SPECIAL: Resident's view on Nephrology

What Inspired me about Nephrology?  

I always found physiology interesting in medical school  In residency, I was faced with  many good choices  "Nephrology vs Cardiology vs Pulm critical care." After rotating through each subspecialty I was confident what was the best field for me- Nephrology. I enjoyed the multifaceted part of nephrology- the dialysis, transplant, electrolytes and glomerular diseases. As a resident, I was seeing inpatient consults but also had experience in the  outpatient clinics, transplant clinics, peritoneal dialysis patients, hemodialysis patients, and procedures ranging from simple "Procrit " shots to kidney biopsies and femoral catheter placements.  

Mentorship played a major role in my decision as well. Not only the field was interesting but the people who I dealt with were approachable and great physicians.  As opposed to other specialties, whereby i would be just another face in the crowd, nephrology made me feel special.  I feel like embracing a resident, taking the time out to  expose them to the field as much as possible, and having a one on one sit down with the chairman, program director, associate program director and attendings speaks for itself.  I am glad I am considering nephrology.

 -Seyyar Khan PGY3 Internal Medicine 

Rise of Interventional Nephrology

Interventional Nephrology – Opportunities Ahead

Over the past century, the field of nephrology has evolved with the successful performance of hemodialysis by G. Haas in 1925, cutting needle kidney biopsy in 1951 by Iversen and Brun, and kidney transplant by Murray and Harrison in 1954. Over the last 5 decades, the field of nephrology saw immense improvements in the technology that support these therapies leading to remarkable change in the quality of care. The introduction of Interventional Nephrology in the late 1990’s has invigorated enthusiasm to the field of Nephrology.

The “bread  and butter” of Nephrology practice revolves around providing adequate dialysis therapy. With the technological innovations, dialysis therapy is now mainly provided by the supportive staff and dialysis centers have been converted in to “well-oiled treatment factories”. Interventional Nephrology brings in a new ray of hope and turns a mundane fellowship into a challenging ‘hands-on skill’ oriented field.

The pioneers of the field, Gerald Beathard, Steven Ash and Jack Work were able to form the American Society of Diagnostic and Interventional Nephrology in 2000 (www.asdin.org), with a mission to promote the procedural aspect of the practice of nephrology. ASDIN has developed training and certification guidelines that are vigorous and well respected by most hospital credentialing committees.

Interventional nephrology includes a variety of procedures - renal ultrasonography, placement and removal of tunneled hemodialysis, placement of peritoneal dialysis catheters, angiography and balloon angioplasty for vascular access stenosis (including central veins), endovascular stent and coil placement for dialysis access dysfunction, and thrombectomy procedures for clotted vascular access. The training for these procedures, which began primarily in the private arena has evolved over the past decade and gradually is being adopted by academic centers. The new field has clearly made a positive impact on the care of dialysis access. Further, Interventional Nephrology is being recognized as a potential tool to attract new trainees and eventually improve the dwindling nephrology work force. The critical balance between the intellectual component, procedural skills and lifestyle hopefully will make it attractive for the future generation of trainees to choose nephrology as a career.

Post by

Dr Tushar Vachharajani

Interventional Nephrologist

In the News: Sub group analyses in Nephrology trials

A subgroup analyses is an evaluation of the treatment effect in subgroups of patients defined by baseline characteristics. The main purpose of doing these analyses is to provide a better understanding of the treatment effect heterogeneity. Often, these analyses tend to deviate from this purpose and mislead the reader and may potentially have adverse clinical practice implications.

To demonstrate fallacy of the subgroup analyses, a recent paper in CJASN by Fishbane etal conducted a thorough literature search of the nephrology RCT’s published between July1, 2010 and June 30,2011(included review of nephrology and transplantation journals and four general medicine journals-NEJM, Lancet, Annals of Internal Medicine and Archives of Internal Medicine) The authors found that approximately one third (37.3%) of the published nephrology RCT’s reported subgroup analyses. They found major deficiencies in reporting in the nephrology trials.

1. The majority failed to pre specify that a subgroup analyses would be performed (77.4%). Failure to prespecify diminishes the credibility of the results. 

2. There was an almost uniform failure to list all subgroup variables analyzed. Failure to do so suggests the possibility that numerous analyses may have been conducted in an effort to find a positive result.

3. Statistical testing was inappropriate, with a test of interaction reported in only 35.3% of subgroup analyses. 

4. It is very common to claim treatment effects based on separate tests for each level of subgroup. In addition, when subgroup analyses were discussed, there was a frequent failure to note the limitations of the analyses and discuss that the results should be viewed with caution. Positive claims are common in discussion sections, with general over interpretation of the importance of the subgroup results.

Fishbane et al summarize their recommendations for reporting of subgroup analyses. Subgroup analyses may be helpful for suggesting heterogeneous effects of treatments, but the results may be misleading and over interpreted. 

Post by Dr. Ashish Kataria, Fellow in Nephrology. 

Obesity and ESRD

CONSULT ROUNDS: Tumor lysis syndrome 2

What dialysis modality is the best for TLS?

On one hand you can have severe hyperkalemia that might require urgent hemodialysis and on other hand there is constant catabolic turnover that might require a continuous modality.

1. Treat the life threatening electrolyte disorder first namely hyperkalemia and might need few hours of HD followed by continuous form of dialysis (CVVH, CVVHD, CVVHDF) to prevent rebound hyperkalemia and combat the catabolic breakdown.

2. The phosphate clearance might be best achieved via a continuous modality in such cases.  High dialysate flows might be necessary.

3. Peritoneal dialysis is usually not recommended mainly because it cannot clear uric acid well.

Topic Discussion: Vitamin D receptor and Renin angiotensin system

Opiate addicts are prone to infection and this has been attributed to ongoing lymphopenia. Morphine is one of the commonly used opiates in pain management.  Morphine is also an active metabolite of commonly abused drug, heroine. Recently, vitamin D receptor (VDR) has been demonstrated to play a role in immune cell function. 

We evaluated the role of VDR in the activation of the renin angiotensin system (RAS) in morphine-induced T cell loss. Morphine treated human T cells displayed down regulation of VDR and the activation of the RAS. On the other hand, a VDR agonist (EB1089) enhanced T cell VDR expression both under basal and morphine-stimulated states. Since T cells with silenced VDR displayed the activation of the RAS, whereas, activation of the VDR was associated with down regulation of the RAS, it appears that morphine-induced T cell RAS activation was dependent on the VDR status. Morphine also enhanced reactive oxygen species (ROS) generation in a dose dependent manner; however, this effect of morphine was inhibited by an opiate receptor antagonist, naltrexone. These findings confirmed the role of opiate receptors in morphine-induced ROS generation. Interestingly, the activation of VDR as well as blockade of Ang II (by losartan, an AT1 receptor blocker) also inhibited morphine-induced T cell ROS generation. Morphine not only induced DNA damage in T cells but also attenuated DNA repair response; whereas, activation of VDR not only inhibited morphine-induced DNA damage but also enhanced DNA repair. Morphine also promoted T cell apoptosis; however, this effect of morphine was inhibited by blockade of opiate receptors, activation of the VDR, and blockade of the RAS.

These findings indicate that morphine-induced T cell apoptosis is mediated through ROS generation in response to morphine-induced down regulation of VDR and associated activation of the RAS.

For full review click here. 

Post by Dr. Pravin Singhal
Professor of Medicine

A resident's view

The renal elective in our institution has allowed now to have residents participate and see the side of nephrology that they might have never seen before- transplantation and peritoneal dialysis.  One of the residents penned her thoughts on her blog about the experience of seeing the transplantation side of nephrology.  Please check out this very well written commentary on her blog.

CLINICAL CASE 60 Answers and Summary

WHICH OF THE FOLLOWING DISEASES IS NOT ASSOCIATED WITH A DYSREGULATION OF THE ALTERNATIVE PATHWAY OF COMPLEMENT?

Dense Deposit Disease 9%

C3 Glomerulonephritis 2%

Atypical HUS 4%

Minimal Change Disease 73%

Chronic FSGS 9%

Dysregulation of the alternative complement pathway can either result in a proliferative glomerular process or a thrombotic microangiopathy.  The 2 proliferative processes are C3 glomerulonephritis and dense deposit disease. The thrombotic microangiopathies can be from acute in terms of atypical HUS or chronic from FSGS. A chronic state of FSGS can lead to a vascular insult and cause chronic alteration of the atypical pathway. A recent case was described where FSGS occurred in association with CFH and C3 polymorphisms and dysregulation of complement pathway. MCD is usually not been associated with this; at least thus far.

NEJM Blog: Stroke and Bleeding in Afib with CKD

Check out a discussion on the latest news: Stroke and Bleeding in Afib with CKD

The rise of Onco-Nephrology

The American Society of Nephrology and many of the renal journals have started focusing on the many areas of interest in nephrology. In the last one year, we have seen the onco-nephrology field growing rapidly. This is an important field as the drugs that are being used for cancer are growing and understanding the renal complications of them is extremely important. 

CJASN has recently put out a series of papers on various topics of interest
Renal toxicities of chemotherapy
Hypercalcemia
AKI in cancer patients
Tumor lysis syndrome
Paraneoplastic Syndromes 

Last year, Seminars in Nephrology did a similar series.

ASN has put forth a work group in Onco Nephrology as well to lead the frontier of taking care of patients with cancer who have kidney disease. Check out Nephronpower's multiple posts in the last 3 years on the topic of onco nephrology and the research ongoing in this area.

CONSULT ROUNDS: Tumor Lysis Syndrome 1

Tumor lysis syndrome(TLS) is a frequent clinical syndrome nephrologists encounter.
The Cairo Bishop classification allows for the diagnosis of TLS
Those are

1. Uric acid >= 8.0
2. K >= 6.0
3. Phos >= 4.6
4. Calcium <7.0
5. AKI
6. Cardiac arrhythmia
7. Seizure or symptomatic hypocalcemia

Two of the four lab criteria have to be met within 24 hours period and 3 days before to 7 days after receiving chemotherapy and no other cause of AKI has to be found.  Interestingly, LDH is not a criteria to help diagnose TLS but is usually the most useful clinically.  If one looks at risk factors, LDH is included along with WBC count, tumor burden, renal function at baseline and baseline uric acid levels.

CONSULT ROUNDS: Minimal Change and Lupus?

A 34 year old female presents with sudden onset nephrotic syndrome. A kidney biopsy confirms minimal change disease. Subsequently, labs reveal a + ANA and + dsDNA and + anti smith antibody.
Is the glomerular disease secondary to SLE?

Initially described in 2005, lupus associated minimal change disease is also called lupus podocytopathy.

A series of patients SLE and proteinuria were studied to determine whether nephrotic range

proteinuria was associated with diffuse epithelial cell foot process effacement in the absence of peripheral glomerular immune aggregate deposition.  Eighteen biopsies were studied, eight from patients with nephrotic-range proteinuria (>3 g/d) and 10 from patients with nonnephrotic proteinuria. Seven of eight biopsies from nephrotic patients demonstrated at least 80% foot process

effacement, whereas no biopsy from a nonnephrotic patient exhibited >20% effacement. No IF or LM findings were found. Interestingly, no full house pattern was noted as well. The single common morphologic feature associated with nephrotic proteinuria was diffuse visceral epithelial cell foot process effacement. That initially manuscript revealed that this entity is more likely SLE related rather than co existence of SLE and minimal change separately, 

In 2009, a letter to the editor in Rheumatology suggested another case of such matter. 

Subsequently, more cases have been described. 

Of recently, cases of collapsing FSGS is described as a variant of lupus podocytopathy. 

Lupus usually presents with a proliferative manifestation in the kidney but perhaps a podocytic variant might exist. More data is needed in this variant of lupus. 

CONSULT ROUNDS: Hematuria and renal failure?

45 year old with IgA Nephropathy has gross macroscopic glomerular hematuria. Following that, an episode of AKI ensues.  Is this pigment nephropathy? How does AKI result from gross hematuria?

1. 25% of patients with gross hematuria associated AKI had adverse long term outcomes
2. Of all the glomerular diseases, IgA is the most common cause of gross hematuria associated AKI
3. Older age seems to be a risk factor for longer recovery time from AKI from the hematuria
4. Severe ATN was the cause on biopsy for cause of late recovery
5. No cases of Alport's Syndrome and AKI with hematuria in the literature and one case of thin basement  membrane disease with Aki with hematuria.
6. Oral anticoagulation related injury has been now described and cases of warfarin associated renal disease have been identified
7. Hemoglobinuria from entities such as paroxysmal nocturnal hemoglobinuria have been associated with AKI due to hemolysis, intra-tubular cast obstruction.
8. Overall, why does hematuria cause AKI and renal damage. Initially, it was thought to be from intra-tubular obstruction from RBCs or hemoglobin casts.
9. Recent data suggest that there is direct tubular toxicity of hemoglobin, heme, iron molecules released from RBCs.  There is decrease in nitric oxide leading to intra renal vasoconstriction and ischemia.

A recent CJASN article summarizes these studies.

Topic Discussion: Iron during infections?

We often hear not to give IV iron during an active infection... Is there evidence for that statement?
Iron is important for growth of many bacteria, viruses and fungi.  Certain organisms are more iron laden than others. In hemochromotosis, certain iron laden infections are more common due to the affinity of the organisms to iron.  Various infections caused by organisms including 
Vibrio vulnificus, Vibrio cholerae, E. coli, Yersinia enterocolitica and pseudotuberculosis,
L. monocytogenes, P. shigelloides, CMV are others that have been reported in association with hemochromatosis. Fungi including A. fumigatus and Rhizopus species have also been described.
Iron is a central regulator of immune cell proliferation and function. All lymphocyte subsets, including B and T lymphocytes and natural killer (NK) cells, depend on iron uptake, the blockade of which leads to diminished proliferation and differentiation of these cells. Iron loading of macrophages results in the inhibition of IFN-g-mediated pathways and hence they lose their ability to kill intracellular pathogens. Excess iron burden does
not only help the propagation of pathogens, but also plays a sentinel role in modifying the host immune mechanism, specifically by impairment of cell-mediated immune responses.

Data in CKD patients are conflicting and recent KDIGO work group for anemia in CKD released guidelines for IV iron use.  Although clinical judgement drives the decision, the work group suggested not to use IV iron in active systemic infection but no grade was assigned as evidence either way is weak.  

Detailed guidelines can be found in Kidney International.

Topic Discussion: ENCAPSULATING PERITONEAL SCLEROSIS (EPS)

Encapsulating Peritoneal Sclerosis (EPS), the most serious complication of peritoneal dialysis (PD) was recognized soon after PD was introduced. It is characterized by extensive intraperitoneal fibrosis and encasement of bowel loops. It is typically characterized by loss of ultrafiltration, resulting in fluid retention and edema. 

From the viewpoint of clinical presentation, it progresses to various stages from early phase of faint inflammation to fibrin exudates and active inflammation. This is followed by formation of encapsulating membrane and sustained inflammation. Finally, thickening occurs and there is moderate inflammation.

Development of EPS is associated with three main clinical factors: prolonged duration of PD, persistent

Or frequent bacterial or fungal peritonitis, and membrane failure. The cumulative duration of exposure to PD fluids is the dominant risk factor for EPS, but young age and kidney transplantation might also be risk factors

It can be diagnosed by above clinical features and radiologically by a CT scan which my show evidence of: Peritoneal thickening, peritoneal calcification, tethering and cocooning of bowel and small or large bowel obstruction.

Treatment usually consists of corticosteroids. Some case studies have used Tamoxifen. Surgical treatment consisting of surgical lysis of intestinal adhesions and stripping of fibrous cocoon has been indicated if there is recurrent bowel obstruction, failing nutritional status or failure to respond to medical therapy. Increase incidence has been noted after transplantation. Unclear why is that the case.

Good references:

http://www.ncbi.nlm.nih.gov/pubmed/11098928

http://ndt.oxfordjournals.org/content/22/8/2412.1.full

http://ndt.oxfordjournals.org/content/16/6/1304.full

Post by Dr.Divya Monga

Invited commentary: Nephrology and ACA decision

Check out an invited commentary on the recent Supreme court decision and how it effects Nephrology care by Dr Straube on eAJKD.

Topic Discussion: Rule of 6s

Hyponatremia- Rule of 6 correction.
The Stern Approach

Correction and then over correction is the concern especially in two populations.

Low Solute intake individuals and Alcoholics.

They are the highest risk for CPM following rapid correction.

The cause of hyponatremia and its reversibility must also be considered when deciding a course of action. In hypovolemia-induced hyponatremia, vasopressin levels decline and sodium levels rise as volume status is restored to normal.

The Stern approach from Rochester has come up with a protocol that is worth noting year after year regarding giving hypertonic saline with ddavp. The reason why trouble arises in the treatment with just 3% in the above population is due to emerging quick water diuresis that sometimes gets not well accounted.

Ddavp administered q6-8 hours has been shown by this same Rochester group to be effective and more practical than hypotonic fluids in preventing overcorrection of hyponatremia. They administer desmopressin immediately without waiting for the onset of water diuresis, and concurrently administer 3% saline solution. Based on their data, this prevents significant rises in Na rapidly and provides the “brakes” with the “acceleration”. The formula of the 6s is recommended. Correction with 6mEq in 6 hours on the first day if symptoms are severe with neurological symptoms. 

Sterns approached was studied in a retrospective manner in a CJASN study found free online.  In another article, this approach is discussed using an alcoholic case in AJKD. Concerns using ddavp is that perhaps there is no control  over the effect once you give it. At least with D5W or hypotonic solutions, one can control the rate. Perhaps, more data will be coming out on this approach as years progress. 

In summary, correction of hyponatremia by 4-6 mEq/l within 6 h, with bolus infusions of 3% saline if necessary, is sufficient to manage the most severe manifestations of hyponatremia. Planning therapy to achieve a 6 mEq/l daily increase in the serum sodium concentration can avoid iatrogenic brain damage by staying well clear of correction rates that are harmful. Administration of desmopressin to halt a water diuresis can help prevent overcorrection; if overcorrection occurs, therapeutic relowering of the serum sodium concentration is supported by data in experimental animals and was found to be safe in a small observational clinical trial. 

Nephrology Crosswords: Divalents

Check out the next in series of Kidney International Crosswords- Topic is Divalents

http://www.nature.com/ki/journal/v82/n4/full/ki2012213a.html