The course of diabetic glomerulopathy in patients with type I diabetes: a 6-year follow-up with serial biopsies.

Diabetic nephropathy is a severe complication and few studies have described the early morphological changes over time. Two kidney biopsies were performed, within a 6-year interval, in 29 primarily normoalbuminuric patients, aged 24 years at the second biopsy. These were examined with light and electron microscopy. Glomerular filtration rate, and effective renal plasma flow were determined with inulin and para-aminohippurate clearances. Urinary albumin excretion rate and the 24 ambulatory blood pressure were determined. Ten patients had developed microalbuminuria and/or hypertension; of these, six were treated with antihypertensive medication for 2 years or more. Significant increases were found in night time diastolic blood pressure and decreases in systolic and diastolic dipping. The glomerular volume, mesangial volume, mesangial matrix volume fraction and foot process width increased significantly. The group that was treated later for complications had the worst long-term metabolic control, thicker basement membranes and larger mesangial matrix and volume at the first biopsy, than the persistent normoalbuminuric group. During the follow-up, the untreated group with complications and the persistent normoalbuminuric group showed an increase in morphological parameters, whereas no progression occurred in the treated patients who also improved their metabolic control. In conclusion, the morphological parameters deteriorated in the normoalbuminuric patients and in those with complications, but were unchanged in the small antihypertensive-treated group with improved metabolic control.

Enhanced chemokine response in experimental acute Escherichia coli pyelonephritis in IL-1beta-deficient mice.

The aim of the present study was to investigate the effects of IL-1beta and Escherichia coli on the expression and secretion of MIP-2, the mouse equivalent to human IL-8, MCP-1 and RANTES in the kidneys of mice with acute pyelonephritis. Female Bki NMRI, as well as IL-1beta deficient mice and their wild-type littermates, were transurethrally infected with either E. coli CFT 073 or injected with NaCl 0.9% (w/v) and thereafter obstructed for 6 h. The Bki NMRI mice were killed at 0, 24, 48 h and 6 days and the IL-1beta-deficient mice at 48 h. Chemokine mRNA and protein levels peaked at 24 h for the tested chemokines with the mRNA expression localized in the tubular epithelial cells and for MIP-2 also in neutrophils. Obstruction per se, also induced a chemokine expression similar to E. coli infection although at a lower level. Interestingly, MIP-2 levels were higher in the IL-1beta deficient mice as compared with the wild-type littermates. Likewise, the inflammatory changes were more frequent and, when present, more widespread in the IL-1beta-deficient mice than in the wild-type mice. Stimulation of a human renal tubular epithelial cell line (HREC), A498 and of primary human mesangial cells (HMC) with the same bacterial antigen depicted gene expression of the same chemokines. A rapid release of IL-8 and MCP-1 was observed from both cell types. RANTES response was delayed both in the HREC and the HMC. We conclude that acute E. coli pyelonephritis induces a MIP-2/IL-8, MCP-1 and RANTES expression and secretion localized primarily to the epithelial cells and that this production is confirmed after in vitro stimulation with the same bacterial antigen of human epithelial and mesangial cells. Blockade of induction of chemokine response may thus be an attractive target for possible therapeutic intervention.

Effects of C-peptide on glomerular and renal size and renal function in diabetic rats.

BACKGROUND: Strict glycemic control and antihypertensive treatment may decrease but not eliminate the risk of progressive nephropathy in diabetic patients. C-peptide has been shown to exert beneficial effects on complications, including incipient nephropathy, in type 1 diabetes. METHODS: Renal effects of 14 days of intravenous infusion of C-peptide or NaCl (placebo) were studied in three groups of rats: one nondiabetic NaCl-treated (normal, N = 7), one streptozotocin diabetic NaCl-treated (D-placebo, N = 7), and one streptozotocin diabetic C-peptide-treated group (D-C-p, N = 7). Metabolic data and albuminuria were measured in metabolic cages every fourth day. After 14 days, the glomerular filtration rate (GFR) was measured by inulin clearance and available renal functional reserve (RFR) by glycine infusion, whereupon one kidney was perfusion fixed for morphological studies. RESULTS: Glucose levels were 36.7 +/- 1.3 and 34.0 +/- 1.7 mmol/L in the D-placebo and D-C-p groups, respectively. The D-placebo group presented a 32% (P < 0.001) larger glomerular volume than the D-C-p group. The D-placebo group also presented a significantly larger renal weight than the normal group in contrast to the D-C-p group. Urinary albumin excretion increased in the D-placebo group in contrast to the other groups. GFR was 1.72 +/- 0.12 mL/min (normal), 3.73 +/- 0.19 mL/min (D-placebo, P < 0.001 vs. normal) and 2.16 +/- 0.16 mL/min (D-C-p, nonsignificant vs. normal). Available RFR was 93 +/- 25% (normal), 10 +/- 4% (D-placebo, P < 0.05 vs. normal) and 57 +/- 13% (D-C-p, nonsignificant vs. normal) of basal GFR. CONCLUSIONS: Physiological doses of homologous C-peptide prevent the development of glomerular hypertrophy, albuminuria, and glomerular hyperfiltration in rats with experimentally induced diabetes.

Ambulatory blood pressure and heart rate in relation to kidney structure and metabolic control in adolescents with Type I diabetes.

AIMS/HYPOTHESIS: To evaluate the relationship between metabolic control, kidney function, ambulatory blood pressure and renal morphology in normoalbuminuric adolescents with Type I (insulin-dependent) diabetes mellitus. METHODS: Metabolic control, clearance of inulin and para-amino hippuric acid, 24 h ambulatory blood pressure and renal biopsies were studied in 41 patients who were 17.8 +/- 0.5 (SEM) years of age and 10.7 +/- 0.5 years after onset of diabetes. RESULTS: Glomerular filtration rate and filtration fraction were higher in diabetic patients than in healthy control subjects. At least one third of the patients had systolic and nocturnal diastolic blood pressures above the 90th centile. Basement membrane thickness was 512 +/- 17 nm, volume fraction of mesangial matrix 10.7 +/- 0.3% and foot process width 415 +/- 6 nm. Nocturnal mean arterial blood pressure, adjusted for body height and gender, correlated directly to the basement membrane thickness, the volume fraction of mesangial matrix and the foot process width. Multiple regression analysis showed that HbA1c, nocturnal heart rate and body height account for 44% of the variations in blood pressure. HbA1c, nocturnal heart rate and body height explained 57% of the variation in basal membrane thickness, and HbA1c, nocturnal heart rate and duration of diabetes explained 43% of Vv(matrix/glom). Actual renal function or urinary albumin excretion rate had no effect. CONCLUSION/INTERPRETATION: Nocturnal heart rate and nocturnal blood pressure, especially the mean arterial blood pressure, seem to be related to glomerulopathy changes in patients in whom persistent microalbuminuria has not yet developed. These findings suggest that a disturbance in sympathovagal balance could have a pathogenic effect.

Renal cytokine responses in acute Escherichia coli pyelonephritis in IL-6-deficient mice.

The aim of this study was to investigate the influence of IL-6 on mortality, bacterial growth and cytokine expression in experimental acute pyelonephritis. Female IL-6-deficient mice and their wild-type counterparts, 8-10 weeks old, were infected with Escherichia coli CFT 073 or injected with NaCl 0.9% (w/v) via the urethra and thereafter obstructed for 6 h. Animals were killed at 48 h, 6 days or 8 weeks and cytokine and bacterial renal levels were assessed at each time point. We found that IL-6-deficient mice had increased mortality and extensive renal bacterial growth on day 6, compared with wild-type mice (P < 0.05) and the histopathological changes were generally more severe and widespread in the IL-6-deficient mice. Peak mRNA expression of IL-1beta, IL-4, IL-10, IL-12 and interferon-gamma (IFN-gamma) occurred 48 h after infection in both IL-6 knock out and wild-type mice. Transforming growth factor-beta (TGF-beta) levels also peaked at 48 h in E. coli-infected wild-type mice, while in the IL-6-deficient strain both TGF-beta mRNA and protein levels were significantly lower at 48 h than wild-type levels (P < 0.0008 and P < 0.03, respectively) and remained stationary throughout the study period. Animals injected with NaCl 0.9% (w/v) displayed a similar decrease in TGF-beta expression (P < 0.02). When splenocytes from the IL-6-deficient mice were incubated with murine recombinant IL-6, TGF-beta levels increased to those of wild-type mice. No increase was observed when splenocytes from wild-type mice were incubated with the same doses of rIL-6. We therefore conclude that IL-6 plays an important role in bacterial clearance and directly influences the TGF-beta levels in experimental acute pyelonephritis. We also demonstrate that urethral obstruction per se induces an increase in TGF-beta the magnitude of which is decreased in IL-6-deficient mice.

Glomerular function and morphology in puromycin aminonucleoside nephropathy in rats.

BACKGROUND: The most characteristic manifestation of minimal-change nephropathy is podocyte cell process broadening. In a previous study in children from our unit, we found an inverse correlation between foot process width, glomerular filtration rate (GFR), and filtration fraction. The aim of the present study was to determine whether this relationship also existed in the puromycin aminonucleoside (PAN) experimental model. METHODS: Sixteen Munich-Wistar-Frömter male rats initially weighing median 247 g (range 171-286) were used. Four rats served as controls. The other 12 rats were divided into three groups receiving daily subcutaneous injections of 1, 1.67, and 2.5 mg PAN/100 g body weight respectively, for 6 days. GFR was determined by clearance of inulin and the fractional urine albumin excretion was measured. Standard stereological methods were used to estimate the glomerular volume, the mean foot process width and the length density of slit pores. RESULTS: GFR decreased with increasing PAN doses. The glomerular volume was increased in the group receiving the lowest PAN dose, while it was decreased in the group with the highest PAN dose, compared with controls. The fractional albumin excretion and the foot process width increased and the total slit pore length decreased with increasing doses of PAN. GFR correlated directly with the glomerular volume as did the foot process width with the fractional albumin excretion. The foot process width correlated inversely with the glomerular volume as did the glomerular volume with the fractional albumin excretion, and GFR with foot process width. CONCLUSIONS: The decreased GFR found in the nephrotic rats was inversely related to foot process width and directly related to glomerular volume, confirming our previous results in children in an early stage of the nephrotic syndrome.

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

Angiotensin II type 1 receptor antagonist (losartan) down-regulates transforming growth factor-beta in experimental acute pyelonephritis.

PURPOSE: To study the effect of an angiotensin II type 1 receptor antagonist, losartan, on cytokine expression, kidney growth and renal scarring in experimental acute pyelonephritis. MATERIALS AND METHODS: Female Bki NMRI mice, 8 weeks old were infected with E. coli CFT 073 via the urethra. Mice were divided into four groups; either left untreated; or treated with NaCl 0.9%; or an angiotensin II type 1 receptor antagonist, losartan, in doses of 1 mg. or 40 mg. /kg. body weight. The treatment was given daily i.p. for 48 hours, 3 weeks or 8 weeks respectively. Kidneys were weighed and sectioned for histo-pathology and in situ hybridization for mRNA of IL-1beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta and IFN-gamma. Homogenized kidneys were used for EIA of TGF-beta and bacterial growth. RESULTS: The mRNA expression of the studied cytokines generally peaked at 48 hours in all four groups. In animals treated with losartan, kidney TGF-beta, IFN-gamma and IL-6 decreased significantly at 3 and 8 weeks as compared with controls, untreated or those treated with NaCl, (p <0.005 respectively). Infection was associated with a declining kidney weight, also in the presence of losartan. A 50% reduction of the spread of renal scarring was observed in the losartan treated group, but this did however not reach significance. The proportion of kidneys showing bacterial growth was not influenced by losartan although in these kidneys the mean bacterial counts at 3 weeks were significantly higher in the losartan treated mice (p <0.006). CONCLUSIONS: Losartan is associated with downregulation of TGF-beta, IFN-gamma and IL-6 and may, in combination with antimicrobial therapy, reduce the risk of cortical renal scarring in recurrent acute pyelonephritis in infants.

Physiological and morphological effects of perfusing isolated rat kidneys with hyperosmolal mannitol solutions.

Recently, we were able to modify the glomerular charge barrier using perfusates with low and normal ionic strengths keeping the osmolality unchanged. The concentration of fixed charges was reversibly reduced from 35 to 12 mEq L-1 as the solution with low content of NaCl was introduced with no apparent effect on the size selectivity. It can be argued however, that the mannitol used for maintenance of osmolality may induce changes in glomerular permeability per se. To explore this possibility, isolated kidneys were perfused at 8 degrees with hyperosmolal mannitol solutions (560 mOsm) and compared with those perfused with standard albumin solutions (295 mOsm). The vascular resistance (PRU100) fell from 0. 14 +/- 0.01 to 0.11 +/- 0.01 mmHg min 100 g mL-1 as the mannitol solution was introduced (P < 0.001). As the blood pressure should remain unchanged, the flow was increased from 8 to 11 mL min-1. The glomerular filtration rate (GFR) increased by 50% from 320 +/- 40 to 490 +/- 20 microL min-1 g-1 (P < 0.001). Despite these changes in haemodynamical parameters, there was no significant change in the fractional clearance for albumin. Kidneys perfused with the mannitol solution showed well-preserved histology, while there was a conspicuous collapse of the cortical tissue and signs of tubular epithelial swelling with the standard perfusate. Moreover, all glomeruli were perfused in the mannitol group, as revealed by fluorescence of FITC dextran, while the distribution was uneven in the control kidneys. We conclude that perfusion of isolated kidneys with a hyperosmolal mannitol solution increased GFR by increasing the number of functionally active nephrons with no apparent effect on the glomerular barrier, a pattern differing from alteration of ionic strength.

Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM.

For the past 10-15 years all the children at our unit with insulin-dependent diabetes mellitus have been repeatedly followed-up with renal function tests. Renal biopsy, examined by light and electron microscopy, was included in the follow-up of 36 adolescents and young adults, aged 13-25 years, with a disease duration of 7-19 years. All subjects had undergone at least three renal function tests before biopsy and none had persistent microalbuminuria. Renal function was evaluated as glomerular filtration rate and effective renal plasma flow determined by clearances of inulin and para-amino hippuric acid. Glomerular filtration rate and filtration fraction were increased before and at the time of the biopsy. Glomerular basement membrane thickness (331-858 nm) and mesangial matrix volume fraction (7.4-17.1%) were increased. Long-term hyperfiltration and hyperperfusion before biopsy correlated inversely with mean glomerular volume. Increased filtration fraction before the biopsy correlated directly with mean of all HbA1c (r = 0.485, p < 0.01) and both variables correlated directly with mesangial matrix volume fraction, basement membrane thickness and structural index (r = 0.433, p < 0.01 and r = 0.626, p < 0.001, respectively). Urinary albumin excretion rate correlated directly with foot process width (r = 0.645, p < 0.001). By multiple regression analysis the most important variable for the increase in basal membrane thickness was the metabolic control while the mean of previous filtration fraction was most important for the increase in mesangial matrix volume. In conclusion, although none of the patients showed constant microalbuminuria, early diabetic structural changes were evident with basal membrane thickening and increased mesangial matrix volume. The structural changes related to long-standing hyperfiltration and poor metabolic control.

Cytokine gene expression during experimental Escherichia coli pyelonephritis in mice.

PURPOSE: We studied nine inflammatory and immunoregulatory cytokines in acute pyelonephritis and urethral obstruction in mice to better understand the processes underlying kidney inflammation and scarring. MATERIALS AND METHODS: Experimental acute pyelonephritis was established in Bki NMRI outbred mice by bladder inoculation of Escherichia coli, followed by 6 h urethral obstruction. The numbers of cytokine mRNA expressing cells for interleukin-1 (IL-1), IL-4, IL-6, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha), TNF-beta, transforming growth factor beta (TGF-beta) and interferon gamma (IFN-gamma) were determined in the kidneys and spleens from the infected, non-infected but obstructed and untouched mice using in situ hybridization with radio-labelled oligonucleotide probes at 12 h, 48 h and 6 d after release of the urethral obstruction. RESULTS: Kidney cell expression of IL-1, IL-6 and TNF-alpha mRNA was observed already at 12 h and persisted on day 6 in the infected animals. A significant proinflammatory cytokine response occurred also in the non-infected obstructed animals, albeit later and at lower levels. A marked increase of IL-4, IL-10, TGF-beta and IFN-gamma mRNA producing cells was also found in the kidneys of these two groups again with higher levels in the infected animals. Very high numbers of splenocytes expressing mRNA for IL-1 were observed especially in the infected animals. A high proportion of splenocytes further expressed mRNA for IL-6, TNF-alpha, IL-4, IL-10, IFN-gamma and TGF-beta, again with highest numbers in the infected group of animals. CONCLUSIONS: The present study extends previous knowledge about the local and systemic cytokine expression profiles during acute pyelonephritis and after urethral obstruction. Of particular interest was the marked kidney cell expression of mRNA for TGF-beta, presumed to be important both for obstructive and post-infectious renal scarring.

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats.

Diabetic nephropathy tends to develop more readily in patients with a family history of hypertension and/or disturbances in sodium transport across the plasma membrane. This prompted us to study the renal effects of diabetes mellitus in a rat strain which is predisposed to develop salt-sensitive hypertension, the Dahl salt-sensitive rat. Diabetes is associated with several aberrations in the renal handling of sodium, such as elevation of tubular Na+, K+ATPase activity. This effect was more pronounced in Dahl salt-sensitive than in Dahl salt-resistant rats. Severe renal lesions, characteristic of the advanced phase of diabetic nephropathy are very rarely observed in rats with streptozotocin diabetes. However, 2 months after induction of diabetes, the Dahl salt-sensitive rats had morphological signs of advanced glomerular disease. The urinary albumin concentration was very high, but did not correlate with the blood pressure. Non-diabetic Dahl salt-sensitive rats as well as Dahl salt-resistant diabetic and non-diabetic rats had little or no signs of glomerular disease and consistently very low urinary albumin concentrations.

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics.

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (VV %) and as the interstitium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P < 0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patient had clearly increased VV values, indicating increased interstitial fibrosis. The mean VV in renal allograft patients was 35% +/- 10% (normal < 16% +/- 5%) and the I/T ratio was 1.07 +/- 0.60 (normal < 0.24 +/- 0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.

Renal biopsy in children: indications, technique and efficacy in 119 consecutive cases.

Consecutive renal biopsies were performed on native kidneys in 109 children and adolescents, aged 0.1-19.8 (mean 9.9) years (119 biopsies). Bleeding diatheses were excluded or treated pre-operatively with intravenous desmopressin acetate. Biopsies were performed by a radiologist under ultrasound imaging, using an automated spring-loaded device allowing selection of the length of the needle movement and score size. Diagnostically adequate tissue was retrieved in 118 of 119 (99.2%) biopsy procedures; 24-h post-biopsy ultrasonography disclosed a small haematoma of the biopsied kidney in 26% of the cases. No correlation was seen between the occurrence of haematoma and (treated) prolonged bleeding time or a decrease in the haemoglobin level. No major complications occurred. Newly developed macroscopic haematuria was reported by 7% and micturition pain by 7% of patients. Painful body movements were reported by 37%. We conclude that the use of ultrasound imaging and an automated gunshot technique is a safe and efficient method for performing renal biopsies in paediatric patients.

Evolution of diabetic nephropathy in kidney grafts. Evidence that a simultaneously transplanted pancreas exerts a protective effect.

Thirty-six renal transplant biopsies were obtained from 20 diabetic patients 1-6.5 years after successful combined pancreatic and renal transplantation (PKtx). An additional 36 renal transplant biopsies were obtained from 30 diabetic recipients 1-6.8 years after kidney transplantation only (Ktx). Light microscopic lesions indicating diabetic nephropathy were evaluated by a semiquantitative score ranging from 0 to 9. Within 2.5 years after transplantation, light microscopy showed no or only slight diabetic changes in both groups (nephropathy score = 0-2). Later, a nephropathy score > or = 3 was seen in only 1 of 15 biopsies (6.7%) in the combined PKtx group, but in 11 of 24 biopsies (45.8%) in the Ktx group (P < 0.05). Twenty-eight of the biopsies from the PKtx group and 26 of them from the Ktx patients were examined with electron microscopic morphometry to evaluate the glomerular basement membrane thickness (BMT) and the relative volume of the mesangial tissue (Vv). Of the biopsies taken < 2 1/2 years after transplantation in PKtx patients, and of those similarly taken in the Ktx patients, 93.8% vs. 88.9% had BMT values within 2 SD of the normal (NS). Of the kidney biopsies taken > or = 2.5 years after transplantation, 91.7% in the PKtx group still had a normal BMT, while only 35.3% of the biopsies in the Ktx group had a normal BMT (P < 0.01). In the PKtx group, the Vv was normal in 12/16 (75.0%) of the biopsies taken < 2 1/2 years after transplantation, and in 9/11 (81.8%) of the biopsies obtained > or = 2.5 years after transplantation. In contrast, the Vv was normal in only 1/9 (11.1%) and 2/17 (11.8%) of correspondingly obtained biopsies from Ktx patients (biopsies < 2.5 years after transplantation, P < 0.01, and biopsies > or = 2.5 years after transplantation, P < 0.001, respectively). We conclude that a functioning pancreatic transplant can prevent or reduce the various signs of diabetic nephropathy that eventually develop in diabetic patients with a kidney graft only.

Experimental tissue transplantation using a biopsy instrument and radiologic methods.

RATIONALE AND OBJECTIVES: The liver is the most common site for metastases from gastrointestinal tumors, malignant melanoma, and primary liver tumors. Early detection or exclusion of a neoplasm is important for appropriate treatment. The authors introduce a method for tumor transplantation into the rabbit liver for experimental purposes. METHODS: VX2 tumor cells initially were grown intraperitoneally in a New Zealand white rabbit. Using an automated biopsy instrument with an ultrathin-wall biopsy needle, standardized tumor samples were taken from the peritoneal tumor. Using the same technique, a tumor sample was transplanted into the left liver lobe in a series of seven rabbits. RESULTS: Tumor growth was achieved in all cases at the implantation site. The tumors were well delineated from the surrounding liver parenchyma. Metastases occurred only at later stages. CONCLUSION: The method is almost nontraumatic to the animals, and the technical procedure is simple, time-saving, and provides well-localized tumor growth.

Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.

Kidney graft biopsies were performed 2-3 yr after transplantation in eight type I (insulin-dependent) diabetic patients who had previously been subjected to kidney transplantation (six patients) or combined kidney and segmental pancreas transplantation (two patients). In five of the six patients that had undergone only kidney transplantation, light microscopic examination of the graft biopsy revealed changes compatible with diabetic nephropathy, and electron microscopic morphometry showed a thickening of the glomerular basement membrane (GBM). In the two patients who had been subjected to combined pancreas and kidney transplantation, the kidney graft biopsy showed no light microscopic changes suggestive of diabetic nephropathy, and electron microscopy showed no thickening of the GBM. Thus, it appears to be possible to prevent the recurrence of diabetic nephropathy in human kidney allografts by simultaneous pancreas transplantation.