Gunnela Nordén

Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30).

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

Low absolute glomerular filtration rate in the living kidney donor: A risk factor for graft loss

Background. There is no defined lower acceptable level of glomerular filtration rate (GFR) in potential living kidney donors. Considerations focus on the risk for the donor. We wanted to evaluate the outcome in the recipient in relation to the GFR of the living donor. Methods. There were 344 living donated kidney transplantations performed January 1985 through February 1997 which were evaluated. Two thirds of the donors shared one haplotype with the recipient and 15% shared both. Of the donors 18% were above age 60. The median follow-up time (until graft loss) was 63 months. Before nephrectomy, the donors′ GFR had been measured by isotope clearance. Results. Twenty-six donors (7.6%) had an absolute GFR below 80 ml/min, i.e. not adjusted to 1.73 m2 body surface area (BSA). Cumulative graft survival, censored for graft loss because of death of the patient, was significantly reduced in recipients of grafts from donors with GFR <80 ml/min. A significant correlation between GFR and donor age was observed, but donor age per se was not identified as a risk factor for graft loss. In a Cox stepwise proportional hazards analysis, the relative risk for graft loss was 2.28 with a GFR below 80 ml/min (confidence interval 1.183–4.383, P =0.014) and with sharing one or both haplotypes 0.56 (0.313–0.988, P =0.046) and 0.36 (0.139–0.912, P =0.03), respectively. Conclusions. An absolute GFR below 80 ml/min in the living donor more than doubles the risk of graft loss. This fact should be considered when definitions of acceptable limits for donor GFR are discussed.

Blood group A and B antigen expression in human kidneys correlated to A1/A2/B, Lewis, and secretor status.

Background. In the revived interest in crossing ABO barriers in organ transplantation renal A/B antigen expression has been correlated with donor ABO, Lewis, and secretor subtype to predict antigen expression. Methods. A/B antigen expression was explored by immunohistochemistry in LD renal biopsies. Donor A1/A2/B, Lewis, and secretor status were determined by serology and polymerase chain reaction. Results. In the renal vascular bed, three distinct A antigen expression patterns with a major, minor, and minimal staining distribution, and intensity (designated as types 3+, 1+ and (+) respectively) were identified. Type 3+ had a strong A antigen expression in the endothelium of arteries, glomerular/peritubular capillaries and veins. The type 1+ showed an overall weaker antigen expression, whereas type (+) had faint staining of peritubular capillaries only. In all cases, distal tubular epithelium was focally stained, whereas proximal tubules were negative. Type 3+ were all from blood group A1 subtype individuals while A2 cases expressed either a 1+ or (+) pattern. The secretor gene did not appear to influence renal A antigen expression. All B kidneys examined showed a B antigen pattern slightly weaker but otherwise similar to A type 3+. Conclusion. Renal vascular A antigen expression correlates to donor A1/A2 subtypes, whereas B individuals show one singular antigen pattern. From antigen perspective, A1 and B donors are a “major” and A2 individuals a “minor” antigen challenge in ABO-incompatible renal transplantation.

Estimation of renal function in diabetic nephropathy. Comparison of five methods.

Plasma as well as renal clearance of 51Cr-EDTA, serum creatinine, plasma beta-2-microglobulin and endogenous creatinine clearance were compared and evaluated in patients with diabetic nephropathy and in control patients with renal disease of other origin. The difference between the plasma clearance and the renal clearance of 51Cr-EDTA, that is the extrarenal clearance, was found to be higher in diabetics than in control patients (7.0 vs. 3.5 ml/min; p less than 0.001). The serum creatinine correlated well with the glomerular filtration rate (GFR), but in the individual case the GFR was not at all predictable from serum creatinine. The plasma beta-2-microglobulin did not correlate better than serum creatinine to 51Cr-EDTA clearance, and did not permit an earlier diagnosis of renal insufficiency. Endogenous creatinine clearance overestimated GFR by 0-180%. Due to residual urine, the coefficient of variation was higher in diabetic patients than in controls, but the effect of this imperfection was reduced by using multiple collection periods. In conclusion, the renal clearance of 51Cr-EDTA was found to be preferable to the other methods.

ABO‐incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti‐CD20 antibody treatment

Abstract: Background: Blood group ABO‐incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO‐incompatible LD renal transplantation using specific anti‐A/B antibody (Ab) immunoadsorption (IA) and anti‐CD20 monoclonal Ab (mAb) treatment.

Clinical risk factors for recurrence of IgA nephropathy

No clinical risk factors for recurrence of immunoglobulin A (IgA) nephropathy in kidney transplants have been defined. This is a single‐centre retrospect analysis of recurrence in 104 first kidney transplant patients with biopsy‐verified IgA nephropathy. Fifty patients had living donors. All but an identical twin were treated with cyclosporin A. The median follow‐up time was 5 yr. Graft biopsies had been obtained from 35 grafts later than 6 months after transplantation, due to deteriorating graft function or gross proteinuria. Thirteen biopsies showed mesangial glomerulopathy – proliferative in eleven cases – with IgA deposits. Recurrence caused failure of six grafts. Eleven grafts with recurrence were from living donors (p=0.005). No specific human leukocyte antigen (HLA) was identified as a risk factor. Known duration of original disease until end‐stage renal failure was significantly shorter in patients with recurrence (median 5 yr, range 0–25 yr) compared with those without (median of 10 yr, range of 0–37 yr) (p=0.015). Cumulative graft survival was not reduced in living versus cadaveric donor recipients.

Morphologic High-Risk Factors in IgA Nephropathy

Aim: Morphologic risk factors for developing end-stage renal failure (ESRD) due to IgA nephropathy may be difficult to identify in populations where the course is benign in the vast majority. Ours is a high-risk population. Methods: Protocols of 67 biopsies from native kidneys of kidney transplant patients with IgA nephropathy were reevaluated with respect to the prevalence of certain structural findings. Time points for onset of symptoms, biopsy procedure, and ESRD were recorded. Results: Features seen with more than expected frequency were: extracapillary proliferation in 49%, cellular infiltrates in the interstitium in 89%, marked tubular atrophy in 54%, and IgA deposits in the peripheral capillary loops in 71%. With extracapillary proliferation the remaining time to ESRD was 3.5 ± 3.2 versus 7.0 ± 4.2 years without (p < 0.0004). With marked tubular atrophy the remaining time was 3.5 ± 2.7 and 8.2 ± 4.2 years without (p = 0.0002). Cellular infiltrates in the interstitium also signified shorter progression (p = 0.009). Except for the presence of IgA in the periphery, no finding by immune fluorescence was more frequent than expected or correlated with progression. Conclusion: Extracapillary proliferation, interstitial cellular infiltrates, marked tubular atrophy, and IgA deposits in the peripheral capillary loops indicate risk of progressive renal failure in IgA nephropathy, but other findings by immune fluorescence do not.

Diabetic nephropathy: Is dietary protein harmful?

The suggested harmful effect of dietary protein on renal function in diabetic nephropathy was tested in three groups of insulin-dependent diabetic patients: 1) 10 patients without signs of nephropathy in spite of at least 30 years of diabetes; 2) 11 patients with nephropathy and reduced but stable glomerular filtration rate (GFR) (decline less than 4 ml/min per year [mean 1.8] during the last 2 years); 3) 10 patients with progressive nephropathy with GFR declining by an average of 11 ml/min per year. Dietary protein intake was estimated from a dietary history interview, as well as from urinary excretion of nitrogen (mean = 4.7 samples). Both methods showed a wide range of protein intake in all three groups of patients (0.6-2.3 g/kg body weight [BW]). The mean values did not differ between the groups, 1.30, 1.34, and 1.24 g/kg BW by interview, and 1.20, 1.10, and 1.13 g based on urinary nitrogen levels. There was no correlation between rate of decline of GFR and protein intake, even in those patients with no or minimal decline. These results do not support the hypothesis that dietary protein is a factor of importance in the development or progression of human diabetic nephropathy.

Cure of zygomycosis caused by a lipase-producing rhizopus rhizopodiformis strain in a renal transplant patient

A 40-year-old man with renal failure due to membranous glomerulonephritis received a cadaveric renal transplant and immunosuppressive therapy with cyclosporine, azathioprine and steroids. Initially the transplantation was successful. 12 days after the transplantation, however, serous secretion appeared in the wound. Later, black necrosis was seen. Fungal culture showed growth of a zygomycete species. Rhizopus rhizopodiformis, with high in-vitro resistance to amphotericin B, flucytosine, fluconazole, ketoconazole and itraconazole. The MIC value for the allylamine derivative SF86-327 (Exoderil) was 1.6 micrograms/ml. Microscopic examination of sections from a surgical revision showed necrosis of the fat tissue and massive hyphal invasion of the perirenal fat, which contained semi-crystalline material anisotropic as seen in polarized light and characteristically staining with rubeanic acid. These histological data indicate a lipase-induced in-vivo splitting of lipids into fatty acids. In-vitro R. rhizopodiformis showed very high extracellular lipase production. 11 days after initiation of amphotericin B therapy cultures and sections remained positive for rhizopus. Amphotericin B was therefore supplemented with Exoderil orally, cyclosporine and steroids were maintained, and azathioprine was discontinued. The wound granulated, shrank, and healed completely in 10 weeks.

Type 2 Diabetic Patients with Nephropathy in a Scandinavian Kidney-Transplant Population

Twenty-seven patients in a cohort of 1000 who received kidney transplants in Göteborg 1985-1993 were found to have diabetes of Type 2 as primary cause of renal failure. All took insulin at the time of transplantation. Four received concomitant pancreas transplants. Mean age was 53 years (range 40-64). All but four were men. Average waiting time on dialysis was less than a year. One year after transplantation 24 of 27 (89%) were alive, 22 (81%) with functioning grafts. However, during follow-up for a total of 51 +/- 27 months 9 (33%) of the diabetic patients died, mainly of cardiac disease or sudden death (n = 7), compared with 17% of matched controls (NS). Diabetic patients had an increased risk of death with a functioning graft, 6/27 versus 3/54 controls (p = 0.02). Graft survival rates were 56% and 65%, respectively (NS). Morbidity was dominated by cardiovascular events and foot ulcers leading to amputations (six patients) and septicaemia. During follow-up body mass index increased from 24.6 +/- 3.0 to 25.9 +/- 3.4 kg/m2. There was no difference in HbA1c-values although one pancreas-transplanted patient remained insulin-independent. The mortality and morbidity rates in this positive selection from a much larger population of Type 2 diabetic patients supports continued restriction in the acceptance rate for transplantation. Type 2 diabetes is not an indication for pancreas transplantation, which is one reason to distinguish this form of diabetes.