Oral Dialysis

It's an important anniversary for the Brigham and Women's Hospital and as a result there are events planned in all departments of the hospital over the next year. Not to be left out, the Renal Division invited some senior nephrologists to come and talk about their experiences with the world of early dialytic therapies and we had a special Grand Rounds presentation this morning on the topic.

John Merrill was one of the early pioneers of dialysis (and has been called the father of dialysis). He was an advocate for the use of dialysis at a time when many believed that it was unethical and experimental. I realized during the lecture this morning that reviewing the published literature of Dr Merrill would be a good way to learn the history of the dialysis. The first paper that I came across was published in 1949 and describes the early experience using the modified Kolff kidney in the Brigham to treat both AKI and metabolic disorders. My favorite quote from this article comes from a postscript added to the paper by a discussant which suggests an alternative means of dialyzing a patient as an alternative to "in vitro hemodialysis" as HD was then termed:


DR. J. EDWIN WOOD, JR. [Charlottesville, Virginia] : We are fortunate
to hear this excellent presentation and view quantitative results with the
artificial kidney.
It may be interesting to compare results from upper intestinal lavage
with the ones just presented. With a Miller-Abbot tube about three feet
below the pylorus and a Levine tube down to the pylorus we can wash
through and recover a large quantity of suitable lavage fluid in a twentyfour
hour run. Actually, we have been able to remove by this method
as high as 11.9 to 23.2 grams of urea nitrogen in twenty-four hours, and
from 90 to 102.5 mEq of potassium at the same time.
Dr. Thorn's artificial kidney obviously accomplishes the desired result
in a shorter period but intestinal lavage removes enough in twenty-four
hours to warrant serious consideration.

I'm glad that this is not one of the alternatives that we are offering patients today.

(Picture from Flickr user Rob Koopman via Wikipedia)

suPARBaby?

The American Journal of Kidney Diseases published a fascinating letter this month from Jochen Reiser's group concerning the transmission of the suPAR from a mother to her newborn infant. The patient in question had a history of primary FSGS and after her baby was born, the infant had proteinuria which eventually resolved. At the time, this was published as a letter in the NEJM and was used as evidence for the existence of a soluble FSGS "factor" which had yet to be identified.

Now, more than 10 years later, they got their hands on blood from the mother and the infant. The level of suPAR in the mother was 4635pg/ml and in the child was 5225 pg/ml. This compares with a mean of 2884 pg/ml in controls. Unfortunately, the family moved away from the area so there were no follow-up samples. However, the patient's pediatrician reported that the baby's urine was negative for albumin at one year of age.

Although this does not definitively prove that suPAR is the causative agent in primary FSGS, and there is some debate about the true pathogenicity, this, along with recently published data in JASN, adds to the weight of evidence suggesting that this may be the elusive factor we were looking for. Interesting times indeed.

Πάντα ρεί - once more on the (right) fluids

Yet another manuscript evaluating fluids for IV replacement was published in JAMA this week underscoring the importance and controversial nature of the topic. A large meta-analysis involving 10,868 patients from 38 trials showed that hydroxyethyl starch (HES) was associated with an increased risk of mortality and renal failure (RR 1.27; 95% CI 1.09 - 1.47). Of note, a recent large trial published in the NEJM in 2012 did not show an increased mortality but more patients who received resuscitation with HES were treated with renal-replacement therapy.

HES is mainly used by anesthesiologists and surgeons and has the potential advantage of decreasing the amount of total administered volume and sustaining intravascular volume for longer periods of time. The discussion about mortality and renal failure associated with HES has been going on for a long time, as has the discussion about the relative benefits of colloids vs. crystalloids. Despite the lack of strong evidence of superiority of HES over crystalloids, the clinical use has been increasing - even with the associated higher cost and safety concerns.

A major drawback for the supporters of HES was the realization that one of the leading authorities in the field and major proponent of HES, Joachim Boldt, has conducted one of the biggest cases of fraud in anesthesia with “false data published in at least 10 of the 91 articles examined, including, for instance, data on patient numbers/ study groups as well as data on the timing of measurements“. 80 articles have been retracted because the research was deemed unethical. A Cochrane review from 2012 did not find a significant difference in mortality even when the fraudulent studies were excluded. However, the current meta-analysis not only excluded the studies by Boldt, but also included 3 trials published in 2012 contributing more than half of the patients to the collective examined, thereby adding more weight to their analysis over prior ones. There was no difference in mortality when the Boldt papers were included in the analysis.

Side effects of HES mainly occur in the kidney but the exact pathophysiology of AKI associated with HES is unclear. Vacuolization as an injury pattern can be observed as discussed in an earlier post in this blog. In vitro HES showed a dose-dependent decreased viability of HK-2 cells (human immortalized proximal tubular cells) after incubation with HES130/0.4. A necropsy study suggested HES accumulation in the kidney might cause toxicity. 

What can we learn from this? Rigorous analysis and ongoing discussion and evaluation of data are of crucial importance in Medicine and scientific fraud, driven by motives such as recognition and money can cause data to shift to the wrong direction. There does not seem to be a major advantage of using HES over crystalloids and data on mortality and renal failure are tied between no difference and increased mortality/AKI in the HES group. From my perspective there seems to be no indication to use HES and this might be better for the kidney.

Posted by Florian Toegel

eJournal Club

This month's eJournal club concerns early initiation and withdrawal from dialysis in Canada. Over the last 20 years, there has been a move towards starting people on dialysis earlier, at least when this is defined in terms of eGFR. This study found that there was an increased incidence of withdrawal from dialysis in the last 10 years and that the majority of those who withdrew dialysis were >75 years old. Early initiation (defined as a higher eGFR at initiation) was associated with higher rates of withdrawal.

So what does this mean? Are nephrologists watching the eGFR and deciding to start earlier based on this number alone? I think not. In one way, this shows the limitations of using eGFR in epidemiological studies, particularly in the very elderly and in those with very low GFRs. The patients who withdrew from dialysis were more likely to have dementia, cancer and were older. Also, apart from age, the factor with the highest HR for withdrawal was a BMI of  less than 18. This suggests that using creatinine to estimate eGFR may have overestimated GFR in these patients because of a low muscle mass. It would be interesting to know how well their MDRD eGFRs correlated with their true GFRs.

The outcomes for renal replacement therapy in very elderly populations is poor and the higher rate of withdrawal may reflect poor patient choice - should these patients have been started on dialysis in the first place? This is an interesting study and it highlights the importance of proper discussion with patients and families about the consequences of dialysis initiation.

Head over the eJournal Club for the discussion. The paper is available for free here.

It's that time of year again...

The 2013 ASN In-Training Examination for Nephrology Fellows will be administered on Thursday, April 11, and Friday, April 12.  Nephrology fellows may sit for the examination on one of two testing dates. Testing will begin at 8:00 am local time each day.

Registration for the 2013 examination closes on Thursday, February 28.

To register, fellows must be ASN members.  ASN membership is free to nephrology fellows.  When registering, nephrology fellows must choose only one test date (Thursday, April 11, or Friday, April 12) and one testing center.  Fellows may not register at an institution with which they are not currently affiliated without prior permission from the training program director at that institution and ASN.

The registration fee for the exam is $260, payable only by credit card.  If the institution is responsible for payment, the fellowship coordinator must contact ASN Education Coordinator Ryan Russell at rrussell@asn-online.org.

Register here for the 2013 examination.  If you have questions about the ASN ITE for Nephrology Fellows, please contact ASN Education Coordinator Ryan Russell at rrussell@asn-online.org.

International Update on Glomerular Disease

On April 27th 2013, a course on glomerular disease will take place at the North Shore University Hospital in Manhasset, New York. This course is being organized by Dr Kenar Jhaveri who is well known to the blogging community. There is an impressive list of speakers and this one day course is designed to provide an update on the management of glomerular diseases.

Best of all, registration is free for medical students, residents and fellows in training. Here is a link to the course description. and application form.

Does nephrology need personalized medicine?

Systems biology is one of science’s growth areas. Sequencing technologies and software tools developed on the back of the human genome project have reduced the cost of, and therefore increased access to, large and complex datasets (ending in -ome) of genome sequences (genomics), gene expression (transcriptomics) and proteins and metabolites (proteomics and metabolomics). Systems biological techniques integrate these datasets and provide insights into how phenotypes may emerge from interacting biological processes rather than isolated genes or proteins.

A recent editorial in the journal Nephrology Dialysis Transplantation examined this field in general and its relevance to nephrology. The authors mention that –omic datasets have been useful in modeling “self-organized highly interconnected networks”, and that such networks have implicated unexpected candidates in disease pathogenesis (see for example, this paper on cardiac hypertrophy). 

The review goes on to suggest that using the tools of systems biology to finely phenotype individuals will usher in an era of truly personalized medicine. However, it is not clear to me that a definite sequel to this type of analysis will be the personalization of treatment or even that the concept of personalized medicine is particularly suited to our current view of what constitutes clinical evidence.

Diseases such as the ANCA-associated vasculitides (AAV) are now known to exhibit genomic variability. Randomised controlled trials (RCTs) in AAV (such as here and here) have been hampered by: 

1. Short follow-up times 
2. Inter-group heterogeneity which may have affected outcomes. These factors have contributed to ongoing debate about the applicability of the results of these trials (see correspondence here). 
3. Additionally a recent trial in membranous nephropathy, likely to represent another disease with distinct –omic subsets, was marked by slow recruitment. 

 

All these points together suggest that it may be difficult to conduct meaningful clinical studies of distinct –omic subtypes in nephrological diseases. Currently, primacy is given to RCTs when evaluating the efficacy of new treatments; and in nephrology the community is finally beginning to produce the RCTs which have been absent historically. 

If the focus is to switch away from RCTs with their large, well-matched study groups and towards splitting groups up by some -omic fingerprint I am able to envisage a time when one has to choose between giving more credence to the results of larger, “non-personalised” trials or smaller studies featuring –omic data but lacking the controlled element of RCTs.  Would this represent progress?

The Brave New World of Renal ACOs

This past week CMS announced the formation of a new form of payment and service delivery for patients with ESRD - the ESRD Seamless Care Organization (ESCO) - essentially an ACO specifically and exclusively for individuals with ESRD.

The basic guts of the model require that at least a dialysis provider, nephrologist and one other Medicare provider be involved.  The "one other Medicare provider" bit is likely meant to capture the obvious need that dialysis patients have for a multitude of services beyond dialysis and renal specific care.  The ESCO has to have at least 500 members all of whom need to be on dialysis - patients with functional kidney transplants are not eligible.

The hypothesis behind ESCOs is that an alignment of financial incentives with clinical care goals will produce superior outcomes and patient experience at lower per capita health spend than traditional fee for service Medicare where providers are rewarded for the volume of services they deliver.   The 10,000 foot view of "alignment of financial incentives" is that ESCOs will be able to earn a fraction of savings when health care spending is lower than a pre-determined base line and will be at risk for a fraction of overruns when spending is higher.

In order to avoid rationing of high value services, the ESCO model requires that participating groups report and achieve a defined set of quality metrics in order to earn their fraction of savings.  These cross a wide variety of areas including preventative health, chronic disease management, care coordination, patient safety, patient and caregiver experience, and patient quality of life.

The slide deck below from the CMS open door forum forum this past week digs a bit deeper into the details.

Keeping up with the Neighbours

These days, the proliferation of medical journals makes it difficult to keep up with all the changes in our field. There are a number of means that people employ to manage their reading. I personally use google reader and follow all the major renal journals. Another resource that I find useful is Nephrology Now which aggregates some of the more important papers recently published in the field.

One suggestion from Nephrology Now last week was an ipad/iphone application called "Read". This application allows you to follow selected journals but will also pull out articles of interest from journals that you are not necessarily following if they align with your interests. It also allows you to directly search pubmed from within the app, save searches and, if it is freely available, download the pdf of the paper that you are interested in. Best of all, this is free.

I would appreciate any further suggestions from readers regarding ways to stay current.

Vascular rejection – Reassessing its etiology

Vascular rejection has been traditionally considered a severe form of acute rejection characterized by infiltration of mononuclear cells beneath the endothelium or by the presence of arteritis. Though initially reported as an aggressive form of T-cell mediated rejection with poor response to T-cell targeted therapy, newer findings suggest a strong association with alloantibodies. 

 Study from France analyzed 302 patients with biopsy-proven rejection and identified 4 subtypes of acute rejection with different outcomes (Figure): T-cell-mediated vascular rejection (9%), antibody-mediated vascular rejection (21%), T-cell-mediated rejection without vasculitis (46%), and antibody-mediated rejection without vasculitis (24%). Antibody-mediated vascular rejection manifested a median of 1.1 months (0.4–4.4) post-transplant and had the worst prognosis of the four subtypes. Moreover, 71% of cases of vascular rejection, which were mostly graded as v1 and v2 arteritis by the Banff schema, were associated with donor-specific antibodies (DSA). 

Therefore, it seems that the majority of cases of vascular rejection are associated with DSA and therapies to remove and decrease alloantibody production may be warranted. Indeed, this study suggested that antibody-directed treatment involving plasmapheresis, IVIG and rituximab led to better outcomes in this subpopulation. As of today, v1 and v2 vascular lesions are not accounted by the Banff classification in the antibody-mediated rejection category. 

Alloantibodies may bind to endothelium antigens and activate complement, attracting mononuclear cells which express Fc and adherence receptors, initiating the process of vascular infiltration. 

How will this affect our practice? Whenever a biopsy shows a component of vascular rejection, one must send the serum for alloantibody testing, even if biopsy is not classic for antibody-mediated rejection. Furthermore, antibody-directed treatment strategies should be considered, in particular if no response to initial therapy and evidence of DSA. The ideal treatment of the different severities of vascular rejection still remain to be determined.

Pearls for Boards

1) Surreptitious vomiting or diuretic abuse - metabolic alkalosis, Laxative abuse - non-gap metabolic acidosis.

2) Aquaporin 2 -  apical membrane of collecting duct, Aquaporins 3 and 4 - basolateral membrane of collecting duct, Aquaporin 1 - proximal tubule.

3)  Hemodialysis access rule of 6s: 6 weeks after the AV fistula has been placed, the fistula should:
1) be able to support a blood flow of 600 ml/min 2) be at a maximum of 6mm from the surface 3) have a diameter greater than 6mm.

4) Chronic lead exposure: 1) Interstitial nephritis 2) Gout 3) HTN

5) Calcineurin inhibitors, key differences - Tacrolimus: hair loss and higher rates of NODAT. Cyclosporin: hair growth and gum hyperplasia.

Lupus Foundation of America Grant

The Lupus Foundation of America is proud to announce its new Career Development Award RFA. The purpose is to facilitate the professional development of nephrology, dermatology, and rheumatology fellows, in the U.S. and Canada, interested in lupus research towards a career as an independent clinician-scientist at an academic, medical, or research institution, with a research program having considerable focus on the investigation of basic, clinical, translational, behavioral, or epidemiological lupus research.  

To be eligible, applicants must hold an M.D. (or equivalent) from an accredited institution, be a U.S. citizen or legal resident of the U.S. or Canada at the time of application submission, be a first or second year Fellow in an adult or pediatric fellowship program in rheumatology, nephrology, or dermatology accredited by either the American Council on Graduate Medical Education (in the U.S.) or Royal College of Physicians and Surgeons (in Canada).

There is no Letter of Intent. The application deadline is March 29, 2013 and the earliest funding notification is May 10, 2013. The award is for $70,000 (with the possibility of a 1-year renewal) and can be used for salary and/or research, but certain restrictions apply. In addition, awardees of specific grant mechanisms are ineligible. Please see the RFA for complete details.

You can find the Career Development Award RFA at http://www.lupus.org/rfa.

eJournal Club - Hemodiafiltration

A few years ago, a unit that I worked at started using hemodiafiltration (HDF) routinely for the first time. Prior to starting our patients, we visited another unit where they had been using HDF for a few years and interviewed some patients who had undergone both methods. The patients uniformly said that they felt better on HDF than they had before on regular HD. Of course, part of this may have been psychological - the fact that they knew that they were getting a new, "special" treatment.

HDF works by combining diffusion with convection and is known to clear middle molecules better than HD alone. Unfortunately however, some of the proposed benefits of HDF have not played out as expected. HDF has been shown to have no mortality or CVD benefit over HD. Still, there were hints from various studies that there may be a benefit in terms of health-related quality of life (HRQOL) for patients on HDF. For patients on dialysis, this would be a big deal. This month's article highlighted in eJournal club attempted to answer this question.

This was a randomized trial using data from the CONTRAST study comparing HD with HDF. HRQOL was a prespecified secondary outcome. Over an average of two years follow-up all domains of HRQOL declined except for overall health which improved in the HDF patients although there was no significant difference from the HD patients. These results were disappointing.

Head over the eJournal Club to continue the discussion.

Falsification Analysis

Interesting paper this month in JAMA about post-marketing studies of adverse drug effects. Randomized controlled trials are obviously the gold standard for the detection of common adverse events related to treatment. The problem is that, if an adverse event is rare, it is unlikely to be detected by a normal RCT. As a result, there has been a move recently towards conducting post-marketing studies of commonly used drugs to identify rare adverse effects. One such effect mentioned in the study is the association between bisphosphonate use and atypical femoral fractures.

The other commonly cited example recently was the association between PPI use and community acquired pneumonia that has been noted in multiple studies. The putative mechanism is that it is due to a reduction in gastric pH. The problem is the question of residual confounding - is there an alternative reason that these patients have more pneumonia. Are these patients simply sicker overall? Are PCPs who prescribe PPIs more likely to diagnose pneumonia? Just because there is a plausible mechanism doesn't make it true.

One potential solution is to perform a falsification analysis. Once you have determined the primary outcome of the study (in this case pneumonia) with a plausible outcome, you then perform a series of prespecified analyses with other non-plausible outcomes. If all of the outcomes are associated with the use of PPIs, it suggests that the association is more likely related to residual confounding rather than a real effect.

In the study referred to in the JAMA article, the authors, working from registry data, not only found an association between PPI use and pneumonia but also with osteoarthritis, urinary tract infections, rheumatoid arthritis, chest pain, DVTs and skin infections. Thus, they suggested that the association with pneumonia was more likely to be confounded because of the lack of a plausible relationship with these other adverse events. One criticism I would have is that I could think of perfectly reasonable hypotheses for why PPI use could be associated with OA and RA (use of NSAIDs) and chest pain (GERD). Another important point is that if this is not done properly (prespecified adverse events) you could find an association between the use of a drug an some adverse event if you tested enough and it could be used to wrongly refute the association between a drug and a problem.

Still, the whole article is a fascinating insight into the problems with post-marketing studies of drugs in the wider population.

A Gel Coating Your Hairy Endothelium

To follow up on one of Nate’s posts from 2010, hair grows not only on your skin. He describes a glomerular capillary to be hairy. Glycocalyx, a hairy structure attached to the glomerular endothelium, is a mixture of glycosaminoglycans and proteoglycans. The picture of glycocalyx accompanying that post is quite impressive.

Now we know these hairs are coated with another gel matrix called endothelial surface layer (ESL). ESL, together with glycocalyx, is believed to function as a barrier to prevent protein passage from blood to urine. A recent article addressing this topic was published in JASN.

By using an animal model, the authors showed that loss of ESL increases the sieving co-efficient for albumin and that the degree of albuminuria correlates with the degree of ESL loss (by the way their confocal microscopy images of ESL are pretty cool).

The implication of the study is that it’s not just podocyte or GBM that are responsible for the development of proteinuria; ESL, glycocalyx and endothelium appear to play an important role as well. For example, loss of ESL has been reported in patients with diabetes. Maybe it’s not just on the skin where hair loss occurs.

For those who are interested in this topic, there is a nice review article for further reading.  

Posted by Tomoki Tsukahara

Image of the Month - 2

A man in his 50s with a history of diabetes, renal stones, gastric bypass surgery and CKD stage III/IV presented to the clinic with fevers, chills and vague abdominal pain. A urine culture was positive for E Coli and he was treated with a quinolone with resolution of his symptoms. In view of his previous history of renal calculi, a CT abdomen was ordered.

The CT scan revealed a 5 x 2.2 cm mass lesion in the right renal/suprarenal region inseparable from the kidney and the right adrenal gland and the differential diagnosis was either a RCC or adrenal carcinoma. He then proceeded to an MRI abdomen.

This again showed a mass in the right suprarenal region, inseparable from the right kidney and adrenal gland with some central necrosis. At this point, the decision was made to proceed with a partial nephrectomy for likely carcinoma.

This is a low-power view of the renal cortex. There is diffuse global glomerulosclerosis involving approximately 80% of glomeruli. There is also significant tubular atrophy and interstitial fibrosis with associated areas of inflammation.

There was focal perirenal and intrarenal scarring with disruption of the renal capsule.

The adrenal gland was essentially normal apart from some focal inflammation and adhesion to the capsule. There was no evidence of any malignancy and it is likely that the changes seen were a result of infection which had resolved by the time of the surgery.

Higher power view of the preserved glomeruli revealed changes characteristic of diabetic nephropathy - nodular glomerulosclerosis.

Interestingly, he also had many tubules containing oxalate crystals, likely related to his previous gastric bypass surgery. There was associated acute tubular injury.

This case lead to an interesting debate in our conference. Should he have been treated for a longer period with antibiotics and then rescanned prior to the resection. In the end, the consensus was that the treatment he received was appropriate. Multiple imaging studies were done that were suggestive of malignancy and he had constitutional symptoms including weight loss and fever. A review of all tumor nephrectomies performed at BWH a few years ago revealed that 1/110 cases was not actually tumor. It is hard to argue in that setting that delaying the resection is the appropriate management. Of course, in this case, there was the added complication of advanced CKD and he has now lost some of his residual GFR (although his creatinine has returned to the pre-surgery baseline).

One final image: on the MRI scan, he was incidentally found to have multiple gallstones - I just thought that the picture looked really cool.

Click on any image to enlarge

Home Dialysis University

The dates and locations for this year's Home Dialysis University for Fellows have been released. This is a series of courses on home HD and PD aimed at graduating fellows that is sponsored by the ISPD. You can check out the RFN review of the course here and our twitter feed from it here under #HomeDialysisU. The 4 locations are Charlotte, Dallas, Denver and Chicago and they are going to take place once a month from February to May.

The site for the fellows version is here. There is a similar course run for practicing renal physicians although this is starting in just 2 days in New Orleans. The website for the non-fellow's version is here. 

Image of the Month

The renal services were consulted on a man in his late 70s with a distant history of colon cancer, recent pneumonia and NSTEMI, for investigation of worsening renal function. He had sub-nephrotic range proteinuria (2-3 g/24 hours) and an elevated creatinine (2.3 mg/dl). His serum albumin was 1.8 g/dl. Serologies revealed a negative SPEP and UPEP but a positive p-ANCA (MPO 354). His clinical condition deteriorated and he was transferred to the ICU. Notably, his urine sediment contained muddy-brown and granular casts with no dysmorphic red cells and no red cell casts.

At this point, the differential diagnosis included a vasculitis, drug-induced vasculitis (although this is usually associated with higher ANCA titers) or ATN. We proceeded to a renal biopsy.

Low power view of the biopsy specimen reveals the presence of an obvious medium-sized vessel - likely an arcuate artery

Higher power view of the cortex revealed relatively normal-appearing glomeruli with no inflammation and no crescents. There were some chronic changes with approximately 11% globally sclerosed glomeruli but this was not thought to be related to the current presentation.

There was a dense interstitial infiltrate with many plasma cells and occasional eosinophils. The small arterioles looked normal.

There were two sections of arcuate artery on the specimen:

The first section showed some arteriosclerosis and some perivascular inflammation but no vasculitis

This is a two views of the same section of a medium-sized artery. There is massive infiltration of the vessel wall characteristic of a vasculitis -specifically this has the appearance of polyarteritis nodosa. There was significant fibrin deposition on IF within the walls of the vessel. There was also some mesangial deposition of IgG and IgM.

This is a fascinating case. First, this form of vasculitis is not usually associated with a positive ANCA test and this may have been a red herring. Second, the smaller vessels were normal and if the arcuate artery was not present on the specimen, this patient would likely have been diagnosed with an interestitial nephritis. The proteinuria in this case is probably a result of reduced tubular reabsorption given the fact that there is no significant glomerular disease. The low serum albumin was most likely due to GI losses rather than renal.

Bonus History of Nephrology Point:
Although we associate interstitial nephritis with drug use and know that it was classically described in the setting of methicillin use, AIN was initially described in the setting of acute sepsis. Councilman nephritis was first described in 1898 in autopsy specimens of patients who died with sepsis. Given the plethora of drugs that most septic patients are exposed to these days prior to any biopsy, this is a difficult diagnosis to make at this point but it should be remembered that not all AIN is drugs. The image below is a plate from that paper which is available for free online.

Click on any image to enlarge

Diabetic Nephropathy, or not?

A man in his 30s with a history of type 1 DM and chronic hypokalemia was referred to the renal clinic for investigation of CKD. His creatinine was 1.8g mg/dl.  His DM was well controlled without any evidence of retinopathy.  Urinalysis did not show any proteinuria or hematuria.  His renal biopsy showed focal tubular atrophy, dystrophic calcification in the scattered tubules, and did not have any signs of diabetic nephropathy.  His renal biopsy findings were therefore attributed to chronic hypokalemia.

Hypokalemia can cause kidney damage if it persists for longer than one month.   Chronic hypokalemia can cause non-specific vacuolar lesions in the epithelial vessels in the proximal tubules.  Typical renal biopsy will show interstitial nephritis, fibrosis, tubular atrophy and cyst formation.  The pathogenesis of hypokalemic nephropathy is not clear.  The hypotheses are:  1) complement activation and tubular cell damage by hypokalemia induced renal ammonium production 2) stimulation of cell growth and proliferation by intracellular acidosis 3) increased production of growth factors (VEGF, IGF-1) and cytokines by hypokalemia through an uncertain mechanism.

After further work-up, our patient was diagnosed with Giltelman syndrome.  He was started on potassium replacement and his Cr has remained stable since then.  

Posted by Jie Cui