Raimund Hirschberg

Understanding Sources of Dietary Phosphorus in the Treatment of Patients with Chronic Kidney Disease

In individuals with chronic kidney disease, high dietary phosphorus (P) burden may worsen hyperparathyroidism and renal osteodystrophy, promote vascular calcification and cardiovascular events, and increase mortality. In addition to the absolute amount of dietary P, its type (organic versus inorganic), source (animal versus plant derived), and ratio to dietary protein may be important. Organic P in such plant foods as seeds and legumes is less bioavailable because of limited gastrointestinal absorption of phytate-based P. Inorganic P is more readily absorbed by intestine, and its presence in processed, preserved, or enhanced foods or soft drinks that contain additives may be underreported and not distinguished from the less readily absorbed organic P in nutrient databases. Hence, P burden from food additives is disproportionately high relative to its dietary content as compared with natural sources that are derived from organic (animal and vegetable) food proteins. Observational and metabolic studies indicate nutritional and longevity benefits of higher protein intake in dialysis patients. This presents challenges to providing appropriate nutrition because protein and P intakes are closely correlated. During dietary counseling of patients with chronic kidney disease, the absolute dietary P content as well as the P-to-protein ratio in foods should be addressed. Foods with the least amount of inorganic P, low P-to-protein ratios, and adequate protein content that are consistent with acceptable palatability and enjoyment to the individual patient should be recommended along with appropriate prescription of P binders. Provision of in-center and monitored meals during hemodialysis treatment sessions in the dialysis clinic may facilitate the achievement of these goals.

Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats.

The mechanisms whereby growth hormone may increase renal plasma flow (RPF) and GFR are not known, but circumstantial evidence has implicated insulin-like growth factor I (IGF-I) as a mediator of this effect. This study examined whether an infusion of IGF-I will increase RPF and GFR, whether this effect occurs quickly, and if this effect is dependent on eicosanoids or peptide hormones known to affect renal function. Rats fasted for 3 d to reduce IGF-I and IGF-I plasma binding proteins were anesthetized; then the rats received an intravenous injection of 25 micrograms/kg IGF-I, and an infusion of 25 micrograms/kg IGF-I within 20 min. Controls received infusion of the vehicle. RPF (para-aminohippurate clearances), GFR (inulin clearances), renal vascular resistance (RVR), mean arterial blood pressure (MABP), plasma IGF-I, and glucose concentrations were measured repeatedly. At the end of the 20-min infusion, plasma IGF-I tended to be increased in the animals that received IGF-I (P = 0.069), but did not increase in the control rats. IGF-I induced a significant and sustained fall in RVR and rise in RPF and GFR without any change in MABP. A small, transient, but significant decrease in plasma glucose concentrations was observed during IGF-I but not during vehicle infusion. Indomethacin, but not somatostatin, blocked the renal response to IGF-I infusion. Thus, IGF-I infusion increases RPF and GFR and reduces RVR in fasted rats. This effect requires the presence of eicosanoids but does not seem to require other peptide hormones suppressed by somatostatin.

Impaired actions of insulin-like growth factor 1 on protein Synthesis and degradation in skeletal muscle of rats with chronic renal failure. Evidence for a postreceptor defect.

The actions of insulin-like growth factor 1 (IGF-1) on protein turnover and of the IGF-1 receptor (IGF-1R) were examined in skeletal muscle of rats with chronic renal failure (CRF) and sham operated (SO), pair-fed controls. Acidemia was prevented in CRF rats with NaHCO3. Serum IGF-1 and skeletal muscle IGF-1 and IGF-1 mRNA were reduced in CRF rats. Dose-response studies revealed impaired stimulation of protein synthesis and suppressed inhibition of protein degradation by IGF-1 in epitrochlearis muscle of CRF rats. Neither IGF-1 analogues with low affinity to IGF binding proteins nor proteinase inhibitors obliterated the IGF-1 resistance. In CRF rats, skeletal muscle IGF-1R mRNA was increased; displacement ligand binding studies and affinity labeling of the IGF-1R alpha subunit indicated increased total skeletal muscle IGF-1R number with normal affinity. However, both autophosphorylation of the IGF-1R beta subunit (i.e., IGF-1R tyrosine kinase) and the IGF-1R tyrosine kinase activity towards exogenous insulin receptor substrate-1, a natural substrate for IGF-1R tyrosine kinase, were reduced in CRF fats. These data indicate that in skeletal muscle of CRF rats there is resistance to the IGF-1 effects on protein synthesis and degradation and decreased IGF-1 and IGF-1 mRNA levels; IGF-1R mRNA and number are increased; but activity of IGF-1R tyrosine kinase is impaired. This postreceptor defect may be a cause of the skeletal muscle resistance to IGF-1 in CRF.

Renal Bone Morphogenetic Protein-7 Protects against Diabetic Nephropathy

Longstanding diabetes causes renal injury with early dropout of podocytes, albuminuria, glomerular and tubulointerstitial fibrosis, and progressive renal failure. The renal pathology seems to be driven, in part, by TGF-beta and is associated with a loss of renal bone morphogenic protein-7 (BMP-7) expression. Here, the hypothesis that maintenance of renal (especially podocyte) BMP-7 by transgenic expression reduces diabetic renal injury was tested. Diabetic mice that expressed the phosphoenolpyruvate carboxykinase promoter-driven BMP-7 transgene and nondiabetic, transgenic mice as well as diabetic and nondiabetic wild-type controls were studied for up to 1 yr. Transgenic expression of BMP-7 in glomerular podocytes and proximal tubules prevents podocyte dropout and reductions in nephrin levels in diabetic mice. Maintenance of BMP-7 also reduces glomerular fibrosis and interstitial collagen accumulation as well as collagen I and fibronectin expression. Diabetic wild-type mice develop progressive albuminuria, which is substantially reduced in transgenic mice. These effects of the BMP-7 transgene occur without changing renal TGF-beta levels. It is concluded that maintenance of renal BMP-7 during the evolution of diabetic nephropathy reduces diabetic renal injury, especially podocyte dropout. The findings also establish a role for endogenous glomerular BMP-7 as an autocrine regulator of podocyte integrity in vivo.

Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-beta (TGF-beta) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-beta targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-beta in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-beta including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-beta pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-beta pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-beta pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.

Bioactivity of glomerular ultrafiltrate during heavy proteinuria may contribute to renal tubulo-interstitial lesions: evidence for a role for insulin-like growth factor I.

Clinical and experimental data have indicated that heavy proteinuria in renal glomerular diseases is associated with the formation of tubulo-interstitial fibrosis and contributes to the progression of renal failure. Albumin in glomerular ultrafiltrate does not appear to cause this sequelae, rather than compounds that are associated with ultrafiltered plasma proteins. One such protein-bound factor could be insulin-like growth factor I (IGF-I). The present studies show that in nephrotic rats, IGF-I is ultrafiltered in conjunction with IGF-binding protein-2 and is present in proximal tubular fluid at 1.35 nM. Proximal tubular fluid from nephrotic rats autophosphorylates IGF-I receptors in cultured proximal tubular cells. Nephrotic, but not control, rat proximal tubular fluid increases the [3H]thymidine incorporation in cultured tubular cells, and neutralizing IGF-I-receptor antibodies partially inhibit this activity. Incubation of cultured proximal tubular cells with an extract that was prepared from nephrotic rat urine increases the secretion of collagen types I and IV. Secretion of the two collagens is in part ameliorated by neutralizing IGF-I-receptor antibody. In concert, these findings suggest that the IGF-I present in nephrotic rat tubular fluid is bioactive and may contribute to the development of tubulo-interstitial fibrosis in chronic nephrotic glomerular diseases.

Wound healing in the kidney: complex interactions in renal interstitial fibrogenesis.

The degree of renal interstitial fibrosis, i.e. , the poorly organized accumulation of extracellular matrix (ECM) proteins such as collagens (types I, III, and IV), fibronectin, laminins, and others, has emerged as the pathohistologic entity that correlates better with the degree of renal filtration

Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy

Insulin-like growth factor-I (IGF-I) is found in plasma at relatively high levels (approximately 40 nmol/L) but <1% is present in the free form and >99% is bound to specific binding proteins to form high-molecular-weight complexes of approximately 50 and approximately 150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-I-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-I receptors in apical tubular membranes. By this route, ultrafiltered IGF-I may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-I levels (227 +/- 34 ng/mL) were reduced as compared with control levels (319 +/- 33 ng/mL, P = .05), and IGF-binding protein-2 (IGFBP-2) is increased about 2-fold. In diabetic rats, IGF-I undergoes glomerular ultrafiltration and is present in proximal tubular fluid that was collected by nephron micropuncture at 2.54 +/- 0.54 nmol/L but is below the detection limit in tubular fluid from normal rats. IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 are all present in diabetic rat glomerular ultrafiltrate, but IGFBP-2 levels are greater than those of each of the other three IGFBPs. Neither recombinant human IGF-I (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-I and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of 22Na+ in distal tubule-like A6 cells through mechanisms involving apical IGF-I receptors. In normal rats, luminal infusion with rhIGF-I or with diabetic rat glomerular ultrafiltrate into late proximal tubules increases distal tubular Na+ absorption. These findings indicate that diabetic glomerular sclerosis causes glomerular ultrafiltration of IGF-I, and they suggest that tubular fluid IGF-I may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.

Glomerular Hyperfiltration in Sickle Cell Disease

Sickle cell disease (SCD) is a monogenetic, chronic anemia syndrome that is caused by a point mutation in the β-globin gene and affects approximately 100,000 individuals in the United States. Approximately 4 to 5% of these individuals have or will develop stage 5 chronic kidney disease (CKD), and 0.11% of patients who are on long-term maintenance renal replacement therapy have SCD-associated nephropathy (1–3).nnHomozygous hemoglobin S leads to severe, chronic, hemolytic anemia and the propensity for hemoglobin polymerization, and red blood cell (RBC) sickling causes small artery occlusions. SCD is a multiorgan syndrome with involvement of the central nervous system (infarcts, strokes), eyes, heart, lungs (pulmonary hypertension), spleen (infarcts), muscle, bone (avascular necrosis), and kidneys. Renal complications include chronic medullary injury and papillary necrosis and transient macrohematuria, which are thought to be caused by vasa recta occlusive disease as a result of RBC sickling. Medullary injury also causes reduced urine-concentrating ability and a mild form of (type IV) distal renal tubular acidosis. Glomerular abnormalities include micro- and macroalbuminuria and the nephrotic syndrome. Histologically, FSGS is the predominant glomerular lesion in patients with SCD and proteinuria (4). Of note, …

Effects of recombinant human insulin-like growth factor 1 on renal handling of phosphorus, calcium, and sodium in normal humans

The effects of insulin-like growth factor 1 (IGF-1) on renal handling of phosphorus, calcium, and sodium were evaluated in eight healthy men while they lived in a clinical research center for slightly more than 5 days. Subjects received a continuous intravenous infusion throughout the study of 0.45% saline and 2.5% d-glucose at 50 mL/hr (group 1, four subjects) or 150 mL/hr (group 2, four subjects). Recombinant human IGF-1 (rhIGF-1), 60 micrograms/kg body weight, was injected subcutaneously three times daily for 10 doses from day 2 until the beginning of day 5. After commencing the rhIGF-1 injections, there was a marked decrease in the fractional excretion of phosphorus in both groups that was sustained throughout the study. Urine phosphorus excretion also decreased significantly on days 2 to 5 in group 1 and on day 2 in group 2. In group 1, the fractional excretion of calcium decreased on day 2; urine calcium did not change. The fractional excretion of sodium decreased on days 2 and 4; urine sodium decreased significantly only on day 2. In group 2, the fractional and absolute urine excretion of calcium did not change. Fractional sodium excretion was not altered, and urine sodium increased only on day 5. The average serum phosphorus, calcium, and sodium did not change from baseline in groups 1 or 2. The pattern of the circadian rhythms for serum concentrations, urine excretion, and fractional excretion of phosphorus and calcium did not appear to be affected by the rhIGF-1 injections.(ABSTRACT TRUNCATED AT 250 WORDS)