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B J Nankivell

Publications and source records attributed to B J Nankivell.

At least 37 records · Page 2Linked to original sources
PubMed1995

Renal dysfunction in acute rejection. Effect of HLA typing, therapy, and histology.

Acute rejection is a frequent cause of early graft dysfunction in renal transplantation, and serum creatinine is the most important measure of clinical response. However, there is little information on serum creatinine during rejection episodes. In this study, the determinants that might influence the clinical response of serum creatinine during acute rejection were evaluated in 96 renal transplant recipients with 100 episodes of biopsy-proven rejection, by univariate and multivariate analysis. The factors assessed for their influence on serum creatinine in acute rejection included: presence and severity of vascular or cellular rejection on biopsy, time taken to institute therapy, HLA mismatch, and the use of OKT3. The presence of vascular rejection on biopsy (n = 28) was a major determinant of impaired reciprocal area under the curve (AUC) of serum creatinine (P < 0.01), and was correlated with HLA-A and -B mismatch (r = 0.21, P < 0.05). Acute rejection associated with HLA-DR mismatch resulted in a more rapid increase of serum creatinine, a higher maximal creatinine, and a greater AUC creatinine (all P < 0.05). Treatment of acute rejection with OKT3 had a beneficial effect on AUC creatinine (P < 0.05) when compared with intravenous corticosteroids, by multivariate analysis. However, vascular rejection and HLA-DR mismatch had no effect on serum creatinine 1 year after transplantation. The biopsy cellular rejection score had no effect on AUC creatinine, although there was a modest effect on gradient of creatinine prior to biopsy. A minor adverse effect of delay in therapy of acute rejection could be demonstrated in the methylprednisolone-treated subgroup. In summary, HLA-DR mismatch and the presence of vascular rejection were the most important predictors of the severity of rejection assessed by the response of serum creatinine to treatment. Appropriate antirejection therapy should be instituted promptly to optimize clinical response during acute rejection.

Adult↗
PubMed1995

Predicting glomerular filtration rate after kidney transplantation.

Serum creatinine is an important clinical measure of impairment of glomerular filtration rate (GFR) after kidney transplantation. The use of formulas that predict GFR (such as the Cockcroft-Gault) derived from patients with chronic renal failure and standardized against measured creatinine clearance may not be accurate when applied to kidney transplant recipients. The purpose of this study, was to investigate the level of inaccuracy and its causes and then to derive predictive GFR formulas that are appropriate to renal transplantation. Determinants of isotopic GFR, serum creatinine, and muscle mass were evaluated in consecutive kidney recipients (n = 146) using 99mTc DTPA GFR (n = 751) as a reference method. Factors that predicted GFR apart from serum creatinine included sex, height, body weight, serum urea, years on dialysis, numbers of rejections and infective episodes, and prednisolone dose. The relationship between serum creatinine and GFR was highly variable and dependent on factors that alter muscle mass and muscle catabolic rate. The relationship was further altered by ATN and chronic rejection when tubular secretion of creatinine was reduced. Three alternative GFR formulas (which can be applied to renal transplant patients according to the availability of clinical parameters) were derived and tested against six published methods of GFR estimation. Our derived formulas had the highest correlation, no overall bias, least scatter of sum of squares, and least error at low levels of GFR. They represent a better estimation of GFR in kidney transplantation than published formulas, and would allow a standardized approach to the study of long-term renal dysfunction.

Adult↗
PubMed1995

Mechanisms of iron-induced proximal tubule injury in rat remnant kidney.

The proposition that proximal tubule (PT) iron accumulation may cause PT injury by lysosomal destabilization or reactive oxygen species generation in human and animal chronic renal disease was examined in partially nephrectomized [remnant kidney (RK)] and sham-operated (SO) Wistar rats. Electron microscopic histochemistry with horseradish peroxidase indicated iron uptake into and release from lysosomes. PT cytoplasmic iron was seen in RK but not in SO by energy-dispersive X-ray spectrometry. Total (9.66 +/- 1.89 vs. 3.30 +/- 0.31 nmol/mg protein; P < 0.01), low-molecular-weight (1.39 +/- 0.09 vs. 0.91 +/- 0.07; P < 0.001), and catalytic iron (1.88 +/- 0.27 vs. 1.28 +/- 0.09; P = 0.05) were higher in RK cytoplasm than in SO. Lysosomal enzyme activity was greater in RK than in SO [e.g., N-acetyl-beta-D-glucosaminidase (NAG): 0.75 +/- 0.05 vs. 0.57 +/- 0.06 mumol p-nitrophenol.h-1.mg protein-1; P < 0.05] and was increased further by chronic iron loading (e.g., RK and NAG: 0.84 +/- 0.04 vs. 0.60 +/- 0.07; P < 0.05). There was no enzymatic evidence of lysosomal fragility, and chronic iron loading of RK decreased fragility as assessed by NAG release (1.36 +/- 0.14 vs. 2.17 +/- 0.14; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Iron depletion in the remnant kidney.

Urinary and proximal tubular iron are increased after subtotal nephrectomy, and iron depletion has been shown to be beneficial in proteinuric models of chronic renal disease in rats. In this study, iron depletion by low iron pair-fed diet and periodic phlebotomy was induced for 6 months in rats with partial (5/6) nephrectomy, resulting in a reduction in hematocrit and serum iron in all iron-deficiency subgroups. Tubular iron, assessed by energy dispersive analysis and electron microscopy, was reduced in quantity but not number of iron-containing lysosomes only within 1 subgroup of severe iron deficiency (p < 0.05). There was no improvement in serial isotopic glomerular filtration rate measurements, urinary protein and transferrin excretion, tubular damage scores, serum creatinine, or measures of reactive oxygen species (ROS) generation. In a subgroup of rats with no supplementation of sulfhydryl amino acids (cysteine and methionine) which can act as ROS scavengers, iron deficiency increased urinary protein excretion (213.3 +/- 23.0 mg/24 h, mean +/- SEM, vs. 87.4 +/- 16.1, p < 0.001), urinary transferrin excretion (p < 0.05), kidney weight (p < 0.05) and tissue malondialdehyde, a lipid peroxidation product (0.78 +/- 0.16 nmol/mg protein vs. 0.57 +/- 0.19, p < 0.05), consistent with increased ROS generation. Hence, no beneficial effect of iron-deficiency was demonstrated by any measure of structure of function in the remnant kidney, and it may enhance damage if sulfhydryl repletion is not provided.

Amino Acids↗
PubMed1995

Predicting glomerular filtration rate after simultaneous pancreas and kidney transplantation.

Impairment of glomerular filtration rate (GFR) after simultaneous pancreas and kidney (SPK) transplantation is an important marker of chronic renal rejection and recurrence of diabetic glomerulopathy. The use of unmodified serum creatinine to estimate GFR, however, is limited by variations in muscle mass. In this study, predictive factors for long-term GFR were evaluated in consecutive SPK recipients (n = 33) using a Tc99m DTPA GFR reference method between 90 days and 6 years after transplantation (n = 136 measurements). Substantial variability between serum creatinine and isotopic GFR after SPK (R2 = 0.30) high-lighted the inaccuracy of an unmodified serum creatinine in the evaluation of GFR. Factors which predicted GFR apart from serum creatinine included age, sex, height and body weight. A detailed formula was derived for accurate estimation of GFR (ml/min) = [71.4 (male) or 50.4 (female)] + 5520/creatinine (mumol/l) + 0.27 x body weight (kg) - 0.50 x age (yr) - 0.29 x height (cm). This formula was more accurate in estimation of GFR in SPK recipients than six published predictive methods which were derived from chronic renal failure patients using creatinine clearance. All of these methods overestimated GFR at lower levels of renal function. Most correlated poorly with Tc99m DTPA GFR and contained a generalized systematic overestimation of GFR which ranged from 4.7 to 8.4 ml/min (p < 0.05). A simplified version for rapid calculation was also derived as GFR (ml/min) = [25 (male) or 5 (female)] + 5000/creatinine (mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Erythrocytosis after renal transplantation: risk factors and relationship with GFR.

Post-transplant erythrocytosis (PTE) has been increasingly recognized as a complication of kidney transplantation, and several risk factors have been defined. Recent evidence suggests renal function may also play a role in hematological recovery after transplantation and risk of PTE. In this study of kidney transplant recipients (n = 123), simultaneous Tc99m DTPA GFR (n = 710) and hemoglobin levels were compared with possible clinical determinants. The frequency histogram of post-transplant hemoglobin was bell-shaped and continuously distributed above and below the arbitrary definition of PTE, suggesting that PTE is not a separate disease entity. Hemoglobin reached a plateau at 12 months after transplantation and was correlated with isotopic GFR (r = 0.46, p < 0.001). This consistent and statistically independent relationship became prominent 3 months after transplantation. Hemoglobin was independently predicted by multivariate analysis by time after transplantation, presence of polycystic renal disease, greater serum albumin and reduced serum urea (which in turn were reflected by number of infective and rejection episodes), shorter kidney anastomosis time and a higher GFR, but not by immunosuppressive therapy. Rejection or infection episodes impaired hematological recovery. The independent determinants of GFR included hematological recovery. The independent determinants of GFR included hemoglobin level, kidneys from young, male donors, fewer HLA-DR mismatches and rejection episodes, shorter time on dialysis and greater azathioprine dose. Renal function was not altered by therapeutic phlebotomy. Determination of hemoglobin level by both donor and recipient variables supports the relevance of tubular and glomerular function in control of erythrocystosis after renal transplantation. A role for renin-angiotensin mediation in the alteration of intraglomerular hemodynamics and erythropoietin secretion is postulated.

Adult↗
PubMed1994

Diagnostic utility of whole blood cyclosporine measurements in renal transplantation using triple therapy.

Whole blood CsA concentrations measured by specific monoclonal RIA (CYCLO-Trac SP whole blood RIA, IncSTAR) were compared with episodes of renal dysfunction (n = 138) and protocol biopsies (n = 52) that occurred within the first 100 days in consecutive renal allograft recipients receiving triple therapy (n = 92). Histological confirmation of events was available in 98% episodes of acute rejection (n = 60/61), 59% of episodes of CsA nephrotoxicity (22/38), and 100% of the diagnoses of acute tubular necrosis (35/35). Mean, minimum, and maximum CsA levels were elevated in CsA nephrotoxicity compared with all other groups (P < 0.001). Interestingly, CsA levels achieved relative to administered dose also increased at the time of CsA nephrotoxicity compared with other groups (P < 0.01). In the context of acute dysfunction, the sensitivity and specificity of mean CsA levels above 400 ng/ml to predict CsA nephrotoxicity were 32% and 89%, respectively. The negative predictive value of a high CsA level to exclude acute rejection was 88% (at 400 ng/ml), 92% (450 ng/ml), and 95% (500 ng/ml). As a marker of effective immunosuppression, CsA levels were not correlated with in vitro proliferation of PHA-stimulated PBL and did not reduce the severity and degree of cellular infiltration in needle core biopsies during rejection. The sensitivity and specificity of a low CsA level (150 ng/ml) in the diagnosis of acute rejection were 31% and 91%, respectively. The majority of episodes of acute dysfunction, including 63% of CsA nephrotoxicity and 59% of acute rejections, occurred with CsA levels between 150 and 400 ng/ml. In summary, when using low dose triple therapy regimens, CsA levels within the range of 150-400 ng/ml were of little diagnostic value in acute allograft dysfunction. In contrast, levels outside this range were useful in the clinical diagnosis of CsA nephrotoxicity and acute allograft rejection.

Adolescent↗
PubMed1994

Renal graft thrombosis. A survey of 134 consecutive cases.

Despite overall improved graft survival, renal graft thrombosis (RGT) remains an important cause of graft loss. Of 6153 consecutive renal transplants (RTx), 134 index cases of graft loss from RGT were reported to the Australian and New Zealand Dialysis and Transplant Registry between 1980 and 1992. Two groups were selected for comparison: (1) institutional controls (n = 127), the previous RTx at the same institution as each index case; and (2) graft controls (n = 107), the contralateral cadaveric donor kidney of each index case. RGT cases that coincidentally occurred in control groups were deleted from those groups (6 of institutional controls, 2 of graft controls). RGT within the first 30 days after RTx occurred in 1.9% of all RTx and was constant from 1980 to 1992. In contrast, RGT caused an increasing proportion of early (within 30 days of RTx) graft losses (P = 0.01). The cumulative occurrence of RGT in those who thrombose was 62.6%, 83.7%, 90.2%, and 93.5% at 2, 7, 14, and 30 days after RTx, respectively. By comparison, with the control groups, no association with RGT was demonstrated for recipient age or sex, primary renal disease, type of dialysis, treatment with CsA, degree of HLA mismatch, panel reactive antibody levels, perfusion solution and perfusion technique, or immunosuppressive therapy. There was a significantly increased incidence of RGT with both extremes of donor age, female donors, and prolonged total ischemic time.

Adolescent↗
PubMed1994

Dietary protein alters tubular iron accumulation after partial nephrectomy.

Reactive oxygen species (ROS) have been implicated in progression of disease in the rat remnant kidney (RK) model of chronic renal failure. Substantial amounts of iron accumulate in proximal tubular lysosomes of RK and could damage tubules by ROS generation. The effect of dietary protein intake on ROS, tubular damage and iron accumulation assessed by energy dispersive analysis was determined in RK (5/6 nephrectomy, N = 12) and sham-operated kidneys (SO, N = 10). In RK, mean lysosomal iron concentration, urinary iron and protein excretion and morphological damage were increased and GFR decreased. Dietary protein loading (40% vs. 12%) increased the number of iron-containing lysosomes (P < 0.05) and the mean lysosomal iron (P < 0.02) in proximal tubular cells after four weeks. In RK, high protein diet increased renal weight (P < 0.01), numerical density of iron-containing lysosomes and tubular damage (both P < 0.05). ROS generation, assessed by tissue and plasma malondialdehyde (MDA), was also increased (both P < 0.05). Plasma MDA correlated with tubular iron accumulation (r = 0.75). In RK fed a high protein diet (N = 18) treatment with the iron-chelator desferrioxamine reduced serum iron, urinary volume, and tubular iron accumulation and damage compared to controls (P < 0.01). In summary, in RK dietary protein manipulation altered urinary iron and protein excretion, proximal tubular iron accumulation, renal cortical ROS generation and ultrastructural damage. Desferrioxamine treatment reduced tubular lysosomal iron and ultrastructural damage. These results suggest a role for tubular iron as a determinant of tubular injury associated with dietary protein loading in rats with partial nephrectomy.

Animals↗
PubMed1994

Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing.

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11-12 days rats treated with puromycin (10 mg/100 g, i.v.i.) had greater proteinuria (211.6 +/- 35.7 mg/day, mean +/- s.e.m.) and urinary iron excretion (15.4 +/- 2.2 micrograms/day) than saline-treated controls (14.5 +/- 1.4 mg/day and 1.1 +/- 0.2 micrograms/day, respectively, both P < 0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 +/- 64.5 vs 11.9 +/- 8.6 mg%, P < 0.001), and proximal tubular cell damage assessed semi-quantitatively (1.17 +/- 0.10 vs 0.62 +/- 0.10, P < 0.001) were higher and creatinine clearance (0.15 +/- 0.01 vs 0.29 +/- 0.02 mL/min per g kidney weight, P < 0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.

Aging↗
PubMed1994

The role of tubular iron accumulation in the remnant kidney.

Iron has been implicated in the pathophysiology of several models of acute and chronic renal disease. In this study, energy-dispersive x-ray spectrometry was used to quantify and localize iron in rat remnant kidneys (RK) and normal kidneys (NK) and to determine its pathophysiologic significance. Substantial iron accumulation occurred in proximal tubular cell secondary lysosomes of RK (P < 0.001 versus NK) and reached a plateau at 8 wk after partial nephrectomy. In NK, minor increases of iron also occurred with aging (P < 0.02). Proximal tubular iron accumulation correlated independently with protein excretion (r = 0.90) and impairment of GFR (r = 0.70) and was associated with tubular damage and phosphate accumulation (both P < 0.001). Iron nitrilotriacetate (1 mg/kg ip) increased tubular lysosomal iron accumulation and tubular damage (P < 0.001 versus nitrilotriacetate) in NK, comparable to levels seen in untreated RK, and increased cortical cytosolic malondialdehyde, consistent with reactive oxygen species generation. The iron chelator deferoxamine (30 mg/kg per day ip) significantly reduced iron accumulation and tubular damage in RK at 4 wk, compared with deferoxamine chelated to iron and untreated RK. These results suggest that filtered iron enters the remnant tubular lysosomes across the brush border membrane by endocytosis and may produce tubular damage in chronic renal disease by the generation of reactive oxygen species.

Animals↗
PubMed1994

Lysosomal iron accumulation in diabetic nephropathy.

Iron accumulates within proximal tubular lysosomes in several models of renal disease and may play a role in the progression of proteinuric chronic renal disease by the generation of reactive oxygen species. In this study, tubular iron was examined at an ultrastructural level by energy dispersive x-ray spectrometry in streptozotocin (STZ) and BB diabetic rats, and in humans with diabetic nephropathy, and compared to their respective nondiabetic controls. Substantial amounts of iron accumulated in the secondary lysosomes of proximal tubules in STZ diabetic rats (4.16 +/- 0.47 iron-containing lysosomes/microns 2 x 10(-3) tubular area vs. 0.90 +/- 0.29 in controls, p < 0.001). Proximal tubular iron was related independently with urinary protein and transferrin excretion, suggesting increased cellular uptake of iron from the tubular fluid. Lysosomal iron accumulation was also associated with tubular damage (r = 0.55, p < 0.001). Minimal amounts of tubular iron were observed in BB diabetic and nondiabetic littermates. In humans with diabetic nephropathy, increased proximal tubular lysosomal iron concentration (35.6 +/- 13.0 mg% Fe vs. 9.5 +/- 2.7, p < 0.05) and numbers of iron-containing lysosomes were observed compared to nondiabetic controls, and the latter correlated with elevation of serum creatinine (r = 0.94, p = 0.016). These results suggest that filtered iron enters proximal tubular lysosomes across the brush-border membrane and are consistent with a role for iron in causing the tubular damage of diabetic nephropathy.

Animals↗
PubMed1992

Iron accumulation in human chronic renal disease.

Iron, which has been shown to accumulate within proximal tubule lysosomes in proteinuric models of renal disease, may play a role in the progression of chronic renal disease by the generation of reactive oxygen species. Therefore, renal biopsies from humans with proteinuria and/or chronic renal failure were examined at an ultrastructural level for iron by energy dispersive analysis and compared with normal biopsies. Iron accumulated in proximal tubular lysosomes in renal disease (P < 0.05 v normals), accompanied in some cases by phosphorus and silicon. Both the number of iron-containing lysosomes per tubular cross-section (1.86 +/- 0.41 v 0.66 +/- 0.22, P < 0.05) and the mean concentration of lysosomal iron (254.5 +/- 73.4 mg/dL v 81.2 +/- 23.8, P < 0.001) was greater in patients with nephrotic syndrome (n = 12) than in those without (n = 8). Iron accumulation (number of iron-containing lysosomes/tubule) correlated with protein excretion (r = 0.68, P = 0.003, n = 20), but not with glomerular filtration rate. Damaged tubules contained greater amounts of iron than tubules with less damage (288.5 +/- 68.5 mg/dL v 80.4 +/- 13.9, P < 0.01). Further studies are needed to define the possible role of iron in causing tubular damage and progression of renal disease.

Chronic Disease↗
PubMed1991

Peritoneal eosinophilia associated with Paecilomyces variotii infection in continuous ambulatory peritoneal dialysis.

A 65-year-old woman maintained on continuous ambulatory peritoneal dialysis (CAPD) presented with a 5-month history of intermittent cloudy bags and sterile peritoneal and peripheral blood eosinophilia, which failed to clear despite conventional antibiotics. Impaired catheter inflow and delayed effluent drainage gradually occurred and intracatheter streptokinase, administered to rectify catheter dysfunction, dislodged a catheter cast composed of fungal hyphae of Paecilomyces variotii. Fungal peritonitis and Paecilomyces fungemia ensued, which were treated with amphotericin B and catheter removal. Peripheral eosinophilia rapidly resolved. Paecilomyces is a saprophytic fungus found in soil and water that is capable of infecting prosthetic devices. Eosinophils may have accumulated in this case in response to particulate fungal cell antigens being washed into the peritoneal cavity during dialysis. Chronic fungal catheter infection should be excluded in cases of late onset, persistant peritoneal eosinophilia on CAPD.

Aged↗
PubMed1991

Percutaneous biopsy of bladder-drained pancreas transplants.

Percutaneous biopsy is a valuable investigation in the management of allograft rejection for all solid organs. Pancreas transplants have not been biopsed percutaneously, though open and percystoscopic biopsies have proved useful. We have compared percutaneous needle core biopsy with fine-needle aspiration cytology for the diagnosis of rejection in 18 patients receiving combined kidney and pancreas transplants and in one who was transplanted with the pancreas alone. Percutaneous needle core biopsy was successful in 37 of 40 attempts (93%), while fine-needle aspiration yielded diagnostic material on 33 of 47 attempts (70%). Transient hyperamylasemia occurred in 29%, returning to baseline in three days. One patient twice developed transient macroscopic hematuria. There was agreement between needle core biopsy and fine-needle aspiration on the diagnosis of rejection on six occasions and for the absence of rejection on 16. There was an 8% false-positive rate for fine-needle aspiration. In 13 instances of histologically proved renal rejection, concurrent pancreas biopsy revealed rejection in 69%. Pancreas rejection was not, however, seen in the absence of renal rejection. In this pilot study, percutaneous biopsy of the bladder-drained pancreas allograft was shown to be a practicable and valuable investigation without major complications.

Adult↗