Renal arteriolar hyalinosis, not intimal thickening in large arteries, is associated with cardiovascular events in people with biopsy-proven diabetic nephropathy.

AIMS: Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. METHODS: This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. RESULTS: Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. CONCLUSIONS: Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model.

Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3% adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75% adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6% lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6% calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated ß-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.

Rapid deterioration of renal insufficiency after magnetic resonance imaging with gadolinium-based contrast agent.

Gadolinium (Gd)-based contrast media were introduced as alternatives to iodinated media for magnetic resonance imaging (MRI). Although originally thought to be non-nephrotoxic, Gd-based contrast media have recently been reported to be associated with acute kidney injury. The underlying mechanism of Gd-induced renal injury is not completely understood. We report an 80-year-old patient with buccal mucosa cancer for whom MRI with Gd-based contrast agent was conducted 3 times within 3 weeks. The patient developed rapid deterioration of preexisting renal insufficiency, and developed uremic symptoms and pulmonary edema. The patient was hemodialyzed 3 times. This resulted in improvement of renal function and clinical symptoms. This case emphasizes the potential nephrotoxicity of Gd-based contrast media and suggests that renal insufficiency, diabetes mellitus, old age and high dose of Gd-based contrast medium are risk factors for acute kidney injury.

Reversible posterior leukoencephalopathy syndrome in a patient with severe uremic encephalopathy.

A 59-year-old male presented at our hospital with disturbance of consciousness. He had severe neurological disturbances associated with uremia caused by severe renal insufficiency. Cranial computed tomography (CT) was normal on admission. FLAIR-weighted MRI showed increased signal intensities bilaterally in the cortical and subcortical areas of the occipital lobe. Repeated hemodialysis resulted in improvement of the clinical symptoms and blood chemistry, and normalization of the MRI findings. Although the patient was discharged without neurological deficit, he had to be maintained on regular intermittent hemodialysis due to persistent renal failure. These reversible neuroradiological abnormalities may have been caused by reversible brain edema, but other pathoetiological factors should be also considered, such as abnormalities of cerebral metabolism and effects of uremic toxins.

Reversible primary hypothyroidism in Japanese patients undergoing maintenance hemodialysis.

BACKGROUND/METHODS: The presence or absence of hypothyroidism was assessed in 152 consecutive Japanese patients with end-stage renal disease on hemodialysis. Eight patients who had undergone treatment for thyroid disease before starting hemodialysis therapy, and 3 patients with amyloidosis due to rheumatoid arthritis were excluded. RESULTS: Of the remaining 141 hemodialysis patients, 14 (9.9%) (9 males and 5 females, aged 69.1 A+/- 8.8 years with a mean duration of hemodialysis of 69 A+/- 51 months) were in a hypothyroid state, defined as a thyroid-stimulating hormone (TSH) level > 5 mU/l. Antithyroid peroxidase antibodies were positive in only 1 of the 14 patients, while antithyroglobulin antibodies were negative in all of these patients. After iodide restriction, the serum TSH level decreased in all the patients from a mean of 16.49 A+/- 22.80 to 4.44 A+/- 3.35 mU/l after 1 month, 4.25 A+/- 2.24 mU/l after 2 months and 3.97 A+/- 2.22 mU/l after 3 months. The 3 months of iodide restriction were also associated with decreases in systolic blood pressure (142 A+/- 19 to 125 A+/- 16 mmHg, p < 0.05), diastolic blood pressure (79 A+/- 13 to 72 A+/- 9 mmHg, p < 0.05) and thyroid gland volume estimated by ultrasonography (13.7 A+/- 6.3 to 11.6 A+/- 5.2 ml, p < 0.05). CONCLUSION: A high prevalence of reversible primary hypothyroidism was found in end-stage renal disease patients on hemodialysis. Retention of excess iodide may be the mechanism responsible for reversible hypothyroidism rather than immunological perturbations. It is, therefore, recommended to attempt iodide restriction before starting l-thyroxine replacement therapy.

Glomerular crescent formation in renal amyloidosis. A clinicopathological study and demonstration of upregulated cell-mediated immunity.

BACKGROUND: Several studies examined glomerular crescents associated with renal amyloidosis. However, the incidence of crescents, the association between the 2 lesions, treatment and outcome are still controversial. PATIENTS AND METHODS: We studied 107 consecutive biopsies of renal amyloidosis, and found cellular or fibrocellular crescents in 13 cases (12.1%). We investigated the clinical characteristics, pathological findings, treatment and outcome. We also performed immunohistochemical staining using T cell, macrophage and osteopontin (OPN) markers. RESULTS: Amyloid was of the AA type in 12 cases, and all patients had rheumatoid arthritis. Six cases with AA amyloidosis had crescentic glomerulonephritis (CrGN), and 5 presented with rapidly progressive glomerulonephritis (RPGN). The percentage of crescents correlated negatively with serum albumin (r = -0.83, p < 0.001), and positively with serum creatinine (r = 0.72, p < 0.01) and urinary protein excretion (r = 0.85, p < 0.001). All RPGN patients developed end-stage renal disease, and 2 patients died shortly after treatment. Microscopic examination showed inflammatory cells within the glomeruli, and immunohistochemical study revealed abundant intrarenal T cells and macrophages in CrGN cases. Strong expression of OPN was observed in tubular epithelial cells and intraglomerular macrophages. CONCLUSION: Cellular immune responses play a crucial role in glomerular crescents in renal amyloidosis. Immunosuppressive treatment is often ineffective and raises the risk of complications in CrGN with abundant glomerular sclerosis and tubulointerstitial injury.

Two cases of calciphylaxis treated by parathyroidectomy: importance of increased bone formation.

Calciphylaxis (calcific uremic arteriolopathy) is a poorly understood and highly morbid syndrome of both vascular calcification and skin necrosis. The main histopathological finding is calcium deposits within arteriolar and small vessel walls, showing endovascular fibrosis associated with fat necrosis. The therapeutic strategy is to normalize the high calcium-phosphate products (Ca x P). When calciphylaxis is complicated with advanced renal hyperparathyroidism (HPT), parathyroidectomy (PTX) should be performed promptly. However, for patients with low PTH level, calciphylaxis is unresponsive to PTX, and such an approach may worsen hyperphosphatemia and hypercalcemia. We report two patients with calciphylaxis confirmed by skin biopsy. PTX was performed in both patients based on high PTH levels. PTH and Ca x P level decreased in both patients post PTX. In Case 1, the skin ulcers gradually improved and almost disappeared after PTX. However, in Case 2, new ulcers appeared after PTX. In Case 1, alkaline phosphatase (ALP) after PTX was approximately twice its level before surgery and PTX resulted in normalization of uptake on bone scintigraphy. However, no rise in ALP was noted in Case 2, probably due to long-term use of aluminum, which prevented bone formation. These findings suggest that differences in the extent of bone formation explain the different response in post-PTX ulcer healing.

Candida glabrata fungemia in a diabetic patient with neurogenic bladder: successful treatment with micafungin.

A 69-year-old man was transferred to our hospital because of fever and acute renal failure. 5 weeks prior to admission, he was admitted to another hospital and treated with several antibiotics including vancomycin, but fever did not subside and renal dysfunction showed rapid progression. On admission, laboratory findings revealed pyuria, inflammatory changes, acute renal failure, and disseminated intravascular coagulation (DIC). Computed tomography showed left ureteral stone and hydronephrosis. Gallium scintigraphy showed avid uptake in the left kidney. Serum concentration of vancomycin was 57.4 micro/ml. Candida glabrata was isolated from blood, sputum and urine. Under the diagnosis of fungemia and left pyelonephritis, he was treated with micafungin (150 mg/day), gabexate mesilate and insertion of a double-ended pigtail catheter. The above treatment produced regression of systemic inflammation, DIC and acute renal failure. At the last follow-up 3 weeks after discharge, ureteroscopy showed that the ureter stone had already passed but a soft white-yellowish bezoar was detected in the ureter. In this case, neurogenic bladder, poorly controlled diabetes, and long-term antibiotic treatment probably enhanced the development of C. glabrata infection. Antifungal treatment with micafungin is useful in patients with non-albicans Candida infection.

Combination therapy using prednisolone and cyclophosphamide slows the progression of moderately advanced IgA nephropathy.

AIM: We retrospectively examined the effect of combination therapy using prednisolone (PSL) and cyclophosphamide (CPA) on the progression of IgA nephropathy (IgAN) in 45 patients with moderate to severe histological changes. PATIENTS AND METHODS: Patients were recruited from 129 consecutive patients with IgAN seen over 10 years based on semiquantitative histological grading. They were divided into two groups: PSL+CPA group (n = 26, male/female = 11/15, age 40+/-3 years (SEM)) or control group undergone conventional therapy with or without antiplatelet agents (n = 19, male/female = 10/9, age 41+/-3). In PSL+CPA group, PSL and CPA treatment commenced using a dose of 30 and 50 mg/day, respectively. PSL was reduced by 5 mg every month. RESULTS: The clinical parameters at the start of treatment such as age, gender, histological score, blood pressure, urinary protein excretion and serum creatinine concentration (SCr) were not different between the groups. The mean observation period in PSL+CPA group (3.3+/-0.3 years) was not different from the control group (4.0+/-0.7 years). In PSL+CPA group, urinary protein excretion, defined as the ratio of urinary protein to creatinine concentration (UP/UCr), significantly decreased from 3.9+/-0.4 to 1.3 +/-0.2 (p<0.01), whereas it remained high in the control group (3.8+/-0.7 to 2.7+/-0.8). The progression rate (PR), which was determined by the slope of the correlation between time after renal biopsy and reciprocal SCr, was significantly lower in PSL+CPA (0.054+/-0.014) than in the control group (0.172+/-0.032 dl/mg/year, p<0.001). Our results indicated that PSL+CPA combination therapy was effective in slowing the progression of moderately advanced IgAN. CONCLUSION: We suggest that the immunosuppressive treatment with CPA is sometimes necessary to preserve renal function in patients with histologically advanced IgAN.

Optimal hematocrit for the maximum oxygen delivery to the brain with recombinant human erythropoietin in hemodialysis patients.

AIM: Although hematocrit (Ht) around 33 to 36% has been recommended, Ht of 30% is usually achieved as a target level during recombinant human erythropoietin (rHuEPO) therapy in the majority of hemodialysis (HD) patients. The present study aimed at estimating an optimal hematocrit (Ht) for the maximum oxygen delivery to the brain with rHuEPO. PATIENTS AND METHODS: Oxygen delivery was defined as a product of cerebral blood flow and arterial oxygen content (CaO2). The regional cerebral blood flow (rCBF) in each region of interest was measured by positron emission tomography and CaO2 was calculated from hemoglobin concentration, arterial oxygen saturation, and arterial oxygen tension before and after rHuEPO therapy (1,500 units, 3 times a week) in 5 HD patients (the mean age of 52 +/- 2 (SEM) years old and the mean HD duration of 98 +/- 21 months). RESULTS: Ht rose significantly from 21 +/- 1 to 31 +/- 1% (p < 0.001) after the 3-month rHuEPO treatment in association with a significant increase in CaO2 from 7.7 +/- 0.4 to 11.6 +/- 0.3 ml O2/100 ml (p < 0.01). Hemispheric rCBF decreased significantly from 40 +/- 3 to 32 +/- 1 ml/100 g/min (p < 0.02). In all data both before and after rHuEPO treatment, Ht inversely correlated with the hemispheric rCBF (y = 55.7 - 0.76x, where y is rCBF and x is Ht, r = 0.80, p < 0.01), and positively with CaO2 (y = 0.85 + 0.34x, where y is CaO2 and x is Ht, r = 0.95, p < 0.01). By using these correlations, the hemispheric oxygen delivery was expressed as a function of Ht, being y = 47.3 + 18.3x - 0.3 x2, where y is cerebral oxygen delivery and x is Ht. From this curve, Ht at the highest cerebral oxygen delivery in the hemisphere, i.e. an optimal Ht was found to be 35.2%. Above this level of Ht, the hemispheric cerebral oxygen delivery would rather decline. CONCLUSION: The present study indicated that Ht of about 35% is required for a better oxygen delivery to the brain metabolism during anemia correction with rHuEPO.

Strong polarization toward Th1 immune response in ANCA-associated glomerulonephritis.

AIM: Human immune response can be classified into 2 different subsets of T helper cells (Th1 and Th2) based on the pattern of cytokine production. In modern immunology, Th1/Th2 paradigm helps to explain the different inflammatory effector pathways and outcomes in human diseases. The present study was designed to determine the type of immunological response that influences anti-neutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis (GN) using cytokine analysis of peripheral T cells and diseased kidney tissues. PATIENTS AND METHODS: We analyzed peripheral blood Th1/Th2 ratio in 91 patients with primary GN, including 10 cases of ANCA-associated GN. Tissues were immunostained with markers of T cells and macrophages and osteopontin (OPN). Intrarenal expression of IFN-gamma and IL-4 mRNAs was evaluated by reverse transcriptase (RT)-PCR. RESULTS: Peripheral Th1/Th2 ratio was significantly higher in ANCA-associated GN (19.4 +/- 9.4, mean +/- SD, n = 10), than those in healthy controls (7.6 +/- 4.1, n = 27), IgA nephropathy (9.6 +/- 5.6, n = 45), membranous nephropathy (7.1 +/- 4.4, n = 13), minimal-change nephrotic syndrome (8.2 +/- 4.5, n = 13) and focal segmental glomerulosclerosis (8.3 +/- 3.9, n = 10) (p < 0.01, each). In 7 of 10 cases of ANCA-associated GN, Th1/Th2 ratio decreased significantly after treatment with corticosteroid from 21.0 +/- 12.0 to 9.0 +/- 6.6 (p < 0.05). Immunohistochemical staining showed numerous infiltrating T cells, macrophages and OPN-positive cells in both glomerular tuft and cellular crescent; OPN-positive cell distribution was similar to that of macrophages. Intrarenal expression of IFN-gamma mRNA was strongly enhanced whereas a weak expression of IL-4 mRNA was observed especially in advanced cases showing tubulointerstitial injury. CONCLUSION: Both peripheral and renal immune responses are strongly polarized toward Th1 type immune response in ANCA-associated GN. Peripheral Th1/Th2 ratio may reflect the immune responses in renal injury of ANCA-associated GN.

Diffuse proliferative glomerulonephritis after bone marrow transplantation.

A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.

Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney and testis of F344 rats and its modulation by cadmium.

Cellular distribution of the antimutagenic MTH1protein in the liver, kidney, and testis of Fischer rat was evaluated using the immunohistochemical staining with anti-MTH1 polyclonal antibody. The present investigation revealed a non-uniform distribution of MTH1 among cells and among the cytoplasmic, nuclear, and membranal structures of cells within a given tissue. A particularly strong expression of MTH1 was observed for the first time in the perinuclear acrosomic bodies of spermatocytes and in the acrosomic vesicles of sperm heads. Treatment of rats with a single sc dose of 20 micromol Cd(II)/kg body wt. produced histopathologic changes in these organs accompanied by redistribution of the cellular MTH1 protein between the cytoplasm and nuclei. The acute phase of Cd(II) toxicity, that in the liver and especially in the testes (but not in kidneys) led to cell necrosis, was accompanied by a characteristic decrease in the abundance of MTH1-expressing nuclei. Chronic toxicity without necrosis, persisting in the kidney over the entire 14-day study, as well as the survival and proliferation of cells, observed in the liver and testis after the necrotizing phase, were signified by increased number of nuclei expressing MTH1. Thus, unlike previous biochemical studies, immunohistochemistry managed to reveal alterations in the patterns of inter- and intracellular distribution of MTH1, associated apparently with the conditional changes in the dynamics of synthesis of nucleic acids, assisted by this protein.

Protocol biopsy findings in living donor kidney transplant patients treated with once-daily or twice-daily tacrolimus formulation.

BACKGROUND: Once-daily extended-release tacrolimus (Tac-QD) has been shown to have equivalent efficacy and safety to the twice-daily formulation (Tac-BID) in kidney transplant patients. However, detailed comparison of allograft pathology found on a protocol biopsy (PB) in Tac-QD- versus Tac-BID-based regimens has not been described. METHODS: We retrospectively investigated 119 de novo living donor kidney transplant patients treated with Tac-QD (n = 90) or Tac-BID (n = 29) and their 3- and 12-month PB results. Other immunosuppressive drugs administered included basiliximab, mycophenolate mofetil, and methylprednisolone. We evaluated daily doses and trough levels of Tac and serum creatinine levels, and compared pathologic findings. RESULTS: Daily doses were higher in the Tac-QD group, but trough levels and serum creatinine levels were comparable. On 3- and 12-month PB, the frequency of subclinical rejection was similar between the groups, whereas interstitial fibrosis and tubular atrophy (IF/TA) were less common in the Tac-QD group at 12 months (42.2% vs 20.6%, P = .04). Univariate and multivariate logistic regression analyses revealed that allograft rejection (borderline changes or higher) was associated with IF/TA (odds ratio 4.09, 95% confidence interval 1.76-10.10, P = .001). The Tac-QD-based regimen showed a trend toward the absence of IF/TA but it did not reach statistical significance. Tubular vacuolization and arteriolar hyaline changes were also comparable in the two groups. CONCLUSIONS: We found a trend toward milder IF/TA, but no significant differences in kidney allograft pathology in patients who were administered Tac-QD- versus Tac-BID-based regimens at 12 months. The effects of Tac-QD on chronic allograft injury must be studied by longer observation.

Early disappearance of urinary decoy cells in successfully treated polyomavirus BK nephropathy.

BACKGROUND: Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplant patients. Regular screening using polymerase chain reaction for BK virus DNA in plasma and urinary cytology is effective for early diagnosis of BKVN. However, methods of follow-up and therapeutic targets are not well described. METHODS: Ten patients with BKVN who received biweekly urinary cytology and repeat biopsies after diagnosis were retrospectively studied. Histological remission of BKVN was determined when biopsy revealed negative SV40 large T-antigen (TAg) staining. Results of urinary cytology and repeat biopsy findings were compared. RESULTS: Urinary decoy cells disappeared in 8 of 10 patients 55 ± 25 (range 13-79) days after index biopsies. In those cases, allograft function was preserved and the final serum creatinine level was 2.14 ± 1.19 (0.80-4.55) mg/dL after 962 ± 393 (325-1563) days of follow-up. Two cases with persistent urinary decoy cells shedding lost their graft 195 and 362 days later. Amongst 29 repeat biopsies, there were 13 TAg-positive and 16 negative biopsies. In 12 of 13 TAg-positive biopsies (92%), urinary decoy cells were still positive, whereas at the same time in 15 TAg-negative biopsies, decoy cells had already disappeared (94%). CONCLUSIONS: Cytology testing is advantageous because of its cost effectiveness. Clearance of decoy cells from urine was closely related to histological remission of BKVN, and may possibly be a therapeutic target in BKVN.

Parathyroid growth and regression in experimental uremia.

Early 1,25-dihydroxyvitamin D(3) (VD(3)) therapy during the course of renal failure prevents the downregulation of VD(3) receptor (VDR), calcium-sensing receptor (CaSR) or p21, and the parathyroid (PT) growth. We hypothesized that VD(3) could restore the decreased expressions of VDR and CaSR, and cause regression in enlarged PT glands. 5/6 nephrectomized rats fed high-phosphorus diet were killed at 1, 3, 5, or 7 days and at 2, 3, 4, 8, or 12 weeks. VD(3)-treated rats were given VD(3) intraperitoneally for 1, 2, 3, or 4 weeks, starting 8 weeks after 5/6 nephrectomy. PT glands were weighed and subjected to immunohistochemical analyses for VDR, CaSR, p21, Ki67, and Tdt-mediated dUTP nick end-labeling (TUNEL) assay. The area per cell was measured as the parameter of cell size. The expression of VDR and p21 began to decrease at day 1, and Ki67 increased at day 3, but decreased thereafter. There was a significant increase in PT gland weight to week 12 with the increase of cell size. VD(3) treatment significantly increased both VDR and CaSR expressions 2 weeks after the start of injection, and reduced the PT gland weight at week 3 with significant increase of TUNEL-positive cells and decrease of cell size. Our results suggest that PT growth in uremic rats involves both PT cell proliferation and hypertrophy, in association with the reduction of VDR, CaSR, and p21 expressions. In addition, VD(3) treatment could reverse PT hyperplasia and hypertrophy via restoration of these proteins.

Persistent hyperparathyroidism in renal allograft recipients: vitamin D receptor, calcium-sensing receptor, and apoptosis.

The phenotypic changes in parathyroid cells after successful renal transplantation remain to be elucidated. We compared 10 diffuse and 11 nodular hyperplastic parathyroid glands from five renal allograft recipients with persistent hyperparathyroidism, with five diffuse and 13 nodular hyperplasia from seven uremic patients on hemodialysis, and 13 normal glands. Comparisons included expressions of both vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), proliferative activity (Ki67), and apoptosis (TUNEL). Immunoreactivity was assessed semiquantitatively and expressed as labeling index. The area/cell was also measured to assess cellular hypertrophy. The labeling indexes of VDR (587+/-71; mean+/-s.e.m.) and CaSR (45.0+/-2.8) in recipients' diffuse hyperplasia were significantly higher than those in uremic diffuse hyperplasia (224+/-44, 29.3+/-2.3, respectively) (P<0.01, each). However, these expressions remained low in recipients' nodular hyperplasia (42+/-8, 11.8+/-1.4, respectively). Ki67 labeling index in recipients' nodular hyperplasia (7+/-1) was significantly smaller than in uremic patients (24+/-6, P<0.01). TUNEL labeling index in recipients' diffuse hyperplasia (30+/-5) was the highest among the groups. The cell volume tended to be smaller in both patterns of hyperplasia in allograft recipients compared with uremic patients. Our results suggest that the phenotypic change in parathyroid cells after renal transplantation depends on the pattern of hyperplasia, where it is normalized only in diffuse hyperplastic glands in which the number of cells also regresses with significant induction of apoptosis.