Esther Gonzalez

Vitamin D Insufficiency and Deficiency in Chronic Kidney Disease

Background: Kidney disease has been identified as a risk factor for vitamin D deficiency in hospitalized patients, and low levels of 25-hydroxyvitamin D have been suggested to be a risk factor for hyperparathyroidism in patients with chronic kidney disease (CKD). However, little is known about the magnitude of vitamin D deficiency in patients with CKD living in the United States. Methods: In this regard, we examined the levels of 25(OH)D in 43 patients with CKD and serum creatinine between 1 and 5 mg/dl (calculated glomerular filtration rate 111–11 ml/min per 1.73 m2) as well as in 103 patients undergoing hemodialysis. Results: In the predialysis patients, we found that 37 of the 43 patients (86%) had suboptimal levels of vitamin D (<30 ng/ml). Regression analysis indicated that there was a negative correlation between 25(OH)D and intact parathyroid hormone (PTH). Alkaline phosphatase showed a similar but less sensitive relationship. Serum albumin levels correlated with 25(OH)D levels. In contrast to findings reported in normal individuals, the levels of calcitriol correlated with those of 25(OH)D in the patients with CKD. In the group undergoing maintenance hemodialyis, we found that 97% of the patients had vitamin D levels in the suboptimal range, and there was no correlation of 25(OH)D levels with either PTH or serum albumin values. These data indicate that vitamin D insufficiency and deficiency are highly prevalent in patients with CKD and may play a role in the development of hyperparathyroidism. The functional significance of low levels of 25(OH)D in patients with stage 5 CKD remains to be determined.

Prevention and Control of Phosphate Retention/Hyperphosphatemia in CKD-MBD: What Is Normal, When to Start, and How to Treat?

Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients.

Achieving K/DOQI Laboratory Target Values for Bone and Mineral Metabolism: An Uphill Battle

Background: The National Kidney Foundation has recently published the Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (CKD). According to these guidelines, in patients with stage 5 CKD, the adjusted calcium level should be 8.4– 9.5 mg/dl, the serum phosphate should be 3.5–5.5 mg/dl, the calcium phosphorous product should be <55 mg2/dl2 and the intact parathyroid hormone (PTH) level should be 150–300 pg/ml. Methods: In order to evaluate our ability to meet these targets, we reviewed laboratory parameters of bone and mineral metabolism of 140 patients over a 6-month period in an inner city hemodialysis unit. Serum calcium and phosphate levels were determined using standard assays and PTH levels were determined using the Nichols Intact PTH assay. Results: We found that the levels of serum calcium and serum phosphorus fell within the range recommended by the K/DOQI guidelines 49 and 36% of the time respectively. 57% of the determinations for calcium × phosphorus product were <55 mg2/dl2. PTH levels were within the recommended values in 20% of the determinations. Only 7% of the determinations met all four criteria simultaneously in spite of meeting other K/DOQI targets such as hematocrit and dialysis adequacy. Conclusion: These data indicate that current practice for the management of bone and mineral metabolism in hemodialysis falls far short of meeting the K/DOQI guidelines.

Clinical Consequences and Management of Hypomagnesemia

Magnesium deficiency and hypomagnesemia remain quite prevalent, particularly in patients in intensive care units, and may have important clinical consequences. Magnesium should be measured directly in clinical circumstances in which a risk for magnesium deficiency exists and appropriately corrected when found. This commentary reviews the current knowledge of magnesium homeostasis and the risk factors and clinical consequences of magnesium deficiency and outlines approaches to therapy.

Vitamin D in chronic kidney disease

In chronic kidney disease (CKD), abnormalities in vitamin D metabolism contribute to the development of mineral and skeletal disorders, elevations in parathyroid hormone (PTH), hypertension, systemic inflammation, renal and cardiovascular damage. CKD induces a progressive loss of the capacity of the kidney not only to convert 25-hydroxyvitamin D [25(OH)D] to circulating calcitriol, the vitamin D hormone, but also to maintain serum 25(OH)D levels for non-renal calcitriol synthesis. The resulting calcitriol and 25(OH)D deficiency associates directly with accelerated disease progression and death. This chapter presents our understanding of the pathophysiology behind 25(OH)D and calcitriol deficiency in CKD, of the adequacy of current recommendations for vitamin D supplementation and PTH suppression, and of potential markers of renal and cardiovascular lesions unrelated to PTH suppression, a knowledge required for the design of trials to obtain evidence-based recommendations for vitamin D and calcitriol replacement that improve outcomes at all stages of CKD.

The evolution of assays for parathyroid hormone.

Recent progress in the assay of parathyroid hormone has revealed that commercially available assays for intact parathyroid hormone also measure additional parathyroid hormone peptides that appear to be truncated at the amino-terminal region and have the elution position on high-performance liquid chromatography of parathyroid hormone 7-84. Specific assays have been developed that measure only the true or ‘whole’, 84-amino-acid peptide. Such ‘whole’ parathyroid hormone assays have led to the discovery of new findings that suggest that parathyroid hormone fragments such as parathyroid hormone 7-84, which have hitherto been considered to be biologically inactive, may actually have biologic effects. These data, coupled with the emerging discovery of additional receptors for parathyroid hormone peptides, suggest that parathyroid hormone fragments might have potentially important actions, at least in the setting of renal failure.

Extracorporeal Management of Valproic Acid Toxicity: A Case Report and Review of the Literature

The incidence of intentional or accidental valproic acid (VPA) overdose is increasing. Severe VPA toxicity may lead to coma and death. Traditionally the treatment of patients with VPA toxicity has been limited to supportive measures. VPA is highly protein bound and therefore it is considered not to be removable by extracorporeal means. However, studies of VPA toxicokinetics indicate that at blood levels that exceed therapeutic concentrations, VPA protein binding sites become saturated, leading to increased concentration of the free unbound drug. The free unbound drug has a small molecular weight and therefore it is theoretically amenable to removal by extracorporeal means. We present a patient with VPA toxicity who was successfully treated with “in‐series” hemodialysis and hemoperfusion followed by continuous venovenous hemodiafiltration (CVVHDF) and review the literature on the management of VPA toxicity using extracorporeal therapies.

Proceedings: Pathogenesis and Treatment of Renal Osteodystrophy

Renal osteodystrophy is the term used to describe the many different patterns of the skeletal abnormalities that occur in patients with chronic kidney disease. The main two conditions are osteitis fibrosa, characterized by high bone turnover, increased osteoclastic and osteoblastic activity, and high levels of circulating parathyroid hormone (PTH) and adynamic bone disease characterized by low bone turnover and low levels of circulating PTH. Retention of phosphorus, decreased levels of calcitriol in blood, decreased levels of serum ionized calcium, reduced numbers of vitamin D receptors and calcium sensors in the parathyroid gland, and skeletal resistance to the calcemic action of PTH play a major role in the development of renal osteodystrophy. This review will describe the current approach for the treatment of renal osteodystrophy.

Scleroderma Renal Crisis With Minimal Skin Involvement and No Serologic Evidence of Systemic Sclerosis

We describe a 75-year-old male patient who developed end-stage renal failure secondary to scleroderma renal crisis. The patient had cutaneous involvement limited to his fingers and feet, and had repeatedly negative serologic tests for antinuclear antibodies. This case illustrates that scleroderma renal crisis should be considered in the differential diagnosis of unexplained acute renal failure in patients with suspected systemic sclerosis, even if they lack the typical extensive cutaneous changes and the expected serologic findings.

Association of early kidney allograft failure with preformed IgA antibodies to β2-glycoprotein I.

In the current immunosuppressive therapy era, vessel thrombosis is the most common cause of early graft loss after renal transplantation. The prevalence of IgA anti-β2-glycoprotein I antibodies (IgA-aB2GPI-ab) in patients on dialysis is elevated (>30%), and these antibodies correlate with mortality and cardiovascular morbidity. To evaluate the effect of IgA-aB2GPI-ab in patients with transplants, we followed all patients transplanted from 2000 to 2002 in the Hospital 12 de Octubre prospectively for 10 years. Presence of IgA-aB2GPI-ab in pretransplant serum was examined retrospectively. Of 269 patients, 89 patients were positive for IgA-aB2GPI-ab (33%; group 1), and the remaining patients were negative (67%; group 2). Graft loss at 6 months post-transplant was significantly higher in group 1 (10 of 89 versus 3 of 180 patients in group 2; P=0.002). The most frequent cause of graft loss was thrombosis of the vessels, which was observed only in group 1 (8 of 10 versus 0 of 3 patients in group 2; P=0.04). Multivariate analysis showed that the presence of IgA-aB2GPI-ab was an independent risk factor for early graft loss (P=0.04) and delayed graft function (P=0.04). There were no significant differences regarding patient survival between the two groups. Graft survival was similar in both groups after 6 months. In conclusion, patients with pretransplant IgA-aB2GPI-ab have a high risk of early graft loss caused by thrombosis and a high risk of delayed graft function. Therefore, pretransplant IgA-aB2GPI-ab may have a detrimental effect on early clinical outcomes after renal transplantation.