phosphate reabsorption in this group of patients. We looked at serum phosphate level and calculated renal phosphate reabsorption (TP/GFR) in children taking random urine and blood samples at the same time and using the formula TP/GFR = Sp - Up x SCr: UCr, in 30 young sicklers all of whom had normal renal function (mean age 7.3 years) and 40 normal matching controls (mean age 6.5 years). The mean serum phosphate value in young sicklers was significantly lower than in controls (4.3 against 5.3 mg/dl) while the mean value of TP/GFR was 4.09 +/- 0.74 mg/dl in young sicklers compared to 4.65 +/- 0.75 mg/dl in the control group (p = 0.0026). Therefore, the TP/GFR in young sicklers was also significantly lower (p = 0.0026) than in the control group. This may be explained by the high serum level of parathyroid hormone reported previously in patients with sickle cell anemia which is expected to lower phosphate reabsorption (TmP/GFR and TP/GFR are identical in children). The lower serum phosphate value and TP/GFR in younger sicklers seems to be in contrast with the relatively high serum phosphate value and TP/GFR previously reported in adults with sickle cell anemia. Copyright Copyright 1999 S. Karger AG, Basel     

Dipyridamole for renal phosphate leak in successfully renal transplanted hypophosphatemic patients

AIM AND BACKGROUND: Hyphosphatemia can be seen in renal transplant recipients. Hyperparathyroidism, glucocorticoid treatment, renal denervation and impairment of renal tubular phosphate reabsorption are the most common causes of hyphosphatemia in these patients. It is well-known that dipyridamole enhances renal tubular phosphate reabsorption in some clinical conditions. We did not find any information about the effect of dipyridamole in renal transplant recipients (RTRs) with hypophosphatemia. For this reason, we decided to give dipyridamole 11 RTRs with hypophosphatemia. PATIENTS AND METHODS: Eleven RTRs whose serum phosphate and creatinine levels were below 2.5 mg/dl and 2 mg/dl, respectively, were included in this study. None of the patients received drugs altering phosphate metabolism and they did not change their routine diets. Urinary phosphate excretion and tubular phosphate reabsorption (TPR) were calculated before and 3 weeks after dipyridamole treatment. RESULTS: The mean levels of serum-urine (daily) phosphate and TPR before dipyridamole treatment were 1.94 +/- 0.46 mg/dl, 7,187.5 +/- 1,833.49 mg/day and -2.78 +/- 0.62, respectively. After treatment, the mean levels of serum-urine phosphate and TPR were 2.73 +/- 0.46 mg/dl, 4,845.27 +/- 1,138.99 mg/day and -1.48 +/- 0.80, respectively. Serum and urine phosphate levels and TPR were found to be significantly different before and after dipyridamole therapy (p < 0.05). CONCLUSION: Short-term dipyridamole therapy increased TPR and serum phosphate levels and decreased urinary phosphate excretion. We did not observe negative effect on renal functions in these cases. Although the number of the cases included in this study is small, dipyridamole is an effective choice in management of hypophosphatemic RTRs.     

The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients

We performed indium-111-DTPA plasma clearance studies in 61 pediatric kidney and liver recipients treated with cyclosporine to compare true glomerular filtration rate with calculated GFR (cGFR). The mean true GFR of 61.9 +/- 36.6 ml/min/1.73 m2 indicated renal impairment. The mean cGFR of 85.2 +/- 22.4 ml/min/1.73 m2 was significantly higher (P less than 0.001), and overestimated GFR by 38%. cGFR alone did not accurately reflect the degree of renal dysfunction. A group of 48 pediatric orthotopic liver transplant recipients was studied in more detail: 73% of these patients had a true GFR less than 70 ml/min/1.73 m2, while 85% had a true GFR below 90 ml/min/1.73 m2, the lower limit for normal GFR in children. The mean true GFR for patients treated more than 24 months with CsA was lower (P = 0.02) than patients treated with CsA for 12 to 24 months. OLT patients with normal true GFR (greater than 90 ml/min/1.73 m2) had significantly lower plasma CsA levels, and 50% of patients with a true GFR less than or equal to 50 ml/min/1.73 m2 had hypertension. There was no effect on true GFR of age, liver function, azathioprine use, or peritransplant treatment with other nephrotoxic drugs. We conclude that true GFR is significantly impaired in long-term CsA-treated allograft pediatric recipients. Calculations of GFR underestimate the degree of renal dysfunction. As patients treated greater than 24 months had the lowest true GFRs, the fall in GFR may be progressive.     

Role of neutrophil derived oxidants and elastase in lipopolysaccharide-mediated renal injury

Gram-negative bacterial sepsis is frequently associated with acute renal failure but the specific effects of lipopolysaccharide (LPS) and other bacterial products on kidney function are not known. Since either LPS or formyl-methionyl-leucyl-phenylalanine (FMLP)--a chemotactic peptide from bacterial cell walls--activate neutrophils (PMN) to release a number of potentially toxic factors in vitro, we determined the effect of adding PMN with LPS and/or FMLP to isolated perfused rat kidneys. Isolated rat kidneys perfused with LPS alone or LPS and normal PMN had normal glomerular filtration rates (GFR) and tubular Na reabsorption (TNa). Kidneys perfused with FMLP alone or FMLP and normal PMN also had normal GFR and TNa. In contrast, addition of PMN with both FMLP and LPS caused progressive renal dysfunction. For example, after 60 minutes of perfusion, GFR was reduced from 610 +/- 31 to 147 +/- 17 microliters/min/g and TNa from 97 +/- 1 to 72 +/- 2%, both P less than 0.01. Perfusion with the O2 metabolite scavengers catalase or dimethylthiourea afforded no protection while perfusion with the neutrophil elastase inhibitor Eglin C conferred substantial, but not complete, protection: GFR 492 +/- 34 microliters/min/g; TNa 91 +/- 3%. However, perfusion with both Eglin C and catalase completely prevented the toxic effects of LPS and FMLP-treated PMN on renal function. We conclude that in isolated kidneys, 1) the toxic effects of LPS requires FMLP-treated PMN and that 2) LPS and FMLP treated PMN cause progressive renal injury which is mediated by both O2 metabolites and neutrophil elastase.     

Effects of the adenosine A1 receptor inhibitor FK 838 on proximal tubular fluid output in rats.

BACKGROUND: Adenosine A(1) receptor blockade has been suggested as a treatment in conditions with sodium and fluid retention because it increases urinary Na(+) excretion and increases proximal tubular fluid output. In the present study, we examine the time course for the renal responses to adenosine A(1) receptor blockade in order to investigate whether the effects may be prolonged and not just temporary. METHODS: The acute effects of the adenosine A(1) receptor inhibitor FK 838 on segmental tubular Na(+) handling were examined by a renal clearance technique in conscious chronically instrumented rats. Lithium clearance (C(Li)) was used as a clearance marker of proximal tubular fluid output. RESULTS: Acute adenosine A(1) receptor inhibition did not affect the glomerular filtration rate (GFR) significantly. In contrast, the inhibition led to significant increases in C(Li) (from 290+/-28 to 431+/-28 microl/min/100 g), fractional Li(+) excretion (FE(Li)) (from 33+/-2 to 47+/-3%) and fractional Na(+) excretion (FE(Na)) (from 0.44+/-0.07 to 2.03+/-0.42%). Sodium excretion, expressed as a fraction of proximal tubular fluid output (C(Na)/C(Li)), rose from 1.3+/-0.2 to 4.2+/-0.4%, suggesting that the natriuretic effect was supported by inhibition of distal nephron Na(+) reabsorption. All values returned to baseline values during the clearance study and thereby indicated that neither proximal tubular fluid output nor urinary sodium excretion remained elevated for a prolonged time. CONCLUSION: It is concluded that in conscious unstressed rats, acute adenosine A(1) receptor inhibition by FK 838 led to a significant natriuresis that was caused by inhibition of proximal tubular Na(+) reabsorption, possibly with a contribution from inhibition of distal nephron Na(+) reabsorption. The increased proximal tubular fluid output and the increased urinary Na(+) excretion returned to baseline values during the clearance study, indicating that none of these effects of adenosine A(1) blockade were long lasting.     

Non-invasive evaluation of bilateral renal regional blood flow and tubular dynamics during acute unilateral ureteral obstruction.

BACKGROUND: Global renal haemodynamic responses to acute unilateral ureteral obstruction (AUUO) have been studied extensively in animals, yet little is known about the concurrent changes in haemodynamics and tubular fluid dynamics that occur within the distinct regions of the kidney during AUUO. The advent of electron beam computerized tomography (EBCT) now allows us to evaluate non-invasively intrarenal haemodynamics and tubular fluid dynamics in vivo. METHODS: Using EBCT, we quantified total, cortical and medullary renal blood flow (RBF, C-RBF and M-RBF), and the concurrent intratubular fluid contrast concentration (ITCC) from contrast media dilution curves, prior to, and at 30 and 90 min after the onset of AUUO in five pigs. RESULTS: At 30 min after AUUO, there was a small 17+/-7% fall in C-RBF that did not quite reach significance (P = 0.076), whereas RBF, M-RBF, glomerular filtration rate (GFR) and ITCC were preserved. At 90 min, both C-RBF and RBF had fallen by 54+/-8 and 45+/-5%, respectively (P<0.05). GFR also tended to decrease (by 49+/-8%, P<0.06), whereas there was preservation of M-RBF. ITCC increased in the proximal and distal tubules, and tended to increase in Henle's loop. In the contralateral kidney, AUUO did not alter the haemodynamics, but transiently decreased ITCC in all tubular segments. CONCLUSION: EBCT allows evaluation of AUUO-induced changes in intrarenal haemodynamics and tubular fluid dynamics. AUUO decreased cortical, but not medullary perfusion of the ipsilateral kidney, and increased the ITCC in most tubular segments, suggesting increased tubular reabsorption that may have helped maintain GFR and tubular fluid flow.     

Acute and chronic changes in renal function following unilateral nephrectomy

Free-flow micropuncture was used to assess proximal and distal tubular function in rats immediately (2 to 5 hours), five days and 30 days after uninephrectomy (UN); results were compared with those in sham-operated littermates. Excretion rates of water, sodium and potassium were approximately doubled in the remaining kidney of UN rats. Two to five hours after UN there were small increases in glomerular filtration rate (GFR) and single nephron GFR which at this stage were not accompanied by an increase in absolute proximal reabsorption; that is, fractional proximal reabsorption fell. After five days, GFR and single nephron GFR had increased further; at this stage absolute proximal reabsorption was also significantly elevated. After 30 days, kidney weight, GFR, single nephron GFR and absolute proximal reabsorption had all increased by approximately 40%, and glomerulotubular balance in the proximal tubule had been fully restored. Data derived from distal tubular collections indicated that at every stage after UN: (a) fluid delivery to both early and late distal puncture sites was increased; (b) in contrast, there was no increase in sodium delivery to the late distal tubule, suggesting that the natriuresis resulted from reduced sodium reabsorption beyond the distal tubule and/or increased delivery of sodium from deep nephrons; and (c) there was a marked increase in potassium secretion into the accessible portion of the distal tubule which was more than adequate to explain the observed kaliuresis.     

Increased reabsorptive capacity after ureteral obstruction reduces the ability of glucose to inhibit phosphate reabsorption in rat kidney

Background: Proximal tubular reabsorption of glucose (G), phosphate (Pi) and amino acids is energized by the transmembrane Na⁺ gradient, which explains why decreased concentration of one solute can enhance the transport of another. Accordingly, we postulated that the consistent increase in Pi reabsorption seen in the post-obstructed kidney (POK) could be caused, in part, by the low filtered load of glucose and reversed by glucose loading. Methods: Renal function was examined before and after i.v. glucose loading in POKs (after release of 24 h of unilateral ureteral obstruction) and control kidneys (CK) of 10 adult rats. Brush-border membrane vesicle (BBMV) transports of Pi and glucose were assessed in POKs and CKs. Results: In POKs GFR, urine flow and Na⁺ excretion were significantly reduced and tubular reabsorption of both Pi (TP/GFR) and glucose (TF/GFR) were significantly increased: TP/GFR, 2.0±0.2 vs 1.36±0.1; TmG/GFR, 23.4±1.7 vs 18.9±1.1 mmol/l. Glucose loading inhibited TP/GFR only in the CK. Initial Na⁺ gradient-dependent uptakes of D-glucose and Pi were similar in BBMVs from POK and CK. Conclusions: The increases in TP/GFR and TG/GFR seen in the POK do not result from decreased glucose delivery or from alterations in BBM Pi and glucose transporters. The reduced ability of glucose to inhibit Pi reabsorption in the POK results primarily from a generalized increase in proximal tubular reabsorption of Na⁺ and cotransported Pi and glucose. A specific rise in distal Pi transport capacity may be an additional adaptive response to the low filtered load of Pi in the POK. In addition, absent distal glucose reabsorption may further facilitate Pi reclamation at these sites.     

Acute Ureteral Obstruction and Glomerulotubular Function in Rats

Urinary tract obstruction is a common cause of acute renal failure (ARF). During unilateral ureteral obstruction (UUO) arteriolar vasoconstriction, increase in tubular pressure, and ultrafiltrate retrodiffusion occur. We studied renal function of rats with surgical UUO for 24 hr. After this period of UUO, the contralateral kidney was removed and the right ureter was deobstructed. The control uninephrectomized group consisted of normal rats submitted to left uninephrectomy (UNx). Functional studies were performed 12 and 24 hr, and 7 days after deobstruction and UNx. We measured creatinine clearance, and fractional excretion of sodium and lithium. Using conventional formulas we calculated fractional proximal and distal sodium reabsorption. Initially we observed a reduction in glomerular filtration rate (GFR) after deobstruction (12 and 24 hr). However, after 7 days, the GFR was significantly higher in deobstructed rats than in controls (340.3 ± 18.3 vs. 286.4 ± 9.3 μL/min/100 g, p < 0.01). The dry kidney weight was also increased in these rats. The fractional sodium excretion was increased in deobstructed rats, mainly in early studies (12 and 24 hr). Whereas fractional proximal reabsorption was reduced in both groups, the fractional distal reabsorption was significantly decreased in the deobstructed group compared to UNX controls (93.9 ± 0.9 vs. 98.9 ± 0.1% after 24 hr, p < 0.01). Our data showed that UUO influenced both glomerular and tubular functions. A salient finding was the overcorrection of GFR 7 days after deobstruction. The renal release of hormones and growth factors could mediate these alterations in renal function through their vascular, tubular, and proliferative actions.     

Long-Term Deterioration of Kidney Allograft Function

Although long-term survival after kidney transplantation is critically dependent on maintaining stable allograft function, few studies have examined renal allograft function over time. Using pooled data from 10 278 consecutive transplants at five centers, we calculated slopes of estimated glomerular filtration rates (eGFR) measured after 1, 6 and 12 months in 9515, 8861 and 7359 patients surviving > or =1, > or =6 and > or =12 months, respectively. Slopes of eGFR progressively diminished for patients transplanted during 1984-1989, 1990-1993, 1994-1998 and 1999-2002 (analysis of variance p < 0.0001 and p = 0.1245 for slopes measured after 1 and 6 months, respectively). Slopes measured after 12 months were less in the most recent era: -2.2 +/- 7.2 mL/min/1.73 m(2)/year, -2.3 +/- 6.6 mL/min/1.73 m(2)/year, -2.4 +/- 7.4 mL/min/1.73 m(2)/year and -1.4 +/- 10.9 mL/min/1.73 m(2)/year, respectively, p = 0.0058. Slopes measured after 1, 6 and 12 months each were less for transplantations during 1999-2002, after adjusting for multiple transplantation characteristics (p < 0.0001). Similarly, in Cox proportional hazards analysis, the risk (95% CI) for a 25% reduction in eGFR was 0.92 (0.85-1.01), p = 0.0736 during 1990-1994; 0.94 (0.82-1.08), p = 0.4111 during 1995-1998 and 0.78 (0.64-0.95), p = 0.0110 during 1999-2002 (compared to 1984-1989). We conclude that the rate of decline in allograft function after kidney transplantation has improved, suggesting that stable, long-term function may be achievable.     

Effects of chronic renal denervation in conscious restrained rats

Sodium (Na), calcium (Ca), inorganic phosphate (Pi) and water excretion were measured in nondiuretic (ND) and extracellular fluid (ECF) volume expanded (VE) conscious restrained rats four weeks after denervation or sham-denervation of the left kidney. On the day of the study the animals were lightly anaesthetized with ether and the femoral vessels on one side were catheterized. Urine was collected from both kidneys. The animals were allowed to recover for 3 hours and studied in a restraining chamber. In ND animals isotonic saline containing inulin and para-amino-hippuric acid (PAH) were given at a rate of 0.067 +/- 0.002 (SE) ml/min/kg body weight (BW). In VE animals the infusion rate was 0.24 +/- 0.04 ml/min/kg BW. Kidney catecholamine content was measured after the experiments. Clearances of PAH and of inulin (GFR) were the same in both kidneys. Urine volume (V), sodium excretion (UNa V/GFR), inorganic phosphate excretion (UPi V/GFR) and calcium excretion (UCa V/GFR) were significantly higher in the denervated kidneys. Values in sham denervated kidneys were not greater than those of the right kidney. Denervation was proven by demonstrating absent or very low catecholamine content in the kidneys. The results demonstrate that: chronic renal denervation in rats leads to diuresis and natriuresis even in the conscious state, thus confirming previous results from our laboratory; such changes occur independently of the state of the ECF volume and of renal haemodynamic changes; the increased excretion of Ca++ and Pi after denervation demonstrates that renal nerves affect the reabsorption of these ions either independently or by way of their effect on sodium reabsorption. These data allow us to suggest that a renal tubular dysfunction, which was proved in anaesthetized denervated animals, can also be observed in the conscious state.