Increased urine transforming growth factor ß1 (TGF-ß1) and serum uric acid are associated with an early decline of glomerular filtration rate in kidney transplant recipients.

BACKGROUND: The renin-angiotensin system (RAS) and transforming growth factor ß1 (TGF-ß1) may play a role in the pathogenesis of fibrosis in kidney allografts. Experimental hyperuricemia shows activation of intrarenal RAS. However, the association between uric acid (UA), RAS, and TGF-ß1 in allograft recipients has not been demonstrated. Therefore we investigated the association between serum UA levels, RAS, and TGF-ß1 in kidney transplant recipients during the 1st year after transplantation. METHODS: Sixty-two transplant recipients were included in the study. Serum UA level, plasma renin activity (PRA), and urine TGF-ß1 concentration were studied at 3, 6, and 12 months after transplantation. Statistical correlation was demonstrated with the use of Spearman rank correlation coefficient. Receiver operating characteristic curve analysis and area under the curve were performed to assess the diagnostic performance to discriminate between estimated glomerular filtration rate (eGFR) <60 and ≥ 60 mL/min/1.73 m(2). RESULTS: For all 62 patients, urine TGF-ß1 and serum UA had a tendency to increase during the 1-year follow-up period, despite no statistically significant change in eGFR. We found that increased urine TGF-ß1 was correlated with rising serum UA levels and a decrease of the eGFR (r = 0.27 [P = .01]; r = -0.38 [P = .0003]). In contrast, there was no significant change in PRA and it was not correlated with eGFR or TGF-ß1 (r = -0.01; P = .93). CONCLUSIONS: Increased urine TGF-ß1 and serum UA level during the 1st year after transplantation correlated with a decline in eGFR. The evaluation of these parameters in the early post-transplantation period may identify patients at risk of allograft dysfunction.

Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells.

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.

Bone mineral density and histology in distal renal tubular acidosis.

BACKGROUND: Chronic metabolic acidosis in distal renal tubular acidosis (RTA) has been implicated in the pathogenesis of enhanced bone resorption and osteopenia, resulting in a loss of bone mineral content. However, histomorphometric and bone densitometric studies of patients who suffered from long-standing distal RTA have rarely been done. METHODS: A cross-sectional study to determine the alterations of bone mineral density (BMD) and histology was done in 14 nonazotemic RTA patients (11 females and 3 males) who had never received alkaline therapy before enrolling into this study. The mean age was 32.7 +/- 11.9 years. BMD measurements and transiliac bone biopsy were done in all patients. Blood chemistries, intact parathyroid hormone level, and a 24-hour urine collection for the determination of urinary calcium, phosphate, sodium, and potassium were obtained from the RTA patients at the time of bone biopsy. Data from 28 age-, sex-, and body mass index-matched, normal controls who were residents in the same area were also obtained. RESULTS: Urinary excretion of calcium was 2.05 +/- 1.59 mmol/day. No patient had hypercalciuria. The serum intact parathyroid hormone level was 15.92 +/- 8.48 pg/mL. RTA patients had lower BMD in most areas when compared with normal controls. There were two patients who suffered from a pathologic fracture at the femur. Bone histomorphometry from RTA patients shows a significantly decreased bone formation rate (0.02 +/- 0.02 vs. 0.07 +/- 0.045 microm(3)/microm(2)/day, P < 0.05), not significantly decreased osteoblastic surface (0.78 +/- 1.03% vs. 2.6 +/- 1.1%) and osteoclastic surface (0.05 +/- 0.03 vs. 0.13 +/- 0.23%), but significantly increased osteoid surface (31.47 +/- 24.52 vs. 5.79 +/- 4.39%, P < 0.05) and osteoid volume (2.95 +/- 3.09 vs. 0.92 +/- 1.05%, P < 0.05) when compared with those of normal controls. There was no difference in osteoid thickness (10.65 +/- 6.10 vs. 8.69 +/- 2.14 microm). Only one distal RTA patient who had a marked increase in osteoid thickness justified the diagnosis of osteomalacia. CONCLUSIONS: This study demonstrates that low bone mass is common in distal RTA patients. Chronic metabolic acidosis results in suppression of bone formation and resorption, which in turn may contribute to the development of low bone mass in distal RTA patients. Although minor elevations in osteoid surface and osteoid volume are found among distal RTA patients, overt osteomalacia is not the predominant bone lesion.

Lupus nephritis: a challenging cause of rapidly progressive crescentic glomerulonephritis.

The outcomes of 32 lupus patients with rapidly progressive crescentic glomerulonephritis were studied. Lupus nephritis accounted for 51.6% (32/62) of all patients with biopsy proven rapidly progressive crescentic glomerulonephritis during a six year observation period that includes 961 consecutive native kidney biopsies. Median entry serum creatinine was 221 micromol/l. All patients received induction therapy with pulse methylprednisolone (n =27) or intravenous cyclophosphamide (n = 5). Maintenance therapies included prednisolone alone (group 1), prednisolone plus intermittent pulse intravenous cyclophosphamide (IVCY) (group 2) and prednisolone plus daily oral cytotoxic drugs (group 3). Twelve patients eventually had uremia. Seven further patients died of infection during therapy. One patient still had renal insufficiency and twelve patients had favorable clinical outcome (serum creatinine < 200 micromol/l). Patients in group 3 were more likely to have favorable clinical outcome than group 2 (P = 0.01; Fisher's exact test). Survival analysis found that the three year survival of 'group 2' was 27.6% while that of 'group 3' was 83.3%. Our results suggest that lupus nephritis is not an infrequent cause of crescentic glomerulonephritis. Therapy with IVCY is not necessary associated with good outcome. Selected patients can be effectively treated with daily oral cytotoxic drugs as a reasonable alternative therapy.

Antineutrophil cytoplasmic antibody (ANCA) and rapidly progressive crescentic glomerulonephritis in Thai population.

The impact of vasculitis as a cause of primary rapidly progressive crescentic glomerulonephritis (RPGN) was examined in patients with Thai ethnic by antineutrophil cytoplasmic antibody (ANCA) test. Thirty patients found in a six years study period were included. Patients' mean age was 34.8+/-16.4 years. Mean crescent score was 86.2+/-22.9%. ANCA proved positive in fifteen patients. This helps to differentiate vasculitis associated (ANCA positive) from nonvasculitis (ANCA negative) RPGN. Incidence of immune complex type RPGN (46.6%) is higher than the Caucasians while the incidence of antiglomerular basement membrane antibody (anti-GBM disease) is much lower. More vasculitis patients were treated with cyclophosphamide (n = 11) than the nonvasculitis group (n = 2). Mean renal survival time of ANCA and non-ANCA associated patients were 26.69 and 14.16 months, respectively. Renal survival of all patients is significantly worse if associated with a high entry creatinine (>6 mg/dl). Our results show that vasculitis associated RPGN is not an uncommon disease in the Thai population and can be recognized initially by ANCA test.