Kidney Stone riddle: the answer

The commenters nailed it.

He had primary hyperparathyroidism and went for a parathyroidectomy. The recurrent laryngeal nerve was severed during the procedure and that left him unable to speak.

He suffered in silence for 6 months before going for a procedure which pushes the vocal cords on the paralyzed side medially. This allows the normal cord to meet the still paralyzed, but medially displaced cord and phonate.

Kidney Stone Riddle

I was at my great aunt's 90th birthday party on Tuesday and was chatting with a neighbor. He mentioned that after being treated for kidney stones he couldn't speak for 6 months.

My face screwed up as I tried to figure out what the hell he was talking about. His next sentence explained everything.

What happened?

Other hints: his stone were conventional calcium oxalate stones, and he had recurrent stones.

I'll leave the answer later today or tomorrow.

Online endocrine textbook

This looks pretty cool.

Here is the link to the section on kidney stones written by Murray Favus. On my brief overview it looks good.

Being in the textbook business in the era of free online textbooks, UpToDate and wiki's has got to be a world of hurt.

Internal Medicine Board Review: Fluids, Electrolytes and Acid Base

The chief resident at Providence asked me to do a board review class for the third-years. They have small sessions weekly (?) in the physician lounge. This afternoon we went over fluids, electrolytes and acid-base. We did the first 14 questions. Seems like it went pretty well.

Board Review Questions and Answers

Comment on Loin Pain Hematuria Syndrome

The Renal Fellow Network did a nice pocket review of Loin Pain Hematuria Syndrome recently. However they left off an important diagnosis which also presents with hematuria and unilateral pain, Nut Cracker Syndrome. This refers to impingement of the left renal vein between the aorta and superior mesenteric artery.

These patients usually come to the nephrology office with a history of mysterious kidney stones which have been difficult to visualize.

In Nut Cracker Syndrome the pain is always on the left side.

Nice review with imaging studies are found in this NDT article from 1995.

(a) MRI revealed a dilated left renal vein (black arrows) after passing between the aorta (A) and superior mesenteric artery (white arrowhead).
(b) MRA showed that the diameter of the left renal vein (black arrow) was larger in the left part adjacent to the aorta (A) compared with the right adjacent part. A prominent left ovarian vein (white arrow), implicating formation of a collateral circulation, was also noted. IVC = inferior vena cava.
(c) Digital subtraction MRA found the impingement of the left renal vein (LRV) between the aorta (A) and superior mesenteric artery (white arrowhead).

Craig Langman's Editorial on the Melamine Crisis from The Journal

Craig Langman (who has made a previous appearance on PBFluids) wrote an editorial for the Melamine article and pair of letters to The Journal (one from Wang et al. from Taiwan and the other from Ho et al. from Hong Kong).

He recommends the same advice I have been giving for Americans who have adopted Chinese infants:

How should physicians in other parts of the world care for Chinese infants who may have been exposed to melamine-contaminated powdered infant formula? The American Society of Pediatric Nephrology suggests a conservative approach in asymptomatic infants,^PDF since stones presumed to have been induced by melamine ingestion appear to be passed easily after hydration, and there are currently no follow-up reports on the children studied by Guan et al. and Wang et al. Performance of abdominal ultrasonography in all potentially exposed Chinese children living in the United States would be likely to cost many millions of dollars, an expenditure difficult to justify, given that both unaffected and affected children may have no symptoms and that the meaning of a stone in an asymptomatic child is uncertain.

Langman emphasizes that each study is unable to estimate a true incidence because the populations studied were not representative of the population at risk.

He also teases the reader by mentioning that stones, which are increasing in frequency among adults, seem to be increasingly common among children. He states that this may be due to dietary and lifestyle issues but doesn't even entertain the possibility that melamine exposure here in the U.S. and around the world may be responsible. This possibility was first suggested in an insightful article in Slate. We know that melamine is found in the U.S., we don't know how long it has been here.

My personal sense is that the Slate article is just scaring people unnecessarily. if the increase in stones was do to melamine we would know it. We would know it because stones that are removed by interventions are always analyzed in a stone lab. The stones in China that were due to melamine were made of uric acid and melamine. If even a single stone in the U.S. was found to be melamine the whole medical world would go ape.

The Jounal Delivers a Bumper Crop of Melamine Articles.

The primary article is an analysis of 589 children by Na Guan

Methods

All of the children's parents were given a survey to establish demographic data and judge exposure. The investigators questioned parents on the brand and amount of formula ingested and matched it up to government data on the amount of melamine in each brand. Children were then put through varying degrees of biochemical and ultrasound testing.

All the children were under 36 months of age, the population most at risk of melamine stones.

The primary outcome was the presence of kidney stones.

The General Administration of Quality Supervision and Quarnatine of the PRC analyzed 22 brands of formula and reported the amount of melamine. The researchers then categorized each formula as:

1. High melamine (over 500 ppm)
2. Moderate melamine (less than 150 pm)
3. No-melamine.
   

Ultrasounds were reported as:

1. Definite stones
2. Suspected stones (increased sporadic, punctiform echogenicity in the kidneys or pyelocalyceal system)
   
3. No stones

Result

The all important table 1.
In 589 exams they found definite 50 stones, 112 suspected stones and 427 children were stone free.

Most of the children with stones did not oliguria, dysuria or edema. Only two of 34 stone formers (6%) had hematuria and only 1 had leukoturia (3%). None of the children with suspected stones had hematuria and only one had leukocyturia (1.3%).

Microalbuminuria was found in more of the children with stones (10%) or suspected of having stones (13.6%) compared to the stone free children (5.6%). Symptoms were not helpful in distinguishing stone formers from the stone free.

Fifty-six children had serum creatinine checked (22 with stones, 21 with suspected stones and 13 without). All of the creatinines were normal.

Interestingly 62 of 404 children had a calcium to creatinine ratio that exceeded age based targets. The 15% rate of hypercalciuria was not associated with stone risk in this study (p=0.34).

In multivariate analysis exposure to high-melamine milk (7x as likely) and pre-term birth (4.5x as likely) were significantly associated with stone formation.

The primary conclusion is that the physical and biochemical lab add nothiong to the evaluation of melamine stones. The birth history and the melamine exposure assessment are critical but need to be followed up by an ultra-sound.

The authors note that only 23 of 121 children exposed to high-melamine formula developed stones

Kidney stone question

Great question.

I would look at the March 2008 Seminars in Nephrology which is an entire issue devoted to nephrolithiasis.

The issue was guest edited by John Asplin, one of the best teachers I had during my fellowship. We co-authored a chapter on potassium and I tutored medical students for his renal physiology class. He is medical director of Litholink, a independent clinical lab which provides deep clinical information on the metabolic abnormalities found in patients with kidney stones. I use litholink for all of my stone patients and love it.





It also has multiple articles by Fred Coe and Elaine Worcester. Dr. Coe ran a weekly fluid and electrolyte conference that was one of the highlights of my fellowship experience. Every week a fellow would bring a set of electrolytes and Coe would tell you all about the patient simply from the numbers. It was uncanny how good he was.

My favorite quote from Dr. Coe was:

What you do is serious nephrology [he was referring to acute and chronic renal failure]. What I do is just civilian nephrology. [referring to nephrolithiasis]

Elaine and I co-authored a chapter on calcium, magnesium and phosphorous. We had a great collegial relationship during my fellowship and only after I graduated did I realize how large she was in the field of nephrolithiasis.








Craig Langman also wrote one of the articles in this issue of Seminars in Nephrology. He is a pediatric nephrologist and I spent a couple of months with him at Children's Memorial during my second year of fellowship. He's a great teacher. He is now on the lecture circuit for Genzyme. If he comes to town, go. He's one of the great teachers in nephrology.

Update: Dr. Langman sent me a note stating that he is not "on the circuit." But my advice stands, if he comes to town, don't miss him.

Kidney Stone Primer

When a patient needs a metabolic evaluation for kidney stones the twnety-four hour urine should include at minimum:

• Calcium
• Oxalate
• Citrate
• Uric Acid
• Volume
• pH
• Creatinine

A complete evaluation adds:

• Sodium
• Potassium
• Chloride
• Urea nitrogen
• Phosphorous
• Magnesium
• Ammonia
• Sulfate

Hypercalciuria is defined as over 300 mg/day in a man and over 250 mg in a woman. Normal urinary calcium is 150-170 mg per day.

Urine oxalate over 90 mg/day should trigger an evaluation for enteric hyperoxaluria or primary hyperoxaluria.

Hypocitraturia is defined as a citrate below 325mg/day. Hypokalemia can trigger hypocitraturia (along with metabolic acidosis) so be careful when prescribing a thiazide for hypercalciuria, the resulting hypokalemia could surpress citrate and increase rather than lower the risk of developing a kidney stone.

While bowel disease is usually associated with calcium oxalate stones, patients often have decreased urine pH which predisposes them to uric acid stones.

Kidney Stones and Chronic Kidney Disease

One of the biggest stories coming out of Renal Week 2008 was this abstract which linked kidney stones to the development of CKD. This is an important study but I filed it under "no duh." Patients with kidney stones tend to be heavier, have more hypertension, get episodes of acute renal failure and have repeated instrumentation on the kidneys. They also have gout, and associated hyperuricemia, an increasingly important progression factor for CKD and hypertension.

The most important aspect of this is the question that was left unanswered: do kidney stones cause CKD. The association makes sence but causality would be much more important because we have good tools to prevent kidney stones and it would be wonderful if by preventing kidney stones we could also be preventing future kidney failure.

Hopefully this question will be answered in the near future.

[F-FC202] Kidney Stones Are Associated with an Increased Risk of Developing Chronic Kidney Disease

Andrew Rule, Eric Bergstralh, L. Joseph Melton, Xujian Li, Amy Weaver, John Lieske Nephrology, Mayo Clinic; Health Sciences Research, Mayo Clinic

Background: Kidney stones lead to chronic kidney disease (CKD) in patients with rare genetic diseases (e.g., primary hyperoxaluria), but it is less clear if kidney stones are an important risk factor for CKD in the general population.

Methods: A cohort of all Olmsted County, MN residents with incident kidney stones in the years 1984-2003 were matched 3:1 to controls in the general population based on index date (first stone diagnosis for stone formers and any clinic visit for controls), age, and sex. Diagnostic codes (yrs: 1935-2007) and serum creatinine levels (yrs: 1983-2006) were captured with the linkage infrastructure of the Rochester Epidemiology Project. Risk of incident chronic kidney disease was assessed using clinical diagnostic codes, end-stage renal disease (dialysis, transplant or death with CKD), sustained (>90 days) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), and sustained estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Proportional hazards models adjusted for age, sex, and baseline and time-dependent co-morbidities (diabetes, obesity, gout, hypertension, hyperlipidemia, alcohol, tobacco, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease).

Results: After excluding persons with prevalent CKD, 4424 stone formers and 10995 controls were identified with a mean follow-up of 8.4 and 8.8 years, respectively. Stone formers had an increased risk of developing a clinical diagnosis of CKD [hazard ratio (HR)=1.6, 95% CI: 1.4-1.8, see figure], end-stage renal disease (HR=1.4, 95% CI: 0.9-2.2), a sustained elevated serum creatinine (HR = 1.4, 95% CI: 1.2-1.7), and a sustained reduced eGFR (HR = 1.4, 95% CI: 1.2-1.6).

Conclusions: These data argue kidney stones to be an important risk factor for chronic kidney disease.

Some details on one of the deaths from the melamine milk contamination

This article talks about the family of the first infant to die from melamine milk contamination. The child, Yi Kaixuan was only 6 months old. He died back in May, months before any information about the contamination came out.

But on April 20, the baby wouldn't stop crying and had problems urinating. Jiao took him to the village clinic, but they couldn't pinpoint a problem.

Alarmed, Yi left his construction job and returned home. The family headed for the Gansu provincial capital, Lanzhou. On April 30, they took the baby to two city hospitals. Doctors were stunned, Yi said. They said they'd never seen a child with so many kidney stones, and the situation was critical.

A frenzy of testing followed, and the bills piled up past $145. The parents didn't sleep all night, waiting.

Around noon the next day, a doctor came to tell them their baby had died.

Tragic.

Former Felllow makes good

Rakesh Lattupalli just graduated from our fellowship in June. He was an exceptional fellow. He just finished a scientific article on the Melamine outbreak. Rakesh was the person who got me interested in the subject. The article is a nice overview of some of the scientific data on melamine toxicity.

Like me, he feels that melamine is not likely to be the entire story and a second co-factor will be identified that is critical to the development of nephrolithiasis. He suggests cyanuric acid as a possible candidate.

Melamine milk poisoning continues to make headlines

White Rabbit candies are being pulled from the shelves for failing to have less than 2.5 mg/kg melamine.

The Chinese press reported another 380 sick children in Beijing at the same time as they are declaring the milk safe. Though this seems to be a contradiction, my feeling is that stones in children will be showing up for months after the milk supply is clean as kidney stones can lie asymptomatic for months (years?) in the renal pelvis before spontaneously moving into the ureters where they cause pain, obstruction and hematuria.

The Taiwanese press provides a shockingly sophisticated article on the problems with our current toxicity knowledge of melamine and the associated debate on limits of safety. In addition to discuss limits of tolerability it goes into the differing methods of detection including high performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS). The LC-MS/MS method is apparently the most sensitive assay. One confusing aspect of the article is they swithc freely between mg/kg and ppm. One mg/kg is equal to 1 ppm.

A friend was staying with us over the week-end. She and her husband adopted a little girl from China. She was drinking chinese formula 6 months ago. She is doing well, no symptoms and when she came over she had a "kidney test." The mother asked me if she should do anything. My answer was that her daughter likely was exposed to melamine as it looks like this practice of spiking milk with melamine has been going on for awhile. I added that since her daughter was doing well and not having colicky pain, a diagnosis of nephrolithiasis would not change what you do. I recommended against doing a renal ultra-sound and wait for any symptoms which would likely never occur.

Melamine Crisis: "There is no problem"

"There is no problem," Xiang Yuzhang, the national quality watchdog's chief inspection official, told reporters in Beijing.

Love the close of this article with a quote by the Chinese equivalent of Baghdad Bob.

This on the same day that 5 cases of kidney stones in children surfaced in Taiwan.

Melamine Milk Poisoning and Kidney Stones

Nephrology rears its ugly head in the news cycle.

The NYT weighs in. China Says Complaints About Milk Began in 2007

The top food official resigns. I bet he is happy to get away with a forced resignation compared to Zheng Xiaoyu, former head of the chinese FDA who was executed for corruption following the tainted phamaceutical debacle last year.

The interesting is that the same toxin, melamine, was implicated in the pet food renal failure problem in 2007. At that time, the US FDA provided lots of assurances that malamar is not that toxic. Is this a pediatric issue? In some of the articles following the pet food issue a second compound, cyanuric acid, was implicated in the pathophysiology. I have not read anything about cyanuric acid.

More on this as it develops.

The only data I could find on the concentration of melamine in the milk products comes from this ChinaDaily article.

The highest concentration of melamine was found in Sanlu products. Tests show every kg of Sanlu milk food contains 2.56 g of melamine, which can make milk appear rich in protein in quality tests. The chemical is usually used to make plates, bowls, mugs and sundry other products, but is banned from being used in the food industry.

The other tainted products contain between 0.09 mg to 619 mg of melamine per kg.

During the pet food scare of 2007, there was concern that some of the melamine contaminated pet-food reached live-stock and ended up contaminating the food supply. The FDA estimated the tolerable daily intake of melamine at 0.63 mg/kg.

The point of departure (POD) is the NOAEL of 63 mg/kg/day from the rodent subchronic bioassay. This POD was then divided by two 10-fold safety/uncertainty factors (SF/UF) to account for inter- and intra-species sensitivity, for a total SF/UF of 100. The resulting Tolerable Daily Intake (TDI) is 0.63 mg/kg bw/day. The TDI is defined as the estimated maximum amount of an agent to which individuals in a population may be exposed daily over their lifetimes without an appreciable health risk with respect to the endpoint from which the NOAEL is calculated.

Using the concentrations from the China Daily article and the FDA limits on tolerability a 7 kg baby would need to ingest 1.7 liters of Sanlu milk to exceed this safe limit (of note, at the highest concentration only 7 mL would exceed the safe limit). Either the safety estimate was off or there is an additional compound causing the toxicity.

Google search for melamine