Pregnant women with chronic kidney disease ckd are at risk of adverse maternal and fetal outcomes. We conducted a systematic review of observational studies that described this risk.

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we searched several databases from their date of inception through june 2010 for eligible articles published in any language. We included any study that reported maternal or fetal outcomes in at least five pregnant women in each group with or without ckd. We excluded pregnant women with a history of transplantation or maintenance dialysis. Recent guidelines stage chronic kidney disease ckd according to levels of kidney function irrespective of the type of kidney disease 1 .

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Diseased kidneys may be unable to adapt to the normal physiologic changes of pregnancy leading to perinatal complications 4 ,5 . Although a number of observational studies have shown that women with ckd have an increased risk of developing adverse maternal and fetal outcomes, a robust synthesis of this information is lacking 2 ,6 x02013 13 . We conducted this systematic review to determine the following: 1 the risk of adverse maternal outcomes in women with ckd compared with women without ckd comparator group and 2 the risk of adverse fetal outcomes comparing the two groups of women. We conducted and reported this systematic review according to published guidelines using a prespecified protocol 14 ,15 . We included any observational study that reported maternal or fetal outcomes in five or more pregnant women with ckd and five or more pregnant women without ckd as a comparator group.

Primary studies defined ckd as any of the following: abnormal serum creatinine/abnormal gfr and/or proteinuria with a specific primary or secondary kidney disease. The comparator group consisted of women without ckd and these women may or may not have had other comorbidities such as diabetes mellitus or systemic lupus erythematosus. Adverse maternal outcomes were as defined by the primary study authors and included gestational hypertension, pre eclampsia, eclampsia, and maternal mortality. Adverse fetal outcomes included premature births, intrauterine growth restriction iugr , small for gestational age sga , neonatal mortality, stillbirths, and low birth weight. We included full text papers and abstracts published in any language that reported at least one outcome of interest. We excluded studies of women with ckd with a history of kidney transplantation or maintenance dialysis, as well as studies of women with acute kidney injury or a single kidney. We designed and implemented a systematic literature search with the help of an experienced librarian.

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We searched the following electronic databases from the date of inception up to june 2010: medline and premedline ovid, 1966 through 2010 , embase ovid, 1980 through 2010 , biosis previews 1969 through 2010 , the isi science citation index expanded 1981 through 2010 , cochrane controlled trials register wiley interscience, all years , scopus 1966 through 2010 , and specialty search engines google scholar and elsevier's scirus. The search strategy included a combination of key words and mesh terms and was adapted for each database to account for differences in indexing. We also searched gray literature sources nephrology conference proceedings and web of science database and conference abstracts. We conducted citation tracking using scopus and the isi science citation index, and used related articles features in pubmed, ovid, elsevier's scirus, and google scholar. We retrieved the full text for any article considered potentially relevant by at least one reviewer. To ensure accuracy, two reviewers then independently screened full texts articles for inclusion in this review.

We resolved disagreements by discussion or with the help of a third reviewer a.d. 641 649 november 2013 doi:10.1038/nrneph.2013.147 justin silver amp tally naveh many about the authors the metabolic changes that occur in patients with chronic kidney disease ckd have a profound influence on mineral and bone metabolism. Ckd results in altered levels of serum phosphate, vitamin d, calcium, parathyroid hormone pth and fibroblast growth factor 23 fgf 23 the increased levels of serum phosphate, pth and fgf 23 contribute to the increased cardiovascular mortality in affected patients. Fgf 23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25 dihydroxyvitamin d₃. In addition, the high levels of pth associated with ckd contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low molecular weight fibroblast growth factors from the bone matrix, which stimulate fgf 23 transcription. A prolonged oral phosphorus load increases fgf 23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone.

Other factors such as dietary vitamin d compounds, calcium, and metabolic acidosis all increase fgf 23 levels. This review discusses the mechanisms by which secondary hyperparathyroidism associated with ckd stimulates bone cells to overexpress fgf 23 levels. For many years it had been known that a humoral factor was responsible for the phosphaturia occurring in hyp mice x02014 a murine model of x linked hypophosphataemia. This finding was based on elegant parabiotic studies in which the phosphaturia of hyp mice was induced in wild type mice. 1 transplantation of kidneys from hyp mice into wild type mice did not cause phosphaturia nor was the phosphaturia of hyp mice corrected by transplantation of kidneys from wild type mice.

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2 genetic analyses of families with autosomal dominant hypophosphataemic rickets adhr led to the cloning of fgf 23 and the identification of causative mutations. 3 fgf 23 was soon also confirmed as the causative factor in tumour induced osteomalacia. 4 fgf 23 acts through its receptor, the klotho x02013 fibroblast growth factor receptor 1 fgfr1 complex, to decrease the expression and activity of the sodium x02013 phosphate cotransporters napi2a and napi2c in the renal tubules, as well as the activity of 25 hydroxyvitamin d₃ 1 x003b1 hydroxylase. 5, 6 these effects lead to phosphaturia and a decrease in serum phosphate levels and 1,25 dihydroxyvitamin d₃ 1,25 oh ₂ d₃ synthesis.

Serum fgf 23 levels are remarkably high in patients with ckd and correlate with mortality in these patients. 7, 8, 9 secondary hyperparathyroidism is a major complication in many patients with ckd, and is characterized by phosphate retention, low levels of 1,25 oh ₂ d₃. 10 understanding the contributions of high fgf 23 levels and secondary hyperparathyroidism to the changes in bone and mineral metabolism that occur in patients with ckd is a challenge. Previous reviews on the effects of fgf 23 in ckd have added to our understanding of this rapidly developing field. 11, 12, 13, 14, 15 this review focuses on the pathogenesis of increased fgf 23 levels in the secondary hyperparathyroidism of ckd. Early stages of ckd, both in dogs with experimental uraemia induced by renal artery ligation, and in humans, are associated with an increase in phosphaturia, which correlates with increasing levels of serum pth. 16 the stimulus for the increased pth secretion was once thought to be the complexing of serum calcium with retained phosphorus and the deposition of this complex in soft tissues.

Deposition of calcium x02013 phosphorous complexes results in small decreases in levels of ca 2+. 17 more recent studies over the past 20 years, however, show a direct effect of phosphate on the parathyroid gland. Notably, these direct effects require the tissue architecture of the parathyroid gland to be maintained by a signalling pathway that involves phospholipase a2 metabolism. 18, 19, 20, 21 the mechanism by which phosphate levels in the extracellular fluid are sensed is unknown. One possibility is that phosphate retention signals to the parathyroid gland through a small decrease in ca 2+ level, which would be sensed by the parathyroid calcium receptor and lead to increased pth secretion. In bone, phosphate retention would increase fgf 23 expression by altering hydroxyapatite synthesis and bone matrix metabolism figure 1 . For example, use of medium with a high phosphate concentration increased the expression of osteogenic genes in cultured mouse smooth muscle cells.

23 this effect was caused by the formation of calcium x02013 phosphate nanocrystals of 150 nm in diameter and was prevented by the mineralization inhibitor, pyrophosphate. 23 in addition, mice given increasing loads of dietary phosphorus have shown clear incremental increases in serum fgf 23 levels. 24 the main source of fgf 23 is the osteocytes in the bone matrix, which are exposed to bone matrix particles. The osteocyte is also exposed to circulatory factors via interconnecting canaliculi that connect to blood vessels in bone. 58 bone remodelling regulates fgf 23 production through the release of low molecular weight fgfs, which activate canonical fgf receptors on osteocytes. Phosphorus could alter the ratio of inorganic phosphate to pyrophosphate in the bone matrix, which together with calcium directly regulates hydroxyapatite formation and deposition of bone matrix. Pth increases fgf 23 transcription and might increase bone remodelling indirectly.

1,25 oh ₂ d₃ and its analogues increase fgf 23 transcription as do leptin and oestrogens. The metabolic acidosis of chronic kidney disease, cklotho and intravenous iron therapy also all increase fgf 23 levels. 1,25 dihydroxyvitamin d₃ cklotho, cleaved klotho dmp 1 dentin matrix protein 1 fgf, fibroblast growth factor phex, phosphate regulating neutral endopeptidase. Full size figure and legend 31 kb figures and tables index download high resolution power point slide 138 kb laboratory studies have also been informative in understanding the sequence of changes in serum levels of ca 2+. Rats with experimental renal failure had increased levels of fgf 23 and pth and decreased levels of 1,25 oh ₂ d₃.