Przemyslaw Hirszel

Low-Protein Diet Suppresses Serum Insulin-Like Growth Factor-1 and Decelerates the Progression of Growth Hormone-Induced Glomerulosclerosis

A low-protein (LP) diet has been associated with amelioration of renal function in glomerulosclerosis (GS). However, the mechanisms involved are still unclear. We have used a mouse transgenic for bovine growth hormone (GH), which develops progressive GS and exhibits consistently elevated levels of circulating GH and insulin-like growth factor (IGF)-1, to study the effect of dietary protein restriction. LP (6% protein) and normal-protein (NP, 20% protein) diets were maintained for 30 weeks in mice with established GS of mild/moderate degree. The degree of GS was markedly attenuated in LP compared to NP mice. Quantitative analysis revealed a significantly lower GS index (1.4 ± 0.9 in LP vs. 2.8 ± 0.8 in NP) and glomerular volume (0.8 × 106 ± 0.1 × 106 µm3 in LP vs. 1.2 × 106 ± 0.1 × 106 µm3 in NP) in mice with restricted protein intake. These morphologic changes were accompanied by a significant reduction in renal expression of α1 type-IV collagen (2.4-fold) and tenascin (1.4-fold) in LP mice. Serum IGF-1 decreased by 40% and showed a significant correlation with α1 type-IV collagen expression with the LP diet. The present finding supports the use of the LP diet to decelerate the progression of GS and furthermore suggests that one of the mechanisms involved in this process is the GH/IGF-1 regulation by protein intake.

The Role of the Capillary Wall in Restricting Diffusion of Macromolecules

In 5 nephrectomized rabbits the peritoneal clearance of neutral dextrans from plasma to dialysate decreased from 7.8 to 3.3 microliters/kg/min as molecular mass increased from 17,000 to 43,000 daltons, and was relatively constant at 2.8 microliters/kg/min from 49,000 to 97,000 daltons in accord with prior studies. The clearance from dialysate to plasma was measured by determining the distribution volume, which averaged 72 ml/kg, and the plasma concentration 5 h after intraperitoneal instillation. Inward clearances ranged from 11.4 to 19.9 microliter/kg/min, did not correlate well with solute size and were significantly higher than outward clearances. The data suggest that while the capillary wall is the major barrier to macromolecule transfer, absorption can bypass vascular capillaries and occur via the lymphatics. It is suggested that lymphatic flow rate from the peritoneum exceeds 16 microliter/kg/min.

Radiocontrast Removal by Dialysis Membranes

To examine the effect of membrane characteristics on radiocontrast mass transfer, we studied in vitro clearances with cuprophane and polyacrylonitrile (PAN) dialyzers and with polysulfone hemofilter. A perfusate of saline at 37 degrees C, with 7.5 mmol/l (45 mg/dl) of urea and either Renografin (molecular weight 723) or Hexabrix (1405), was pumped through the blood path of dialyzers at 200 ml/min for 5 min. Each radiocontrast agent (RCA) and dialyzer was tested at 0, 150, and 250 or 300 mm Hg transmembrane pressure. In experiments with the use of hemofilter, clearances were tested at the perfusate flow of 50, 100 and 150 ml/min. RCAs were measured by fluorescent excitation analysis of iodine. Mean urea clearance was 16% higher in PAN than in cuprophane dialyzers. Clearance of RCAs was 1.5-3 times higher in PAN than cuprophane dialysers. With the latter, increases in transmembrane pressure resulted in a small amount of ultrafiltration (UF) and little increment in RCA clearance. With the former, increases in transmembrane pressure resulted in massive UF and remarkable increases in RCA clearance. Renografin clearance generally exceeded that of Hexabrix, which we attributed to Renografins lower molecular weight. With the hemofilter, sieving coefficients were approximately 0.8 for each RCA. Yet, because of the lack of diffusive transport and a small surface area even at the highest perfusate flow rates, RCA clearance by the hemofilter was 20-50% less than that of cuprophane dialyzers. We conclude that PAN dialyzers are more efficient for RCA removal than cuprophane dialyzers or polysulfone hemofilters.

Urinary Charcot-Leyden Crystals in the Hypereosinophilic Syndrome With Acute Renal Failure

A 48-year-old man with idiopathic hypereosinophilic syndrome (IHS) developed blast crisis along with a fulminant autoimmune hemolytic anemia. Hemoglobinuria and anuric acute renal failure (ARF) ensued. Urinalysis revealed countless Charcot-Leyden crysals (CLC). This is the only known report of Charcot-Leyden crystalluria. The CLC protein (lysophospholipase) should normally undergo glomerular filtration and catabolism by the tubules during reabsorption. Its abundant presence in the urine of our patient may reflect impairment of tubular reabsorption, saturation of the tubular reabsorptive process by excessive CLC load through residual functioning glomeruli, or a combination thereof. The extreme degree of hypereosinophilia suggests a massive load of CLC protein and acute tubular necrosis implies impaired tubular function, so both mechanisms should have been operative. At the autopsy, no eosinophilic infiltrates were present in the kidneys, which points against a local spillage of CLC protein into the tubules.

Growth Hormone Increases Low-Density Lipoprotein Receptor and HMG-CoA Reductase mRNA Expression in Mesangial Cells

A dysregulation of the negative feedback mechanism of the low-density lipoprotein receptor (LDL-r) induced by hormones and cytokines may contribute to the development of glomerular injury and specifically could underlie growth hormone (GH)-induced glomerulosclerosis. The present study investigates the role of GH in the regulation of LDL-r and HMG-CoA reductase mRNA expression in mesangial cells. Mouse mesangial cells were equilibrated in a medium containing 5% lipoprotein-deprived serum (LPDS) for 48 h, prior to addition of GH (0.25 µM). Transcript levels of LDL-r, HMG-CoA reductase and GH-receptor (GH-r) were measured at days 2 and 4 and intracellular lipid content was evaluated by oil red-O staining. The addition of GH significantly increased both the LDL-r and HMG-CoA reductase transcript levels at day 2 compared to control. Oil red-O positive staining increased following the initial period of 48 h lipoprotein deprivation, but addition of GH in a subsequent 48-hour period did not alter lipid content to a measurable degree compared with control. The present study demonstrates that GH significantly increased HMG-CoA reductase and LDL-r transcript levels in mesangial cells deprived of lipoproteins suggesting that abnormal levels of GH may play a role in glomerular lipid accumulation.

Prolonged intraperitoneal dwell decreases ultrafiltration coefficient in rabbits.

In rabbits undergoing peritoneal dialysis, hypertonic (6% dextrose) dialysis solution increased the net ultrafiltration rate (UF) from 233 to 462 microL/kg/min, which was not proportional to the increment in the osmotic gradient, so the ultrafiltration coefficient decreased. As intraperitoneal dwell of hypertonic dialysate was prolonged, the gross and net UFs and ultrafiltration coefficients decreased, and the UF per dextrose absorption declined. The decrement in UF was multifactorial, including a component of fluid and solute stagnation, increasing the distance over which osmotic forces must exert their effects. Excessively hypertonic dialysis fluid should be used only briefly to achieve ultrafiltration efficiently and to avoid the high dextrose loading.