My First Experience in Interprofessional Education: A Missing Piece in Our Training?

Having completed four years of medical school, three years of residency, and now a few months away from my completing my training as a nephrology fellow, I experienced a new type of learning – interprofessional education (IPE). IPE is defined as an occasion when learners from two or more professions in health and social care learn together with the objective of cultivating collaborative practice to provide patient-centered care. As nephrology fellows, we have significant interactions with other health professions everyday: dialysis nurses, technicians, medical/surgical nurses, patient care assistants, nurse practitioners, and physician assistants.

IPE has been endorsed by the Institute of Medicine (IOM) and described as an important step in advancing health professional education for many years. Not surprisingly, the IOM states that patients receive safer, higher quality care when health care professionals work effectively as a team, communicate productively, and understand each other's roles.

The IPE workshop I participated in was set in an advanced medical simulation center and involved physicians and nurses. The simulation room was complete with a monitor for vital signs and telemetry, a wide variety of medications and medical equipment, and a jarringly realistic patient mannequin who not only blinked and talked, but also had palpable pulses, audible heart and lung sounds, and even ultrasoundable tissue.

The simulation began with the assignment of roles (i.e. physician, nurse, respiratory therapist) and the description of a clinical scenario. Our first scenario was a patient with altered mental status in the setting of profound hypoglycemia. After the simulation began, we were recorded on video and also observed by a “debriefer” with whom we would discuss the simulation afterwards. The vital signs, physical exam findings, and voice of the patient were controlled by other members of the simulation team (who were behind a one-way mirror) in response to our actions in the simulation. Subsequent simulations involved situations where the patient experienced anaphylactic shock after receiving an antibiotic, crushing chest pain concerning for myocardial infarction, and cardiac arrest.

The debriefing session with the debriefer and all simulation participants, perhaps the most enlightening portion of the activity, allowed the entire team to talk about what went well and what didn’t go so well. Most importantly, we discussed how our teamwork and communication skills could improve. Had tasks been delegated effectively? Did all members of the team know their role and feel part of the team? Was the ultimate goal clear? When and why did communication breakdown?

The discussions often led to thoughts on perceived perceptions of other professional roles and important clarifications of what each team member can contribute. In one simulation, our “actual” roles were reversed, which led to an even richer discussion during the debrief session. We briefly discussed and received feedback on clinical management, though clinical performance was not the main focus of the debrief session.

Though this type of activity requires the participants to buy in to the simulation experience to maximize its effectiveness, it provides a unique opportunity to practice and learn from an almost real-life setting. Before attempting venipuncture on a patient, trainees can practice on their colleagues. Before placing central venous catheters or performing cardiopulmonary resuscitation (CPR), trainees may practice on mannequins. Interprofessional communication is a core skill set that everyone needs to practice and hone. Mastery of this skill set will ensure the delivery of the highest quality of care. I believe that we, as a medical community, need to start including IPE into the curriculum at all levels of medical training. If practice makes perfect, shouldn’t we all start practicing how we interact with other professionals?

Samira Farouk, MD
NSMC Intern 2018
Chief Nephrology Fellow, Icahn School of Medicine at Mount Sinai

Of Mice and…Kidney Fibrosis: 6 Ways to Study Fibrosis in Mice

Kidney fibrosis is the common final pathway where all forms of kidney diseases converge– whether it is diabetic nephropathy, rapid progressive glomerulonephritis, or chronic allograft nephropathy in transplantation. Once significant irreversible fibrosis or scarring has developed, nephrologists are faced with the unfortunate position of realizing a point of no return. Though our understanding of kidney fibrosis has progressed significantly over the past few decades, the complex pathogenetic mechanisms underlying the initiation and progression of fibrosis remain somewhat elusive. Thus, our therapeutic options remain limited.

Mice have been increasingly used to study kidney disease, not only because of their small size and homology with humans, but also because of the ability to manipulate genes by knockdown, knockout, and over expression systems. Scientists have produced a variety of inbred strains with varying degrees of susceptibility to kidney injury. Over the last several decades, the development of multiple kidney fibrosis models has allowed for sophisticated study of fibrotic pathways that ultimately has led to not only a better understanding of fibrosis, but also a model in which potential therapeutic agents can be tested. For example, if we knockout gene X and then induce kidney fibrosis, the resulting kidney pathology may provide some insight into gene X’s role in kidney fibrosis. The most robust studies use a combination of the models below and it is important not to rely on only one model.

Let’s review some of the most popular models of fibrosis:

1. Unilateral ureteral obstruction (better known as “UUO”): As the name implies, the UUO model involves physically tying off one of the ureters with a suture which leads to interstitial fibrosis due to both hemodynamic and metabolic changes. This model has been used since the 1970s in a wide variety of animals: first in lambs, and later possums, rabbits, pigs, dogs, monkeys, rats, and mice. The obstruction leads to tubular injury and cell death by apoptosis and necrosis, glomerulopathy, infiltration of macrophages and cytokine release, proliferation of fibroblasts, and eventually severe fibrosis seven days after the obstruction in wild type mice. The surgery is relatively easy to perform and can be completed in 15 – 20 minutes. While the contralateral kidney can serve as the control kidney in UUO experiments, it also compensates for the injured kidney and thus markers of kidney function such as serum creatinine and urea provide limited information. While this is a convenient model to induce fibrosis, many have argued that the mechanism of fibrosis in UUO is rapid and extensive and thus might not be reflective of human CKD. However, UUO remains one of the most popular methods.

2. Sub-Total Nephrectomy: Like the name implies, this is surgical removal of just about all kidney parenchyma. To achieve this, unilateral nephrectomy is first performed followed by either ligation of the contralateral renal artery branches (which leads to infarction of both renal poles) or ablation and excision of 50% of the contralateral kidney. Though the ligation model cannot be performed as easily in mice due to limited renal artery branching branching, this model leads to more severe proteinuria. The remnant kidney develops both glomerulosclerosis and tubulointerstitial fibrosis. This model is most commonly performed in rats, as there can be some variability with mice depending on the strain and amount of tissue excised. Interestingly, one strain of mice carries only one copy of the renin gene and thus fibrosis phenotypes may be less severe given the pathogenic importance of the renin-angiotensin system.

3. Aristolochic-acid (AA) nephropathy: While AA-induced nephropathy commonly shows up on the nephrology board exam, intraperitoneal injection of AA into wild type mice leads to a phenotype similar to chronic tubulointerstitial fibrosis that is seen in humans. Unlike UUO, the development of fibrosis can take several weeks depending on the AA dosing and frequency of administration.

4. Adriamycin nephropathy: In 1977, a case of kidney injury due to the anthracycline Adriamycin (doxorubicin) was described. In rodents, doxorubicin also induces a phenotype similar to chronic proteinuric kidney disease with histological changes of focal segmental and global glomerulosclerosis, podocyte fusion, and tubulointerstitial inflammation and fibrosis. Changes can be seen as early as 1-2 weeks after intravenous administration and become more severe by week 4. Unlike the relative ease of UUO or intraperitoneal administration, intravenous injections in rodents can be challenging due to small vein sizes.

5. Folic acid nephropathy: The seemingly harmless water-soluble B vitamin can cause acute tubular necrosis and chronic interstitial fibrosis when administered in mice intraperitoneally at extremely high doses. Folic acid both obstructs the tubular lumen by forming crystals and is directly toxic to the tubular epithelial cells.

6. Ischemia-Reperfusion Injury (IRI): The IRI model is commonly used to study acute kidney injury (AKI), but long term outcomes include tubular atrophy, interstitial fibrosis, and inflammation. In a model of bilateral IRI, clamping of renal pedicles for 21 minutes led to significantly elevated levels of serum creatine and urea at 1 year. Histology at one year revealed significant scarring and immune infiltration. Though the development of fibrosis here requires a longer period of time, the IRI model closely mimics IRI experienced by deceased donor kidney transplants.

In addition to these 6 models, numerous other models have been utilized to induce fibrosis. Share your favorite models in the comments below.

Samira Farouk, MD
NSMC Intern 2018, Chief Nephrology Fellow
Icahn School of Medicine at Mount Sinai

Another Great Masquerader: Amyloidosis

A middle-aged man with a history of microcytic anemia, well-controlled diabetes mellitus (DM)/hypertension (for 15 years), and a 16 month history of diarrhea with a 30-pound weight loss, and a creatinine of 1.9 mg/dL.

Laboratory tests showed a urine protein to creatinine ratio of 0.35 mg/g, hemoglobin of 9.3 g/dL, white blood cell count of 13.5 x 10^9/L, and a platelet count of 662 x 10^9/L. A workup for chronic diarrhea revealed an elevated erythrocyte sedimentation rate and C-reactive protein of 85 mm/hr and 18 mg/dL, respectively. Serologies for systemic lupus erythematosus, mixed connected tissue diseases, tuberculosis, hepatitides, and monocolonal gammoapthies were also unrevealing. Computed tomography of the abdomen, EGD, and colonoscopy were unrevealing – biopsy specimens of both the small and large bowel did not show evidence of inflammation. His urine sediment did not have red blood cells (RBCs) or RBC casts.

Despite his long-standing DM and hypertension, a kidney biopsy was performed – which revealed AA amyloidosis (see immunohistochemistry staining for amyloid A protein and an electron microscopy images below)

Endoscopic biopsies were subsequently stained for amyloid A protein – which was also positive.

Serum amyloid A (SAA) is part of a family of apolipoproteins associated and an acute phase reactant whose production is upregulated by the liver typically in the setting of infection or inflammation, which leads to increased expression of inflammatory cytokines like interleukin (IL)-1, IL6, and TNF-alpha. Increased SAA levels ultimately lead to the formation of amyloid fibrils that are immune to proteolysis.

The differential diagnosis of AA amyloidosis is broad – including autoimmune disorders, inflammatory arthritis, inflammatory bowel disease, lymphoma, familial Mediterranean fever, IgG4-related disease, Castleman disease, and chronic infection. A study of the natural history and outcome in systemic AA amyloidosis of a few hundred patients found that the underlying disorder was inflammatory arthritis in 60%, chronic sepsis in 15%, and periodic fever syndromes in 9%. The underlying disorder was unknown in 6% of cases.

Like most other secondary diseases processes, treatment for AA amyloidosis is treatment of the underlying disease. Other therapies should enhance clearance of amyloid deposits, decrease or interrupt fibril assembly, and decrease fibril deposition. For example, two agents that have been used with some success are a monoclonal antibody to IL-6 (tocilizumab) and the newer agent eprodisate, which directly interferes with amyloid fibril formation and deposition. SAA levels may predict disease progression and prognosis. These therapies would be potential options in this patient who did not have a proven underlying disease process.

To conclude, the presentation of amyloidosis can be nonspecific and the differential is widespread. It is important to remember that kidney biopsy can change management in a significant percentage of cases – even in a case like this, where the urinalysis was misleading and masked underlying amyloidosis.

*This is a fictionalized case based on a true account, details have been modified/changed

Samira Farouk, MD
Chief Fellow, Division of Nephrology
Icahn School of Medicine at Mt. Sinai

Tramadol and Hyponatremia

A patient presents to the emergency department with complaints of pain. 

This is a common scenario seen over and over again in emergency rooms around the world on a daily basis. The recent crackdown on opioid prescriptions over the last several years have led to the proliferation of other medications given for pain in which significant toxicities exist. One of those with the most egregious offenses is Tramadol. See Tweet thread below from David Juurlink

“What’s wrong with tramadol?” is something I get asked a lot

Answer: Plenty

Thread ->

— David Juurlink (@DavidJuurlink) October 21, 2017

In this case the patient was started on tramadol just 2 weeks before presentation for leg pain. Now the patient is back in the ED for new onset nausea and continued leg pain. No other medications or illicit drug use was noted. On physical examination, the patient was euvolemic with a normal neurologic exam. Cardiac and pulmonary examination was within normal limits. An electrocardiogram revealed bradycardia (heart rate 56) and normal sinus rhythm. Computed tomography of the head without contrast revealed no abnormalities.   

Typical Laboratory tests in this scenario show only mild hyponatremia. In this presentation severe hyponatremia (109 mg/dL) was seen.

• serum hypoosmolality (254 osm/kg)
• urine hyperosmolarity
• urine sodium (95 meq/L).

All other studies included TSH were normal.

Given the physical examination and laboratory tests, a diagnosis of inappropriate secretion of ADH was made. The patient had no obvious source of inappropriate ADH secretion other than tramadol use and nausea. The nausea was likely a symptom of severe hyponatremia.

Tramadol was discontinued as it was the likely culprit and fluid was restricted to 1L over 24 hours.

-On day 1 of hospitalization, serum sodium rose from 109 meq/L to 115 meq/L over the first 4 hours and then to 119 meq/L over the following 24 hours.
-Day 2, the patient’s nausea had improved and the urine sodium level decreased to 40 meq/L.
-Day 3 of admission, serum sodium rose to 128 meq/L.

In hospitalized patients, hyponatremia (defined as serum sodium level less than 135 meq/L) is the most common electrolyte abnormality. Within the last two years, one retrospective cohort study revealed a 2-3 fold increased risk of hyponatremia in patients who used tramadol compared with codeine use. The mechanism of hyponatremia is thought to be related to increased antidiuretic hormone (ADH) release in response to morphine receptor agonism as well as increased serotonin release which can also stimulate ADH secretion.

Tramadol is a commonly prescribed medication, ranking as the 20th most prescribed medication among thousands of available medications in a study done in 2011. As the opioid epidemic continues to grow, we must be vigilant of the severe adverse effects of these commonly prescribed medications.

Samira Farouk, MD
Chief Fellow
Division of Nephrology
Icahn School of Medicine at Mount Sinai

*this is a fictionalized case based on a true account, details have been modified/changed

Interstitial Nephritis in the Renal Allograft: Rejection, Infection or Both?

In renal transplant recipients with allograft dysfunction, differentiating between a viral infection or acute cellular rejection as the etiology of interstitial nephritis can be difficult – especially as they can commonly occur concurrently.

We recently saw a 40-year-old woman who received a deceased donor kidney transplant less than one year ago who presented with an initial complaint of gross hematuria and an elevated creatinine (2.2 mg/dL from nadir of 1.4 mg/dL). The allograft ultrasound showed thickening of the urothelium. Prompt biopsy of the allograft revealed acute cellular rejection (ACR 1B), and she was treated with high dose steroids and anti-thymocyte globulin.  

Over the next several weeks, she continued to complain of intermittent gross hematuria. Cystoscopy was unremarkable. One month later she presented with worsening renal function, cough and shortness of breath. A nasopharyngeal respiratory viral panel ultimately revealed…adenovirus – which was also then found both the blood and urine (millions of copies in each). A repeat allograft biopsy was consistent with adenovirus nephropathy.

Adenovirus is a double-stranded DNA virus with more than 50 distinct serotypes. Though adenovirus infection is relatively common, adenoviral infection of the renal allograft is rare and also difficult to diagnose if viral inclusions are not present in the biopsy (see image above, black arrows indicating nuclear viral inclusion bodies). Based on a limited number of reported cases, patients typically present with fever, hematuria, dysuria, and acute kidney injury. Adenoviremia and viruria are present, as well as decoy cells similar to those seen with BK virus infection. Though it is possible that this patient may have had only ACR from the beginning (a close re-review of the 1^st biopsy revealed no viral inclusions), it’s plausible that the adenovirus was responsible for the gross hematuria and thickened urothelium that were present from the start.

Adenoviral infection usually affects multiple organs and can be life threatening, though some patients are able to clear the virus and recover complete allograft function. After anti-viral treatment with intravenous cidofovir, our patient’s creatinine rose to 9 mg/dL. Unfortunately, she remains dialysis dependent and is undergoing re-evaluation for a second transplant.  This challenging case is a reminder that both rejection and infections must be considered when interstitial nephritis – and that one may be a decoy for the other!

Posted by Samira Farouk
Chief Fellow, Division of Nephrology
Icahn School of Medicine at Mount Sinai