Don't Eat the Leaves

Hyperoxaluria is an important risk factor for kidney stones, approximately 80% of which are primarily composed of calcium oxalate. Hyperoxaluria is typically diagnosed by performing a 24 hour urine collection and levels above 45 mg/day are considered abnormal although, depending on the other urine constituents, the risk of CaOx stones increases when the urinary oxalate level is above 20 mg/dl. It is important to distinguish between hyperoxaluria that results from increased oxalate production (endogenous) and increased oxalate ingestion (enteric).

The classic disease associated with increased oxalate production is primary hyperoxaluria. There are 3 identified types although all result from defects in glycoxylate metabolism leading to oxalate accumulation. At first, the manifestations are primarily renal leading to nephrolithiasis and nephrocalcinosis. However, as the disease progresses,  the serum oxalate concentration increases eventually resulting in extra-renal oxalate deposition. Vitamin C is metabolized to oxalate also so that patients with oxalate-containing kidney stones should probably avoid excess vitamin C supplementation as this could increase the risk of stones.

Enteric hyperoxaluria results from increased absorption of oxalate in the large bowel. In general, there are 3 ways in which this might occur:

• Increased dietary oxalate ingestion
• Decreased dietary calcium intake - calcium binds oxalate in the gut and reduces absorption. This is why low calcium diets are not recommended in patients with idiopathic kidney stones. Calcium supplements are a different issue as they may contribute to hypercalciuria and not decrease oxalate ingestion, particularly if they are not taken at mealtimes
• In the setting of malabsorption syndromes and GI disease. This occurs in patients following bariatric surgery, fat malabsorption and inflammatory bowel disease. The mechanism is thought to be related to binding of calcium to fatty acids thus reducing the availability of calcium for oxalate-binding, along with increased large bowel permeability. There have been multiple cases of patients developing severe oxalosis following jejuno-ileal bypass surgery.

The treatment of hyperoxaluria depends on the cause. For all patients, increasing fluid intake is good advice. Some patients with primary hyperoxaluria respond to treatment with pyridoxine which promotes conversion of glycoxylate to glycine instead of oxalate. Recently, a bacterium has been identified that metabolizes oxalate in the gut and this has been proposed as a potential treatment for hyperoxaluria. Interestingly, antibiotic treatment has been shown to decrease oxalobacter colonization in individuals with peptic ulcer disease.

Of course, all patients with hyperoxaluria should be advised to reduce oxalate consumption in the diet. Foods high in oxalate include spinach, rhubarb, tea, chocolate, star fruit and soy products. A full list can be found here.

Rhubarb is an interesting case. In the First World War because of the lack of access to fresh vegetables, the British government recommended that families supplement their diets with rhubarb leaves which were not traditionally eaten. It turns out that this was very bad advice. Rhubarb leaves contain considerably more oxalate than the stalks and there was a flurry of case reports towards the end of the war detailing cases of oxalate poisoning from rhubarb leaf consumption (see also and this). The toxicity of the leaves was probably increased by advice to cool the leaves with soda which increases the solubility of oxalate. Although the MD50 of oxalate would require the ingestion of about 5kg of rhubarb leaves, one could imagine that much lower doses would be toxic in patients with chronic kidney disease.

One last point about oxalate. It is a terminal metabolite and was thought to not have any positive role. However, recent data have suggested that oxalate is important for chloride transport in the proximal tubule where it acts similarly to formate..

Kidney Stones - What's the diagnosis? - Answer

This was an interesting case and all those who responded correctly identified that the patient had bowel pathology. However, only one person figured out that the issue was an ileostomy. This patient had a low urine volume and an extremely low urinary citrate and sodium. The low citrate could indicated a renal tubular acidosis except that the urinary ammonium was high and the urine pH was very low indicating preserved ability to acidify the urine. This points to a metabolic acidosis. The urine sodium in an average US resident is between 100-200 mmol/day. Outside of the amazon, it's hard to imagine that anyone could take in this little salt. This points towards loss of sodium bicarbonate and water from the GI tract.

Finally, in the setting of IBD, generally it is accompanied by hyperoxaluria. There are a number of potential mechanisms for this; decreased metabolism of oxalate by oxalobacter formigenes, decreased calcium binding to oxalate because of the relatively increased binding of calcium to malabsorbed fat in the GI tract. In any case, in order to have hyperoxaluria, it is necessary to have a functioning large bowel. In this case, the patient's urinary oxalate was 28 which is in the low normal range and not suggestive of hyperoxaluria. Thus, the diagnosis is high output of alkaline fluid from an ileostomy.

The treatment in this case is to increase fluids and treat with a combination of sodium and potassium citrate. Even a small rise in urine pH would significantly reduce the risk of uric acid stones while the citrate and increased volume should reduce the calcium oxalate stone risk.

Kidney Stones - What's the diagnosis?

A 65yo man was reviewed in the clinic for assessment of kidney stones. He has a history of stones for at least 8 years and has been passing small calculi on a regular basis for the last few months. His 24 hour urine results are shown below (results are 24 hour total values unless otherwise specified):

Volume, Liters	0.71	Sodium, mmol/day	7
Supersaturation Calcium Oxalate	10.11	Potassium, mmol/day	45
Calcium, mg/day	78	Magnesium, mg/day	52
Oxalate, mg/day	28	Phosphate, mg/day	0.76
Citrate, mg/day	11	NH4, mmol/day	68
Supersaturation Calcium Phosphate	0.71	Chloride, mmol/day	48
Urine pH	5.6	Sulphate, mEq/day	39
Supersaturation Uric Acid	2.71	Urea Nitrogen, g/day	11
Uric Acid, mg/day	0.499	Protein Catabolic Rate	1.2
Creatinine	1292

He has a high risk for calcium oxalate and uric acid stones. His urine citrate and sodium are remarkably low and he has a very low urine volume. His BP in the clinic was normal as were his labs apart from a serum creatinine of 1.3mg/dl

What is the underlying diagnosis (an important  piece has been left out of his background history)?
What is the best approach to treating his kidney stones?

Answers in the comments please (if this proves popular we may make it a regular feature).

Fruit Flies and Kidney Stones

Developing accurate animal models of human diseases is a well-established research goal but a recent paper reporting a new animal model of nephrolithiasis caught my attention. Kidney stones are an important cause of morbidity and dealing with them is estimated to cost more than $5 billion yearly in the US alone. The majority of cases are due to calcium oxalate stones which variously results from increased urinary calcium excretion or increased urinary oxalate (which may be due to increased production or gut absorption of oxalate).

A group in the Mayo clinic and Glasgow have developed a fruit fly model of calcium oxalate nephrolithiasis. Fruit flies have a single transparent kidney tubule and feeding the larvae a diet high in oxalate for just two days leads to the formation of visible calcium oxalate kidney stones.

The upper panel of the image above shows a renal tubule dissected out from a fruit fly fed with oxalate compared with one fed with a normal diet. The second panel is a high power view of the tubule along with a nice picture of some calcium oxalate crystals. The lower 3 panels are a series of pictures of a tubule kept in a bath high in oxalate where you can see the crystals forming over a period of hours - the authors helpfully included a video if this happening in the supplemental data of the manuscript. There are also some micro-CT images of the fruit flies with the stones in situ. The rapid formation of stones in these flies makes it an excellent model for the study of nephrolithiasis.

Also, it's really cool.

From acid to nephrocalcinosis to stones

Can you have an acidosis with normal serum bicarbonate? Of course you can, it's just incomplete. Incomplete distal renal tubular acidosis (idRTA) that is.

RTA was first described in 1935, confirmed as a renal tubular disorder in 1946, and designated “renal tubular acidosis” in 1951 (see here for an excellent review). Now it gets complicated, not only with regard to nomenclature but also with mechanisms.

I was a little surprised to hear that you can have distal RTA with a normal bicarbonate. It is just disguised. Patients with incomplete distal RTA have persistently high urine pH but are still able to excrete acid under normal conditions (therefore the normal serum bicarbonate). However, in states of high acid loads (high protein diet, catabolic stress) they are unable to excrete that acid which then triggers alkali release from the bone and thus causes greater bone resorption, therefore these patients have frequently osteopenia and osteoporosis.

Distal RTA occurs with a number of conditions, amongst them classically Sjogrens syndrome but also other autoimmune conditions. Cisplatin has been mentioned as one of the causes of idRTA in this blog earlier. idRTA is a common cause of nephrocalcinosis - with or without stones - and it has a number of prominent victims as also mentioned in a previous post.

idRTA can be diagnosed by induction of a systemic metabolic acidosis by means of acid loading. This is  commonly done with ammonium chloride (NH4Cl) but there is also a furosemide and fludrocortisone test that apparently causes less abdominal discomfort. Failure to acidify urine to a pH of less than 5.3 is consistent with incomplete distal renal tubular acidosis. However, testing is a little bit tedious and therefore not commonly done. The urinary citrate is commonly low in dRTA which contributes to nephrocalcinosis and stone formation.

A recent study from Switzerland showed that 6.7% of 150 male recurrent calcium stone formers (RCSFs) had idRTA, i.e., 1 out of 15 male RCSFs can be expected to have idRTA. They therefore suggest that idRTA is overall underdiagnosed.

Posted by Florian Toegel

"Hey Doc, I think my kidneys hurt."

How many of you have spoken with patients who complain of mid-back pain and tell you that their kidneys hurt? While dull, aching pain in the mid-lower back is more likely to be associated with musculoskeletal etiologies, kidney-related pain typically presents as sharp, colicky flank pain. Kidney pain usually results from distension of the well-innervated renal capsule due to subcapsular swelling. Specific causes include:

1. Nephrolithiasis. A kidney stone lodged in a ureter or in the kidney parenchyma can obstruct the flow of urine and cause subcapsular swelling and hence, pain. Pain is classically severe, localized to the flank with occasional radiation to the groin, colicky in nature, and may be associated with nausea and vomiting.

2. Pyelonephritis/UTI. Infection and inflammation of the renal parenchyma can also lead to swelling and distension of the renal capsule.


3. Renal masses. This can be in the form of cysts (i.e. polycystic kidney disease) or tumors such as renal cell carcinoma or angiomyolipomas, either of which may distend the renal capsule and cause pain.


4. Renal hemorrhage (intraparenchymal bleeding due to injury or trauma).


5. Hydronephrosis.


6. Renal infarction. A rare cause of kidney pain, this can be due to a thromboembolic event or an in situ thrombosis of the renal artery or its branches. It typically presents with sudden onset, acute flank pain or abdominal discomfort, usually associated with nausea and vomiting. Fever can sometimes be seen as well.


7. Renal vein thrombosis. Can be more insidious or present acutely like renal infarction with sudden onset flank pain.

History of Cystoscopy

I stumbled across a bit of Nephrology/Urology history the other day while strolling around a hospital in Paris: this plaque commemorating one of the key steps in the invention of ureteroscopy and cystoscopy. The plaque can be found at Hopital Necker-Enfants Malades, a large hospital now especially renowned for the treatment of pediatric illnesses (and also happens to be the birthplace of the stethoscope by Laennec in 1816).

A free article on the Development of the Modern Cystoscope via Medscape can be found here. The French instrument described above was not the first attempt at endoscopy, but was apparently one of the earliest. It is described as a "long metal channel through which a mirror reflected light from a petroleum-fueled lamp," and could be used to demonstrate the presence of gallstones and kidney stones in some situations. However, one of its major limitations was that the metal heated up pretty quickly and caused significant patient discomfort. I can't imagine being one of the first patient subjects trying out the new, experimental cystoscope...

Differential diagnosis of hypouricemia

Hypouricemia is defined as a serum uric acid level less than 2mg/dL. Although it is generally considered benign, hypouricemia has been associated with several important conditions relevant to nephrologists, including acute kidney injury, uric acid nephrolithiasis, and SIADH as examples. Here's a brief differential diagnosis of hypouricemia, which can be broken down into two main categories: decreased uric acid synthesis, and decreased renal reabsorption of uric acid.

I. Decreased uric acid synthesis:

1. allopurinol effect: allopurinol is an inhibitor of xanthine oxidase, the rate-limiting step in the synthesis of uric acid. Thus, allopurinol is a common cause of hypouricemia, though rarely does it cause a complete loss of uric acid synthesis.

2. congenital hypouricemia: individuals with the autosomal recessive disease hereditary xanthinuria have mutations in the gene encoding xanthine oxidase and as a result accumulate the uric acid precursors xanthine, which is fairly insoluble. As a result, individuals with hereditary xanthinuria develop xanthine nephrolithiasis and myopathy due to xanthine deposits in muscle, and typically have a profoundly low serum uric acid level.

3. liver failure: as a majority of xanthine oxidase is synthesized in the liver, individuals with severe cirrhotic liver disease may have a low serum uric acid level.
II. Decreased renal uric acid reabsorption.

1. Fanconi's Syndrome/proximal tubule dysfunction: since a majority of renal uric acid reabsorption occurs in the proximal tubule, it makes sense that any type of proximal tubular dysfunction will lead to hypouricemia (along with a host of other metabolic abnormalities such as proteinuria, glucosuria, aminoaciduria, hyphosphatemia, etc.)

2. SIADH: a clinical pearl often helpful in the diagnosis of SIADH is that it is very often associated with a very low serum uric acid level, allowing one to distinguish SIADH from other causes of hyponatremia. One possible mechanism for this is that ADH stimulating V1 receptors reduces renal uric acid uptake; this is based on the observation that individuals with SIADH experience a more profound hypouricemia than patients treated with ddAVP (which should selectively stimulate the V2 receptor).

3. Drugs. Some drugs can induce hypouricemia, including probenicid (a direct inhibitor of the organic anion transporter which is responsible for the tubular reabsorption of uric acid) and Bactrim, for instance.

4. Familial Renal Hypouricemia: this is a rare congenital disorder (most common in non-Ashkenazi Jews and Japenese individuals) caused by loss-of-function mtuations in the organic anion exchanger; individuals can exhibit a fractional excretion of uric acid that is greater than 95% due to an inability to reabsorb uric acid. Not surprisingly, these individuals are at high risk for urate nephrolithiasis.

Dietary modifications for prevention of nephrolithiasis

Secondary prevention of nephrolithiasis is often overlooked, but since a large percentage of 1st-time stone formers will go on to develop another episode of nephrolithiasis, it makes sense to make simple dietary modifications that can minimize the risk of this occurring. This is important not only from the perspective of preventing the pain associated with an episode of nephrolithiasis, but also to cut down on the risk of complications associated with nephrolithiasis (e.g., need for a urologic procedure, obstructive renal failure, nephrocalcinosis, etc.)

There are a few dietary measures which have been shown to reduce the risk of nephrolithiasis. Amongst the most important are the following pieces of advice:

1. Drink plenty of water (e.g., maintain a urine output of greater than 2-2.5 Liters a day).

2. Eat a diet low in animal fat.

3. Eat a diet low in sodium.

4. For individuals who form calcium oxalate stones (the most common form of nephrolithiasis in the general population), avoid excess oxalate-rich foods, which include spinach, beets, rhubarb, and (unfortunately) chocolate.

A recent article by Taylor et al in this month's JASN, "DASH-Style Diet Associated with Reduced Risk for Kidney Stones," suggests a similar strategy for kidney stone prevention: using the "DASH" (Dietary Approaches to Stop Hypertension) diet to reduce the risk of nephrolithiasis. In this study, investigators looked at individuals enrolled in several large cohorts (the Health Professionals Follow-Up Study, the Nurse's Health Study I, and the Nurse's Health Study II) and categorized each individual into separate quartiles according to their "DASH" score--that is, how closely each individual adhered to the DASH diet, which is high in fruits and veggies, moderate in animal fat, and low in animal protein. Interestingly, the greater the adherence to the DASH diet, the less the chance of having kidney stone formation. The beneficial effect of the DASH diet even persisted when controlled for hypertension (which is reduced with the DASH diet and also has been epidemiologically linked to nephrolithiasis). This study provides further proof that some of the dietary interventions are indeed effective at preventing stone formation and furthermore provide a dietary framework with specific recommendations that could be suggested to patients eager to prevent further episodes of nephrolithiasis.

Another interesting finding of the study: the highest quartile DASH scorers (which had the lowest risk of kidney stones) also had the highest dietary calcium intake. It's somewhat counterintuitive that calcium-based kidney stones cannot be prevented simply by taking in less calcium, but this and other studies have proven this paradox again and again.

Calcium Phosphate Stones

Calcium phosphate stones are actually pretty rare. While calcium oxalate stones comprise about 80% of all instances of nephrolithiasis, calcium phosphate stones typically occur only in a small subset of patients--about 5 to 10% of patients according to this source. In particular, calcium phosphate nephrolithiasis is encouraged by an alkaline urine. Thus, three conditions in which calcium phosphate nephrolithiasis may commonly occur are distal renal tubular acidosis, primary hyperparathyroidism, and milk-alkali syndrome.

In patients with distal (type I) RTA, there is a direct effect of acidosis which decreases renal calcium reabsorption; in addition, acidosis stimulates bone resorption (which increases serum calcium and phosphate levels) which can contribute to supersaturation of calcium and phosphate in the tubular lumen.

Urine Crystals: Pattern Recognition

One of the easier aspects to taking an examination like the boards is pattern recognition: there are certain images or associations that should be immediate triggers for a particular diagnosis. One good example of this is a knowledge of what different types of urine crystals (causing nephrolithiasis) look like under the microscope. A quick review with examples I swiped from the Internet:

1) Ca-oxalate stones. Crystals of calcium oxalate can take two basic forms. The dihydrate form looks like little square envelopes:


The monohydrate form in contrast looks like elongated rods or sometimes dumbells. Monohydrate crystals are the predominant form of oxalate crystal seen with ethylene glycol poisoning.
Uric acid crystals in the urine are more tricky because they are pleimorphic--they can have many shapes. Some look almost football-shaped; other look more like crystal aggregates. They generally only form in an acidic urine.


Struvite stones are easy--they look like "coffin lids" and are usually found alkaline urine often with evidence of a UTI.
Though uncommon, cystine stones (seen in the genetic condition cystinosis) are hexagonal-shaped crystals. This is pathognomonic.
Finally, different medications can form urine crystals which may have a characteristic shape. One website with a lot of good images documenting many of these drug crystals can be found here.

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.

Stone Disease in ADPKD

Patients with ADPKD are predisposed to nephrolithiasis. The postulated reasons for this increased prevalence of stone disease have ranged from metabolic abnormalities (previous reports have shown an increased tendency for hyperoxaluria, hypercalciuria, hypocitraturia, hyperuricosuria, and distal RTA) to anatomic abnormalities (large, obstructing cysts and dilated tubular lumens may create a situation of tubular stasis, which predisposes to stone formation).

A recent paper in C-JASN seeks to address the risk factors for nephrolithiasis in ADPKD patients. The researchers looked at a total of 125 patients with ADPKD and had them undergo both CT scan and Renal Ultrasound, as well as 24-hour urine analysis, looking for evidence of nephrolithiasis. About 25% of patients had evidence of stone disease on CT scan (which was significantly more sensitive than Renal Ultrasound). Although the researchers found a high prevalence of metabolic abnormalities in ADPKD patients (especially hypocitraturia) there were no excessively increased risk of stone formation in the presence of such metabolic abnormalities. In contrast, anatomical abnormalities DID seem to predict an increased risk of nephrolithiasis: those with a renal volume >500ml had an increased risk of stone disease.

Renal Complications of ESWL

Extracorporeal shock wave lithotripsy (ESWL), invented during the 1980s in Germany, uses concentrated pulses of sound waves to break up kidney stones too large to pass on their own into smaller pieces, which will then have a chance to be eliminated in the urine.  While this therapy has been an extremely useful and much less invasive tool for urologists to use in the treatment of kidney stones, there are nonetheless some side effects which nephrologists should be aware of.  

For instance, the trauma-induced by ESWL sound waves upon thin-walled vessels in the kidney can lead to microscopic hemorrhage, which later results in an influx of inflammatory cells and can potentially result in significant renal scar tissue if the exposure is great enough.  This would be most likely to occur in patients who have multiple rounds of ESWL for recurrent stones.  Interestingly, there is an emerging literature demonstrating that ESWL is associated with increased (though mild) diastolic hypertension, suggesting that this renal damage could be significant, and biomarkers of renal damage have been demonstrated to be elevated immediately post-ESWL.  In addition to these complications, there are others.  "Steinstrasse" is a German term (translated as "stone street") describing the post-ESWL accumulation of multiple small stone fragments, which may plug up the ureter and result in obstruction.  Hematuria, either gross or microscopic, is relatively common for a few days following the procedure.  Finally, bacterial sepsis and its resultant complications (due to translocation of bacteria in the bladder into the bloodstream during ESWL-induced damage to these tissues) can also result.