Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive enzyme defect of purine metabolism that usually manifests as 2,8-dihydroxyadenine (2,8-DHA) nephrolithiasis and more rarely chronic kidney disease. The disease is most often misdiagnosed and can recur in the renal allograft. We analyzed nine patients with recurrent 2,8-DHA crystalline nephropathy, in all of whom the diagnosis had been missed prior to renal transplantation. The diagnosis was established at a median of 5 (range 1.5-312) weeks following the transplant procedure. Patients had delayed graft function (n=2), acute-on-chronic (n=5) or acute (n=1) allograft dysfunction, whereas one patient had normal graft function at the time of diagnosis. Analysis of allograft biopsies showed birefringent 2,8-DHA crystals in renal tubular lumens, within tubular epithelial cells and interstitium. Fourier transformed infrared microscopy confirmed the diagnosis in all cases, which was further supported by 2,8-DHA crystalluria, undetectable erythrocyte APRT enzyme activity, and genetic testing. With allopurinol therapy, the allograft function improved (n=7), remained stable (n=1) or worsened (n=1). At last follow-up, two patients had experienced allograft loss and five had persistent chronic allograft dysfunction. 2,8-DHA nephropathy is a rare but underdiagnosed and preventable disorder that can recur in the renal allograft and may lead to allograft loss.

Chronic renal failure secondary to 2,8-dihydroxyadenine deposition: the first report of recurrence in a kidney transplant.

We report a case of adenine phosphoribosyltransferase deficiency in which the initial presentation was chronic renal failure. Diagnosis was made after infrared microscopy analysis of microcrystalline deposits on a kidney allograft biopsy specimen. This type of presentation is rarely seen, the most frequent manifestation of this disease being urolithiasis. This is the first report of recurrence of the microcrystalline nephritis in a kidney transplant with subsequent loss of allograft function.

Effect of 22-oxa-calcitriol on calcium metabolism in rats with severe secondary hyperparathyroidism.

The purpose of the present study was to examine the effect of a two day and a five day administration of 22-oxa-calcitriol (OCT) on calcium metabolism in rats with advanced chronic renal failure and severe secondary hyperparathyroidism. A first series of 27 uremic rats received either placebo, OCT or calcitriol (0.3 microgram i.p./rat) 48 and 24 hours before sacrifice. A second series of 18 uremic rats received either placebo, OCT (0.3 microgram i.p./rat) or calcitriol (0.05 microgram i.p./rat) for five days. We found that after 48 hours (series 1) both calcitriol and OCT increased blood ionized calcium (Ca2+) as compared to vehicle (1.23 +/- 0.04 and 1.10 +/- 0.02 mM, P < 0.01 and P < 0.05, respectively vs. control, 1.02 +/- 0.03 mM). Duodenal Ca transport (S/M) using the everted gut sac technique was not stimulated by OCT, even though it increased from 2.8 +/- 0.4 to 7.0 +/- 0.6 (P < 0.01) with calcitriol. In contrast, duodenal calbindin-D9k mRNA expression and protein content increased to a similar extent with OCT and calcitriol. Calcitriol was more potent in reducing plasma iPTH1-34 levels than OCT: 344 +/- 75 pg/ml (calcitriol) versus 632 +/- 46 pg/ml (OCT) compared with 897 +/- 74 pg/ml (control), P < 0.01. In the second series of rats, the injection of OCT (0.3 microgram i.p./rat) over five days was less effective than the lower dose of calcitriol (0.05 microgram i.p./rat) in reducing circulating iPTH: 110 +/- 26 (calcitriol) and 281 +/- 64 (OCT) versus 624 +/- 135 pg/ml (control), P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

A circulating inhibitor of the RBC membrane calcium pump in chronic renal failure.

A humoral inhibitor of the membrane calcium pump was studied in plasma from 28 normal controls, 33 patients receiving long-term hemodialysis, and 26 with chronic renal failure (CRF; creatinine clearance range was 6 to 97 ml/min). Calcium pump activity was measured as the rate of Sr2+ efflux in normal erythrocytes (RBCs) loaded with Sr2+ (a substitute of Ca2+ in the calcium pump). Plasma, and plasma ultrafiltrates from hemodialysis patients strongly inhibited calcium pump activity compared with controls without plasma (36 +/- 18 vs. 25 +/- 12, %INHIBITION/CONTROL, P < 0.05). Inhibition markedly decreased with acute hemodialysis (16 +/- 12 vs. 5 +/- 14, %INHIBITION/NORMAL PLASMA, N = 15, P < 0.001). In CRF, degree of inhibition correlated with the serum creatinine concentration (r = 0.75, P < 0.001). A kinetic study showed that plasma decreased the maximal rate of the Ca2+ pumps (Vmax) without affecting the apparent affinity for internal cations (KSr). Moreover, the plasma inhibitory factor had a low molecular weight, and was dialyzable and heat stable. In conclusion, we found evidence for an RBC membrane calcium pump inhibitor in uremic plasma, which correlates with the degree of renal insufficiency. Possibly, it may increase calcium content in RBCs and other cells and could thus be related to uremic toxicity and/or hypertension.

Plasma kinetics of 125I-labelled amyloid P component in beta 2M amyloidosis: a possible approach to quantitate disease activity.

Dialysis amyloidosis is one of the most incapacitating complications of long-term dialysis treatment. Quantitative assessment of amyloid deposition using radiolabelled tracers has been recently proposed but convincing evidence of its validity in uraemic patients remains to be provided. We studied the plasma kinetics of i.v. administered 125I-labelled serum amyloid P component (125I-SAP) in 20 chronic haemodialysis patients compared with those of nine healthy volunteers and three non-dialysed patients with systemic amyloidosis. Plasma clearance of the tracer was abnormal in 17 of 20 dialysis patients in whom plasma radioactivity declined in a bi-exponential mode, in contrast to the single-exponential slope observed in all healthy controls. 125I-SAP plasma half-life of the second component, probably reflecting metabolic clearance, was significantly prolonged in these dialysis patients compared with the healthy controls (35.3 versus 24.6 h, P < 0.001). Among the long-term haemodialysis patients the calculated extravascular distribution of 125I-SAP was significantly greater in those with severe arthropathy than in asymptomatic patients. These findings demonstrate for the first time that SAP clearance is disturbed in haemodialysis patients due to both failing renal elimination and retention in extravascular sites. The extravascular diffusion is greatly enhanced in patients with clinical evidence of amyloidosis. Therefore the study of plasma 125I-SAP kinetics promises to be a valuable tool to quantitate the extent of amyloidosis.

Short- and long-term efficacy of total parathyroidectomy with immediate autografting compared with subtotal parathyroidectomy in hemodialysis patients.

A retrospective study was performed in chronic hemodialysis patients comparing total parathyroidectomy (PTX) followed by immediate autografting (IA) (total PTX+IA) with subtotal parathyroidectomy (subtotal PTX). One hundred six patients with severe, uncontrolled hyperparathyroidism were referred to this center and underwent surgery during the period from 1980 to 1990. Long-term follow-up after PTX was available in 49 of them: 28 patients had total PTX+IA and 21 had subtotal PTX. The two surgical methods were evaluated with respect to preoperative severity of hyperparathyroidism, immediate postoperative results, and long-term parathyroid status, as evaluated by an RIA measuring intact immunoreactive parathyroid hormone (intact iPTH; normal values, 15 to 65 pg/mL). The initial degree of hyperparathyroidism was comparable in the two groups. An excellent short-term control of hyperparathyroidism was achieved in the great majority (95%) of patients with either surgical procedure. However, long-term normalization of parathyroid gland activity was achieved in only one third of patients whereas 33% had elevated intact iPTH levels (> 130 pg/mL; i.e., higher than twice the upper range of normal) and 32% had low intact iPTH levels (< 15 pg/mL), consistent with permanent hypoparathyroidism. No difference was found in the immediate failure rates: 0 of 28 cases after total PTX+IA compared with 2 of 21 cases after subtotal PTX. Similarly, long-term intact iPTH levels were comparable: 400 +/- 105 versus 212 +/- 82 pg/mL (mean +/- SE; P = not significant). Interestingly, long-term serum intact iPTH levels were higher in patients with nodular (N = 18) than with diffusely (N = 26) hyperplastic glands: 556 +/- 146 versus 126 +/- 52 pg/mL (P < 0.001) and recurrence of hyperparathyroidism was more frequent with nodular hyperplasia (11 of 18) than with diffuse hyperplasia (4 of 26) (P < 0.02). In conclusion, although excellent short-term results were obtained with both procedures, satisfactory long-term control of parathyroid gland function was achieved in only one third of the patients, the other two third remaining either hypoparathyroid or developing recurrent hyperparathyroidism. Last, the histological subtype of parathyroid glands was partially predictive of the recurrence of hyperparathyroidism.