Pregnancy in the Dialysis Patient

While recently reading about hypogonadism in the dialysis population, I came across this review on the pregnancy outcomes in women on dialysis, summarizing observational studies published between 1995 and 2009. I have participated in only a few pregnancy-planning discussions with women with CKD, but they have all been emotionally tough. None of my patients were dialysis patients, however, whom I would have predicted would have even worse outcomes with pregnancy as has been reported for CKD (for example, a rate of preterm delivery of 63% and perinatal death of 4% reported recently here).


The results of this review suggest that the outcomes in women on dialysis, while better than expected in some aspects (for example rate of live birth of 79%), still carry significant risks for the mother and baby (for example, a perinatal death rate of 17.6%).


Among women of childbearing age on dialysis, DaVita reports that only 1-7% can get pregnant – due to complete cessation of the menstrual cycle, or anovulatory cycles. However, some women continue to have menstrual cycles – as you’ll be smart to remember next time you’re asked about a female PD patient with a bloody peritoneal fluid effluent.


Among those who do get pregnant (222 pregnancies studied in this review), an astonishing 79% resulted in a live birth, although only 8% were term births (71% were premature for an overall preterm delivery rate of ~85%!). The two most common reasons for premature birth were premature labor (approximately 1/3rd) and fetal distress (another 1/3rd). Of the remaining 1/3rd, intrauterine growth restriction and hypertensive disease were most common. The rate of delivery by c-section in the subgroup where this data was available, was 37%.


Among the fetal/neonatal complications, prematurity was most common. Three cases of fetal abnormalities were reported, including one case of right-sided pulmonary agenesis. The rate of polyhydramnios was 32%, postulated to be due to increased diuresis by the fetal kidneys due to elevated urea. There were 19 neonatal deaths and 28 perinatal deaths among 159 live births for which this data was reported, yielding a neonatal mortality rate of 11.9% and perinatal mortality rate of 17.6%. It is not clear if perinatal mortality includes neonatal mortality in this article, though the latter percentage by itself is a sobering figure.


Among the maternal complications, hypertensive disease was the most common, though at a reported 30% it is much lower than I would have predicted. Among the 14 women in the cohort on PD, 4 developed peritonitis and 2 developed uterine bleeding so significant to require surgical intervention and, in one case, hysterectomy. The specific adjustments to renal replacement management for pregnant women were not discussed in detail, though included increased time and frequency of dialysis, which was associated with decreased rate of polyhydramnios and improved fetal outcomes.


As it is still a relatively rare event, I would love to hear from any of you who have helped manage pregnant women on dialysis.


Marta Hristova MD

The power of T

A talk recently about the HIM study at MGH (Hypogonadism In Men, Clin trial NCT00114114) prompted me to wonder about testosterone from the renal perspective.

Testosterone is important for several aspects of male health, including fertility, bone density, fat and muscle mass, and sexual function. Men with prostate cancer who are chemically or surgically castrated lose bone mass, lean body mass, have an increase in fat and a loss of libido and erectile function. However, the effects of testosterone at levels between what is considered normal (~500 ng/mL) and very low ( under 100 ng/mL in chemically castrated men) are still unclear and the subject of the HIM study.

Men on dialysis have a lot of the same changes reported with low testosterone levels: loss of lean muscle, loss of fertility, loss of libido and sexual function. Consistent with this, in a recent study of dialysis patients, testosterone levels in 47% of men were below 300 ng/mL (=hypogonadism); previous studies had reported that up to 2/3rds of men on dialysis have hypogonadism by this definition. Increased time on dialysis/ higher clearance apparently has no effect on testosterone levels. Part of the low testosterone comes from disruption of the normal pituitary pulsatile secretion of gonadotropin releasing hormone (GnRH) in renal failure, which is not restored with dialysis.

Hypogonadism has been associated with anemia, and one of the goals of this study was to see if daily testosterone gel application will reduce the need for rhEPO in a male dialysis cohort (it did not). Interestingly, the article discussed that prior to rhEPO, one of the available therapies for anemia in dialysis patients were IM injections of androgens.

Unfortunately, topical application of testosterone (100mg daily for 6 months) in this dialysis cohort of 66 randomized men also failed to improve lean muscle mass, bone density, sexual function or mood (as assessed by questionnaire), although the rise in serum testosterone with therapy was modest at best.

Interest in improving or affecting testosterone levels in the dialysis population was recently increased after this prospective study linked low serum testosterone (in this case defined as levels under 233 ng/mL) to increased cardiovascular mortality. Here, a cohort of 126 male HD patients was followed for an average of a little over 3 years. 52% of the men had a testosterone deficiency (here defined as  less than 288 ng/mL, similar with prior studies), and only ~20% had testosterone levels in the normal range.

The authors then divided the group in those that had a testosterone level below the 33rd percentile (below 233 ng/mL) vs the rest. The group with the lowest levels seemed overall slightly sicker (lower albumin, more inflammatory markers, higher epo dose, more baseline CVD). Over the observation period, ~50% of the cohort died, with the majorty of deaths from cardiovascular causes. Low testosterone levels (below the 33rd percentile) seemed predictive of mortality, even after adjustment for a history of CVD, although the significance was lost after adjustment for serum creatinine levels, perhaps reflecting a common etiology.

While these results are interesting, and even if a direct causal link is proven between low testosterone and CV mortality in the dialysis population, the difficulties of testosterone supplementation highlighted in the prior study give me pause.

Dr. Marta Hristova

A new drug for bone loss in renal patients?

At a recent meeting on bone biology, several talks were devoted to a new class of drugs targeting osteoporosis. Since these drugs are antibodies and thus not cleared by the kidney, I paid close attention, as they have the potential to be useful in patients with renal failure, where we generally shun bisphosphonates.


But first, lets talk about bone remodeling (see also this tutorial). Bone constantly remodels through a delicate interplay between two types of cells on the bone surface: the bone-producing osteoblasts, and the bone-resorbing osteoclasts (One source suggests that approximately 10% of the adult skeleton turns over every year). Osteoclasts are activated in part by a signal made by osteoblasts called RANKL (receptor activator of NFkB ligand), which binds to its receptor on osteoclasts. Once activated, osteoclasts start resorbing bone by acidifying the section of bone immediately underneath them (called a resorptive pit) to help digest and release the protein matrix (mostly collagen) and free up calcium and phosphate.


Denosumab, sold under the tradename Prolia by Amgen (FDA approved June 2010), is a monoclonal antibody against RANKL. It thus prevents activation of osteoclasts and the initiation of resorption. Denosumab is given every six month subcutaneously. In a randomized trial (The Freedom trial), which enrolled over 7800 women between the ages of 60 and 90 with a T score on their dexa scan between -2.5 and -4.0, denosumab prevented the radiological evidence of vertebral fractures (primary endpoint), as well as reduced the risk of hip fractures and non-vertebral fractures, increased bone mineral density at the lumbar spine and hip, and did so with minimal adverse effects.


No patients with ESRD were included, though a stratification of patients based on renal function reveals 74 patients with CrCl 15-29 (avg Cr 1.5+/-0.3), 2817 patients with CrCl of 30-59 (avg Cr 0.9) and 4059 with CrCl 60-89 (avg Cr 0.8). Comparing the patients with severe renal impairement to those with mild, the first set of women were older (80 vs 71 yo), thinner (avg weight 53 vs 66 kg) and had worse femoral neck and hip BMD T scores (-2.8 vs -2.1 and -2.8 vs -1.8). Despite this perhaps less healthy population, the primary endpoint, radiological vertebral fractures, was reduced in this sub-group as well, with an incidence of 9.1% in the placebo group vs 3.2% in the active drug.


One major issue with this drug in this sub-group, was the increased incidence of serious infections: 11 in the denosumab group (31 pts received the drug, so the rate was ~30%) vs 4 in the placebo group (33 patients received placebo, for a rate of 12%). It appears that the infections are mostly cellulitis. While this difference was not statistically significant, it would give me pause. Given that the population in this trial was probably “healthier” (Calcium had to be normal for study entry; PTH was not checked), I think more data is needed before we can consider denosumab safe in patients with renal dysfunction.

Beyond the kidney

Mostly I think about the bladder, in a professional sense, as a possible site for obstruction to be ruled out. Occasionally, when I’m personally reminded about it, I wonder how much urine it can hold. (Pearl from residency: never start a procedure on an empty stomach or with a full bladder) Recently, I had a chance to learn about the bladder while researching an article and discovered several fun facts:


- urine empties into the bladder every 10-15 seconds
- the bladder can hold comfortably between 350-550 cc (12-18 oz) of urine for several hours;
- the urge to urinate usually starts when it has anywhere between 150-300 cc or urine; it can be overridden voluntarily to volumes of 600-800 cc
- speaking of causes of bladder outlet obstruction, the largest bladder stone ever removed (per Guinness world records, 2007 edition) weighed 1.9 kg and measured 17.9 by 12.7 by 9.6 cm


The bladder is able to stretch to accommodate such swings in urine volume thanks to two properties of its epithelium. The first one is a folded apical membrane, which unfolds as the bladder is filling, changing the shape of the top layer of urothelial cells – also called umbrella cells -- from a rounded one to a more flat, squamous one. The second feature is a collection of membrane vesicles, tethered close to the apical surface by cytoskeletal fibrils. As the cell stretches and becomes flatter, the vesicles fuse with the apical membrane, increasing its surface.


The bladder is normally impermeable to the components of urine: molecules, such as urea, ammonia, and water, which usually freely travel through epithelial membranes. Aside from the presence of tight junctions between cells, this impermeability is a function of the composition of the lipid bilayer of the apical epithelial membrane, where the specific arrangement of lipid hydrocarbon tails impairs travel of these molecules across the bilayer. In addition, special proteins, called uroplakins, form aggregates called plaques. These plaques occupy 70-90% of the surface of each cell and help keep urea and water out. When uroplakin was knocked out in mice, their urothelium became permeable to urea, and, to a lesser extent, water.


Interestingly, the urothelium has amiloride-sensitive ENaC–type channels, present at very low levels in normal human bladders (and with different subunit stoichiometry in different mammals). Channel expression may increase in states of elevated bladder pressure, such as in bladder obstruction, an observation consistent with a recent report suggesting that the role of the ENaC -type channels appears to be more important in mechanosensation.


Some interesting reviews and relevant articles can be found here, here, here and here.


Posted by Marta Hristova, MD, PhD