The urine's the thing...

Vomiting or nasogastric tube (NG) decompression can lead to metabolic alkalosis, often associated with hypokalemia. When asked what the source of the K loss is, most people assume it is lost in the gastric fluid. However, gastric fluid only contains about 9 mEq/L of potassium, hardly enough to lead to profound hypokalemia. While it is true that cellular shift due to alkalosis could explain some of the hypokalemia, the primary source of potassium loss is via the urine.

Metabolic alkalosis induced by GI loss leads to volume depletion. In this setting, secondary hyperaldosteronism ensues, leading to sodium retention and potassium wasting, hence the hypokalemia. Further, such GI losses are also associated with chloride depletion. Maintenance of electroneutrality usually obligates chloride reabsorption along with sodium retention. But in chloride depleted states, this is not possible. Instead the lumen-negative gradient (due to sodium reabsorption without chloride following) obligates cation excretion, usually potassium or hydrogen ions. Additionally, the hyperaldosteronism increases H+ excretion via effects on the H-ATPase. Together these explain the paradoxical aciduria associated with GI loss-induced metabolic alkalosis as hydrogen is excreted despite alkalemia. The chloride depleted state, as well as the sodium retention induced by volume depletion, also lead to maintenance of the alkalosis by limiting bicarbonate excretion by a variety of mechanisms. It is for this reason that such alkaloses are termed saline responsive, indicated by a low urine chloride - administration of saline leads to correction of hypovolemia and therefore removes the stimulus to aldosterone, while at the same time chloride replenishment allows for the excretion of bicarbonate while minimizing H+ excretion, leading to an appropriately alkaline urine and rapid correction of the electrolyte abnormalities.

But is metabolic alkalosis the only acid-base disturbance that results from NG decompression? Some anecdotal experience suggests not. As noted above gastric fluid contains little potassium and almost no bicarbonate. So at first glance the answer seems to be no. However, there is a not-so-infrequent clinical scenario where NG decompression can result in metabolic acidosis. More distal fluids, such as bile, pancreatic secretions, and small bowel fluids all have high concentrations of bicarbonate (45, 92, and 50 mEq/L respectively). When NG suction is employed to decompress a small bowel obstruction, more distal fluids can be suctioned, leading to bicarbonate loss. In general though, the suctioned fluid will also contain gastric acid and there will be limited net change in acid-base status. However, if gastric acid production is limited by a proton pump inhibitor, metabolic acidosis can ensue. This was the case with a patient we were consulted on with a metabolic acidosis and bicarbonate of 13 in the setting of NG decompression for a partial small bowel obstruction. The patient was also on a PPI. He was not having diarrhea. To test our theory, we checked the pH of his NG fluid (pH testing was more readily available than electrolytes). The pH was 6.9, far above what would be expected from a PPI alone. We suggested holding his PPI. His acidosis resolved quickly, though in the context of discontinuation of NG decompression and bicarbonate administration, so we can't say for sure that holding the PPI during NG decompression solved the problem. Nonetheless, sharing our case with other colleagues revealed similar anecdotal experiences, suggesting that the phenomenon of metabolic acidosis resulting from upper GI loss of bicarbonate in the setting of partial or complete small bowel obstruction, NG decompression, and concomitant PPI administration should at least be kept in the back of the mind.

Renal Malignancy Syndromes

I had a patient come to see me last week with the rare disorder, Birt Hogg Dube Syndrome (BHD). She was referred with a mildly elevated serum creatinine and microalbuminuria against a background of a single kidney following nephrectomy for renal cancer, which, along with skin abnormalities, is a feature of the syndrome (see left). She initially presented to dermatology with multiple small papule like lesions on the face, which on biopsy were fibrofolliculomas (skin follicle hamartomas). Her renal cancer presented as an incidental finding in 1993 with a 10cm lower pole tumor attached to small bowel. It was removed and pathology was a chromophobe tumor. It has not recurred despite it's large size and local invasion at presentation.
BHD may present with multiple or bilateral renal cancers; it is also associated with oncocytomas of the kidney, and with pulmonary cysts and spontaneous pneumothorax (which she does not have). It is due to a loss of function mutation of a gene on chromosome 17 which may be a tumor suppressor gene and the gene product is folliculin.

We see a lot of patients (relatively) in our clinic with Tuberous Sclerosis Complex, as we are a referral center. TSC is also rarely associated with renal cancer (in 1-2% of cases). There are numerous skin manifestations of TSC, including facial angiomas. Other major manifestations include lymphangiomyomatosis of the lung, cardiac rhabdomyomas, CNS cerebral tubors and renal angiomyolipomas (AML's), as well as renal cysts. It is an autosomal dominant condition. TSC has two genotypes. The gene defect for TSC1 is on Chromosome 9 (encodes for Hamartin); the gene defect for TSC 2 is on Chromosome 16 (encodes for Tuberin). Hamartin and Tuberin are involved in cell cycle regulation.


Finally, Von Hippel Lindau (VHL) is much more frequently associated with renal cell cancer. It is also autosomal dominant with the loss of function defect on chromosome 3 which is also tumor suppressor gene. VHL is associated with

• Hemangioblasomas of the brain, retinal angiomas
  
• Pheochromocytoma
• Pancreatic neuroendocrine tumors
• Renal cysts
• Renal cell cancer - usually a clear cell cancer

Posted by David Steele MD

Cyclosporine in Membranous Nephropathy: A non-immune modulatory effect to maintain remission?

This is the story of a 64 year old male mason with past medical history notable for hypertension and hyperlipidemia who was referred to me for evaluation of proteinuria.

The patient noted onset of lower extremity edema nine months prior to the clinic visit. At the time, he was admitted to the hospital due to increasing complaints of lower extremity edema and shortness of breath, and received the presumptive diagnosis of congestive heart failure. He had an echocardiogram showing preserved ejection fraction and no valvular abnormalities. A chest CTA was negative for pulmonary embolism and imaging of the lower extremities was negative for deep venous thromboses. His serum albumin at the time was 2.5 g/dl down from his baseline of 4.0 g/dl a few months prior. No urinalysis data was available from that admission. He was treated with furosemide to which he responded with resolution of his shortness of breath, but with no effect on his notable 3+ pitting edema. He was discharged from the hospital with cardiology follow up as an outpatient.

Teaching point: not all edema is heart failure! A simple urinalysis would have been revealing.

Now back to the case...

During this time period, the patient’s lower extremity edema and exertional dyspnea had not improved in spite of escalating doses of furosemide. He was admitted to the hospital again two months prior to the renal clinic visit, this time for hypertensive emergency treated with intravenous labetalol followed by escalation in his anti-hypertensive regimen which included beta blocker, calcium channel blocker and a small amount of ACE inhibitor. A urinalysis sent at this time showed 3+ protein. He was also subsequently noted to have a serum albumin of 1.3 g/dl. Of note, his renal function was normal at his baseline of 1.0 mg/dl on presentation to renal clinic. Quantification of his proteinuria revealed 13 gms/day.

The patient denied a family history of kidney disease or any known past episodes of kidney problems. He denied fever, headache, chest pain, visual problems, rashes, joint pain, muscle pain, abdominal pain, nausea, vomiting, dysuria, hematuria, or hemoptysis. He had noticed foamy urine over the past few months. He also complained of occasional dyspnea on exertion, which was markedly different from his baseline a year prior. Renal ultrasound was notable for kidneys measuring 14 cm bilaterally with no hydronephrosis and no masses. Ultrasound evaluation of the renal arteries revealed no renal artery stenosis.

He underwent a renal biopsy which revealed membranous glomerulonephritis.

The patient was initially managed with angiotensin converting enzyme inhibitor, angiotensin receptor blocker and diuretics. After a six month period -- fifteen months since the onset of symptoms -- during which there was no sign of spontaneous remission, we initiated treatment with Cyclophosphamide and high dose Prednisone.

The patient developed severe leukopenia, so Cyclophosphamide was discontinued. While we have some experience with Rituximab at our institution, this patient had normal renal function and therefore appeared to be a good candidate for a trial of Cyclosporine. We therefore initiated treatment with Cyclosporine at a dose of 3 mg/kg/day.

He responded well with reduction of his proteinuria to less than 2 gms/day. However, due to an episode of VZV/shingles, the Cyclosporine dose had to be decreased to 1 mg/kg/day, which resulted in trough levels less than 40 ng/ml. In spite of Cyclosporine levels well below these known to have a significant immunomodulatory effect, the patient achieved a surprising partial remission. It is of course conceivable that his remission was spontaneous, but this is not supported by the fact that he had been persistently nephrotic for 1.5 years prior to initiation of Cyclosporine treatment. Furthermore, the fact that the patient continues to be in remission 3 years later suggests that Cyclosporine may continue to exert a beneficial effect.

It is not surprising that Cyclosporine can be successfully used to achieve remission in patients with IMN. However, past experience has shown that many patients with IMN have recurrence of proteinuria once Cyclosporine is removed. On the other hand, the chronic use of Cyclosporine is known to result in a decline of renal function, and nephrologists have been reluctant to use it for a prolonged period of time in the nontransplant setting. It would therefore seem advantageous to devise therapeutic strategies for the use of low dose Cyclosporine to prevent recurrence of nephrosis.

Intriguingly, a 2008 study by the Mundel group suggests that Cyclosporine may have a new target: the glomerular podocyte. The authors present data in mouse models of acquired proteinuria, and specifically in mice that have been genetically modified to express calcineurin in a constitutive fashion. Interestingly, these mice develop severe albuminuria. Through a series of experiments, the authors subsequently determine that Cyclosporine confers an anti-proteinuric benefit through its protective effect on a critical, podocyte-specific molecule called synaptopodin. The preservation of synaptopodin ensures that the podocyte cytoskeleton remains intact, preventing the disruption of the glomerular filtration barrier.

These findings challenge our understanding of Cyclosporine as an immune modulatory agent for proteinuric kidney disease, and our long held belief that Cyclosporine puts patients in remission through its effects on T-cell activity. These data necessitate a closer look at the effects of traditional “immune modulatory” agents on the podocyte cytoskeleton.

Extrapolating from these data, is it possible to maintain podocyte health – and keep nephrotic patients in remission – by using Cyclosporine, or preferably targeted agents with similar podocyte-specific effects?

My patient enjoys a partial remission (currently proteinuria is less than 0.8 gm/day) on what would be considered "subtherapeutic" levels of Cyclosporine. However, if we begin to think of Cyclosporine as a podocyte-modulating agent, perhaps we also need to redefine what levels are “therapeutic.” This case suggests that lower doses may allow us to use Cyclosporine to maintain patients in remission with less concern for its nephrotoxicity. We have now employed this approach in a few other patients with IMN, with encouraging results thus far. Moreover, the use of low dose Prograf in some of our patients with FSGS has also proven to be effective in maintaining remission. Future clinical studies on these questions will be revealing. In the meantime, we are hard at work in the lab to identify new podocyte-specific anti-proteinuric agents.

Renal Stress Testing

According to the most recent NHANEs data, 15.5 million Americans have CKD III, a figure that has increased by over 40% in less than a decade. CKD III is primarily a marker of global health outcomes, and affected patients are at increased risk for overall mortality, cardiovascular disease and hospitalization. Although many may be referred, few (less than 5%) will ever progress to the point of needing dialysis or transplantation. In fact, in the Tromso study, a 10-year prospective follow-up of patients with CKD III, only 2% reached ESRD compared with a third dying from other causes, mostly cardiovascular disease. A major challenge for Nephrologists, if we are not to be swept away by a massive tide of referrals, is to develop tools which permit the identification of individuals who will develop progressive kidney disease. These may be referred for specialist Nephrology follow-up, while people at low-risk for progression could be managed by primary care.

Renal stress testing is not a new idea. It has been primarily studied in the pediatric setting and, while a little cumbersome in its present form, has potential. The most frequently studied version involves measurement of GFR augmentation after oral protein loading. The relative increase in GFR - normally around 20% - is taken to reflect renal reserve. This reserve is often reduced or absent in hyperfiltration states such as early diabetic nephropathy but, interestingly, often not in uninephrectomized patients (a group who tend to do well). Theoretically, patients without renal reserve are at the limit of their renal autoregulatory capacity, and are at greatest risk for progressive CKD (and AKI). Unfortunately, there are no quality follow-up studies of these patients. A typical protocol can be found in the methods of this article.

A second method tests tubular function as opposed to reserve GFR. Patients are given a large creatinine bolus (88.4 mmol/kg), targetting a serum creatinine of 4-6 mg/dL, and urinary creatinine excretion is measured. An impaired tubular secretory response to a creatinine load appears to be a more sensitive index of reduced functioning renal mass than serum creatinine or GFR. Again, a prospective study is lacking, but the results are stimulating. Seems like an interesting side-project for a renal fellow with some spare time on his or her hands - do such creatures exist?

Surviving lactic acidosis; lessons from turtles

Lactic acidosis is frequently seen in the hospital setting. Diverse etiologies account for the accumulation of lactic acid as reviewed by Nathan last year. The main impetus for the production of lactate is having a hypoxic state either in the entire organism, the cellular level or an isolated vascular bed. Most cells in the body break down glucose to form water and carbon dioxide. This is a two-step process. First, glucose is broken down to pyruvate through glycolysis. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation. This second step requires oxygen. The net result is ATP, the energy carrier used by cells. If oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate and released from the cell into the bloodstream, where it accumulates over time.

I met Nathan at the Origin's of Renal Physiology Course at Mount Desert Island, Maine a few years ago. This is an outstanding course where you get hands on experience exploring renal physiology using marine life just as Homer Smith did. I remember learning that the painted turtle, Chrysemys picta is able to survive extreme lactic acidosis. As a renal fellow we are frequently consulted for this devastating entity. Unfortunately, we are mostly unable to intervene as the answer in a majority of these cases is to correct the underlying problem. Interestingly, many aquatic vertebrates can remain submerged underwater for remarkably long periods of time. A prime example is the painted turtle, Chriysemys picta, a freshwater species found in Canada and the U.S. Its natural winter habit is to continuously submerge itself in ice-covered ponds for months. The turtle is able to sustain vital organ function for long periods of time despite severely hypoxic or even anoxic conditions. Lab studies have shown that these turtles an fully recover for submergences lasting 3 months at 3 C. The plasma concentration of lactate have been measured as high at 200mM. How is this possible?

The turtle has adapted to this environment by using several unique mechanisms. First, the major extracellular buffer, bicarbonate, is particularly high at baseline (40 mM) in the plasma as well as the peritoneal fluid (80 mM) and pericardial fluid (120 mM). This however, does not account for all of the buffering capacity needed to sustained such profound acidosis. The second and most interesting mechanism is its use of is bone-like shell. The shell accounts for 32% of the turtles total body mass. The portion of its skeleton not incorporated into the shell represents an additional 5.5%. Besides the obvious role it plays as a protective armor, the turtle's shell is also the major mineral reservoir for the body. Over 99% of the total body calcium, magnesium and phosphate and 60% of the body's sodium reside in the shell and bone.

Two mechanisms account for the shells buffering of lactate. First, supplemental buffers are released from the shell directly when needed. During periods of extreme anoxia. Plasma levels of calcium and magnesium increase dramatically. Likely, this is a passive process by which the shell is demineralized by acids. Mainly, calcium carbonate is released. So much calcium is sequestered in the shell that little loss is evident even with prolonged periods of acidosis. A similar process occurs during untreated acidosis in CKD. However, the calcium stores are not quite as profound in the human body. The second mechanism involves the uptake on lactate and a proton directly by the shell. The enormous buffering capacity of the shell allows for this.

Chriysemys picta's unique habit of hibernating during the winter months have allowed for this interesting ability to survive profound lactic acidosis by using its shell as a buffer. Unfortunately, lactic acidosis in the hospital setting is typically extremely difficult to control as the buffering capacity of the body cannot tolerate lactate accumulation for an extended period of time. Research performed on marine life, like at Mount Desert Island, allow for the discovery of novel and interesting ways to survive extremes in physiology.

Lessons from the Haiti earthquake for nephrologists?

In the Lancet April 3, 2010 issue, the Renal Disaster Relief Task Force (RDRTF) of the International Society of Nephrology reflected on some of the lessons learned from the Haiti relief efforts after the January 12, 2010 earthquake.


Crush syndrome resulting in rhabdomyolysis and acute kidney injury is the second most frequent cause of mortality after direct trauma after major earthquakes. After the Haiti earthquake, efforts were made to set up a functioning dialysis unit and the team encountered many problems related to communication, infrastructure, and logistic hurdles. For example, there was no running water or electricity. After several days, the dialysis unit was up and running. 19 patients with crush syndrome were ultimately referred for hemodialysis and the team ran 64 dialysis sessions. The authors attributed the low number of patients who were dialyzed to the fact that most people who were severely injured died early on.

What can we as nephrologists learn from the Haiti disaster relief efforts? Vanholder et al. for the RDRTF summarized in the Lancet:

1. “need for better interagency communication to provide awareness of services available in the disaster area”
2. “the necessity of early fluid resuscitation”
3. “the value of the iSTAT point-of-care device for early diagnosis.” By measuring the potassium, BUN, creatinine, the medical team was able to identify patients quickly who were in need of renal replacement therapy.

Haiti, considered the poorest nation in the Western Hemisphere, has only four known nephrologists for its nine million people. There was a symposium at the American Society of Nephrology annual meeting last year on disaster relief, which was particularly timely. The role for nephrologists in disaster relief efforts and ways to improve mobilization, logistics, and communication remain ongoing topics for discussion.

Posted by Julie Paik M.D.

ASN launches renal fellow website

The American Society of Nephrology (ASN) announced the creation of a "fellow's" website today. You can locate this site by following the link or going to the "training" tab of the main ASN website (www.asn-online.org). The ASN fellow's webpage contains many useful resources for Renal fellows with plans to add more in the future. A link is provided with grant opportunities specifically geared to Renal fellows from government, non-profit and private organizations. Different educational opportunities are highlighted as well. From conferences to courses to the Mount Desert Island National Course for Renal Fellows (The Origins of Renal Physiology). A touching tribute to Nathan Hellman is included with a link to Renal Fellow Network. This site is a welcome resource for Renal fellows navigating the busy fellowship program. Much of the information provided on this site used to be passed down from fellow to fellow. Now we have a portal where all types of resources can be immediately accessed. Cheers to the ASN for making this site.

The Earlier The Better

I am currently writing a chapter about Living Kidney Donation “the Gold Standard”. With that in mind and two recent discussions with my co-fellows, I decided to discuss a little bit about the choice of the kidney donor in transplantation. Let’s though start with a board-type quiz:

A 65 year-old man with a GFR 10ml/min is undergoing transplant evaluation. He has a question about whether he should wait for a cadaveric kidney or get a preemptive kidney transplant from a living donor. Assuming the cadaveric donor is available right away, which donor will give him the best chance for graft survival?

a. 45 yr old male cadaveric donor 6 out of 6 HLA matched
b. 25 yr old male cadaveric donor 4 out of 6 HLA matched
c. His 25 year old daughter with one haplotype match
d. His 55 yr old wife with 2 out of 6 HLA match
e. a + c
f. c + d

Couple of more interesting points before the answer. A preemptive transplant leads to the best allograft survival for both cadaveric and living kidney transplants. The longer you stay on dialysis, the worse the allograft outcome is. However, transplantation at any time is always better than staying on dialysis. Since our waiting list has just reached 85,000 patients this week and the annual number of deceased kidney donors is around 8,000 in the US, preemptive living kidney donation is the best option for patients with ESRD – deemed no contraindications for transplant exit.

Although deceased kidney donor survival depends on the degree of HLA match, HLA matching is not as important for living kidney donors with the exception of identical twins, which have the best outcomes. Therefore, the right answers is f. The graft survival from the daughter’s or wife’s kidney will likely be very similar. However, many transplant centers would advocate doing a nephrectomy on the wife rather than the young daughter because of her age and long-term potential consequences, presumed both cross-matches are negative.

Most important learning point: refer your advanced CKD patient early for transplant evaluation!!!!

Two landmark articles below:

Meier-Kriesche, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000. 58:1311-1317.
Terasaki , et al. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995.333:333-336.

An excursion into Magnesium homeostasis

Magnesium (Mg++) is a predominantly intracellular divalent cation which is critical for many metabolic processes and participates in >300 enzymatic reactions. It is essential for many critical transporters including the Sodium/Potassium ATPase cotransporter. Mg++ also has a critical role for DNA replication, transcription and translation.

Mg++ intracellular homeostasis is complex because it is compartmentalized in different organelles in the cell with different concentration.
The distribution of Mg++ in the human body is interesting.

• Serum 0.3%
  
• RBCs 0.5%
• Soft tissue 19.3%
• Muscle 27%
• Bone 52.9%
  

Therefore measuring serum Mg++ represents an inaccurate way to assess total body Mg++ stores and can be misleading. In addition, there is no standardized normal range for Mg++ and values vary from lab to lab. E.g., at the Brigham & Women's (1.8-2.5mg/dl), Mass General (1.4-2.0mg/dl) and VA (1.8-2.4 mg/dl) hospitals there is quite a discrepancy in what is considered a normal range.

Clinical signs of hypomagnesemia (from mild to severe) include loss of appetite, nausea/vomitting, fatigue, weakness, numbness, tingling, muscle contractions/cramps, seizures, nystagmus, personality changes, hypokalemia, hypocalcemia, arrhythmias and coronary spasms.

Causes of hypomagnesmia can be reduced intake and/or absorption e.g. in malabsorption syndromes, change in redistribution e.g. during exchange transfusions and last but not least reduced renal re-absorption which is the most likely etiology. Causes include alcoholism, diabetes mellitus, hyperthyroidism, hypercalcemia and several medications (loop diuretics, aminoglycosides, cisplatin, calcineurin inhibitors, etc.).

Approximately 75-80% of serum Mg++ is filtered in the glomerulus. 15-20% are re-absorbed in the PT, ~65-75% are re-absorbed in the TAL and 5-10% are re-absorbed in the DCT. The DCT is the site of fine regulation of Mg++ excretion. The fractional excretion of Mg++ can range from 0.5% to 80% but typically is in the range of 3-5%.

How Mg++ re-absorption is regulated in the kidney is still unclear. Compared to other electrolytes there was no hormonal or regulatory known until recently. Its re-absorption appeared to be coupled to Calcium re-absorption. However, rare inherited Mendelian forms of Mg++ disorders have given insight into the molecular mechanisms of abnormal Mg+ homestasis:

Condition: Gene Mode of inheritance tubular location Urine Ca excretion
FHHNC: Claudin16 AR TAL High
BARTTER’s: CLCNKB AR TAL High
ADH: CaSR AD TAL&DCT High
FHH: CaSR AD TAL&DCT Low
NSHPT: CaSR AR TAL&DCT Low
GS: NCCT AR DCT Low
HSH: TRPM6 AR DCT Low
IDH: NaK-ATPase AD DCT Low
Mitoch.: tRNAile Maternal lineage DCT Low

Abbreviations:

FHHNC = Familial hypomagnesemic hypercalciuria and nephrocalcinosis
AR = Autosomal recessive
AD = Autosomal dominant
ADH = Autosomal dominant hypocalcemia
FHH = Familial Hypercalcemia with hypocalciuria
NSHPT = Neonatal severe hyperparathyroidism
GS = Gitelman syndrome
HSH = Hypomagnesemia with secondary hypocalcemia
IDH = Isolated dominant hypomagnesemia
CaSR = Calcium-sensing receptor
NNCT = Sodium-Chloride Cotransporter
TRPM6 = transient receptor potenetial cation channel, subfamily M, member 6.

A few comments on these inherited diseases which may be relevant. FHH and NSHPT feature typically elevated serum Mg++ levels. Disorders of hypomagnesemia located to the DCT have typically low urine calcium excretion compared to disorders located to TAL which have hypercalciuria. Another difference based on location of defect in the tubulus is degree of "hypermagnesuria". TAL defects result typically in higher FeMg++ of 15-50%, whereas hypomagnesemia caused by defects in the DCT results in lower levels of FeMg++ (5-15%). Patients with mutation in the gene Claudin 19, a paracellular tight junction protein, have similar phenotype to FHHNC caused by Claudin 16 (Paracellin). It turns out that Claudin 16 and Claudin 19 form a channel like structure to transport Mg++ through paracellular pathway in the TAL. This may be the most important mechanism of Mg++ transport in the TAL.

An interesting new chapter on Mg++ homeostasis began in 2007 based on a report by Bindel and colleagues in JCI. They reported that the EGF receptor may regulate TRPM6, a Mg++ channel in the DCT and that EGF is a magnesiotropic hormone. They reached that conclusion by reporting a family with a recessive form of hypomagnesemia with a loss-of-function mutation in Pro-EGF, a precursor of EGF, leading to lower EGF levels. Further evidence for this mechanism was shown in patients treated with Cetuximab, an anti-EGF-receptor antibody which causes hypomagnesemia.

In summary, Mg++ deficiency is probably more prevalent than recognized since serum Mg++ may or may not reflect intracellular Mg++ stores. Hypomagnesemia is linked to human disease since patients with low serum Mg++ have poorer outcome. Mg++ homeostasis is still poorly understood, however inherited forms of hypo- and hypermagnesemia provide the best understanding of its regulation.

Nathan Hellman Memorial Award

Nate Hellman MD PhD, the founder of the Renal Fellow Network, died tragically just over two months ago. He was a wonderful person, who possessed a strong sense of humanity, humor and compassion. Nate touched the lives of many people and is dearly missed by all who knew him.

A graduate of the Medical Scientist Training Program at Washington University, Nate loved the mysteries of basic science and clinical medicine and who took immense pleasure in teaching and sharing knowledge. Presently, his family is working with Washington University to establish the Nathan Hellman, M.D., Ph.D. Memorial Award, which will be given annually to recognize an outstanding medical student in the School of Medicine, a fitting legacy for an incredibly accomplished physician and scientist such as Nate.

If you would like to donate to this endowment student award, details may be found here.

PD vs HD in the elderly

Patients over 65 tend not to choose peritoneal dialysis for a host of reasons, not the least of which is PD is underutilized in the US in general. However, a recent study suggests that PD may be preferable to HD in the elderly, at least for those with the cognitive and functional ability to perform PD.

The BOLDE (Broadening Outcomes for Long-term Dialysis in the Elderly) trial out of the UK looked at health-related quality of life measures in PD vs HD patients over 65. Results have not yet been published but were recently presented at the Annual Dialysis Conference in Seattle in March. Using a cross-sectional design, the study matched PD and HD patients (age, gender, time on dialysis) and compared health related quality of life via several validated assessment tools. Mean age was 73, most were men (70%), and ~25% lived alone in both groups. Patients in both groups were on dialysis for on average about 2.5 years. Education level was similar in both groups. Disease intrusiveness scores were lower in PD than in HD patients (22.0 in PD vs. 26.0 in HD) as assessed by the Illness and Intursiveness Rating Scale. The study also found that depressive symptoms were less common in the PD group, as were common dialysis-associated symptoms (headaches, dry mouth, taste changes, dizziness, and unsteadiness), with the exception of lower extremity edema, which was more common in patients with PD. For more details see the author's presentation data here and a review article here.

With the aging of the population, modality choice in the elderly will be a decision encountered more frequently, and at the very least this study should lead us to seriously entertain, if not encourage, PD in the elderly population. Further, as many of you know, Centers for Medicare and Medicaid Services (CMS) will be implementing the bundle payment system in January 2011. In short, dialysis treatments in the US will be reimbursed with one lump some that will cover all the costs of the treatment, including labs, medications etc. Reimbursement for home dialysis will be comparable to in-center dialysis, providing some incentive to increase the use of home modalities which are generally cheaper. Taken in this context, PD enthusiasm in general should increase, both for quality of life and, for better or worse, financial, reasons.

Eeuuuw... too much information!

Almost one year ago, Nate posted here about the results of a large GWA study of chronic kidney disease by Kottgen et al. This project was the result of a collaboration between 4 groups, and produced many exciting results, including the identification of the UMOD gene as being associated with CKD, reviewed here. Since then, these investigators have formed a collaboration with 16 other studies to form the CKDGen consortium, containing data on over 90,000 members of the general population of European ancestry. This past weekend they published the results of their latest GWAS, identifying no less than 13 further novel loci associated with chronic kidney disease, defined as eGFR < 60 ml/min. Of note, an independent consortium published the results of their CKD GWAS on the same day, identifying several of the same genes (ALMS1/NAT8 and SCL7A9). Some very interesting candidate genes emerge from this body of work, so I'll briefly touch on a few of them here:

• SLC7A9: encodes an amino acid transporter expressed in renal proximal tubule cells, mutations in which cause cystinuria and are associated with cysteine nephrolithiasis. 
• SLC34A1: encodes the Na-Pi co-transporter in the proximal tubule, mutations in which cause hypophosphatemic nephrolithiasis.
• ALMS1: Mutations in this gene are associated with renal ciliopathies, as well as the Alstrom syndrome, an autosomal recessive condition characterized by retinal degeneration, hearing loss, obesity, diabetes and renal failure. 
• NAT8: This interesting candidate gene is involved in drug metabolism via de-acetylation, suggesting that polymorphisms in it may confer susceptibility to drug-induced nephrotoxicity. Also, there are reported associations between NAT8 polymorphisms and systolic blood pressure and renal function.
• DAB2: an adaptor protein in the proximal tubule which physically links megalin and non-muscle myosin heavy polypeptide 9 (MYH9), a critical susceptibility allele for non-diabetic kidney disease in African Americans, see blog posts here and here.
• VEGFA: Vascular endothelial growth factor A plays a key role in renal angiogenesis and vascular permeability. 

The paucity of therapeutic options in Nephrology can lead to a certain diagnostic nihilism, and a large body of patients carry loosely applied clinical diagnoses such as "nephrosclerosis", and "interstitial renal disease". Studies such as this shed light on the real underlying causes of such presentations, and hint at an exciting new molecular toxonomy on the horizon.

Organophosphate poisoning ... a rare cause of AKI?

A colleague of mine at another academic institution recently informed me about a patient that had been admitted to the ICU with organophosphate poisoning. In spite of aggressive treatment, the patient remained critically ill with multiorgan dysfunction and developed acute kidney injury requiring continuous venovenous hemofiltration. While the AKI may have been caused by a period of hypotension, there was speculation that it may have been directly caused by the organophosphate. I had never learned in medical school, residency, or even fellowship that organophosphate toxicity could involve the kidneys and decided to investigate this a little further. It turns out that organophosphate poisoning indeed has been documented as a rare cause of AKI.

Organophosphates are chemicals that are commonly used for both household and industrial purposes. Organophosphates can be divided into insecticides (malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion), herbicides (tribufos [DEF], merphos), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon). When ingested accidentally or deliberately, these chemicals inhibit the active site of acetylcholinesterase (AChE), an enzyme present in the central and peripheral nervous systems at neuromuscular junctions, and on RBCs which is responsible for the degradation of acetylcholine. The consequence is excessive acetylcholine available to bind to nicotinine and muscarinic receptors, which produces the constellation of symptoms that can be seen with toxicity. Common symptoms include salivation, lacrimation, urination, defecation, GI upset, and emesis (SLUDGE syndrome), though bradycardia, hypotension, bronchospasm, severe respiratory distress, muscle fasciculations, and weakness can also ensue. Pralidoxime and atropine have traditionally been the accepted therapies for organophosphate poisoning.

Nephrotoxicity is rare but has been reported in a few cases of severe organophosphate poisoning:

1. One early case report documented the development of amorphous crystalluria and reduced urine output in a patient following ingestion of dimpylate in a suicidal attempt (Wedin et al JAMA 1984). The patient initially presented with vomiting, diaphoresis, and bradycardia and was treated with IVF hydration and atropine. Shortly after admission, urine output was found to decrease to 22 mL/hour, appearing dark and cloudy. Urinalysis revealed moderate amorphous crystals which could not be identified by the laboratory. IVF were increased, and pralidoxime was started. Urine output subsequently improved, though the amorphous crystalluria persisted for several days before spontaneously resolving. Interestingly, serum BUN and creatinine remained normal throughout the hospitalization. The patient was eventually discharged. Whether the crystalluria was directly induced by the dimpylate could not be established.

2. A second case report documented the development of AKI in a patient who had ingested the organophosphate methamidophos in a suicidal attempt (Agostini et al Human Exp Toxicol 2003). On admission, the patient had a serum creatinine of 100 umol/L (1.14 mg/dL) with strong urine output; he was treated with atropine 2mg and pralidoxime 2g bolus with 8g/day infusion. However, within hours, his urine output decreased to 0.5 mL/kg/hour and was not responsive to IVF hydration or furosemide. At 72 hours, the patient was anuric and volume overloaded with a serum creatinine of 6.25 mg/dL. CVVH was initiated and continued for 12 days, at which time the serum creatinine decreased to 3.29 mg/dL and urine output improved to 3.3 L/day. The patient remained in the ICU for 25 days and upon discharge his renal function had returned to normal. The authors proposed that CVVH may be a life-saving therapy for AKI associated with organophosphate poisoning.

Currently, there is not much experimental data demonstrating direct nephrotoxicity from organophosphates. Some mechanisms for AKI that have been proposed include increased intratubular organophosphate concentration, rhabdomyolysis, and prerenal azotemia from hypovolemia. One study in JASN (Poovala et al JASN 1999) examined the toxicity of the organophosphate bidrin in vitro using renal tubular epithelial cell line (LLC-PK1), using LDH release as a surrogate for cell death, and suggested a possible role of reactive oxygen species in the pathogenesis of tubular cytotoxicity. Another study (Bloch-Schilderman et al J Appl Toxicol 2007) demonstrated that injection of sarin in rats lead to a 45% decrease in GFR, 50% reduction in urine output, and hematuria and glucosuria 24-48 hours following the dose. These findings were transient and reversible after 3-8 days; interestingly, treatment with atropine 1 minute after the sarin dose did not prevent the renal injury.

In summary, multiorgan dysfunction and AKI are rare events following organophosphate poisoning but have been documented are usually associated with a high mortality rate. More studies need to be performed to establish a more definitive causal relationship between these toxins and renal injury.

The great salt war; population-wide salt reduction

Population-wide salt reduction is gaining increased media and political attention over the last few years. The most notable example is the National Salt Reduction Initiative (NSRI) spearheaded by New York City Mayor Michael Bloomberg. This initiative was unveiled in January of 2010 in New York City and currently multiple cities around the US have joined forces. Public policy to limit salt intake is not a new concept around the world as the NSRI was modeled after the Food Standard Agency's efforts to reduce salt intake in the UK which started in 2003. Canada, Australia, Finland, France, Ireland and New Zealand have launched similar initiatives. This effort is not without its detractors. An increasingly skeptical US public is enduring an era of less and not more government involvement. Weighing the available evidence has always been an important part of medical advancement. When this in juxtaposed with public policy and politics is when these debates begin to get controversial. The benefits of salt reduction in lowering blood pressure and reducing cardiovascular risk have been consistently seen in the medical literature both in randomized clinical trials (DASH diet) and observational studies (INTERSALT). The US diet is extremely high is salt. The average American man and woman is estimated to consume 10.4 and 7.3 grams of salt per day respectively. The US Department of Agriculture and Health and Human Services recommends 5.8 g of salt (2.3 g sodium), with a lower target of 3.7 g of salt per day for most adults (people over 40, blacks, patients with hypertension). A recently published paper by Bibbins-Domingo et al. in the February 18 NEJM attempts to answer important questions about the cardiovascular and economic benefits of population-wide salt reduction.

This study is not a randomized clinical trial nor is it a observational cohort. This study utilizes a computer-simulated cohort called a "Markov" cohort. "Markov" chains are named after Andrey Markov and are commonly used for statistical modeling in finance, economics, social sciences, physics and medicine. Bibbins-Domingo utilized the Coronary Heart Disease (CHD) model which has been used to describe trends in CHD and the effects of interventions intended to reduce the risk of CHD and cost associated with treating CHD. This model inputs known data in regards to most accurate epidemiological data in the US (census, death rates, CHD rates, heath care expenditure, risk reduction estimates etc.) into a complex "Markov" chain to determine the cardiovascular and economic benefit of reducing the salt consumptions by 3 grams per day.

Results
Reducing the number of new cases/year of

• Coronary heart disease (CHD) by 60,000 to 120,000
• Stroke by 32,000 to 66,000 (750,000 per year in US)
  
• Myocardial infarction by 54,000to 99,000 (1.25 million per year in US)
  

Reduce the annual number of deaths from any cause by 44,000 to 92,000.
Save 194,000 to 392,000 quality-adjusted life-years
Save $10 billion to $24 billion in health care costs annually

The results of this "study" are provocative and intriguing. Would this "Markov" cohort play off as predicted in the "Real" world? If so, the reduction of 3 grams of sodium from the diet would have a huge economic and medical impact. These efforts would be akin to weight reduction and smoking cessation initiatives. Even if this reduction of sodium intake was only by 1 gram per day we would likely see huge benefits. However, achieving salt reduction will be a major feat. Lowering salt intake would require change on two important fronts; the public policy approach and the individual approach. The later will likely prove to be the most difficult to curtail as the "salt appetite" of the US population is increasingly fed with processed food products. An interesting editorial exploring this phenomenon by Philip Klemmer appeared in the April 2010 AJKD entitled "salt appetite". He subjected himself (and several UNC renal fellows) to an extremely low salt diet. Being from North Carolina myself I know first hand that this is an extremely difficult task. They each had an average drop in weight of 1.4 kg with a drop in blood pressure. The group finished the "experiment" and went back to their normal eating habits. Salt has endured as an important part of our culture. The word "salary" was used to describe how Roman soldiers were paid for their duties with salt. Salt was used as a way to preserve foods before the widespread use of refrigerators, but its usage has persisted and has perhaps grown in popularity.

For now, recommending a low salt diet is an important part of blood pressure control. But, one can argue that this is an important part of each of our diets. We will see how the public policy debate plays out in this "great salt war". Any decrease in "added" salt to food will be a welcomed improvement. Curtailing the "salt appetite" will likely prove to be more challenging than any spirited political debate.

Cerebral salt wasting: is it all in the head?

I recently saw a patient in clinic who had sustained a head injury and developed hyponatremia that persisted after discharge. In his chart was a great deal of debate over the cause of his hyponatremia: SIADH or cerebral salt wasting? I decided this was a good time for a refresher on cerebral salt wasting (CSW), as I have seen far less of it than SIADH as a clinical fellow.


CSW is characterized by extracellular volume depletion and presence of hyponatremia due to renal salt wasting. It is most seen in patients with cerebral disease, suggesting a neurologic cause. Urine sodium is usually high, though low levels have been documented in patients on low Na diets, and the urine is concentrated. Hypouricemia is also usually present, due to an increase in FE urate. These findings suggest that the proximal nephron, where urate reabsorption and the bulk of Na reabsorption occur, is the main site of action in CSW. While the mechanism is still unclear, several theories predominate. One proposed hypothesis is that decreased sympathetic input to the kidney leads to alterations in salt and water reabsorption. Another is that cerebral damage causes an increase in circulating ANP or BNP, which leads to natriuresis. In either scenario, a decrease in circulating volume would cause an increase in arginine vasopressin, thus creating an “appropriate” increase in ADH.


Because the treatment for CSW is volume repletion with isotonic fluids, and the mainstay for SIADH therapy is water restriction, differentiation between the two conditions is desirable. The main distinguishing feature between SIADH and CSW is volume status, patients with SIADH being euvolemic and those with CSW, volume deplete. As many of us are aware, it is often extremely difficult to assess volume status, especially in the neurology intensive care units. Some other distinguishing tests have also been suggested. While serum uric acid tends to be low in both SIADH and CSW, some studies have shown that when hyponatremia is corrected in SIADH, uric acid levels rise, while they remain low in CSW despite normalization of serum Na. Another study has suggested that measuring the FE phosphate can be helpful—an FE phosphate >20% was a reliable indicator of CSW (presumably indicating additional effects on the proximal tubule).


One question that remains unanswered in the literature (and is important in the case of my patient) is how long these syndromes persist: is it likely that my patient will be able to come off his salt tablets and water restriction? For right now, he’s living a thirsty life.

Preventing Chronic Rejection: Can it B?

For the past 5 years, alloantibody measurement has become a standard of practice in recipients of kidney transplants experiencing worsening allograft function. This week, I admitted a patient who had a rising creatinine and on biopsy mild-moderate interstitial infiltration. No peritubular C4d stain or tubulitis. Transplant glomerulopathy (TG) was seen in 2 out of 10 glomeruli, but C4d stain was negative as well. She had received a deceased kidney transplant 3 years prior and Luminex assay showed that she has now positive donor specific alloantibodies.

Looking at the Banff criteria for humoral rejection, she would be classified as borderline rejection. Even though she had positive alloantibodies, the absence of complement fragment deposition on biopsy excludes this case from the current humoral rejection category.

The finding of rising antibody titers and negative complement deposition is being increasingly recognized and has become a gray zone in transplantation. Some pathologists are starting to call it: smoldering antibody mediated rejection, since it does seem that antibodies are been deposited in the glomeruli capillary leading to the TG. Moreover, TG is a poor prognostic marker. Lastly, the presence of alloantibodies predicts worse allograft outcome and in the presence of C4d positive biopsies, requires therapeutic action: Plasmapheresis + IVIg + pulse dose steroids.

Current immunossupressive regimens used in transplantation target mainly T cells, therefore the rational for targeting B cells seems reasonable, especially since B cells are the origin of plasma cells. There are now 4 clinical trials addressing multiple questions about the benefit of rituximab posttransp. If you are considering giving to one of your patients, please check if he/she would be eligible to one of these trials. That is the only way we can help our community to address the risk/benefit questions of this approach. Other B cell-oriented therapies are also coming in the market soon, like inhibitors of B cell cytokines (BAFF and APRIL) and complement inhibitors.

What about my patient? She received the full course Plasmapheresis + IVIg + pulse dose steroids, despite her borderline classification. We decided not give her rituximab at this time since there was only mild evidence of antibody injury, considering a rebiopsy later to readdress it.

Finally, the preemptive use of rituximab prior to the development of AMR will also become an important question, with a recent trial in cynomolgus monkeys showing capability of decreasing alloantibody production and chronic rejection when combined with calcineurin inhibitors. New era of preemptive B cell targeting? Too early to tell...

Physiology of serum free light chains

Monoclonal gammopathies generally arise from an abnormal clone that has developed from a single cell of B-cell lineage. The monoclonal protein can be intact immunoglogulin (often associated with free light chain), free light chain (FLC) in isolation, or more rarely immunoglobulin heavy chain, either in isolation or with associated free light chain.


Intact immunoglogulin molecules have two light chains of identical subtype, either kappa or lambda. In order to acheive the correct assembly of intact immunoglobulin, the production rate of FLCs is approximately 40% higher than that of heavy chains. The FLCs which are not incorporated into immunoglobulin molecules are released into the serum.

Around twice as many plasma cell produce kappa than produce lambda, but this is not reflected in their relative serum concentrations:
kappa FLCs

• Typically circulate as monomers
• Molecular weight of 22.5 kDa
• Renal clearance of 40%
• Serum half life of 2-4 hours

Lamba FLCs

• Circulate as dimers
• Molecular weight 45 kDa
• Renal clearance of 20%
• Serum half life of 3-6 hours

Note that the proximal tubules can reabsorb up to 30g of filtered protein per day, ensuring FLCs are present only in minute concentrations in healthy individuals.

Therefore, the measurable kappa/lamba ratio depends on the integrity of renal function. In people with normal kidney function, the kappa/lambda ratio is around 0.6, primarily due to the baseline higher clearance of kappa chains. As renal function declines, the role of the reticuloendothelial system in FLC removal takes on increasing importance. This process is not influenced by the molecular weight and so results in a progressive increase in the kappa/lambda ratio from 0.6 to 1.2 in patients with CKD 5.

The presence of monoclonal production of free light chain will result in an abnormal kappa/lambda ratio, with a monoclonal kappa producing a high ratio and a monoclonal lambda producing a low ratio. However, it’s important to remember that the reference range was developed from a population with normal renal function.

These are important principles to be aware of to allow proper interpretation of these tests in clinical practice.

Posted by Finnian McCausland MD