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Marked hyperleptinaemia and metabolic acidosis are common findings in patients with chronic renal failure. In animal models, both leptin administration and acidosis reduce food intake. However, leptin causes loss of body fat, while acidosis induces muscle wasting. Whether a low pH and leptin production are related has not been studied. Leptin secretion was measured in cultured 3T3-L1 adipocytes exposed to acid or control pH for up to 96 h. In addition, serum leptin was compared between acidotic and bicarbonate-treated uraemic Wistar rats using the remnant model. Leptin levels in the culture medium were decreased at an acid pH of 7.1 compared with a control pH of 7.5 at 96 h (562±78 and 831±103 pg·48 h-1·well-1 respectively; mean±S.E.M.; P = 0.037). Similarly, serum leptin in uraemic rats was found to be lower in the acidotic group than in the bicarbonate-treated group, although this observation fell just short of statistical significance (1273±171 compared with 2059±376 pg/ml; P = 0.07). In conclusion, acidosis decreases leptin secretion from cultured adipocytes. Accordingly, acidotic uraemic rats seem to exhibit lower serum leptin levels than their bicarbonate-supplemented counterparts. This study is the first report providing a link between acidosis and leptin levels.

BACKGROUND Glomerulosclerosis and interstitial fibrosis, which are cardinal features of the end-stage kidney, result from accumulation of extracellular matrix proteins, particularly collagen, in the glomerular mesangium and renal interstitium. This study examined the effect of D-penicillamine (DPC), which inhibits collagen deposition, on disease progression in the remnant kidney. METHODS Two groups of 10 rats underwent two-thirds nephrectomy and were pair-fed 20% casein paste (Gp 1) or the same paste supplemented with 90 mg/kg body wt per day of DPC (Gp 2). Two further groups of five non-nephrectomized animals also received 20% casein paste either alone (Gp 3) or supplemented with DPC (Gp 4). In a further experiment, systolic blood pressure was compared at 1 and 4 weeks after nephrectomy in eight DPC-treated remnants and eight untreated controls. RESULTS Gp 2 developed significantly less proteinuria than Gp 1 (41 +/- 9 vs 142 +/- 33 mg/24 h at 6 weeks, P < 0.005; 136 +/- 36 vs 282 +/- 59 mg/24 h at 12 weeks, P < 0.05). At sacrifice after 12 weeks, glomerular filtration rates were higher (1.34 +/- 0.08 vs 1.07 +/- 0.1 ml/min, P < 0.05), kidney total collagen content was lower (14.9 +/- 1.5 vs 26.9 +/- 5.4 mg/kidney, P < 0.05) and glomerular abnormalities, interstitial fibrosis and lymphocytic infiltration were less marked in Gp 2 compared with Gp 1. DPC had no effect on protein excretion, total kidney collagen or GFR in non-nephrectomized rats, and did not influence the early rise in blood pressure seen after two-thirds nephrectomy. CONCLUSIONS These findings demonstrate that DPC reduces renal injury in the remnant kidney, and raise the possibility of a therapeutic role for DPC in the treatment of patients with chronic renal failure.

Metabolic acidosis causes renal growth and proteinuria, and may contribute to the progression of CRF. This study assessed the effects of HCI-induced acidosis on the structure and function of normal kidneys. Acidosis was induced in 12 rats by dietary HCl. After 2 weeks, acidotic animals had higher kidney/body weight ratios (0.47 +/- 0.10 vs. 0.35 +/- 0.10 g%, p < 0.001) and higher kidney protein content (123 +/- 3 vs. 111 +/- 4 mg/kidney, p < 0.05) than controls, but tubular nuclear densities were lower, suggesting tubular hypertrophy. Acidotic animals developed tubular proteinuria (16.4 +/- 2.6 mg/day after 2 weeks of acidosis vs. 2.9 +/- 0.3 mg/day at baseline; p < 0.001), and the pattern of immunohistochemical staining for Tamm-Horsfall protein suggested tubular injury. These data suggest that a tubulotoxic effect of metabolic acidosis may contribute to the progression of CRF.

1. Metabolic acidosis invariably accompanies chronic renal failure, and short periods of metabolic acidosis cause renal growth and proteinuria in normal rats. Rates of ammoniagenesis are increased in chronic renal failure, and it has been suggested that this contributes to disease progression. This study assessed (i) whether prolonged acidosis causes chronic renal injury in the normal kidney and (ii) whether abrogation of acidosis slows disease progression in the remnant kidney. 2. Metabolic acidosis was induced in normal rats by dietary hydrochloric acid. Urinary excretion of total protein, lysozyme and albumin increased, peaking at week 8 but returning to baseline by week 14. At killing after 14 weeks, kidney weights, glomerular filtration rates and serum creatinine were the same in both groups, but kidney/body weight and kidney/heart weight ratios were greater in the acidotic group. All kidneys were normal by light microscopy. 3. Rats subjected to five-sixths nephrectomy were given sufficient dietary bicarbonate to abolish uraemic acidosis, and their outcome was compared with that of non-alkalinized remnants (controls). Proteinuria, glomerular filtration rates, blood pressure, histological injury and time to the development of terminal uraemia were no better in bicarbonate-supplemented animals than in controls. 4. These data demonstrate that metabolic acidosis neither causes nor exacerbates chronic renal injury. We conclude that the treatment of uraemic acidosis is unlikely to influence disease progression in patients with chronic renal failure.