Vitamin D resistance in chronic kidney disease (CKD).

BACKGROUND: Previous studies have shown that treatment with ergocalciferol in patients with CKD stage 3 + 4 is not effective with less than 33% of patients achieving a 25-OH vitamin D target of >30 ng/ml. The aim of this study was to test the response to cholecalciferol in CKD. We attempted to replete 25-OH vitamin D to a target level of 40-60 ng/ml using the response to treatment and PTH suppression as an outcome measure. METHODS: This retrospective cohort study identified patients (Stages 2-5 and Transplant) from 2001-2010 who registered at the Chronic Kidney Disease Clinic. Patients received cholecalciferol 10,000 IU capsules weekly as initial therapy. When levels above 40 ng/ml were not achieved, doses were titrated up to a maximum of 50,000 IU weekly. Active vitamin D analogs were also used in some Stage 4-5 CKD patients per practice guidelines. Patients reaching at least one level of 40 ng/mL were designated RESPONDER, and if no level above 40 ng/mL they were designated NON-RESPONDER. Patients were followed for at least 6 months and up to 5 years. RESULTS: 352 patients were included with a mean follow up of 2.4 years. Of the CKD patients, the initial 25-OH vitamin D in the NON-RESPONDER group was lower than the RESPONDER group (18 vs. 23 ng/ml) (p = 0.03). Among all patients, the initial eGFR in the RESPONDER group was significantly higher than the NON-RESPONDER group (36 vs. 30 ml/min/1.73 m2) (p < 0.001). Over time, the eGFR of the RESPONDER group stabilized or increased (p < 0.001). Over time, the eGFR in the NON-RESPONDER group decreased toward a trajectory of ESRD. Proteinuria did not impact the response to 25-OH vitamin D replacement therapy. There were no identifiable variables associated with the response or lack of response to cholecalciferol treatment. CONCLUSIONS: CKD patients treated with cholecalciferol experience treatment resistance in raising vitamin D levels to a pre-selected target level. The mechanism of vitamin D resistance remains unknown and is associated with progressive loss of eGFR. Proteinuria modifies but does not account for the vitamin D resistance.

Meta-analysis: the efficacy and safety of paricalcitol for the treatment of secondary hyperparathyroidism and proteinuria in chronic kidney disease.

INTRODUCTION: Previous studies have demonstrated the safety and efficacy of using Paricalcitol for the treatment of secondary hyperparathyroidism (SHPT) in patients on dialysis. The aim of the current meta-analysis was to assess the safety and efficacy of Paricalcitol for the management of SHPT in patients with chronic kidney disease (CKD) not yet on dialysis. A secondary aim was to determine if sufficient data was available to assess the effect of Paricalcitol for the management of proteinuria. METHODS: A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software. RESULTS: Paricalcitol is effective in lowering PTH in patients with CKD not yet on dialysis and is also effective in lowering proteinuria in diabetic CKD patients. However, we uncovered a safety signal identifying an elevated calcium phosphate product and a trend towards the development of hypercalcemia. A phosphate elevation was not demonstrated because the target used in the clinical studies was a P > 5.5 mg/dl, a value appropriate for dialysis patients and not CKD patients. CONCLUSION: Although Paricalcitol is effective in lowering PTH, we advise caution in the use of any active Vitamin D analogues in patients with CKD because of the potential risk of exacerbating vascular calcification.

Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.

OBJECTIVE: Numerous studies have evaluated the prevalence and importance of vitamin D deficiency among patients with chronic kidney disease and end-stage renal disease; however, little is known about vitamin D levels in acute kidney injury (AKI). We evaluated the association between vitamin D metabolites and clinical outcomes among patients with AKI. DESIGN: Prospective cohort study. PATIENTS: A total of 30 participants with AKI and 30 controls from general hospital wards and intensive care units at a tertiary care hospital were recruited for the study. MEASUREMENTS: Plasma levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2 D], 24R,25-dihydroxyvitamin D3 , vitamin D binding protein (VDBP) and fibroblast growth factor 23 (FGF23) were measured within 24 hours of AKI onset and 5 days later. Bioavailable 25(OH)D and 1,25(OH)2 D levels, defined as the sum of free- and albumin-bound 25(OH)D and 1,25(OH)2 D, were estimated using equations. RESULTS: Compared to controls, participants with AKI had lower levels of 1,25(OH)2 D [17 (10-22) vs 25 (15-35) pg/ml, P = 0·01], lower levels of VDBP [23 (15-31) vs 29 (25-36) mg/dl, P = 0·003] and similar levels of bioavailable 25(OH)D and 1,25(OH)2 D at enrolment. Levels of bioavailable 25(OH)D were inversely associated with severity of sepsis in the overall sample (P < 0·001). Among participants with AKI, bioavailable 25(OH)D, but not other vitamin D metabolites, was significantly associated with mortality after adjusting for age and serum creatinine (adjusted odds ratio per 1 SD ln [bioavailable 25(OH)D] = 0·16, 95% confidence interval = 0·03-0·85). CONCLUSIONS: Bioavailable 25(OH)D could have a role as a biomarker or mediator of adverse outcomes among patients with established AKI.

FGF-23 levels in patients with AKI and risk of adverse outcomes.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 plays an important role in regulating phosphate and vitamin D homeostasis. Elevated levels of fibroblast growth factor 23 are independently associated with mortality in patients with CKD and ESRD. Whether fibroblast growth factor 23 levels are elevated and associated with adverse outcomes in patients with AKI has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study had 30 participants with AKI, which was defined as an increase in serum creatinine ≥ 0.3 mg/dl or ≥ 50% from baseline, and 30 controls from the general hospital wards and intensive care units. Plasma levels of C-terminal fibroblast growth factor 23 and vitamin D metabolites were measured within 24 hours of AKI onset and 5 days later. The composite endpoint was death or need for renal replacement therapy. RESULTS: Enrollment fibroblast growth factor 23 levels were significantly higher among participants with AKI than controls (median [interquartile range]=1471 [224-2534] versus 263 [96-574] RU/ml, P=0.003). Enrollment fibroblast growth factor 23 correlated negatively with 25-hydroxyvitamin D (r=-0.43, P<0.001) and 1,25-dihydroxyvitamin D (r=-0.39, P=0.003) and positively with phosphate (r=0.32, P=0.02) and parathyroid hormone (r=0.37, P=0.005). Among participants with AKI, enrollment fibroblast growth factor 23 (but not other serum parameters) was significantly associated with the composite endpoint, even after adjusting for age and enrollment serum creatinine (11 events; adjusted odds ratio per 1 SD higher ln[fibroblast growth factor 23]=13.73, 95% confidence interval=1.75-107.50). CONCLUSIONS: Among patients with AKI, fibroblast growth factor 23 levels are elevated and associated with greater risk of death or need for renal replacement therapy.

Radiographic periodontal bone loss in chronic kidney disease.

BACKGROUND: We examined the extent and severity of radiographic periodontal bone loss in patients with different stages of chronic kidney disease (CKD) and explored a potential dose-response relationship between bone loss and CKD-related biomarkers. METHODS: Panoramic radiographs were obtained from 129 CKD patients (78 males and 51 females; mean age: 63.5 years, range: 24 to 91 years), including 63 patients undergoing dialysis for an average of 3.3 years (range: 0.5 to 14 years). Glomerular filtration rate (GFR), dialysis dose, and levels of serum biomarkers were obtained through a hospital database. Interproximal bone loss was assessed as a percentage of root length. RESULTS: Twenty-nine participants were edentulous (23.8% of those on dialysis versus 21.2% of those with residual kidney function; χ(2) test, P = 0.724). The extent of bone loss was higher among dialysis patients (analysis of variance [ANOVA], P = 0.007), but no clear dose-response association between CKD stage and extent was evident. GFR, dialysis dose, and levels of serum biomarkers did not differ between edentulous and dentate individuals, and only serum albumin was lower in patients with extensive bone loss (ANOVA, P = 0.030). After adjusting for dialysis status, the severity of bone loss was positively associated with glucose levels (multiple regression, P = 0.019) and white blood cell count (P = 0.032), whereas the number of teeth present was positively associated with plasma phosphorus (P = 0.008) and negatively with glucose levels (P = 0.011). CONCLUSION: Despite a higher extent of bone loss in dialysis patients, the lack of a dose-response association between bone loss and CKD stage or the levels of CKD-related serum biomarkers underscores the complex relationship between the two conditions.

Elevated FGF-23 in a patient with rhabdomyolysis-induced acute kidney injury.

Rhabdomyolysis-induced acute kidney injury (AKI) is characterized by hyperphosphataemia and hypocalcaemia. Despite appropriate secondary elevation of parathyroid hormone (PTH) in response to hypocalcaemia, rhabdomyolysis and AKI are associated with acute deficiency of 1,25-dihydroxycholecalciferol (1,25(OH)(2)D(3)), and yet, the mechanism responsible for such a deficiency remains unclear. Fibroblast growth factor 23 (FGF-23), a potent phosphaturic hormone that inhibits 25-hydroxyvitamin D(3)-1alpha-hydroxylase, could explain the deficiency of 1,25(OH)(2)D(3) in this setting. Here, we document, for the first time, elevated levels of FGF-23 in a patient with rhabdomyolysis-induced AKI.

Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate.

Active vitamin D derivatives attenuate the severity of secondary hyperparathyroidism but often increase serum calcium (Ca) and phosphorus (P) as a result of enhanced intestinal absorption. The calcimimetic cinacalcet HCl lowers parathyroid hormone (PTH) and tends to decrease Ca x P. A 16-wk, open-label clinical trial was conducted in adult hemodialysis patients who had controlled PTH (biointact PTH [biPTH] 80 to 160 pg/ml) and elevated Ca x P (> 55 mg2/dl2) and were receiving paricalcitol > 6 microg/wk (or an equipotent dose of an alternative active vitamin D derivative). At the start of the study, active vitamin D derivatives were decreased to a mean equivalent dose of paricalcitol 6 microg/wk, and cinacalcet was titrated from 30 mg/d to a maximum possible dose of 180 mg/d. Of the 72 study patients, 53 (74%) completed 8 wk of dose titration with cinacalcet. In response to cinacalcet, the following mean percentage changes were observed: biPTH, -1.8%; Ca, -9.7% (P < 0.0001), phosphorus, -11.1% (P < 0.0001), and Ca x P, -20.1% (P < 0.0001). At the end of the study, approximate Kidney Disease Outcomes Quality Initiative targets for biPTH (< or = 160 pg/ml) were achieved in 85% (45 of 53) of patients and for Ca x P (< or = 55 mg2/dl2) in 72% (38 of 53) of patients. Concurrent achievement of both targets occurred in 47% (25 of 53) of patients. In this open-label clinical trial, hemodialysis patients who had controlled PTH but elevated Ca x P and were taking moderate- to high-dose active vitamin D derivatives achieved improved control of mineral metabolism with a combination of low-dose active vitamin D derivatives and cinacalcet. The long-term effects of this treatment regimen on clinical outcomes should be tested prospectively.

Process dissociation using a guided procedure.

A method for achieving process dissociation is described that places less emphasis on participants' understanding and remembering interpretations of test cues than does the standard procedure. The proposed method, called the guided procedure, tests memory with a sequence of two prompts, one requesting word-stem recognition, followed by another for word-stem completion. Inclusion and exclusion conditions are produced by requesting completion of recognized stems to form previously presented or new words, respectively. Estimates of automatic and conscious memory produced by the standard and the guided procedures are compared in studies modeled after Toth, Reingold, and Jacoby (1994). Although not significantly different in many aspects, the outcomes differ in ways that may reflect less reliance on a generate-recognize strategy of participants tested with the guided procedure. Additional measures of memory available only with the guided procedure are presented.

Fludarabine treatment of cryoglobulinemic glomerulonephritis.

Three patients (one hepatitis C positive) presented with renal insufficiency and nephrotic-range proteinuria resulting from mixed cryoglobulinemia and glomerulonephritis. All three patients received two to four cycles of intravenous fludarabine (each cycle consisted of 25 to 50 mg/d for 4 to 5 days). All patients responded to therapy with a decrease in proteinuria, increase in serum albumin, and decrease in serum creatinine. This response was evident by 2 months and persisted for 2 to 5 years. In two patients, this response was accompanied by disappearance of cryoglobulins, at least transiently. One patient developed tuberculosis with neutropenia. Transient blindness and neutropenia were seen in another patient. These results suggest that fludarabine may be a useful treatment in cryoglobulinemia with glomerulonephritis, although its use may be accompanied by side effects.