Dialysis in Neonates

Recently, there was an article in Slate magazine that detailed the very difficult decision that had to be made by a pregnant woman who discovered at 18 weeks gestation that her baby had complete bladder outlet obstruction with resulting bilateral megaureters and likely hypoplastic lungs. One of the questions related to the issue of dialysis in a newborn. In the past, this was generally not offered because of the presumption of a very poor prognosis. However, survival in neonates with ESRD has improved and it is becoming more routine in some units to offer RRT. It seems appropriate then, that KI just published a retrospective analysis of dialysis in neonates over the last 15 years.

In total, 254 patients from 32 countries started dialysis before one month of age and about half were in the first week. The most common causes of ESRD were congenital abnormalities of the kidney and urinary tract, cystic kidneys (mostly ARPKD) and cortical necrosis. More than 90% started with PD with most of the remainder starting HD because there was a contraindication to PD (e.g. recent abdominal surgery). One patient had a transplant in the first week but died shortly afterwards. Fifteen individuals had some later recovery of renal function and were able to come off dialysis, at least temporarily.

Overall, survival was excellent - 2-year survival was 81% and 5-year survival was 76.4%. In cases where the cause of death was known, about 2/3 were due to sepsis. Interestingly, the only factor that was significantly associated with an increased risk of death was the presence of concomitant neurological disorders (HR 5.2, CI 1.7-15.4). This may suggest that there was considerable selection bias with neonates who were considered unlikely to survive due to the presence of severe co-morbidities not being commenced on dialysis.

Long term, 45 patients received a transplant in the first 2 years of life. The 5-year patient and graft survival in these individuals was 84.2%.

As expected, there were significant co-morbidities present in these children. 20% had neurodevelopmental delay and 12% had pulmonary problems, mostly hypoplasia (the kidneys are an important source of amniotic fluid which is required for proper lung development). Birth length was below the 3rd percentile in 43% and 63% had growth retardation at 2 years. About 40% were on antihypertensives at 2 years and about 86% required treatment with EPO.

Overall, survival in this very vulnerable group was much better than I would have expected. Of course, given the presence of multiple co-morbidities, it is uncertain what their longer term outcomes would be. However, it does provide some hope to a group who, not so long ago, would have been considered hopeless. Consider that in 1998, a survey of French neonatologists found that 24% would never consider RRT in a neonate whereas a more recent survey suggested that 98% of neonatologists would offer RRT in at least some patients.

Nail-Patella Syndrome

Too long have I seen the "Nail-Patella Syndrome" included in the differential diagnosis of renal disease without understanding anything about it...that ends today!

The Nail Patella Syndrome (NPS), also referred to as Hereditary Onychoosteodysplasia, is an autosomal dominant inherited disorder which is caused by mutations in LMX1B, which encodes a transcription factor important in the development of the limb, eye, and kidneys.  Although it most commonly results in nailbed deformities such as the one depicted and also dysplasia of the patellae or other bones, in about 1/3 of cases it can result in a nephropathy.

The nephropathy of Nail-Patella Syndrome typically presents with either hematuria, proteinuria, or both.  Both frank nephrotic syndrome and progression to ESRD are possibilities, though occur in a minority of patients.  Biopsy shows fibrosis, and the presence of collagen fibrils which cause GBM thickening.  It can probably be classified as a "podocytopathy" in the sense that knockout mice lacking the LMX1B gene show a deficit in podocyte development.  The current thought is that patients with mutations which are more severe are the ones most likely to develop kidney disease. 

EAST Syndrome

A relatively recent study by Bockenhauer et al in NEJM reports the identification of a new disease gene in a rare tubulopathy syndrome that sheds light on the physiologic mechanisms of salt transport in the kidney.

The article describes children with an autosomal recessive inherited condition termed "EAST Syndrome", which stands for epilepsy, ataxia, sensorineural deafness, and tubulopathy. Specifically, patients had evidence of renal salt wasting with low-normal blood pressure, resulting in activation of the renin-angiotensin system and a resultant hypokalemic metabolic alkalosis. Individuals also demonstrated significant hypomagnesemia and hypocalciuria. Genetic studies identified the cause of EAST Syndrome: mutations in the gene KCNJ10, a potassium channel which is expressed in all of the affected tissues (brain, inner ear, and kidney) in this disorder. They go on to demonstrate that mice made deficient for KCNJ10 show a similar salt wasting phenotype as in affected humans.

What does KCNJ10 do? The authors propose that this potassium channel sits at the basolateral membrane of tubular epithelial cells where it recycles potassium, which is necessary for maintaining the activity of the Na/K-ATPase. Although rare, EAST Syndrome helps provide greater molecular detail of how the kidney absorbs salt, and suggests that researchers look for polymorphisms in this gene which may explain some of the genetic predisposition towards hypertension and salt handling by the kidney.

Genetics of Wilms Tumor

Wilms Tumor--named after the German surgeon/pathologist Max Wilms (pictured at left)--is an embryonal tumor that derives from developing kidney tissue. Wilms was the first to postulate that tumors may arise from precursor cells which arise during development, and indeed study of the molecular pathways active in these "nephroblastoma" shed light on normal kidney development.

There are several genes associated with patients with Wilms Tumor. Here are some of the main ones:

1. WT1 is a transcription factor and considered a tumor suppressor gene. Mutations in WT1 account for between 10-15% of sporadic Wilms tumor. It interacts with p53, a classic tumor suppressor involved in a wide variety of cancers. Denys-Drash Syndrome, a familial and severe form of Wilms tumor, is usually caused by congenital WT1 mutations.

2. beta-catenin is a key component of the canonical Wnt signaling pathway, long known to be a key player in kidney development. Interestingly, most patients with WT1 also have gain-of-function point mutations in the beta-catenin gene which result in increased stability of the beta-catenin protein and subsequent unregulated Wnt signaling.

3. WTX is mutated in a different subset of patients than those with WT1 mutations, and is found on the X-chromosome.

4. BDNF (brain-derived neurotrophic factor): mutations in this growth factor are postulated to result in the WAGR Syndrome--a constellation of symptoms that includes Wilms Tumor along with aniridia, GU abnormalities, and mental retardation.

5. BRCA2: interestingly, mutations in the well-known breast cancer-susceptibility gene can also lead to Wilms tumor.

Tiny Tim: Victim of Renal Tubular Acidosis?

Pictured on the left is Bob Cratchit and his crippled son, Tiny Tim, two beloved characters from Charles Dickens' A Christmas Carol.  In this fun 1992 article by the pediatrician D.L. Lewis, the case is made that Tiny Tim suffered from renal tubular acidosis.  

So what's the evidence? Dickens describes Tim's illness as being a syndrome of short stature, asymmetric crippling, and intermittent spells of weakness.  The book also implies that there is some medical treatment available for this illness (which the Cratchits are initially unable to afford given the tight-fisted nature of Cratchit's boss, Ebeneezer Scrooge), and without such treatment Tim would be condemned to death within the year. Fortunately, after his encounters with the Ghosts of Christmas Past, Present, and Future, Scrooge is able to reverse his selfish ways, supplying Cratchit with a much-welcomed bonus with the implication that Tiny Tim will now be able to afford said medical treatments and survive. 

The author of the above article performed a review of available pediatric textbooks within the time frame of the book's setting (1830s-1850s) and determined that the likely treatment regimen for Tim's condition would involve alkali-containing compounds such as sodium bicarbonate and sodium citrate, along with potassium repletion and vitamin D repletion. A distal (Type I) RTA would fit nicely with these symptoms as his crippling could potentially seen as osteomalacia with pathologic fractures (the skeleton can develop severe weakness in the setting of prolonged acidemia), his spells of weakness could potentially be explained by hypokalemic muscle weakness, and his impending death could potentially be explained by the resultant renal failure that could result from chronic nephrocalcinosis, another aspect of RTAs.  

Another possibility would simply be that Tiny Tim suffered from severe vitamin D deficiency and resultant rickets--a relatively common affliction during this time period.

The more recent "real-life" Tiny Tim--the absurdist ukulele player--did not have kidney problems to my knowledge.

Speaking of Ethylene Glycol Poisoning...

If you've never heard the biochemical sleuthwork involved in the legal case of Patricia Stallings, it's definitely worth reading about: a good summary of the case can be found here.

Briefly, it involves a St. Louis-area woman who, in 1989, was sentenced to jail for the alleged poisoning of her baby son after he was hospitalized twice, and eventually died, due to apparent ethylene glycol toxicity. The diagnosis was made due to the presence of characteristic lab abnormalities (anion gap, osmolar gap), crystals deposits in the brain (felt to be oxalate crystals) as well as the documented presence of ethylene glycol--though the lab test used was apparently an older and less reliable gas chromatography method of measuring ethylene glycol in retrospect.

Fast forward several months later, when Patricia Stallings gave birth to a second child while in prison--who developed a similar illness and was diagnosed with a rare autosomal recessive error of metabolism: methylmalonic aciduria (MMA), which causes a chronic metabolic acidosis. The same type of disorder can also occur with severe vitamin B12 deficiency. Geneticists at St. Louis University and Yale University, alerted to the possibility that the first child's death might have been due to this genetic disease rather than ethylene glycol poisoning, re-examined the older blood samples, which were still available. They found that the original samples DID have an abundance of methylmalonic acid, and with a more accurate lab test did not have ethylene glycol. Patricia Stallings was determined to be innocent and subsequently released.

The legal aspects of the case, as it turns out, are just as interesting as the medical aspects: it involves the prosecuting attorney for the case actually initiating much of the detective work after the conviction which helped prove Stallings' innocence.

5-Oxoprolinuria as a Cause for Metabolic Acidosis

One of the rare (but potentially underdiagnosed) causes of anion gap metabolic acidosis is acquired 5-oxoprolinuria due to excessive Tylenol ingestion.  To explain how this works, you need to familiarize yourself briefly with the gamma-glutamyl cycle, a series of enyzmes and reactions involved in the metabolism of glutathione, an amino-acid derivative which appears to be important in the prevention of oxidative injury.  This cycle is shown below, taken from a 2005 AJKD paper by Humphreys et al.

  

You can see that acetaminophen inhibits glutathione.  Normally, glutathione performs a type of negative feedback control on the cycle by inhibiting gamma-glutamyl cysteine synthetase.  Without glutathione, then, this feedback inhibition is removed, and there is an upregulation of this enzyme, resulting in increased amounts of gamma-glutamyl cysteine, which itself is a precursor to the organic acid 5-oxoproline.  One of the key aspects of diagnosing this disorder, aside from having a clinical suspicion in the setting of anion gap metabolic acidosis without another explanation, is the detection of 5-oxoproline in the urine.  The disorder appears to be more common in elderly women or individuals with multiple comorbidities, in whom glutathione levels may already be low.  Although there is not much data in support of it, it makes sense that Mucomyst (N-acetyl cysteine, which augments glutathione levels) might work.

From the genetics angle, there are some pediatric, congenital causes of 5-oxoprolinuria which not surprisingly involved defects in enzymes of the gamma-glutamyl cycle (in particular, mutations in glutathione synthetase and 5-oxoprolinase have been identified in these patients). 

Lesch-Nyhan Syndrome

I remember learning about Lesch-Nyhan and thinking it was fascinating early on during a college course on neurology & behavior: affected children with this X-linked disorder develop the bizarre but highly characteristic behavior of self-mutilation, intentional biting of the tongue and lips for instance. The neurologic basis for these behavioral changes is not entirely understood, but the underlying basis for the disorder has to do with uric acid metabolism: the affected gene in Lesch-Nyhan syndrome is the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) gene, which is necessary for the salvage pathway of purine synthesis for DNA. The absence of HGPRT results in elevated levels of uric acid which result in uric acid nephrolithiasis, gout, and gouty nephropathy in addition to the disturbing CNS manifestations mentioned above. The gold standard for diagnosis is discovering low levels of HGPRT enzyme activity in cultured cells from the affected individual.

A recent article in AJKD describes the use of Rasburicase to treat elevated uric acid levels in Lesch-Nyhan syndrome in an affected neonate. Rasburicase is an urate oxidase enzyme which rapidly reduces serum uric acid levels; it will be interesting to see if this reduction translates into an improvement in neurologic symptoms seen in this syndrome.

Congenital analbuminemia

Plasma oncotic pressure is important to prevent edema, right? And you would think that albumin, which plays a critical role in the binding of multiple plasma proteins and ionized calcium, is essential to life, right?

The rare, autosomal recessive disorder congenital analbuminemia would seem to suggest otherwise. Although it is extremely rare (estimated at less than one in a million), it is able to teach us important physiologic lessons. The disease is caused by mutations in the human serum albumin (HSA) gene which result in a markedly decreased serum albumin concentration (estimated at between 1/100th to 1/1000th of the normal serum albumin concentration), individuals with the disorder generally do well, usually with only mild edema that may even go unrecognized in childhood. Individuals do not have proteinuria but often have hyperlipidemia. It is postulated that oncotic pressure is maintained in part by an increased hepatic synthesis of other plasma proteins to compensate.

The generally mild phenotype is fairly surprising in my opinion because of the many physiologic roles ascribed to albumin in biology. It also hints that perhaps something other than the hypoalbuminemia and subsequent loss of oncotic pressure observed in patients with nephrotic syndrome is responsible for their edema.

Pendred Syndrome

Pendred Syndrome is an autosomal recessive disorder caused by mutations in the solute carrier family 26 member 4 gene (SLC26A4) which has some relevance to nephrology and acid-base metabolism. Its main phenotypic manifestations are thyroid goiter and sensorineural deafness. Where does the nephrology come in? It does not appear that these individuals have acid-base problems at baseline, but there are reports of their developing a severe hypokalemic metabolic alkalosis when treated with thiazide diuretics. I'll explain.

The SLC26A4 gene product encodes an ion transporter which enables (1) iodine ion transport (hence the goiter) and (2) chloride-bicarbonate exchange. In the inner ear, impaired bicarbonate secretion leads to acidification of the endolymph and damage to the underlying hair cells, hence the deafness. In the kidney, the SLC26A4 gene product is expressed in beta-intercalated cells of the collecting duct. Recall that the collecting duct has two flavors of intercalated cells: the alpha-intercalated cells (which secrete protons) and the beta-intercalated cells (which secrete bicarbonate). A decreased ability to secrete bicarbonate, coupled with reduced NaCl reabsorption from thiazide diuretics, could therefore explain the metabolic alkalosis seen in Pendred Syndrome patients.

Have I ever seen a case? Not that I can think of, though I wouldn't necessarily know as I mentioned before that individuals don't typically get metabolic alkalosis unless treated with diuretic. It's uncommon but not that uncommon, as many sources cite Pendred Syndrome as accounting for up to 10% of heritable deafness.

Orthostatic Proteinuria

Orthostatic proteinuria occurs in between 2-5% of all adolescents--it is primarily a pediatric condition, rarely occurring after age 30. Orthostatic proteinuria refers to the condition of an individual having proteinuria only while upright; the urine protein level returns to normal while lying down. I use the term "condition" rather than "disease" because orthostatic proteinuria carries with it a benign prognosis with no danger of worsening renal function.

In order to make a diagnosis of orthostatic proteinuria, one can obtain either a 24-hour urine collection, or one can do it using separate urine protein/creatinine ratios. If using the 24-hour urine collection, the first morning void is initially discarded. Then, a 16-hour upright collection is obtained between 7am-11pm; ideally, the patient should lie down 2 hours before finishing the upright collection, to avoid "contaminating" the supine collection with urine formed during the upright position. Then, a separate overnight 8-hour collection between 11pm-7am is obtained. In order for a diagnosis of orthostatic proteinuria to be made, there must be abnormal proteinuria (e.g., >100mg/16 hrs) during the upright collection but normal urine protein (e.g., <50mg/8> during the overnight collection. Alternatively, spot urine protein/creatinine ratios from specimens taken first thing in the morning versus in the afternoon can be compared.

What is the pathogenesis of orthostatic proteinuria? There are several theories, though the precise etiology is not known. One possibility is that individuals with an exaggerated hemodynamic response to being in the upright position--manifested by increased secretion of angiotensin II and norepinephrine--might lead to transiently increased glomerular permeability to protein. Another theory is that some degree of "nutcracker syndrome"--in which the left renal vein is squeezed or kinked between the aorta and superior mesenteric artery--is at play more commonly in the upright position than while lying down.

The Legendary Walkerton, Ontario HUS Outbreak of 2000

In a recent Kidney International Supplement issue dealing entirely with TTP/HUS, there are two interesting articles regarding the Walkerton, Ontario HUS Outbreak: the largest public health disaster involving municipal water in Canadian history.

In May 2000, approximately 2300 residents (out of about 5000) of this rural farming town came down with a diarrheal illness caused by E. coli O157:H7. Essentially, a breakdown in public health checkpoints led to contamination of the water supply with the bacteria (shed by 20% of the cattle raised in the area) after a period of heavy flooding.

Not surprisingly, a significant number of cases of childhood HUS was reported: a total of 24 cases. One of the articles in this issue reports on the outcome of 22 of these 24 patients.

Patients with HUS were identified based on the development of anemia, hemolysis on blood smeark, a platelet count <> 95% for age and gender, and/or the appearance of hematuria or proteinuria. The mean age was about 5 but had a wide range. Eight of the children required dialysis, all of which was administered as peritoneal dialysis. There was one child who unfortunately died; of the survivors all fortunately were able to come off of dialysis eventually and a 1-year follow-up showed a GFR > 90cc/min per 1.73 m² in all but 2 patients.

The outbreak is interesting at a number of levels, including giving a large enough sample size to estimate the risk of developing HUS as a result of E.col O157:H7 exposure--only 24 of 564 children with diarrhea went on to develop HUS, leading to an estimate of about a 4% risk. This estimate is lower than previously suggested rates.

I wonder if there are any genetic differences to explain why certain children develop HUS in response to infection whereas others do not? This would certainly seem like a suitable and large enough sample size to begin asking these types of questions.

Dent Disease

Dent Disease is a rare, X-linked inherited disease of pediatric nephrology.  It can be filed under the category of "renal tubular dysfunction" and is also known as "X-linked Recessive Nephrolithiasis."

Clinical characteristics of Dent Disease include recurrent renal stones, nephrocalcinosis, hypercalciuria, low molecular weight proteinuria, and a gradual progression to ESRD, usually within childhood.  

The disease is caused by mutations in the gene CLCN5, a chloride channel present in proximal tubular cells which appears to be necessary for the processing of endosomes.  It is not clear why these individuals are so predisposed to nephrolithiasis and hypercalciuria.  There is no good therapy for Dent Disease, though a logical case could be made for treating with oral citrate supplementation and thiazide diuretics in an attempt to mitigate hypercalciuria and delay the nephrocalcinosis-induced renal failure as much as possible.

Routine Urinalysis Screening?

Is it a good idea to screen the pediatric population at-large for hematuria and proteinuria?  

This is  a controversial topic, as generally speaking isolated hematuria or isolated proteinuria are almost always benign findings in pediatric populations, and overly-aggressive work-up (e.g., renal biopsy) in all individuals with these abnormalities would likely result in measurable morbidity.

In favor of routine screening are some studies from Asian populations where urinalysis screening has been more routinely adopted--specifically, this study from Korea and this study from Taiwan--which demonstrate that the rate of pediatric ESRD dropped from 19 per million to 8 per million following these interventions, much of which could be explained by a drop in glomerulonephritis-induced kidney injury.  

In the United States, the American Academy of Pediatrics currently recommends that urinalysis be performed only when there is a specific complaint.  

What is Intestinal Dialysis?

We are well-versed in describing to our soon-to-be ESRD patients their options: kidney transplant, hemodialysis, or peritoneal dialysis. However, in many developing countries, these options do not exist, or there may be a significant delay in getting them set up. A different type of renal replacement therapy is intestinal dialysis.

In intestinal dialysis, the diet is supplemented with soluble fibers such as acacia gum, which is digested by colonic flora, thereby increasing the amount of nitrogen that is eliminated as fecal waste. Apparently when acacia fibers are added to a low protein diet in children with advanced CKD who do not have access to dialysis, their serum BUN levels were slightly lower and they experienced a decrease in uremic symptoms. Admittedly, this would appear to be a much less viable option than PD or HD, but in situations of limited resources it may be valuable.

Potter's Syndrome/Sequence

Potter's Syndrome--perhaps more accurately referred to as Potter's Sequence as it refers to the pathophysiologic consequences of lack of kidney function in utero--is characterized by absence of renal function, oligohydramnios, pulmonary hypoplasia, and a characteristic "Potter's facies", in which there is a flattened nose, recessed chin, prominent epicanthal folds, and low-set abnormal ears. In addition to other serious cardiovascular, ophthalmologic, and skeletal malformation, Potter's Syndrome also occurs frequently with sirenomelia (a.k.a. "mermaid syndrome", as pictured in the X-ray above.

Any form of severe renal dysfunction in utero can be the root cause of Potter's Syndrome. More common causes include bilateral renal agenesis, autosomal recessive polycystic kidney disease, and congenital obstruction/hydronephrosis. When the kidneys do not produce urine, there is oligohydramnios (since fetal urine production accounts for the majority of amniotic fluid during the 2nd and 3rd trimesters of pregnancy). Since amniotic fluid is also responsible for proper alveoli expansion, these patients commonly get pulmonary hypoplasia and potentially serious respiratory problems at birth.

The syndrome is named after pathologist Edith Potter, who initially characterized this sequence of events.

WAGR

The WAGR Syndrome is a rare genetic syndrome whose acronym stands for Wilms tumor, Aniridia (an absence of the iris), Genitourinary abnormalities, and mental Retardation. It is caused by a deletion of chromosome 17p.

The genitourinary abnormalities may take the form of gonadoblastoma (a gonadal tumor), or in boys hypospadias or undescended testicles. Occasionally (though not commonly) renal failure can accompany the syndrome. The fact that these individuals often get Wilms tumor is because the WT1 (Wilms tumor) gene, a tumor suppressor, lies on the deleted portion of chromome 17. A subset of individuals with the WAGR syndrome also have obesity--potentially due to whether the gene BDNF (brain-derived neurotrophic factor) is deleted or not.

Neonatal Lupus

Neonatal lupus occurs when autoantibodies are transmitted from the mother to the fetus; it usually manifests as a transient and mild lupoid rash which lasts 3-6 months, but can also result in more serious manifestations such as congenital heart block, immune thrombocytopenia, cholestatic liver disease, or autoimmune hemolytic anemia.  The autoantibodies anti-Ro (SSA) and anti-La (SSB) (also seen in Sjogren's Syndrome) are the culprits here; they are present in about 30% of SLE patients.