Hormones – Cytokines – Signaling
Kidney International (2000) 57, 423–436; doi:10.1046/j.1523-1755.2000.00862.x
Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy
Peter M Jehle, Antje Ostertag, Klaus Schulten, Walter Schulz, Daniela R Jehle, Sylvia Stracke, Roman Fiedler, Heinz J Deuber, Frieder Keller, Bernhard O Boehm, David J Baylink and Subburaman Mohan
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Ulm, Ulm; Institute of Nephrology and Osteology, III, Department of Internal Medicine, Municipal Hospital of Bamberg, Bamberg; and Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Halle, Germany; and Musculoskeletal Diseases Center, Jerry L. Pettis VA Medical Center, Loma Linda, California, USA
Correspondence: Peter M. Jehle, M.D., University of Ulm, Internal Medicine II, Division of Nephrology, Robert-Koch-Stra
e 8, 89081 Ulm, Germany. E-mail: peter.jehle@medizin.uni-ulm.de
Received 30 March 1999; Revised 15 July 1999; Accepted 9 September 1999.
Abstract
Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy.
Background
The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism.
Methods
In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values 
SEM are given.
Results
With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1.6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover.
Conclusion
Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.
Keywords:
osteopenia, low bone turnover, dialysis, uremic bone disease, end-stage renal failure
Abbreviations:
B-ALP, bone alkaline phosphatase; CRF, chronic renal failure; CRF I°, mild renal insufficiency; CRF II°, moderate renal insufficiency; CRF III°, complex uremic syndrome; ESRF, end-stage renal failure; HD, hemodialysis; HTO, high bone turnover; IDDM, insulin-dependent diabetes mellitus; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; LTO, low bone turnover; OSC, osteocalcin; pHPT, primary hyperparathyroidism; PD, peritoneal dialysis; PICP, procollagen type 1 C-peptide; PTH, parathyroid hormone; RIA, radioimmunoassay; RTX, renal transplantation; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; sHPT, secondary hyperparathyroidism
