Toshihito Haba

Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism

Abstract. Although it is well known that chronic renal failure induces parathyroid hyperplasia, the pathogenesis and development of this parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of parathyroid tissue in nodular and diffuse hyperplasia in renal hyperparathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing parathyroidectomy for advanced renal hyperparathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperparathyroidism parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperparathyroidism are refractory to medical treatment, requiring parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery.

Diabetes mellitus after transplant: relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy.

Objective. The purpose of this study was to identify pretransplantation and posttransplantation indicators for the development of diabetes mellitus in the first 2 months after renal transplantation and to examine the influence of a cyclosporine A (CsA)-based versus a tacrolimus-based immunosuppressive regimen on these risk factors. Methods. Key variables associated with the development of posttransplant diabetes mellitus (PTDM) in the first 2 months after transplantation were assessed in 48 patients who underwent living-related renal transplantation and who were treated with a CsA-based or a tacrolimus-based immunosuppressive regimen. The insulinogenic index (I Index) and glucose infusion rate (GIR) were measures of insulin secretion and insulin sensitivity, respectively. Results. Eight patients developed PTDM. I Index (odds ratio, 0.000384) and GIR (odds ratio, 0.349) were significant risk factors for PTDM development. The cumulative steroid dose had a borderline association. PTDM developed in 4 of 28 CsA-treated patients and in 4 of 20 tacrolimus-treated patients. CsA therapy increased the mean I Index from 0.713±0.071 preoperatively to 1.130±0.140 postoperatively (P <0.01), whereas in tacrolimus-treated patients, I Index remained unchanged (1.09±0.264 preoperatively and 0.949±0.296 postoperatively; P =not significant). Age, duration of pretransplant dialysis, and body mass index did not predict PTDM development. All eight patients with PTDM had hypertension. Conclusions. Pre- and posttransplant abnormalities of insulin secretion and sensitivity are significant predictors of PTDM. Corticosteroid cumulative dose may affect the incidence of PTDM during the first 2 months after transplantation. CsA treatment increases insulin secretion in patients with a high pretransplant risk of PTDM.

Circadian Blood Pressure Rhythm Is Disturbed by Nephrectomy

We recently illustrated a close relationship between glomerular filtration rate and circadian rhythm of blood pressure (BP) in patients with chronic kidney disease. However, it remains undetermined from such cross-sectional findings which occurs first, the loss of kidney function or the lack of nocturnal BP fall. In the present study, we examined whether circadian rhythm of BP is affected by unilateral nephrectomy for kidney donation to clarify this important issue. Fifteen healthy subjects (4 men, 11 women; aged 33 to 65 years; mean age 55±2 years) who underwent unilateral nephrectomy for kidney donation were studied. Ambulatory BP was monitored for 24 h, while serum and urinary samples were collected to estimate creatinine clearance before and on the 8th day after nephrectomy. Then, changes in the night/day ratios of mean arterial BP were analyzed in relation to the decrease in 24-h creatinine clearance as a marker of glomerular filtration rate by nephrectomy. Creatinine clearance was reduced by 29% in average from 84±6 to 60±4 ml/min by nephrectomy, while 24-h mean arterial BP values were 91±3 and 94±4 mmHg (p=0.08) before and after nephrectomy. Although mean BP (daytime, nighttime or night/day ratio) was not altered significantly by nephrectomy, the decrease in creatinine clearance was positively correlated with the increase in the night/day ratio of mean BP (r=0.61, p=0.017). The decrease in creatinine clearance was not correlated with changes in either 24-h, daytime or nighttime mean BP. Our results suggest that unilateral nephrectomy disturbs the circadian rhythm of BP as a function of renal dysfunction without affecting absolute levels of BP. Non-dipping of BP seems the consequence of the loss of renal function, rather than the cause.

Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation.

Background. Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR. Methods. Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive. Results. All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P <0.05). Conclusions. C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

Clinical Features and Hyperplastic Patterns of Parathyroid Glands in Hemodialysis Patients With Advanced Secondary Hyperparathyroidism Refractory to Maxacalcitol Treatment and Required Parathyroidectomy

Abstract:  We have previously suggested that when parathyroid glands progress to nodular hyperplasia, secondary hyperparathyroidism (2HPT) may be refractory to medical treatments, including treatment with Maxacalcitol (OCT). In the present study we evaluated the clinical features and hyperplastic patterns of parathyroid glands in patients who underwent parathyroidectomy (PTx) after being withdrawn from OCT. One hundred and eighty‐seven advanced 2HPT patients who had been withdrawn from OCT and required PTx were enrolled. At the start of OCT treatment, the patients had a mean age of 55.3 years and had been receiving hemodialysis (HD) for a mean period of 149 months. At the start of OCT treatment and at PTx, the mean intact PTH (i‐PTH) levels were 772.8 ± 446.0 and 855.5 ± 420.5 pg/mL, respectively. The main reasons for withdrawal of OCT treatment were persistently high PTH (n = 148), hypercalcemia (n = 79), hyperphosphatemia (n = 65), and progressive symptoms (n = 60). We classified the parathyroid glands by hyperplastic pattern into four categories: diffuse hyperplastic gland (D), early nodularity in diffuse hyperplastic gland (EN), nodular hyperplastic gland (N), and single nodular gland (SN). The mean total excised gland weight was 2592.6 mg. Out of a total of 706 glands, 118 were classified as D, 66 as EN, 436 as N, and 86 as SN. All patients had at least one nodular hyperplastic gland or single nodular gland. The mean number of nodular hyperplastic glands and/or single nodular glands was 2.9. All hemodialysis patients with advanced OCT‐refractory 2HPT who underwent PTx had at least one nodular hyperplastic gland or single nodular gland.

Cardiovascular complications caused by advanced secondary hyperparathyroidism in chronic dialysis patients; special focus on dilated cardiomyopathy.

BackgroundThe frequency and prognosis of dilated cardiomyopathy (DCM) caused by secondary hyperparathyroidism (2°HPT) is not known. The purpose of this study was to determine the morbidity of DCM caused by 2°HPT and the efficacy of parathyroidectomy (PTx) in chronic dialysis patients with advanced 2°HPT was analyzed prospectively.MethodsBetween November 2000 and January 2003, 237 dialysis patients who underwent total PTx with forearm autograft at our department were enrolled in this study. Cardiac complications that existed before PTx were examined. Ten patients (4%) had DCM without valvular disease (VD) or ischemic heart disease (IHD). In these 10 patients with DCM before operation, we estimated left ventricular (LV) function at 6 months after PTx, according to echocardiography findings and clinical symptoms.ResultsSix months after PTx, left ventricular ejection fraction (LVEF) in these 10 patients was significantly improved, from 31.0 ± 9.8% before PTx, to 56.8 ± 13.5% (P = 0.0003), and left ventricular end-diastolic dimension (LVDd) was reduced, from 59.8 ± 9.7 mm to 46.3 ± 7.0 mm (P = 0.0014). The symptoms due to DCM and the fall of blood pressure that had occurred during dialysis were clearly improved after PTx.ConclusionsAdvanced 2°HPT can influence LV function, and in patients who suffered from DCM, LV function was dramatically improved by PTx. PTx should be performed immediately in patients with DCM caused by 2°HPT.

Reoperation for renal hyperparathyroidism

Abstract Reoperation for secondary hyperparathyroidism (HPT) due to uremia (2HPT) may be required among patients with persistent renal failure if not all parathyroid glands are removed at the initial operation. Between March 1981 and July 2001, altogether 1110 patients underwent total parathyroidectomy with forearm autograft for advanced 2HPT in our department. In this study, we evaluated the clinical features of patients who required reoperation and classified them into persistent HPT [the lowest intact parathyroid (PTH) level after initial operation remained higher than 60 pg/ml] and recurrent HPT (the lowest intact PTH level was normalized after surgery but reelevated became high enough to require reoperation). Removal of residual glands was indicated in 30 (2.7%) cases for persistent or recurrent HPT. All remaining glands were detected by preoperative imaging diagnoses. In 44 (4.0%) patients persistent HPT was recognized and in 15 of them (1.4% of all cases) reoperation was required. In 11 cases, the responsible glands were supernumerary ones removed from the mediastinum. In 4 cases, the glands were resected from the neck. In 15 cases (1.4%), reoperation was performed for recurrent HPT when residual glands were left either in the neck or in the thymic tongue. In all but one case, the missed glands were supernumerary. This study reveals that it is often difficult to avoid persistent HPT induced by mediastinal supernumerary glands and recurrent HPT caused by small glands left in the neck. Our findings indicate that patients with uremia should be closely followed considering the possibility that persistent or recurrent HPT may occur after parathyroidectomy.

Parathyroidectomy for patients with renal hyperparathyroidism refractory to calcitriol pulse therapy

Since Slatopolsky reported that the intermittent high doses of calcitriol could suppress PTH secretion effectively in secondary hyperparathyroidism due to chronic renal failure, intravenous and oral calcitriol pulse therapy have enjoyed widespread acceptance. However, patients with far-advanced renal hyperparathyroidism are refractory to calcitriol pulse therapy and parathyroidectomy is required. Out of 157 cases who underwent parathyroidectomy for renal hyperparathyroidism between January 1991 and April 1994 at our department, 37 cases (23.6%) required parathyroidectomy because they were refractory to calcitriol pulse therapy. From evaluation of the preoperative and histopathological findings, we assessed the limitations of calcitriol pulse therapy. Our criteria as indications for parathyroidectomy in renal hyperparathyroidism include high PTH (C-PTH ≧20 ng/ml or M-PTH ≧50 ng/ml), the detection of swollen parathyroid glands by image diagnosis, high turnover bone or osteitis fibrosa findings on X-ray film and being refractory to medical treatment. In all but one case, the PTH level exceeded our citeria. In 4 cases, ectopic calcification, especially vascular calcification advanced and patients complained of ischemic symptoms. We emphasize that parathyroidectomy should be performed in patients with our criteria, before progression of vascular calcification and skeletal deformity. Some, 95% of these cases had more than one nodular hyperplastic glands. We estimated by previous pathophysiological examination that nodular hyperplasia was aggressively hyperplastic, with a high growth potential, abnormal PTH secretion and a diminished number of vitamin D receptors.These clinical and pathophysiological results imply that when renal hyperparathyroidism is advanced, our criteria for parathyroidectomy indication are met, or when the parathyroid glands develop nodular hyperplasia, even calcitriol pulse therapy is not effective for hyperparathyroidism and so parathyroidectomy is required.

Acute humoral rejection of kidney allografts in patients with a positive flow cytometry crossmatch (FCXM)

The patients with a positive flow cytometry crossmatch (FCXM) are categorized as a high‐risk group causing hyperacute or accelerated acute rejection after kidney transplantation. According to the successful results of ABO‐incompatible renal transplantation, we have performed the living related transplant operations in the recipients with positive FCXM for donor T cells, but having a negative complement‐dependent lymphocytotoxic reaction test. We have followed the clinical course of 4 FCXM‐positive patients, and 2 of them have developed acute humoral rejection. We report the strategies for FCXM‐positive living kidney transplantations and the characteristics of pathological findings of acute humoral rejection in FCXM‐positive renal transplants. We have had few episodes of acute humoral rejection in ABO‐incompatible kidney transplantations under immunosuppressive regimens, including cyclophosphamide, but 2 patients of 4 with FCXM‐positive kidney transplantations developed acute humoral rejections. The differences in immunosuppressive regimen between ABO‐incompatible and FCXM‐positive kidney transplantations concern anti‐lymphocyte globulin (ALG) and splenectomy. We have not performed splenectomy and ALG administration in FCXM‐positive kidney transplantations. Severe acute rejection episodes have been experienced on post‐operative days 7 and 9 in 2 of 4 FCXM‐positive recipients. The early acute rejection episodes were clinically and pathologically diagnosed as typical humoral rejections. We have examined an immunofluorescent study to prove the diagnosis of humoral rejection in FCXM‐positive kidney transplantations; both immunoglobulin M and C3 were positive for the whole course of humoral rejection. The 2 patients with acute humoral rejection recovered after treatment with double filtration plasmapheresis or plasma exchange to remove their anti‐donor antibodies. The gold standard of success in FCXM‐positive kidney transplantations is to suppress the production and reduce the level of anti‐donor antibodies after transplant operations.

Calciphylaxis: A Rare Complication of Patients Who Required Parathyroidectomy for Advanced Renal Hyperparathyroidism

Calciphylaxis is a relatively rare but life-threatening complication in uremic patients. Clinical findings and prognosis were evaluated in six patients who developed calciphylaxis from a group of 1499 patients who underwent parathyroidectomy (PTx) for advanced renal hyperparathyroidism (HPT) in our department from July 1972 to July 2003. The frequency of calciphylaxis was 0.40% (6/1499). Two patients were women and four were men. The mean age was 50.5 years, and the mean duration of hemodialysis (HD) treatment was 14.0 years. In five of six patients, calciphylaxis was classified as distal type; in one case, as proximal type. In three patients, calciphylaxis was diagnosed at the time for PTx. In two patients, calciphylaxis was identified after PTx, although the serum parathyroid hormone (PTH) level was within the appropriate range for dialysis patients. In two patients, calciphylaxis improved after PTx, but two patients required leg and toe amputations after PTx. In one patient with the proximal type of calciphylaxis, the condition occurred when a high PTH level recurred after the initial PTx. The patient died as a result of a serious infection due to uncontrollable skin ulcers. Calciphylaxis is a rare complication in patients who require PTx for renal HPT. Especially the proximal type has a poor prognosis. High levels of the Ca × P product and/or PTH are risk factors. Therefore, this syndrome should be kept in mind and attention should be paid to reduce risk factors. It is important that PTx being performed at the right time in patients with advanced renal HPT refractory to medical treatment.