Volume 70, No. 4/2008(October)
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 Clinical Nephrology
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Original
Vitamin D receptor ligand therapy in chronic kidney disease
Abstract
E.A. González
Division of Nephrology, Saint Louis University, St. Louis, MO, USA
Chronic kidney disease is a growing public health concern, and secondary hyperparathyroidism is one of the most serious associated comorbidities. In healthy individuals, precisely controlled feedback loops dynamically modulate parathyroid hormone (PTH) levels. As kidney function declines, phosphate retention, decreased 1a,25-dihydroxyvitamin D3, and a tendency to hypocalcemia leads to overstimulation of PTH production and parathyroid hyperplasia. Vitamin D receptor (VDR) ligands are essential tools for controlling parathyroid activity. This review highlights the current clinical and biochemical VDR ligand studies, focusing on the differences between selective and nonselective VDR ligands. It is apparent that VDR ligands have important roles in the management of secondary hyperparathyroidism. Selective VDR ligands, in particular, may offer additional benefits in the treatment of bone disease, and may potentially reduce adverse effects related to cardiovascular disease.Correspondence to:
E.A. Gonzalez, MD; Associate Professor of Medicine, Division of Nephrology, Saint Louis University, 3635 Vista Ave., St. Louis, MO 63110, USA
Email: gonzalea@slu.edu
Original
Improvements in renal osteodystrophy in patients treated with lanthanum carbonate for two years
Abstract
H.H. Malluche1, G.A. Siami2, C. Swanepoel3, G.H. Wang1, H. Mawad1, S. Confer4, M. Smith4, R.D. Pratt4 and M.-C. Monier-Faugere1 on behalf of the SPD405-307 Lanthanum Carbonate Study Group
1Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, KY, 2Division of Nephrology, VA Medical Center, Vanderbilt University, Nashville, TN, USA, 3Department of Medicine and Surgery, University of Cape Town, Cape Town, South Africa, 4Shire Pharmaceuticals, Wayne, PA, USA
Aims: To investigate the evolution of renal osteodystrophy in patients on maintenance dialysis, treated with lanthanum carbonate (LC) vs. standard phosphate-binder therapy (Stx). Materials and methods: This was a 2-year, randomized, prospective, open-label study during which patients on dialysis received LC titrated to a maximum of 3,000 mg/day or their previous phosphate binder treatment with the aim to achieve target phosphorus levels of £ 5.9 mg/dl. Paired bone biopsy samples for histomorphometric analysis were available at baseline and 1 year (LC 32, Stx 33), and at baseline and 2 years (LC 32, Stx 24). Results: With similar phosphorus control, Stx was associated with numerically higher serum calcium levels at most visits. Results of osteocalcin and bone-specific alkaline phosphatase in LC patients were higher throughout the study and correlated with parameters of bone formation; however, the differences were not significant. Histological changes in bone turnover and volume were analyzed with respect to normal ranges. There was an improvement in bone turnover in the LC group, which was significant in the 1-year group, and an improvement in bone volume which was significant in the 2-year group. No significant changes in bone turnover or bone volume were observed in the Stx groups. In the 2-year LC group, 1 patient had osteomalacia at baseline and end of therapy, and a mineralization defect developed in 2 other patients. Several possible factors for a mineralization defect were present in these patients, but no single cause could be clearly identified. Histomorphometric parameters of bone, including formation and mineralization, did not correlate with bone lanthanum. No mineralization defect was observed in the Stx groups. Conclusion: These findings show that similar phosphorus control with Stx and LC results in higher bone turnover after 1 year and higher bone volume after 2 years with LC.Correspondence to:
H.H. Malluche, MD; Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky Medical Center, 800 Rose St, Lexington, KY 40536, USA
Email: hhmall@uky.edu
Original
Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease Stages 3 – 5
Abstract
G. Lehmann1, U. Ott1, D. Kämmerer3, J. Schütze2 and G. Wolf1
1Department of Internal Medicine III, University of Jena, 2University of Applied Sciences Jena, and 3Department of General and Visceral Surgery, Central Clinic Bad Berka, Germany
Aims: Precise identification of renal osteodystrophy requires bone histomorphometry. Several markers of bone turnover may be useful to predict classification and severity of renal osteodystrophy, but there are only limited data whether these markers correlate with bone histomorphometry. Methods: In 36 patients with chronic kidney disease (CKD) Stage 3/4 and in 96 patients with CKD Stage 5 bone histomorphometry was performed and renal osteodystrophy was classified according to the standardized international nomenclature. Blood samples were taken at the time of bone biopsy, stored and analyzed at the end of the study. Results: Osteitis fibrosa (OF) was the most frequent histomorphometric form, occurred in 47.2% in CKD Stages 3 – 4 and in 61.4% in CKD Stage 5. There was no difference in the frequency of adynamic renal bone disease (ARBD). The correlation coefficients between bone turnover markers and histomorphometric parameters were higher in CKD 5 patients with high bone turnover lesions. The predictive value for high versus low/normal bone turnover status was comparable for alkaline phosphatase (APH), bone alkaline phosphatase (BAP), pyridinoline (Pyd), desoxypyridinoline (Dpyd), tartrat-resistent acid phosphatase (TRAP Vb) and parathyroid hormone (PTH) in CKD Stage 5 patients, but was insufficient for APH and TRAP Vb in CKD Stage 3 – 4 patients. Conclusions: Besides parathyroid hormone, biochemical parameters of bone turnover provide a moderate discrimination and prediction of bone turnover status only in patients with CKD Stage 5. Due to a large variability, they are of limited use in predicting the histomorphometric type of renal osteodystrophy. Bone histology remains necessary for an exact classification of underlying pathology.Correspondence to:
G. Lehmann, MD; Clinic for Internal Medicine III,
University of Jena, Erlanger Allee 101, 07747 Jena, Germany
Email: gabriele.lehmann@med.uni-jena.de
Original
Osteoprotegerin affects the responsiveness of fibroblast growth factor-23 to high oral phosphate intake
Abstract
S. Kagami1, I. Ohkido1, K. Yokoyama1, T. Shigematsu2 and T. Hosoya1
1Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, 2Department of Internal Medicine, Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, Wakayama, Japan
Background: Both fibroblast growth factor-23 (FGF-23) and osteoprotegerin (OPG) are associated with phosphate metabolism, and are produced by bone tissue. Methods: In order to clarify the influence of bone turnover on phosphate metabolism, we examined the response of FGF-23 to an oral phosphate load in 4 groups of mice (2 OPG knockout (KO) and 2 wild-type (WT) groups) given either a high-phosphate diet or a normal diet by performing serum and urinary biochemical assays. Results: Although there was no significant difference in serum phosphate/ calcium levels between the groups, the decrease in tubular reabsorption rate of phosphate (%TRP) by oral phosphate load was smaller in the OPG KO mice than in the WT mice. FGF-23 level was significantly increased by a high-phosphate diet in WT mice, but not in OPG KO mice. However, there was no significant difference of intact PTH and calcitriol levels between the OPG KO and WT mice. Conclusion: Therefore, OPG may play a key role in mediating the response of FGF-23 to an oral phosphate load in bone cells.Correspondence to:
S. Kagami, MD; Division of Nephrology and Hypertension, Department of Internal Medicine,
The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan
Email: shino@jikei.ac.jp
Original
Race is a major determinant of secondary hyperparathyroidism in uremic patients: comparative study of Blacks and Hispanics
Abstract
D. Omije1,4, K. Norris1,2, J. Wang3, D. Pan1, D. Kermah1 and A. Gupta1,2
1Department of Internal Medicine, Division of Nephrology, Charles Drew University of Medicine and Sciences, 2David Geffen School of Medicine at University of California at Los Angeles, 3Kaiser Permanente, Fontana Medical Center, Fontana, CA, 4University of Texas SouthWestern, Dallas, TX, USA
Background: Racial differences in bone and mineral metabolism are characterized by higher circulating intact parathyroid hormone levels (iPTH) in Black vs. White patients with end-stage renal disease (ESRD). The susceptibility of Hispanic patients to secondary hyperparathyroidism is not known. Method: This is a cross-sectional study that compares bone and mineral parameters of 48 Black and 61 Hispanic ESRD patients attending a single outpatient hemodialysis center. Result: The mean iPTH level was significantly higher in Blacks vs. Hispanics, despite similar levels of serum bone-specific alkaline phosphatase (BSAP), calcium, phosphorus and similar dosages of vitamin D analogs. After adjusting for independent variables including age, diabetic status and plasma levels of C-reactive protein, phosphorus and albumin significant predictors of iPTH were race (p < 0.01), gender (p < 0.05), serum calcium (p < 0.05), BSAP (p < 0.0001) and doses of vitamin D analogs (p < 0.001). Adjusted predictors of serum BSAP were PTH (p < 0.0001), gender (p = 0.01) and serum albumin (p < 0.005), but not race. There was no significant difference in serum BSAP between Blacks and Hispanics despite 60% higher iPTH levels in Blacks. Conclusions: Amongst ESRD patients, Blacks have higher iPTH levels compared with Hispanics despite similar BSAP levels, these finding support the emerging evidence of racial/ethnic differences in response of bone to PTH action.Correspondence to:
A. Gupta, MB, BS, MD; Division of Nephrology and Hypertension, Charles Drew University of Medicine and Sciences, Los Angeles, CA, USA
Email: ajaygupta@cdrewu.edu
Original
Converting hemodialysis patients from intravenous paricalcitol to intravenous doxercalciferol – a dose equivalency and titration study
Abstract
S.Z. Fadem1, F. Al-Saghir2, G. Zollner3 and S. Swan4
1Kidney Associates, Houston, 2Michigan Kidney Consultants, Pontiac, 3Nephrology and Hypertension Associates, Langhorne and 4DaVita Clinical Research, Minneapolis, MN, USA
Aims: Doxercalciferol and paricalcitol are used to treat hyperparathyroidism in chronic kidney disease. This study was conducted to define equivalent dose requirements to convert patients from intravenous paricalcitol to intravenous doxercalciferol. Methods: Following a 4-week baseline period using a fixed dose of paricalcitol, 42 adult hemodialysis subjects were assigned to receive a fixed dose of doxercalciferol for 4 weeks using a conversion factor of either 50 or 65% of the prior paricalcitol dose. During a 12-week titration period the doxercalciferol dose was adjusted to optimize iPTH levels into the range of 150 – 300 pg/ml. Annual costs to achieve equivalent iPTH control were calculated for both vitamin D analogs. Results: During the doxercalciferol fixed-dose period, the average dose of doxercalciferol was 2.1 ± 1.3 µg and 3.1 ± 1.8 µg in the 50 and 65% dose conversion groups, respectively. During this period mean iPTH in the 50% dose conversion group increased by 24 pg/ml (p = 0.017). During the dose titration period, doxercalciferol was increased to bring iPTH within the target range. Calcium control was maintained with both conversion factors, while slightly better phosphorus control was seen in the 65% dose conversion group. Annualized treatment cost for doxercalciferol was 28% less expensive per patient than paricalcitol. Conclusion: Patients can be managed safely and effectively with conversion and dose titration from paricalcitol to doxercalciferol. Both conversion strategies maintained iPTH at clinically satisfactory levels. Furthermore, doxercalciferol therapy resulted in drug acquisition cost-savings.Correspondence to:
S.Z. Fadem, MD, FACP, FASN; Kidney Associates, 6624 Fannin, Suite 1400, Houston, TX 77024, USA
Email: fadem@bcm.edu
Original
Mild-to-moderate renal impairment is associated with platelet activation: a cross-sectional study
Abstract
A. Thijs1, 6, P.W.B. Nanayakkara1, 6, P.M. ter Wee2, P.C. Huijgens3, C. van Guldener4 and C.D.A. Stehouwer5, 6
Departments of 1Internal Medicine, 2Nephrology, 3Hematology, VU University Medical Center, Amsterdam, 4Department of Internal Medicine, Amphia Ziekenhuis, Breda, 5Department of Internal Medicine, Academic Hospital Maastricht, Maastricht and 6Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
The high incidence of cardiovascular disease in patients with moderate renal impairment is not fully explained by traditional atherothrombotic risk factors. Independently from these factors, blood platelet activation may increase the cardiovascular disease risk of patients with mild-to-moderate renal impairment. Blood platelet activation has not been studied in nondiabetic patients with mild-to-moderate renal impairment. Therefore, we measured the extent of platelet activation by means of fluorescence cytometry in 93 nondiabetic patients with MDRD-estimated creatinine clearance ranging from 13 – 63 ml/min/1.73 m2. As platelet activation parameters we used the expression of CD62P (P-selectin), CD 63 (glycoprotein 53), PAC-1 (activated fibrinogen receptor), CD42b (von Willebrand factor receptor) and CD41 (fibrinogen receptor) on the platelet surface membrane. The expression of CD62p, CD63 and PAC-1 was statistically significantly inversely related to the estimated glomerular filtration rate in these patients (standardized b –0.28, –0.32 and –0.39, respectively). We conclude that nondiabetic mild-to-moderate renal impairment is associated with blood platelet activation. Whether this contributes to the increased cardiovascular risk in these patients needs further study.Correspondence to:
A. Thijs, MD; Department of General Internal Medicine, VU University Medical Center, Room 4 A 44, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
Email: a.thijs@vumc.nl
Original
Effects of nocturnal oxygen therapy on sleep apnea syndrome in peritoneal dialysis patients
Abstract
T. Kumagai1,2, Y. Ishibashi1,2, H. Kawarazaki1,2, W. Kawarazaki1,2, H. Shimizu1,2, S. Kaname1,2,3 and T. Fujita2
1Division of Total Renal Care Medicine, 2Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, and 3Kyorin University School of Medicine, Mitaka, Tokyo, Japan
Sleep apnea syndrome (SAS) is common in patients with end-stage renal disease (ESRD). Although the treatment of choice is continuous positive airway pressure (CPAP) particularly for obstructive SAS, long-term compliance is not satisfactory. We investigated the effectiveness of nocturnal oxygen therapy on sleep apnea and autonomic nervous dysfunction in peritoneal dialysis (PD) patients with SAS. Methods: 40 patients on PD in our outpatient clinic were screened for SAS by pulse oximetry. We set the indication for nocturnal oxygen therapy at 4% oxygen desaturation index (4% ODI; defined as the number of falls of oxygen saturation ³ 4% per hour) > 5 or average nocturnal saturation < 95%. For SAS patients, 2 l per minute of oxygen was given during sleep and polysomnography was performed before and 1 month after oxygen administration. The heart rate variability was analyzed to assess autonomic nervous activity. Results: 23 patients fulfilled the indication for oxygen therapy and 11 patients agreed to participate in the study. After oxygen therapy, the apnea-hypopnea index (AHI) and the frequencies of hypopnea and central apnea were significantly decreased (AHI: from 31.1 ± 8.8 to 12.7 ± 8.5, p < 0.01; hypopnea: from 19.5 ± 4.3 to 3.5 ± 3.2, p < 0.01; central apnea: from 4.0 ± 4.0 to 0.8 ± 1.2, p < 0.05), whereas that of obstructive apnea was not changed. An analysis of heart rate variability showed that oxygen therapy did not alter autonomic activity after 1 month of oxygen therapy. Conclusions: Nocturnal oxygen therapy decreases hypopnea and central apnea in PD patients with SAS. Nocturnal oxygen therapy may be useful for the treatment of SAS in PD patients, particularly when central apnea and hypopnea are predominant.Correspondence to:
T. Kumagai, MD; Division of Total Renal Care Medicine, Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Email: tkuma-tky@umin.ac.jp
Case Report
Early IgG glomerulonephritis recurrence in a kidney transplant recipient
Abstract
N. Jourde-Chiche1, V. Moal1, L. Daniel2, R. Purgus1, T. Legris Jr.1, H. Vacher-Coponat1, J. Moussi-Frances1 and Y. Berland1
1Université de la Méditerranée, Assistance Publique des Hôpitaux de Marseille, Centre de Néphrologie et Transplantation Rénale, Hôpital Conception and 2Service d’Anatomie Pathologique, Hôpital Timone, Marseille, France
We report a second case of mesangial IgG glomerulonephritis recurrence after kidney allograft transplantation. Mesangial IgG glomerulonephritis is considered a distinct glomerulonephritis. To date, only 1 recurrence after transplantation has been reported. In the present case, recurrence occurred 3 months after transplantation, following an acute rejection episode. Three sequential graft biopsies describe the onset of glomerular lesions.Correspondence to:
Dr. N. Jourde-Chiche; Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, 147 Bd Baille, 13005 Marseille, France
Email: noemie.jourde@ap-hm.fr
Case Report
Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy
Abstract
S. Okuyama1, H. Wakui2, N. Maki2, J. Kuroki1, T. Nishinari1, K. Asakura1, A. Komatsuda2 and K. Sawada2
1Department of Internal Medicine, Yuri Kumiai General Hospital, and 2Third Department of Internal Medicine, Akita University School of Medicine, Akita, Japan
A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.Correspondence to:
H. Wakui, MD; Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan
Email: wakui@med.akita-u.ac.jp
Case Report
Hyperkalemia in familial mitochondrial cytopathy
Abstract
J. Shimizu1,2, A. Inatsu1, S. Oshima1, E. Shimizu1, H. Hirata1, H. Yasuda1 and T. Kubota1
1Department of Medicine, The Japan Self Defense Forces Central Hospital, Tokyo and 2Department of Immunology, St. Marianna University School of Medicine, Kawasaki, Japan
Aim: To contribute to understanding the pathogenesis of hyperkalemia that often occurs in patients with diabetes. Materials and methods: We describe 3 familial cases of mitochondrial diabetes mellitus. The mitochondrial A3243G point mutation was confirmed in a mother and her 2 children. We examined their clinical features and pathological findings, and assessed heteroplasmy of mutant mitochondria DNA (mtDNA) by molecular analysis. Results: The second son had spontaneous hyperkalemia and hyporeninemic hypoaldosteronism. Histopathological examination revealed severe tubulointerstitial and vascular changes around the juxtaglomerular apparatus. The mother only showed intermittent hyperkalemia concurrently with the aggravation of heart failure, and the pathological changes in her kidneys were mild. Heteroplasmy was more severe in the second son than in the mother. Conclusion: Heteroplasmy of mitochondrial cytopathy combined with diabetes mellitus led to abnormalities resembling those seen in Type IV renal tubular acidosis.Correspondence to:
J. Shimizu, MD; Department of Medicine, The Japan Self Defense Forces Central Hospital, Ikejiri 1-2-24, Setagaya-ku, Tokyo, 154-8532, Japan
Email: hemijun@nyc.odn.ne.jp
Letter to the Editor
Alternative treatment for systemic involvement in a child with postdiarrheal hemolytic-uremic syndrome
Abstract
E. Oki1, K. Tsuruga1, K. Tsugawa1, K. Suzuki1, T. Shinagawa1, T. Nakahata2, E. Ito1 and H. Tanaka1
1Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki and 2Section of Pediatrics, Mutsu General Hospital, Mutsu, Japan
