Beads on a String

A 41 year old gentleman with no past medical history presented to ER for nausea, vomiting and abdominal pain. Abdominal CT showed bilateral renal infarcts. His labs were notable for a Cr of 1.4, LDH 500 ESR 102.

The commonest causes of renal infarcts are emboli from atrial fibrillation, infective endocarditis, or fat, renal artery or aortic dissection, fibromuscular dysplasia and vasculitis. Work-up including an EKG, ECHO, hypercoagulable panel and antiphospholipid antibodies were all negative. We performed an angiogram which showed diffuse visceral microaneurysms leading to a diagnosis of polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that affects medium sized vessels. It was first described by Dr. Kussmaul and Dr. Maier in 1866. The incidence of the disease is 2 to 33 per million population, with a male to female ratio of 1.5:1. The major environment factor associated with PAN is HBV infection.

There are 5 variables that predict an increased risk of mortality in PAN (Five factors score FSS): 1) Proteinuria>1g/day

2) Renal insufficiency (Cr>1.58)

3) GI involvement (bleeding perforation, infarction or pancreatitis)

4) Cardiomyopathy

5) Central venous system involvement.

Without treatment, the 5 year mortality in patients with 0 risk factor is <12%, 1 risk factor 25% and 2 risk factors 56%. The standard treatment for FSS>1 is 12 months Cytoxan with steroids. Renal failure is rare in PAN patients and uncontrolled or relapsing vasculitis is the most common cause of death.

In our case, the patient was started on cytoxan and prednisone and his abdominal pain completely resolved. His creatinine unfortunately is still elevated and the plan is to continue with treatment for at least 6 months.

Posted by Jie Cui

Palliative Care Experience of US Internal Medicine Subspecialty Fellows Survey

Kenar Jhaveri and colleagues are conducting a survey looking to help further the understanding of the palliative care experience of current US internal medicine subspecialty fellows during their residency and fellowship training.

If you're interested, check it out here.

In "Nate's method"... what is the diagnosis?

Nate Hellman, the founder of this blog, was a personal friend. We trained together as MGH Renal Fellows. It has been three years since his passing. I often wonder how much he would have achieved by now. For sure, he would be on staff at Mass General and on faculty at Harvard Medical School. He would be well immersed in setting up his independent research career. He would be the caring doctor we all knew him to be. And most certainly, he would be writing this blog.

Those of us who knew him personally, know that Nate had the ability to write and release his brilliant thoughts to the world with little worry or inhibition, one of many traits I always admired in him. I think it came from his wonderful ability to laugh at himself and remain honest and real, no matter what. I have decided to start blogging, in an effort to remind myself, all of us here at MGH and all of you out there of “Nate’s method.” At least, I intend to try…

Here is the unknown case that was presented to me at the MGH Renal Grand Rounds this past Tuesday. One of our Renal Fellows, Dr. Jie Cui, presented the case, and will be blogging on her own thoughts on PAN soon (I have inside information here!):

HPI:

41 yo M with no PMH was admitted with acute onset pain radiating to his R groin, 10/10, sharp and persistent. In the ER, he was found to have BP 188/116, mildly elevated Cr to 1.3, and elevated LDH 520. His CT showed bilateral renal infarcts and renal artery clot.

Home Medication: None

Physical Exam:

Vital Signs: T 98 HR 76 BP 120/90

GEN: Well appearing man in NAD

HEENT: MMM, oropharynx clear; PERRL.

Cards: NSR, RRR, normal S1, S2, no murmur/gallops/rubs

Chest: CTA B/L, no wheezing/rales/rhonchi

Abd: Soft/ND, + BS, RLQ (+) tenderness, no rebound/guarding, no bruits

Back: no CVA tenderness

Ext: normal tone, no edema, 5/5 muscle strength, no joint tenderness or deformities

Skin: no rash

Results:

NA 135, K 3.7, CL 101, CO2 23, BUN 10, CRE 1.42, EGFR 55, GLU 80
CA 8.8, MG 2.3, TBILI 0.5, TP 6.9, ALB 3.5, GLOB 3.4, LDH 363 CRP 11.8
ALT/SGPT 18, AST/SGOT 12, ALKP 73, TBILI 0.5
FE 33, TIBC 194, TIBC 161
WBC 9.84, RBC 3.98, HGB 12.7, HCT 36.1, MCV 90.7, MCH 31.9, MCHC 35.2, PLT 226
PT 14.5, PT-INR 1.1, PTT 59.0,

Hypercoagulable work up (-) antiphospholipid antibodies (-), homocysteine (-)
ANA (-), ANCA (-), C3, C4 normal, Cryo (-),hepatitis (-), HIV (-),

Urine protein/cr: 0.12, 24 hour urine creatinine clearance: 54ml/min

Urine sediment: 1-2 WBC, 1-2 normal RBCs, no casts.

All Cultures were negative.

CT abdomen and pelvis:

1. Bilateral renal artery clot

2. There is a focal, geographic area of decreased perfusion involving the upper pole of the right kidney.

3. A focal area of cortical volume loss and decreased enhancement in the left kidney is also noted, suggestive of scarring.

Questions for the discussant:

1. What is the differential diagnosis?

2. What diagnostic procedure would you perform?

We discussed the following differential:

The differential of acute flank pain is:

Renal calculus – but no evidence on CT

Pyelonephritis – but cultures were negative

Other abdominal pathology as source of the pain – pancreatitis, cholecystitis – but no evidence on CT

Renal Infarct – yes, there is evidence for this on CT

This brings us to the differential for renal infarct:

Thromboembolic – from heart or aorta – but echocardiogram, including transesophageal echo with bubble study were negative, also cultures remained negative at all times

In situ thrombosis – no clear evidence for this

Renal artery occlusion from aortic dissection – no evidence for this on CT

Spontaneous or iatrogenic renal artery dissection – no evidence for this on CT

Fibromuscular dysplasia – no evidence for this based on history (no h/o HTN for example)

Segmental arterial mediolysis – possible, but again not supported by the CT

Complication of anti-phospholopid syndrome – but entire hypercoagulability panel was negative

Cocaine use – this could easily be the cause of this bilateral renal artery thrombosis, the patient continued to deny cocaine use, but this was strongly suspected, urine tox studies were apparently negative, but timing may have been the issue there...

Polyarteritis nodosa – interesting and also likely, the patient is HBV negative, but could be “idiopathic” PAN.

Given the above differential, a renal angiogram was performed which was read as consistent with medium vessel vasculitis, suggestive of PAN.

The patient was treated with steroids and cytoxan and is presently doing well, with creatinine stable in the 1.4 range and no new symptoms.

Still, we were left a bit dissatisfied with this outcome, as the diagnosis of PAN is not consistent with bilateral renal artery clot, which was clearly seen on CT in this patient.

I am still worried about cocaine use or another etiology…

Please comment and let us know your thoughts!

Vividiffusion

"The physicians are now constructing a machine capable of doing the work necessitated by a volume of blood circulating the a body weighing up to 20 pounds and, inasmuch as they have determined to their own satisfaction that the procedure is not inimical to life, there is no reason why it should not be applied to human beings when the occasion arises"

This line is from a 1914 article that appeared in the New York Times describing the work of John Abel who experimented in dialyzing dogs at Johns Hopkins in Baltimore. Cotton-based hoses, leech extracts for anticoagulation, glass tubes, salt, water, science and determination set the foundation for what would become a life-saving procedure.

Below see a video clip of the first recorded dialysis - performed on a dog in 1915 - a classic silent movie. The dog survived!

Posted by Kassem Safa, MD

Combined heart-kidney transplant - when less is enough

A 50 yo male with non-ischemic cardiomyopathy with ejection fraction of 15% presented with worsening dyspnea and renal failure (Cr 3 mg/dl). He was started on inotropes and was evaluated for heart transplantation.

Nephrology was called since the treating physician thought this patient might benefit from a combined heart-kidney transplant. The presented argument on the first phone call was that by doing a combined transplant, we would decrease the need for a repeat surgery in the near future for a kidney transplant and possibly benefit of the lower rejection rate provided by combined organ transplantation.

In the past, renal failure was considered a contraindication for heart transplantation. Nowadays, we realize that many of these patients have a considerable improvement in renal function once the cardiac output is optimized with the new heart. However, can we predict which patients might require a combined kidney/heart transplant rather than a heart alone?

There are no randomized trials but a nice retrospective analysis from Columbia University suggest that neither the cause of heart failure nor the level of creatinine or proteinuria could reliably predict the renal pathologic diagnosis or the degree of tubular atrophy/interstitial fibrosis (TA/IF) of the native kidneys. The figure below shows the absence of correlation between eGFR at time of transplant and extent of TA/IF.

For example, two patients with ischemic cardiomyopathy, minimal proteinuria (100 mg/24 hr) and eGFR of 27.0 and 29.0 mL/min had TA/IF of 50% and 5%, respectively. Therefore, it seems prudent to perform a kidney biopsy on these patients. Certainly, other factors such as a prior high creatinine value and chronic changes on imaging could help, but based on the scarcity of organs, I believe the more information you have, the best decision you will make regarding organ allocation.

Overall, patients that undergo combined heart-kidney transplant (HKT) do well and the rejection rate is lower than after a single transplant. The immunological explanation might be related to an increase number of circulating donor leukocytes that could induce a microchimerism and promote tolerance. However, this simplistic theory is not accepted by all. Patients with significant renal scarring are probably the ones who might benefit the most of combined HKT. In addition, a retrospective analysis of UNOS data suggested that low-risk heart transplant recipients with eGFR less than 30 ml/min would benefit the most (as an example, a younger patient not on LV assist device and not dialysis-dependent). More info here.

The patient above had a kidney biopsy that showed ischemic nephropathy with less than 5% fibrosis. He was listed for a single heart transplant. His creatinine went down to 1 mg/dl one month after his heart transplant.

Low Anion Gap

Classically, we are taught to look out for an elevated anion gap in patients with a metabolic acidosis. Although much less common, a low anion gap can also be a useful sign and there are a variety of causes.

The commonest cause is lab error, particularly in the measurement of the serum sodium. As previously discussed, high serum lipids or high serum proteins can lead to spuriously low serum sodium measurements thus altering the AG. Severe hypernatremia can also lead to errors in measuring the sodium concentration (usually underestimating the real result) and will lower the AG. Similarly, errors in measuring the chloride or the HCO3 will alter the perceived AG. The bicarbonate is usually measured indirectly and allowing the sample to sit without separating the cells can lead to increased production of CO2 and thus lower the AG.

Apart from lab errors, the commonest cause of a low AG is due to alterations in serum protein levels. Most of the AG is due to negative charges on circulating proteins, primarily albumin so that if the albumin concentration falls, the AG will fall also. It is generally accepted that the AG should be corrected upwards by 2.5 for every 1g/dl fall in the serum albumin. This applies also for patients with an elevated serum albumin; the AG should be corrected downwards in that scenario. Although they do not normally contribute significantly to the AG, immunoglobulins can be important in patients with paraproteinemias. IgG tends to be cationic while IgA is an anion. Thus, patients with an IgG paraproteinemia and a high tumor burden can have a low or even negative AG. In contrast, patients with IgA paraproteinemia will have an elevated AG.

Calcium and magnesium could theoretically decrease the AG if they are significantly increased. In practice, however, hypercalcemia does not usually cause a lowered AG unless it is due to hyperparathyroidism. Other causes of hypercalcemia are not associated with changes in the AG. It is uncertain why this is the case. Hypermagnesemia usually does not affect the AG because it is normally accompanied by sulphates and as these are unmeasured anions, they balance each other out.

Several drugs are associated with reductions in the AG. As mentioned by Nate before, bromide intoxication is a rare cause of a negative anion gap. At first, this does not appear to make sense; bromide is an anion, similar to chloride. As a result, elevated bromide levels should cause an increase in the AG. However, bromide interferes with the chloride analyzer – every 1 mEq increase in bromide leads to a reported 3 mEq increase in chloride. Thus, patients with bromide intoxication can have extremely negative AG. Iodide can also interfere with the chloride assay and lead to a negative AG.

Lithium is a cation, in the same family as sodium and thus lithium poisoning will lead to a reduction in the AG although usually only when the level is above 4. This can be a clue to a lithium overdose in a patient with suspected poisoning where there is no ready access to lithium levels.

I would recommend an excellent review of the uses of the anion gap published in CJASN in 2007 that addresses all of these in great detail.

The ABCs of ADME in AKI

The pharmacokinetics of a drug refers to the study of the absorption, distribution, metabolism and elimination of that drug (often referred to as ADME). Each of these characteristics can be greatly altered in a patient presenting with acute kidney injury (AKI). Historically, dosing in AKI has not been distinguished from that of chronic renal insufficiency (CRI). Newer evidence suggests that pharmacokinetic alterations differ between AKI and CRI, and; therefore, dose adjustments may also be different.

Absorption

The bioavailability of a drug can be influenced by GI transit time, gastric pH, and intestinal drug metabolism. Gastric pH can be increased in patients presenting with AKI, which may decrease dissolution and ionization of the oral drug and lead to reduced absorption. In CRI, intestinal metabolism can be reduced potentially resulting in increased absorption. The effect of AKI on intestinal metabolism has not been well-studied.

Distribution

Drug distribution is dictated by many factors, one of which is a medication’s ability to bind to plasma proteins, such as albumin. Patients with AKI may present with low serum albumin levels, leading to a higher free-fraction of albumin-bound drugs (e.g. warfarin, phenytoin, valproic acid, and salicylates) and consequently, increased biological effect.

Other factors affecting drug distribution include serum pH and fluid status. AKI is frequently associated with acidosis, which may affect the ionization and ultimately the distribution of the drug into the tissues. Lastly, increase in fluid volume in the blood can lead to low drug concentrations.

Metabolism

Many drugs undergo metabolism prior to elimination. A myriad of co-morbid conditions frequently associated with AKI may affect drug metabolism such as liver and cardiac dysfunction. Non-renal clearance can be decreased in the setting of CRI, possibly due to a chronic accumulation of uremic by-products causing an impairment of drug metabolic enzymes. As this is a chronic process, the same may not hold true in the early stages of AKI.

Elimination

AKI may have opposite effects on drug elimination. While significant nephrotic syndrome may increase the clearence rate of large molecules and highly protein-bound drugs, acids and bases may accumulate in AKI and compete for transporters, thus diminishing tubular secretion of drugs eliminated by anionic and cationic transport systems.

In sum, the pathophysiologic process in AKI is different from that of chronic CRI, and the pharmacokinetic parameters of medications may differ in the two disease states. Therefore, drug dosing principles studies in CRI may not hold true for patients presenting with AKI, and further research will be necessary to ensure proper dosing of medications in AKI and better guide us in our daily clinical decisions.

Craig A. Stevens PharmD, PGY1 Pharmacy Practice Resident

Steven Gabardi PharmD, BCPS, Organ Transplant Clinical Specialist at BWH

References

Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001;40:159-68.
Klotz U. Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet 1976;1:204-18.
Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998;34:25-56.

AKF Kids Calendar Art Contest 2013

The American Kidney Fund’s Calendar Kids Art Contest recognizes kids with kidney disease for their artistic talent and helps to increase awareness of kidney disease. The contest winners have been selected but help is needed to choose the artwork for the 2013 calendar cover!

This lucky winner will receive a trip to Washington, D.C., and will attend the American Kidney Fund’s annual gala, The Hope Affair.

Follow the link to browse the artwork below and vote for the image that you want to see on the cover!

Isolated C3 deposits on an inflammed glomeruli

Six months after a kidney transplant, a patient developed a rising creatinine, significant proteinuria (~2g/day), hematuria and low C3 levels. A kidney graft biopsy showed severe glomerulonephritis with mostly occluded capillary loops with immunofluorescence staining negative for immunoglobulins but strongly positive for C3 (representative picture on left). On EM, subendothelial and mesangial electron dense deposits were visualized. The features are characteristic of the so-called C3 glomerulonephritis (GN).

C3 GN is part of the same family as dense deposit disease (DDD) and fall into the new proposed classification of C3 glomerulopathy. Compared to C3 GN, DDD is characterized by extremely electro-dense intra-membranous deposits on EM. Both entities can present with features of MPGN, once significant chronic endothelium glomeruli damage occurs. These glomerular pathologies shared in common its pathogenesis, which involves complement dysregulation.

Classically, immunoglobulins that deposit in the glomeruli are the major triggers of glomeruli inflammation. In rare settings such as C3 GN, complement proteins are present in the glomerular lesions in the absence of immunoglobulins. Abnormal activation of the alternative pathway is implicated on this finding. Either an acquired or inherited defect in the control of alternative complement pathway should be investigated.

The following tests are generally recommended:

** Levels of C3 and complement factors B/H/I

** Presence of C3 nephritic factor (C3 NeF)

** Genotyping for certain complement mutations (common in kids)

Our patient underwent complement testing and was found to have circulating C3 nephritic factor. This factor is an IgG autoantibody that directly stabilizes the C3-convertase activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H, leading to continuous activation of the complement cascade and consequent deposition of complement by-products in the glomeruli.

Although atypical hemolytic uremic syndrome (aHUS) is also strongly associated with a dysregulation of the alternative pathway, glomerular lesions in aHUS do not exhibit C3 deposits or electro-dense deposits on electron microscopy, differentiating from C3 glomerulopathies. How changes in complement regulation leads to very diverse presentations might be related to the underlying defect. Nonetheless, atypical HUS could be placed in one side of this spectrum of renal diseases associated with alternative complement dysregulation (figure below; adapted from Servais et al. 2007).

While the pathogenesis is complicated, even harder is the treatment challenge of C3 GN in our patient above. There are a couple of new promising approaches and markers that might help guide therapy. I will try to cover them on my next blog.

Antibiotics and encephalopathy

Recently I was involved in the care of a renal transplant recipient who was admitted with C. Difficile colitis that was complicated by a bowel perforation. He had a history of hepatitis C with relatively preserved hepatic function. He had a complicated post-op course requiring prolonged treatment with intravenous antibiotics but was gradually improving clinically.

Over a period of 24-48 hours, he developed altered mental status. He had myoclonus, initially was perseverating and eventually became relatively unresponsive. He had a low grade fever with no obvious source. His renal function was improving towards baseline and his serum ammonia level was normal. A CT brain was also normal. He was treated with thiamine, electrolyte repletion and antibiotics but showed no improvement after 48 hours.

At that point, the ID attending suggested stopping his cefepime. 24 hours after stopping, he was already less confused and within 2 days, he was back to baseline.

Cefepime-induced encephalopathy is a rare but important complication of this antibiotic that is more common in patients with renal disease and appears to be dose-related. It is characterized by decreased consciousness, agitation, aphasia, myoclonus progressing to convulsions and coma and carries a high mortality. It is not limited to cefipime but can happen with any cephalosporin. EEG findings include diffuse slow-wave activity. The treatment is prompt cessation of the drug and this diagnosis should be considered in any patient with renal failure who develops otherwise unexplained encephalopathy while on a cephalosporin.

In our patient, his measured creatinine probably overestimated his GFR because of his marked muscle-wasting. he was being treated with high-dose cefepime for presumed ascending cholangitis and this accumulated over a period of days.

Survey for Fellows and Fellowship Directors

The good people at East Carolina University’s Brody School of Medicine are doing a survey study of the quantity and quality of nephrology fellows’ end-of-life care education and their readiness to provide that care to the elderly.

If you're interested you can take the Fellowship Program Directors survey here. Or the Fellows survey here.

Picture: Ball's Pyramid off the coast of Australia

Handling anticoagulation peri-kidney biopsy

Kidney biopsy is considered the most invasive procedure nephrologists are involved. Though complication rates are small, bleeding requiring surgery has been reported to occur in 1 in 1,000 kidney biopsies. More commonly, patients may develop a decrease in hemoglobin by 1 point (~50% of cases) and/or gross hematuria (3-18%). The risk of bleeding complications become much higher in patients that require peri-biopsy anticoagulation.

A new evidence-based guideline was just published on Chest 2012, summarizing the best approach to anticoagulation in a number of different scenarios. Overall, the new recommendations are more conservative than before regarding anticoagulation peri-procedure.

To illustrate that, let’s use a theoretical patient on anticoagulation with coumadin (6mg daily) due to Factor of V Leiden mutation and prior history of thrombosis (more than 6mo ago).

In preparation for the procedure, the physician would recommend stopping coumadin 5 days prior to the kidney biopsy and bridging with either UFH or LMWH. This is usually started on day 3 prior to the procedure. The major difference in approach now is related to when should the bridging anticoagulation be stopped and restarted. The novel guidelines recommend the following:

* If on IV heparin, stop infusion 4-6 hours prior to procedure

* If on LMW, last dose should be 24 hours prior to procedure (rather than 12 hours before)

* Resuming coumadin should occur 12-24 hours after procedure if no evidence of bleeding

* Bridging anticoagulation with LMWH or UFH should be restarted 48-72 hours after the procedure (rather than 24 hours after surgery). Since most of the bleeding after kidney biopsy will occur in the first 24 hours, I believe delaying for another 24 hours would only be warrant in major surgeries with higher bleeding risks)

Most of these recommendations are grade 2C (weak), therefore individual interpretation is warranted.

My take-home summary of anticoagulation peri-kidney biopsy in high risk patients for thromboembolism would be:

Stop coumadin 5 days before procedure; admit the patient with renal failure 3 days prior to biopsy for bridging with UFH; stop UFH at least 4 hours prior to procedure; resume coumadin/UFH 6-24 hours after bx if no evidence of bleeding (stable Hb, vital signs and no significant hematuria).

Though this is a general suggested approach, remember to assess the thromboembolic risk for each individual patient before proceeding with a kidney biopsy. As an example, I would favor restarting anticoagulation much earlier after bx in a patient with history of multiple clots (6 hours after biopsy).

Below additional general recommendations about anticoagulants from the new guidelines:

- Dosing of UFH: 80U/kg bolus followed by 18U/kg/hour

- Dosing of coumadin: loading with 10mg daily for first 2 days [[personal opinion: this loading dose may be too high for elderly or cachetic patients]]

- Dosing of enoxaparin: 1mg/kg BID; if GFRb below 30 ml/min: 1mg/kg daily

- Dosing of fondaperinox: 5mg daily if less than 50kg; 7.5mg if 50-100kg and 10mg if more than 100kg. Avoid if GFR less than 30 ml/min.

- Dosing of dalterapin : 200 U/kg daily. Accumulation expected in renal failure but no specific dose adjustment has been recommended, so should likely be avoided until trials available.

- Despite recent publications about benefits of genotyping in predicting response to coumadin, the guidelines recommend against this practice.

Origins of Renal Physiology Course

We've posted several times about the 'Origins of Renal Physiology' held in the Mount Desert Island Biological Laboratory every year. Fellows who have taken the course over the past 5 years have consistently raved about it, with many describing it as transformative in their careers as researchers, teachers and clinicians. It's on again this year September 2-9, 2012.


This year for the first time, 'Origins' will be free for all renal fellows who are admitted to participate.  The organizers are able to do this thanks to a five year R25 research education grant from the NIDDK/NIH. Lodging and meals are included, so the only costs to you are travel.  

Applications are now being accepted; the application will close on April 15.Head over to the course website: www.mdibl.org/courses/The_Origins_of_Renal_Physiology/114/, for a description of the course and the online application form.  

Under Pressure

As a medical student I was taught the CKD hypertension gospel straight from the good book of JNC VII: Thou shalt lower the blood pressure to less than 130/80! This was many years after David Bowe and Freddie Mercury but I got the song stuck in my head when I started thinking about the post so I had to put it up there.

I lived happily with this for many years until one day someone questioned me. Why should you lower the blood pressure to less than 130/80 in someone with chronic kidney disease? Well 'cause the JNC VII says so! Check it out...


Right there in red, blue and black. And supported by two references no less! One of them is the American Diabetic Association going on about diabetes (another story) but reference 21 is KDOQI on CKD... So the rabbit hole gets deeper.

Over at KDOQI we get the following...


They say "controlled trials in essential hypertension conclusively show a beneficial effect of lowering blood pressure to <140/90 mm Hg. Controlled trials in high-risk individuals with diabetes or heart failure suggest beneficial effects of reduction of blood pressure to even lower values. Based on these studies, and on observational studies, a number of guidelines for patients with either diabetes mellitus or congestive heart failure recommend a goal blood pressure of <130/80 mm Hg. There are few studies regarding blood pressure goals for CVD risk reduction in patients with CKD. Thus, the Work Group elected to extrapolate the recommendations for high-risk patients to patients with CKD."

Uhh so, we have no evidence so we took some evidence from other diseases and said do the same thing. It not quite that bad. There is some evidence for less than 130/80 but it has caveats.

The MDRD study randomized patients to aggressive vs standard blood pressure control with achieved average values of 126/77 and 133/80 respectively. At the end of the study there was no overall difference between the two groups in terms of kidney function but in post-hoc analysis the aggressive BP arm had statistically slower rates of renal function decline in patients with over 1g per day of proteinuria mainly driven by patients with over 3g of proteinuria per day. Unfortunately, the aggressive control group were more likely to have received ACE inhibitors than the standard control group so the post-hoc data is a bit muddled.

In the recently published long term followup of the AASK trial, African Americans with hypertensive kidney disease who were initially randomized to either intensive or standard BP control were subsequently followed in a cohort phase in which the BP target was the same in both groups. Followup extended out to 12 years from the initial randomization. The achieved BPs during the trial were 130/78 mm Hg vs 141/86 mm in the intensive and standard groups respectively. In the cohort phase BPs were much closer as expected (131/78 and 134/78 in the intensive and standard groups respectively).

The story is similar to MDRD, among all patients there was no difference in the primary composite outcome of ESRD, doubling of serum creatinine or death throughout the trial and cohort phase. However, in the subgroup with baseline proteinuria of greater than 220 mg per day a significant difference between BP target groups appeared favoring more intensive control.


So no clean randomized prospective data to support the JNC VII target of less than 130/80 in CKD patients. There is a hint from the above subgroup analyses that CKD patients with proteinuria might benefit from having blood pressures controlled to below 130/80. The proteinuria cutpoint at which this might occur is unclear.

It will be interesting to see how JNC VIII, expected sometime later this year, handles the above. Additional information will hopefully come from the randomized prospective SPRINT trial which is looking at systolic BP goals of 140 vs 120 in a large cohort with a reasonable proportion of CKD patients.

Water deprived

Recently in the clinic we were asked to review a patient with suspected diabetes inspidus. She had been taking lithium for more than 20 years for bipolar disorder that was very well controlled. During a routine medical examination, her blood tests revealed a serum creatinine of 1.4 so she proceeded to have a 24-hour urine collection. The result of this showed that her GFR was moderately reduced at 40mls/min but the striking finding was a 24 hour urine volume of 10 liters. The patient herself had no complaints regarding this as she was accustomed to drinking large volumes. She had been advised many years before to take a high salt diet in order to reduce the potential for nephrotoxicity (this sodium would compete for Li uptake in the DCT). Reducing her salt intake cut her urine volume by half which in itself was a great result.

One thing that did not fit entirely with the story was that her serum Na was never >140mEq/L. The impetus for water intake in DI is a high serum Osm but she was often in the 137-138 range suggesting that she was actually keeping her Osm lower than would be expected. The question arose as to whether or not there was a component of polydipsia here unrelated to the possible DI so we admitted her for a water deprivation test.

As mentioned by Nate before, the protocol for this test involves restricting a patient’s access to water and then measuring the plasma and serum osmolarity every 1-2 hours until:

(a) the urine osmolality reaches a normal value (e.g., above 600 mosm/kg, suggesting that both ADH secretion and response to ADH are intact).

(b) the urine osmolality is stable on two successive measurements despite a rising plasma osmolality, or

(c) the plasma osmolality is greater than 295-300 mosm/kg.

At that point DDAVP is administered.

There is one caveat, in the case of this patient, her initial urine Osm was 104 with a serum Osm of 307. According to the protocol above, this would be the time to give her DDAVP. However, her serum Na was only 141. The additional Osmoles were a result of a slightly elevated fasting blood sugar and a high BUN (because of her CKD). Her calculated Osmolarity was 306. As a result, we postponed giving DDAVP at that stage. Her results during the day were as follows:

Serum Na 141 144 149 153 154

Serum Osm 307 315 319 326 329

Urine Osm 104 126 142 154 153

We administered DDAVP when her serum Na was 149 and allowed her to drink again as soon as the next lab was taken. Her final result was after she had been allowed to start drinking again and she was already preventing her Na from increasing any further. The lack of response to DDAVP indicates a diagnosis of nephrogenic DI, almost certainly due to lithium.

The take home points for me here were that a low serum sodium in the steady state does not necessarily mean that the patient does not have DI – in someone like this who has had this problem for years, she has just become accustomed to staying ahead of her thirst. The second point was that a serum sodium always has to be sent with the serum osmolarity as if there are other osmoles around, they can give you a misleading result.

NYT: 60 Lives, 30 Kidneys, All Linked

Interesting article on chain donation in the NYT.

New to the Blogosphere: CJASN eJournalClub

The latest entrant into the blogging community comes to us from CJASN in the form of their new eJournalClub. It's a neat site, the editors choose an interesting article, put it up with an editorial and then have a forum for the public and authors to have at it. The site does require you to login with your ASN membership and has a close to seizure inducing flashing icon of recent CJASN covers that could be toned down.

This month my buddy and co-fellow Cristina Arce, had her recent article on hispanic ethnicity and vascular access use selected for the site which is very cool.

So we've got eAJKD, Kidney International Podcast, the JASN app and now eJournalClub from CJASN. What's going on NDT?

There's no such thing as a contraction alkalosis

We recently discussed an excellent paper on the classification of metabolic alkalosis. The three suggested subtypes were primary and secondary stimulation of collecting duct ion transport and exogenous alkali administration. Another interesting editorial was just published in JASN that further expands on the idea that chloride deficiency is central to the maintenance of a metabolic alkalosis.

The traditional view of a contraction alkalosis was that in a volume depleted patient, there would be increased reabsorption of sodium in the proximal tubule. Because this sodium must be reabsorbed with an anion, bicarbonate was also reabsorbed in the proximal tubule along with this in preference to chloride, thus perpetuating the alkalosis. The first challenge to this viewpoint came in the 1960s when it was shown that a chloride deficient alkalosis generated by diuretics or gastric aspiration was corrected by treatment with NaCl or KCl but not with Na or K repletion without Cl. This did not however deal with the issue of volume depletion.

More recently, the authors of the editorial have shown that a chloride deficient alkalosis could be corrected in rats by infusion of a chloride containing solution despite ongoing volume depletion, while restoration of the ECF volume with albumin did not correct the acid-base abnormality. In fact, the urinary excretion of bicarbonate increased in the rats that received chloride while it fell further in those that received volume expansion with albumin alone.

Finally, they treated normal human subjects with a low chloride diet along with furosemide and Na and K supplementation. These subjects developed an alkalosis that was maintained for 5 days and corrected with oral KCl alone without any expansion of plasma volume. This elegantly demonstrated that volume is not the issue in these cases and that it truly is an effect of chloride depletion alone.

So what is the mechanism for the maintenance of the alkalosis? Previous posts have discussed the role of Pendrin, the HCO3-Cl exchanger in the collecting duct. The main stimuli for pendrin activation are decreased distal delivery of chloride and intracellular alkalosis. However, where there is little or no distal Cl delivery, it is not available to exchange with HCO3 and thus the alkalosis is maintained. This also helps explain the alkalosis induced by hypokalemia. Hypokalemia induces intracellular acidosis which inhibits HCO3 excretion by pendrin thus exacerbating the extracellular alkalosis.

Can we now finally get rid of the concept of a contraction alkalosis?

Extend Medicare Coverage for Kidney Transplant Patients!

Currently many kidney transplant recipients lose their Medicare coverage 36 months after receiving a transplant. In some cases these individuals are then unable to afford the cost of anti-rejection medications and subsequently lose their kidney. When this happens these individuals return to the more costly option of dialysis which is covered by taxpayers.

Let's end the madness. The current policy makes no sense for patients and makes no sense for taxpayers.

Take the time to sign the petition started by Ajay Singh over at The Kidney Doctor in support of the Immunosuppressive Drug Coverage for Kidney Transplant Patients Act introduced into the Senate back in September.

Lead Nephrotoxicity

I saw a patient in the clinic who was referred for evaluation by his PCP with CKD, a bland urine sediment and a history of hyperuricemia and gout. He had no history of diabetes or hypertension and had no obvious (to me) reason for his CKD at first glance. He was a non-smoker and had no family history of renal disease. He worked as a plumber and his examination was entirely normal.

My attending came in and asked him if he was still using as much lead these days as he had in the past – apparently he was down to 4 times monthly. He was using it to fix joints and was regularly exposed to lead vapor. Even at this, his exposure was significantly less than it had been when he was younger before work practices changed.

Lead toxicity is an under-recognized cause of chronic kidney disease. Commoner in the past when lead was ubiquitous and likely less important now as an environmental cause of renal disease, it should be suspected in people who still work with lead regularly (or had a significant past exposure). Plumbers, fishermen (who make their own weights) and hunters (who make their own shot) continue to be at risk.

The renal signs of lead toxicity depend on the duration and degree of exposure. Acute lead toxicity leads to proximal tubular inclusions and an acute fanconi syndrome. Chronic lead toxicity causes a chronic interstitial nephritis with a relatively bland urine sediment. Patients typically have gout and this condition has sometimes been confused with uric acid nephropathy. Even low levels of lead exposure appear to be associated with a decline in GFR. A study in 1992 in the NEJM found that a 10-fold increase in blood lead concentration was associated with a 10-13mls/min decline in GFR in a population of asymptomatic patients. There is a chicken and egg issue here however, as a lower GFR can lead to decreased lead excretion.

The diagnosis is made by first determining if the patient has been exposed to significant amounts of lead and then measuring lead levels in the blood. In patients with a historic exposure, this may not be reliable because of sequestration in the bone and x-ray fluorescence is more reliable.

The treatment involves removing the sources of exposure and, in patients with substantial lead toxicity, chelation therapy. This is not entirely without risk and has been associated with acute renal failure in children. Chelation in the presence of ongoing exposure will actually increase toxicity as it will lead to an overall increase in blood levels.

We are in the process of getting the XFR scan for this patient and it may be that he does not have lead toxicity after all; but it is definitely one to think about in the future.