[[GUIDELINES FOR THE PREVENTION, MONITORING AND THERAPY OF CHRONIC KIDNEY DISEASE-METABOLIC BONE DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE].]

Chronic kidney disease (CKD) is a systemic disease with numerous complications associated with increased morbidity and mortality. Chronic kidney disease-metabolic bone disease (CKD-MBD) starts at early stages of CKD with phosphorus accumulation and consequent initiation of numerous events that result with the development of secondary hyperparathyroidism with changes on bones and extraskeletal tissues. The most important and clinically most relevant consequences of CKD-MBD are vascular calcifications which contribute to cardiovascular mortality. Patients with the increased risk for the development of CKD-MBD should be recognized and treated. Prevention is the most important therapeutic option. The first step should be nutritional counseling with vitamin supplementation if necessary and correction of mineral status. Progression of CKD requires more intensive medicamentous treatment with the additional correction of metabolic acidosis and anemia. Renal replacement therapy should be timely initiated, with the adequate dose of dislaysis. Ideally, preemptive renal transplantion should be offered in individuals without contraindication for immunosuppressive therapy.

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal transplant recipients or comparing sirolimus versus everolimus impact on bone, so only general conclusions could be drawn. Hence, the use of mTORi might be useful in patients with PRO due to their possible potential to inhibit osteoclast activity which might lead to a decreased rate of bone resorption. In addition, it should be also emphasized that they might inhibit osteoblast activity which may lead to a decreased bone formation and adynamic bone disease. Further studies are urgently needed to solve these important clinical dilemmas.

Impaired regulation of calcium excretion in kidney transplant recipients.

Disorders of mineral metabolism and hypercalcemia are frequent in kidney transplant recipients. Calcium to creatinine (Ca/Cr) clearance ratio was used as a criterion to distinguish between different calcium metabolism disorders. The study comprised 91 (53 men, 38 women) kidney recipients aged 23-70 years, with creatinine clearance (CrCl) >60 ml/min. The following parameters related to mineral metabolism were measured in serum: iPTH, total alkaline phosphatase (tALP), telopeptide (bone degradation marker, CTX), 25(OH)D(3), total and ionized calcium, Ca(++), Pi, creatinine (Cr). Creatinine and Ca were also determined in urine, as well as Ca/Cr clearance ratio. According to the Ca/Cr clearance ratio, patients were divided into three groups as follows: <0.01 (found in disorders caused by reduced calcium-sensing receptor sensitivity, N = 30), 0.01-0.02 (normal value, N = 45), and >0.02 (found in hyperparathyroidism, N = 16). In the group of patients with Ca/Cr clearance ratio <0.01, seven patients had hypercalcemia, and four patients had hypercalcemia and elevated iPTH. It seems that impairment of renal calcium excretion may occur in kidney transplant recipients with good kidney function. Inappropriately low calciuria and impaired sensitivity of calcium-sensing receptor may be pathogenetic factors causing hypercalcemia in kidney transplant recipients.

[Importance of biochemical indicators of bone turnover in patients on chronic dialysis and after kidney transplantation]. / Znacenje biokemijskih pokazatelja kostane pregradnje u bolesnika na kronicnoj dijalizi i nakon transplantacije bubrega.

Bone remodeling is a continuous process of removal of microscopic amounts of bone tissue due to synchronized actions of osteoclasts and osteoblasts with the purpose of renewal and repair of bone tissue. During the formation of bone matrix osteoblasts synthesize proteins. Measurement some of these proteins in blood has clinical significance as indicators of bone formation: osteocalcin, procollagen type I propeptide, and bone alkaline phosphatase. During osteoclastic bone resorption, collagen type I breakdown fragments are released in the circulation and excreted in the urine, and measured in serum or urine as bone resorption markers (telopeptide, pyridynolines). Bone metabolism and accordingly bone markers are subjected to considerable biologic variation. The effects of age, sex, race, pregnancy and lactation, fracture, disease and certain drugs cannot be avoided and must thus be considered when interpreting the results. Circadian variation is excluded by obtaining samples in the morning and the effect of exercise prevented. The use of bone markers has been extensively studied in monitoring the effect of antiresorptive treatment in osteoporotic women. A decrease of 30-50% occurs within 3 months after the beginning of hormone replacement therapy or bisphosphonates and remains at this level. In patients on chronic dialysis treatment, bone markers are increased and reflect bone metabolism as assessed by bone biopsy. Although bone markers enable discrimination between high and low bone turnover, they cannot substitute for bone biopsy in determination of the type of renal osteodystrophy. The factors affecting bone disorder in these patients, i.e. dialysis duration or parathyroid function correlate with bone markers. In kidney transplant recipients, an increased bone turnover and its normalization after approximately 2 years can be assessed by bone markers. Similar to chronic dialysis, risk factors for bone disorder after kidney transplantation (e.g., dialysis duration, parathyroid function, age, sex, immunosuppressants, corticosteroids, graft function) are associated with bone markers. We present cross-sectional and longitudinal data on 100 patients on chronic dialysis and 80 kidney transplant recipients. In conclusion, sufficient evidence exists indicating that the measurement of bone markers enables assessment of bone turnover and its dynamics. However, no guidelines or recommendations have been put forward to validate their use in routine clinical practice of chronic dialysis or kidney transplantation bone disorders.

[Primary cytomegalovirus infection after combined cadaveric transplantation of the liver and kidney]. / Primoinfekcija citomegalovirusom nakon kombinirane kadavericne transplantacije jetre i bubrega.

Seronegative transplant recipients are at a high risk of developing primary cytomegalovirus (CMV) infection. The D+/R--constellation produces a 60%-80% probability of CMV disease. In such cases CMV prophylaxis is justified. Presentation of a 12-year old boy who developed a primary CMV infection following A combined liver-kidney transplantation; evaluation of prophylactic options and review of some difficulties in the diagnosis of CMV infection. A cadaveric liver-kidney transplantation (Tx) was done in a 12-year old boy with ESRD due to type I primary hyperoxaluria. CMV status: D+, R-; number of mismatches: 5. PRA 0; kidney cold ischemia time (CIT): 13.54 h; liver CIT: 10.10 h; immediate diuresis; Immunosuppression protocol: anti IL-2 receptor antibodies, steroids, mycophenolate mofetil (MMF); cyclosporine introduced on day 6. Over the first week, daily hemodialyses were done in order to remove oxalate deposits. Kidney and liver biopsies: no ACR, no oxalate deposits. CMV prophylaxis with ganciclovir started on day 0. Routine serology and PCR for CMV follow-up showed: pp 65, IgM and IgG, CMV. DNA (Murex CMV. DNA Hybrid Capture test 2.0): negative over the first 3 months. Day 98: CMV pp 65 positive, IgM neg, DNA neg. Day 108: pp 65 neg, IgM positive, IgG neg. CMV. DNA positive (15 x 105 copies/ml). Clinical status: except for mild Cushing, liver tests and kidney function were normal. Ganciclovir was administered intravenously (i.v.) and after 14 days continued perorally. A few days later, leukopenia with severe neutropenia (neutrophil count: 400) and right otitis media developed. MMF and ganciclovir were withdrawn for a few days and reintroduced after WBC count reconstitution. We had no possibility to monitor MMF. Day 150 pp 65 neg, IgM still positive, IgG neg. No clinical signs of infection. Liver and kidney functions normal. After liver-kidney transplantation in a CMV high-risk pediatric patient (D+/R-), asymptomatic CMV primary infection developed. Although ganciclovir prophylaxis could not prevent the infection, it was mild and delayed. Due to bone marrow suppression, discontinuation of MMF and ganciclovir was necessary. Antigenemia assay pp 65 did not correlate very well with CMV viremia so it could not be recommended as a routine test. It should be used in combination with other CMV tests.

Parathyroid hormone and bone mass after kidney transplantation.

Metabolic bone disorder develops during chronic renal failure and chronic dialysis treatment, continues after successful kidney transplantation, and is further aggravated by corticosteroids and immunosuppressants. The recognized risk factors for bone loss, i.e. parathyroid hormone (PTH) secretion, age, duration of hemodialysis, sex and post-transplantation period, were examined in this cross-sectional study of 91 stable kidney transplant recipients. Patient age was 21-67 years, time spent on dialysis 1-216 months, and post-transplantation period 1-228 months. Bone mineral density was measured by dual energy x-ray absorptiometry at the lumbar spine, femoral neck and radius. T-scores (bone mineral density expressed as standard deviation of healthy young population) were used in statistical analyses to avoid sex differences in bone mass. PTH was measured by a commercial kit (9.07 +/- 11.81 pmol/L). The femoral neck and radius correlated negatively with PTH and hemodialysis duration both in simple correlations and multiple regression, and femoral neck additionally with age. The lumbar spine correlated negatively only with PTH. Post-transplantation time did not correlate significantly with the three densitometry sites. Also, the frequency of osteoporosis or osteopenia for the femoral neck and spine did not differ between the first 12 months and subsequent period, but was positively influenced by hemodialysis duration. There was no sex difference for the variables analyzed in the study. The results indicated that prolonged hemodialysis treatment and consequently increased PTH secretion had unfavourable effect on the femoral neck and radius bone in kidney transplant recipients. Regarding predictors in this study, only PTH was found to adversely affect the lumbar spine. Further deterioration of change in the skeletal status could not be demonstrated, which might be explained by the reduction in PTH secretion and possibly by improvement of the bone disorder.