The Renal Fellow Network (RFN) was established on April 23rd, 2008 by the late Nathan Hellman. RFN was created to provide a forum to discuss interesting nephrology cases, scientific papers, and other topics germane to nephrologists, particularly fellows.
2.Demographic Data & Leading Job Market Indicators: This survey is the primary source for demographic data on nephrologists entering the workforce. Assessments of the job search and availability provide indicators on nephrologist demand and remuneration, stratified by location and practice setting.
I always like to remind my cardiology colleagues that some of the most important drugs used in the cardiovascular arsenal, are in fact exerting their benefits through the kidneys. Case is point, drugs that target the renin-angiotensin-aldosterone system. I must admit that I envy how cardiology has come a long way, thanks in part to the number of randomized clinical trials (RCT) performed.
Nonetheless, nephrology is also moving at a steady pace especially in light of the recent positive findings of the CREDENCE trial. Take a look at the recent NephJC chat regarding the latest trends regarding research in nephrology.
Let’s take a look a recent RCT published in late 2018 in Circulation. The UK-HARP-III trial (United Kingdom Heart and Renal Protection-III) is a randomized double-blind trial of 414 participants randomly assigned to either sacubitril/valsartan 97/103 mg twice a day versus daily irbesartan 300 mg once daily.
In this study patients a total of 414 were randomized 1:1 to receive either sacubitril/valsartan or irbesartan at the end of the run-in period (207 participants in each group). Participants had to have and eGFR of ≥45 and <60 mL/min/1.73 m2 and a urine albumin:creatinine ratio (uACR) >177 mg/g, or an eGFR of ≥20 and <45 mL/min/1.73 m2 (regardless of uACR). In order to maximize blinding the authors used a method called the “double-dummy approach” in which patients received two bottles of medication, one containing sacubitril/valsartan 97/103 mg or placebo and the other bottle irbesartan 150 mg or placebo.
After two week of study patients double their dose of study medication; however only if no hyperkalemia or acute injury was recorded. During the next visits at 1, 3, 6, 9 and 12 months of study, several markers and relevant data were collected. The primary end point of the study was to assess their measured GFR at 12 months. A key strength of this paper was the use of measured glomerular filtration rate (mGFR) with either chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA), techicium-99 labeled diethylenetriaminepentaacetic acid (Tc-DTPA), or iohexol depending on local practice. The same technique used during baseline measurement was applied to the 12 month time point.
No effect on kidney function was demonstrated in regards to change in mGFR (34 to 30 ml/min/1.73m2 in both groups) in the neprilysin group compared to the control group (both containing ARBs). Other results also demonstrated that there was no effect on estimated GFR (eGFR), or albuminuria. However, they did find that sacubitril/valsartan was well tolerated, and no major safety concerns identified. Interestingly, sacubitril/valsartan was found to reduce BP and cardiac biomarkers (troponin I and NT-proBNP) when compared with irbesartan. How these results translate to hard clinical outcomes is uncertain.
The pathophysiology of heart failure of decompensated heart failure is a complex process. While reduced heart function is the sine qua non. The kidneys play a critical role in this process as well. Several neurohumoral mechanisms are upregulated in heart failure to enhance sodium excretion. The natriuretic peptides (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) both serve to induce natriuresis (a true cardio-renal integration).
Enter Sacubitril. Sacubitril is a prodrug that inhibits the enzyme neprilysin (a zinc metalloprotease), which is responsible for the degradation of several peptides including ANP and BNP (and angiotensin II itself and even beta amyloid). Hence, allowing for the prolonged effect of both ANP and BNP and potentially other peptides. But also important that an angiotensin receptor blocker (ARB) be added to the mix. The PARADIGM-HF trial (which made it to the 2nd round of the CardioRenal section NephMadness 2015) showed a favorable mortality benefit with the combination of a neprilysin inhibitor and an ARB. Importantly, the trial also hinted at a slower decline in kidney function. However, this was not a primary endpoint.
Thus, an important question to answer in the UK-HARP-III trial was if there was and effect on kidney outcomes (defined as mGFR achieved after twelve months). Unfortunately, in this short term trial, no apparent benefit was seen. Will the reduction seen in cardiac biomarkers provide a cardiovascular benefit in patients with CKD taking sacubitril/valsartan.
Especially seeing that patients with CKD have such a profound risk of cardiovascular disease. We will have to see. Interestingly, this study paired two different ARBs head to head (in addition to sacubitril and placebo). Valsartan versus irbesartan. The dosing appeared to be equivalent (valsartan 103 BID versus irbesartan 300 mg daily). It is always interesting that they didn’t just use valsartan in both arms. But alas at least it is better than comparing the valsartan/sacubitril combination to the ACEi enalapril like was done in the PARADIGM-HF trial. Will be interested to see how kidney function in altered in patients with concomitant CKD and heart failure.
This annual symposium is open to nephrology and pulmonary/critical care fellows, clinicians, nurses, pharmacists and anyone interested in obtaining a practical understanding of continuous renal replacement therapy (CRRT).
Registration is now open.
When: August 29 and 30, 2019
Where: Hilton Hotel at UAB, 808 20th Street S, Birmingham, AL, 35205
Event Information: Dynamic speakers and networking opportunites will be available along with more hands-on workshops and interactive cases. There will also be a session on CRRT quality metrics and optimization of acute intermittent dialysis in the ICU. A new pre and post-test will be given.
Additional Information: Seating is limited to 80 people.
Registration Fees: $325 for MD’s and Pharmacists $225 for Nurses, Nurse Practitioners, and Physician Assistants $175 for Fellows, Students $165 for UAB RN’s, Pharmacists and Physicians
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with a reported incidence ranging from 1:500 to 1:1000. The genes implicated in the disorder are PKD1 (encoding polycystin 1) and PKD2 (encoding polycystin 2) for ADPKD1 and ADPKD2 respectively.
Up to 10% patients may not have these well-described mutations, but may harbour a mutation in DNAJB11 or in one of the six mutations known to cause autosomal dominant polycystic liver disease(ADPLD) namely, AGL8, SEC61B, SEC63, PRKCSH, LRP5, and especially GANAB).
Even though the disorder is inherited in an autosomal dominant manner, it is to be emphasized that a single mutated gene may not be sufficient for cystogenesis. Rather, the cellular defect is most likely recessive because it is not without a second hit that the tubules produce a cyst. Additionally, though all the tubular cells carry at least one allele of the gene mutation, only a few of them develop cysts (about 1-3%).
Fundamentally, a cyst is a membranous sac – so it has two components- an epithelial lining and the fluid within. For the formation of a cyst, the intracellular pathways need to converge and promote two processes – epithelial proliferation and fluid secretion.
In ADPKD, the common link is cyclic adenosine monophosphate (cAMP). The enzyme adenylyl cyclase catalyzes the cyclisation of adenosine triphosphate (ATP) into cAMP, while another enzyme, phosphodiesterase breaks down the phosphodiester bond in the cAMP and degrades it (See Figure 1). Any event which either stimulates adenylyl cyclase or inhibits phosphodiesterase can lead to an increase in the intracellular levels of cAMP.
Figure 1: Pathways involved in synthesis and degradation of cAMP.
Though the exact mechanism leading to increased cAMP levels is unknown, it has been attributed to increased levels of circulating vasopressin. This may occur in response to loss of urinary concentrating ability seen quite early in the disease process.
While the cysts can arise from all nephron segments in ADPKD (including the glomerulus), microdissection studies done by O.Heggo revealed that the cysts derived from collecting ducts tend to be more numerous and larger.
Supporting this observation, the epithelium of the cysts was demonstrated to stain positive with lectins specific to the collecting duct. Vasopressin receptor 2 (V2R) is an abundantly expressed receptor in this part of the glomerulus. Binding of vasopressin to V2R stimulates adenylyl cyclase and inhibits phosphodiesterase as well leading to elevation of intracellular cAMP (see figure 2).
Figure 2: Vasopressin mediated increase in cAMP
Recently, Su et al described the near-atomic resolution cryo-electron microscopic structure of PC1-PC2 complex in health and in ADPKD-1. The complex of polycystin-1 and polycystin-2 acts either as a mechanosensor or a chemosensor which normally translates the extracellular signals into intracellular increase in calcium.
This is mediated by two pathways – Ca2+ entry into the cells through PC2 and by release of Ca2+ from intracellular stores like endoplasmic reticulum (again mediated by PC2 and also ryanodine receptor). In ADPKD, as a result of the mutation in the genes encoding the aforementioned proteins, intracellular calcium levels are decreased. Please go through NephJC summary (and a video too) of this paper.
In normal kidney epithelial cells, cAMP inhibits proliferation of cells by inhibition of Raf-1/MAP kinase/extracellular signal regulated kinase (B-Raf-1/MEK/ERK), which is basically a pathway mediating cell proliferation. The tricky part here is that B-Raf can independently stimulate MAPK kinase and promote proliferation, but this is kept under check by Akt – which in turn requires normal intracellular Ca2+ levels to act.
When the intracellular Ca2+ levels go down (as happens in ADPKD), Akt is unable to inhibit the kinases and cell proliferation takes off unchecked. See the figure 3 below, from a nice review paper, which explains this schematically.
Also, Bhunia et al demonstrated that expression of PC1 in conjunction with PC2 activates JAK-STAT pathway, thereby upregulating p21.
p21 is essentially a guardian of the cell genome mediating inhibition of cell cycle (and even DNA repair). A defective PC1 or PC2 function, therefore, may hinder this process leading to uninhibited cell multiplication.
Intracellular cAMP levels may also be affected by somatostatin. Receptors for somatostatin, namely SSTR1 and 2 are expressed in the thick ascending limb of Henle, distal tubule and collecting duct and SSTR 3 and 4 are found in proximal tubules. Binding of somatostatin to its receptors inhibits the activity of adenylyl cyclase thereby reducing cAMP levels. Hence the interest in somatostatin analogues in inhibiting cyst growth, though the effect on kidney function was disappointing in the recent trial.
The C-terminal PC1 also has been demonstrated to interact with tuberin encoded by TSC2. By the virtue of this interaction, it inactivates the mTOR, which would otherwise promote cell growth, proliferation and this is the basis for the trials using mTOR inhibitors (sirolimus and everolimus) in ADPKD. The polycystin-tuberin interaction also explains the occurrence of renal cysts in tuberous sclerosis. Since the two genes PKD1 and TSC2 are located close to each other on chromosome 16p13, large deletions may involve both of them – the disease has been termed TSC2/PKD1 contiguous gene syndrome and is characterised by presence of renal cysts as well as angiomyolipomas.
Like probably all the renal epithelial cells, the basolateral surface of cyst epithelia also express Na+-K+-ATPase which functions to extrude sodium out of the cell in exchange for uptake of potassium. Sodium re-enters the cell via basolateral NKCC1 (sodium-potassium-chloride cotransporter), which also brings potassium as well as chloride into the cells. While potassium is returned extracellularly either by basolateral or apical potassium channels, chloride is transported into the cyst lumen principally along the electrochemical gradient via CFTR channel.
The activity of CFTR channel is upregulated in the setting of elevated intracellular cAMP levels. Cl secretion is accompanied by movement of Na and water into the cyst lumen. It is interesting to note that the patients who have the misfortune of having both PKD and cystic fibrosis have slower progression of cystic disease probably mediated by slower cyst growth due to impaired activity of CFTR. The same hypothesis has provided a foundation for pre-clinical trials for the role of CFTR inhibitors in animal models of ADPKD.
The diagram below summarises all the known pathways till date.
As a general rule, in any patient presenting with acute kidney injury without an obvious cause, obstructive nephropathy must be excluded because prompt intervention can lead to improvement or complete recovery of renal function. Therefore, the detection of hydronephrosis is one of the commonest indications for Point of care renal ultrasonography performed by nephrologists and internists.
On the sonogram, hydronephrosis appears as branching, interconnected areas of decreased echogenicity (anechoic or black in general, indicating the presence of fluid) in the renal collecting system. The source of obstruction is usually located distal to the kidney, for example, a stone in the pelviureteric junction, ureter or ureterovesical junction or bladder outlet obstruction from enlarged prostate, stone or a mass.
On the other hand, the collecting system of a normal kidney is not well-visualized unless distended and is embedded in the surrounding echogenic sinus fat. The renal pelvis area is hypoechoic but not ‘black’ unless there is hydronephrosis.
As the hydronephrosis increases in severity, the urine moves proximally into the kidney exerting pressure on the parenchyma. While there is no universally accepted grading system, hydronephrosis is often classified as mild, moderate or severe in routine clinical practice.
In mild hydronephrosis, there is dilatation of the renal pelvis and calyces but the pelvicalyceal pattern is retained and the cortex remains unaffected. Distinct medullary pyramids may be seen in some cases though not necessary to make a diagnosis as pyramids are not always appreciable even in a normal kidney.
In moderate hydronephrosis, medullary pyramids start to flatten due to back pressure in addition to dilatation of pelvicalyceal system and outpouching of the calyces, which is sometimes referred to as ‘cauliflower appearance’. Cortical thickness is preserved.
In severe cases, renal pelvis and calyces appear ballooned and cortico-medullary differentiation is lost making the cortex thin. Ultrasound images as well as illustrations demonstrating these grades of hydronephrosis are shown in Figure 1.
In this context, it is important to note that obstructive nephropathy may be missed due to false negative findings in the setting of acute or partial obstruction, volume depletion and retroperitoneal fibrosis. On the contrary, we have to be aware of the false-positive findings, that is conditions that mimic hydronephrosis to avoid any unnecessary and potentially harmful interventions.
Figure 1. Grades of Hydronephrosis
One of these mimics is an extrarenal pelvis. It is an anatomical variant where major portion of the renal pelvis is located outside the renal sinus and is more distensible than an intrarenal pelvis, which is surrounded by sinus fat. On a sonogram, extrarenal pelvis appears as a hypoechoic or anechoic mass just outside the renal sinus and unlike hydronephrosis, it is not associated with dilated calyces, parenchymal thinning, hydroureter, or enlarged kidney per se.
When you see a big ball of fluid ‘outside’ the renal sinus but wonder why the intrarenal collecting system is not dilated from backpressure, think of this entity. Figure 2 demonstrates sagittal (A) and transverse (B) views of the kidney with an extrarenal pelvis filled with urine (thick arrow) without distended calyceal system. A medullary pyramid (line arrow) can be seen just above the central echogenic portion of the kidney suggestive of preserved corticomedullary differentiation and the absence of compression.
Figure 2. Sagittal (A) and Transverse (B) view of Extrarenal Pelvis
Parapelvic cysts also can mimic hydronephrosis because of their anechoic nature (like urine, clear fluid in the cysts is black on ultrasound) and close proximity to the collecting system. As mentioned above, hydronephrosis appears as branching, ‘interconnected’ anechoic area, while parapelvic cysts are seen as ‘noncommunicating’ renal sinus cystic masses. In addition, a parapelvic cyst is more spherical as opposed to irregular/cauliflower contour of hydronephrosis. When the sonogram is not clear enough, a CT scan with contrast should be considered to differentiate between these two conditions.
Figure 3 demonstrates parapelvic cystson ultrasound [top panel] appearing as hypoechoic areas in the renal pelvis area. However, note that on the transverse view, these areas do not seem to be connected with one another (double‐headed arrow). Contrast-enhanced CT scan [bottom panel] confirms the diagnosis of parapelvic cysts by showing that these structures (white arrows) are separate from the contrast‐filled collecting system (yellow arrows).
Figure 3. Parapelvic cyst on ultrasound (top panel) and CT (bottom panel)
Prominent renal vasculature and vascular malformations can mimic hydronephrosis on grey-scale images because blood also appears black on ultrasound. The simplest way to avoid misdiagnosis is obtaining color Doppler images which demonstrate blood flow if there are vessels in the renal pelvis area.
In fact, we should always obtain a few Doppler images when performing kidney ultrasound irrespective of the suspected etiology. Figure 4 demonstrates anechoic region in the mid‐kidney suggestive of hydronephrosis on grey-scale images [top panel] and color Doppler evaluation of the same area reveals prominent arteriovenous flow suggestive of vascular malformation.
Figure 4. Vascular malformation on grey scale (top panel) and color doppler (bottom panel)
Take-home point: Extrarenal pelvis, parapelvic cysts and vessels in the renal hilum may mimic hydronephrosis on ultrasound. Compare prior imaging studies, obtain color Doppler images and possibly further imaging when applicable for accurate diagnosis.
In an ideal world, patients would present to our clinic with straightforward conditions, allowing us to confidently treat the patient with effective medications which will likely have much more benefit than harm. However, we also commonly encounter patients where the optimal approach to treatment is less clear, and IgA nephropathy can sometimes present this way.
First, a word on renin-angiotensin-aldosterone system (RAAS) blockade as standard of care. We know that RAAS blockade helps to reduce proteinuria. The GISEN group in Italy showed that ramipril reduced proteinuria and rate of eGFR decline in non-diabetic patients with >3 grams per day of proteinuria. More specifically for IgA, the IgACE study in 2007 showed that in patients with biopsy-proven IgA nephropathy and moderate proteinuria, treatment of ACEi reduced progression of kidney damage.
Thus, RAAS blockade remains standard of care for proteinuric kidney disease, and this remains true in IgA nephropathy.
It is useful to review the Landmark Trials in IgA Nephropathy so that we know what we know (and what questions remain) when treating patients with biopsy-proven IgA who have relatively preserved kidney function and some degree of proteinuria. We are not talking about the patient whose only clinical manifestation is microscopic hematuria, nor is this relevant to the patient with rapidly-progressive glomerulonephritis.
One of the first Landmark trials to evaluate steroids for IgA nephropathy was published by Pozzi in 1999. This study randomized 86 patients. Investigators compared supportive therapy with blood pressure control and diuretics to IV methylprednisolone. RAAS blockade was not standard of care at that time, so patients may or may not have received an angiotensin converting enzume (ACE) inhibitor or angiotensin receptor blocker (ARB). This study showed that 6 months of IV steroids reduced proteinuria and protected against deterioration in kidney function, WITHOUT adverse events during follow-up, including specifically infectious serious adverse events.
A decade later, Manno and colleagues randomized 97 patients to ACE inhibition alone versus ACE inhibition plus oral prednisone. Follow up time was relatively long at 8 years, and combination therapy protected against progression of kidney disease. Again, there were no major adverse events, including serious infections.
In the same year, Lv and colleagues published results from a randomized control trial (63 patients) comparing ACE inhibition with or without oral prednisone, with 4 year follow-up, and found similar results. Namely, combination therapy protected against progression of kidney disease, without major adverse events. Based on these studies, steroids were looking pretty good for treatment of this subgroup of patients.
In 2012, the same lead author published a meta-analysis of trials from 1966 to 2011. It was noted that steroid therapy was associated with less kidney dysfunction and proteinuria, but also with a 55% higher risk of serious adverse effects, though NOT severe infections. Most studies used high dose, short term steroids and the data was limited. Additionally, ACEi/ARB was not mandated in most studies.
The STOP-IgA randomized trial (337 patients) in 2015 evaluated supportive care, which included RAAS blockade, with supportive care plus immunosuppression (either steroids for preserved kidney function or cyclophosphamide, azathioprine, and prednisone for eGFR between 30-59.)
Interestingly, this study showed that immunosuppressive therapy did NOT improve outcomes, and was associated with more adverse effects.
Most recently, the TESTING randomized trial (262 patients) set out to find answers, given the conflicting data from previous studies. All patients received blood pressure control including RAAS blockade and were randomized to placebo versus oral steroids. Unfortunately, recruitment was discontinued early due to an excess of serious adverse events, mostly serious infections. The number of primary outcomes are small, but the data do indicate better primary kidney outcomes with steroids compared to placebo.
Like most treatments that we provide to our patients, we must try to weigh the risks and benefits in each individual patient, and further studies are needed to help to guide our clinical decision-making.
Landmark Nephrology is an online learning tool designed to collect landmark trials in nephrology and distribute content that makes learning nephrology fun and easy.
Please visit us to check out our topic-specific content including videos, visual abstracts, quizzes, and a new slide-share portal to facilitate the exchange of educational material within the nephrology community.
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Many groups (both inside and outside the United States) continued to improve and expand on the modality, and by the mid-1960s, home hemodialysis was recognized as an effective and less expensive alternative to in-center hemodialysis. Not only was it able to cut cost by avoiding the requirement of nursing staff to supervise sessions, but it also afforded a greater opportunity for rehabilitation by allowing for more independence. It turned out such impressive results that by 1972 about 90% of all patients who were on dialysis under the Seattle program were on home hemodialysis.
That Fateful Summer of ‘73
Parallel to innovations in the procedure of dialysis, the social and political mobilization in favor of dialysis as a life-sustaining treatment began in the 1960s. The initial efforts were focused on grants that provided funding for research in dialysis, as well as capital to establish “demonstration centers” to determine the effectiveness of the procedure.
Inadvertently, there was a decline in the percentage of patients on home hemodialysis since the application of the program. This was attributed to a change in the patient population that were eligible for dialysis under the Medicare program; older, more medically complicated, and socially restricted patients. There was also a rapid growth in the number of outpatient dialysis units which led to a further reduction in the number of patients on home modalities.
Overall, things seem to be looking up for home hemodialysis – 1.8% might not seem like a lot of patients, and any further growth is also likely going to be slow. On the other hand, this also means that home hemodialysis is the modality with the largest scope for expansion and improvement.
What’s in Store Next?
There is much excitement in the field , especially with programs such as the Kidney Innovation Accelerator (KidneyX) looking to sponsor $2.6 million for innovations in dialysis treatment in an effort to improve patient outcomes and quality of life.
Among the available modalities of renal replacement therapies, home hemodialysis still remains an untapped modality of renal replacement therapy; we must strive for a future in which home hemodialysis becomes as routine and prevalent as in-center hemodialysis.
We will continue our journey through the field in our new “Home Hemodialysis Series” on the Renal Fellow Network. In our subsequent posts, we will cover the key literature as it pertains to the modality and also have a tutorial on how to write a new home hemodialysis prescription. Stay tuned!
Hyponatremia from the Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) is a common consult a fellow encounters on the inpatient service. In addition to stopping potentially offending drugs, management can range from fluid restriction, loop diuretics, demeclocycline, salt tablets, or urea. Utilization of these options may be met with varying success. More recently, vasopressin receptor antagonists have been added armamentarium because as they target the pathophysiology of SIADH. The recommended starting dose of tolvaptan is 15 mg. However, a recent case series of patients with heart failure and SIADH showed variable rates of Na correction and suggested to start tolvaptan at 7.5 mg to avoid an overaggressive water diuresis that may result in too rapid a correction in the serum sodium.We present two fictitious cases designed for educational purposes to illustrate this point.
Patient 1 A 70-year-old woman is seen emergency department due to new onset of confusion and falls. Her workup resulted in a diagnosis of diffuse large B cell lymphoma. During her admission, her serum sodium (SNa) ranged between 130-141 meq/l and she was eventually transferred to the rehabilitation unit. Over the next few days, her SNa decreased to 127 meq/l and then to 124 meq/l with urea nitrogen of 13 mg/dL. She appeared euvolemic and her mental status was unchanged. Her urine osmolality (UOsm) was 450 mosm/kg and urine sodium (UNa) 130 meq/l, both consistent with SIADH in the setting of her CNS malignancy. Thyroid and adrenal testing were normal.
The patient was following a 1L daily fluid restriction. She was initially given 20 mg of IV furosemide with subsequent 250 ml of urine output, though her repeat SNa dropped to 125 meq/l, and SNa was 123 meq/l by the next morning. The decision was made to give her 7.5 mg of tolvaptan, with subsequent urine output (UOP) of 150 ml and a SNa of 124 meq/l (Figure 1). She had a similar poor response to 15 mg and later the dose was increased. With 30 mg tolvaptan daily, her SNa plateaued around 130 meq/l.
The course of patient 1 and response to 7.5, 15 and 30 mg of tolvaptan (T). UNa = urine sodium in meq/l. Uosm = urinary osmolality in mosm/kg. UOP = urine output in ml.
Patient 2 A 90-year-old woman presents to the ED with confusion and cough. Her workup was consistent with pneumonia. Initial labs showed a SNa of 120 meq/l, urea nitrogen 9 mg/dL, Uosm 780 mosm/kg, and UNa 65 meq/l, consistent with SIADH in setting of an acute lung process. She appeared euvolemic and her thyroid and adrenal testing were normal.
As management with hypertonic saline was not in line with goals of care, she received 7.5 mg tolvaptan and over the next 8 hours she produced 2500 ml of urine. Her SNa increased to 128 meq/l. She produced another 1200 ml UOP over the next shift and her SNa continued to rise to 133 meq/l. Over the course of the first 30 hours, she made a total of 5.3 L and required 5% dextrose in water to limit the change in sodium to 11 meq/L. (Figure 2).
The course of patient 2 and response to 7.5 and 3.75 mg of tolvaptan (T). UNa = urine sodium in meq/l. Uosm = urinary osmolality in mosm/kg. UOP = urine output in ml.
The next day, she received a 3.75 mg dose of tolvaptan, requiring dividing of a triangular pill into quarters (Figure 3). This also had a robust effect, leading to another 2L of urine output and an increase in SNa from 131 meq/l to 138 meq/l within 6 hours. Again, sodium had to be lowered with hypotonic fluid infusions. Tolvaptan was then discontinued and further management was pursued with loop diuretics
Tolvaptan comes in a small triangular 15 mg tablet. To get a 3.75 mg dose you need to cut it in half twice, leaving a pill about a 1/8th inch square
Thus, as you can see both patients responded much differently to tolvaptan administration. In the initial SALT trials, the starting dose was 15 mg but could be increased up to 60 mg. In the SIADH subset, only 5.9% (3/51) of patients exceeded the maximum correction rate (>12 meq/l over the first 24 hours). In Europe, post marketing assessments for tolvaptan found that physicians were splitting tablets to allow for a 7.5 mg starting dose out of concern for over correction. A subsequent manufacturer sponsored pharmacodynamic study found that the 15 mg, 7.5 mg, and 3.75 mg doses were all susceptible to over correction (>8 meq/l in 8 hours).
Interestingly, both the 7.5 mg and 3.75 mg doses resulted in similar free water clearance and urine volume. In Italy, a separate study published in 2016 found a 42% over correction rate (>12 meq/l in 24 hours) with the 15 mg dose compared to none in the 7.5 mg group. Recently, Morris et al. examined the use of daily tolvaptan of 15 mg in 28 patients with SIADH and 39 patients with CHF. In patients with a SNa less or equal to 130- 33% of patients with SIADH over corrected (> 8 meq over 24 hours) compared to 5% of the CHF group. Lower baseline SNa (<121 meq/l) and lower baseline serum urea nitrogen (<10 mg/dL) were associated with more rapid 24-hour correction rates. These data show need for caution when using tolvaptan in patients with SIADH and to consider starting the dose less than 15 mg as overcorrection can lead to osmotic demyelination syndrome (ODS). While the reporting of ODS with tolaptan use have been rare most have been with the concomitant use of hypertonic saline ordiuretics. However, it is imperative to remain hyper vigilant about overcorrection as ODS development can lead to permanent neurological damage.
Tovaptan may be an attractive option for SIADH as it directly targets pathophysiology, and let’s face it, as nephrologists we can appreciate dilute urine. However, it is expensive with the risk of potentially serious adverse effects.
In A Tale of Two Cities Dickens wrote: “It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness…”; we find this quote fitting for our experience with these two patients.
Figure 1. A. Finely granular cast B. slightly coarser granular cast C. “urine poker quads” showing a fine (f), coarse (c) and muddy brown (mb) granular cast accompanied by a waxy (wx) cast D. “Muddiness” of mb granular casts is better appreciated at low power field compared to high power field (inset).
Perhaps that most highly sought finding in urinary sediment microscopy is the presence of granular casts. In clinical grounds, granular casts are typically associated with acute tubular injury (ATI) and guide the differentiation between prerenal and overt tubular insult.
The traditional view is that the granularity of granular casts comes from tubular epithelial cell debris that fill the cylindrical structure. However, granular casts are not exclusively found during ATI. Interestingly, early studies looking at the composition of granular casts were performed in small cohorts of patients with glomerular pathologies.
Therein, it was shown that granular casts have a matrix of Tamm-Horsfall (uromodulin) mucoprotein filled with plasma proteins. Thus, the presumption is that filtered plasma proteins in proteinuric pathologies can get “stuck” in a uromodulin gel, but it can also indicate that the granularity may relate to the extravasation of plasma proteins from peritubular capillaries during loss of integrity of the tubular epithelia in ATI.
In general, presence of scattered fine granular casts (Figure 1, panel A) does not carry a strong diagnostic or prognostic value, whereas abundance of the “extreme” of coarsely granular casts, i.e., “muddy brown” granular casts (Figure 1, panel D; Figure 2 panels A-C) present in sheets are considered pathognomonic of ATI and are associated with greater likelihood of dialysis-requiring acute kidney injury. Mitochondrial pigments or lipofuscin have been considered as being responsible for the enigmatic dark brown color of muddy brown granular casts, but that aspect remains a mystery.
Figure 2. A. sheets of muddy brown (mb) granular casts, > 10/lpf, pathognomonic of acute tubular injury B. mb granular cast are commonly clustered at the cover slip edges C. mb granular cast appearance with Sternheimer-Malbin (SM) stain; D. SM-stained coarse granular cast.
Ideally, patients with end-stage kidney disease would begin hemodialysis with a mature, functional arteriovenous access. However, in certain subgroups of patients, central venous catheters (CVCs) are unavoidable. Even for patients who ultimately use an arteriovenous fistula (AVF) or arteriovenous graft (AVG) for long-term dialysis, the significant majority are exposed to CVCs and their associated risks at some point in their lives.
CVC complications may be broadly categorized as infectious or non-infectious. Infectious complications include catheter-related bloodstream infection (CRBSI) and tunnel or exit site infections. Non-infectious complications include mechanical issues (e.g., malpositioned or kinked catheter), central vein stenosis, or thrombosis. In this post, we will explore some common CVC-related complications and how to manage them.
Case 1: You are notified by the dialysis nurse that your patient didn’t quite seem like her normal self when she came to dialysis today. Halfway through her session, she complained of nausea and chills. Oral temperature is 101 F. She dialyzes through a CVC and you immediately suspect CRBSI. Your next step is to:
a. Immediately start treatment with empiric broad-spectrum antibiotics b. Order a STAT chest x-ray and urinalysis c. Ask for blood cultures to be drawn from the peripheral veins d. Ask for blood cultures to be drawn from the catheter lumen and the dialysis circuit
Case 2: You are asked to evaluate a CVC-dependent dialysis patient who presented to the Emergency Department. He reports subjective fevers over the last 3 days and notes that the area around his right internal jugular CVC is red and sore. You obtain blood cultures and cultures of drainage at the exit site and start empiric antibiotics. Cultures come back positive for methicillin-resistant Staphylococcus aureus. In addition to giving appropriate antibiotics with dialysis, you plan to:
a. Remove the current catheter and place a new catheter at a different location b. Lock the catheter with an antibiotic solution following dialysis c. Order washout of the tunnel and guidewire catheter exchanged d. Treat the exit site infection with topical mupirocin
Case 2 represents an exit site infection with concurrent bacteremia. It is seen almost exclusively with Staphylococcal infections. Catheter salvage is reasonable with Staphylococcus epidermidis, but if the infecting agent is Staphylococcus aureus, the catheter should promptly be removed and a new catheter placed in a different location once bacteremia has cleared (choice a).
Case 3: You are rounding in the dialysis unit when the nurse approaches you about a CVC-dependent patient whose machine keeps alarming for high arterial pressures. This has happened before and has usually improved with thrombolytics, but now he can only achieve a maximum blood flow rate of 200 mL/min despite a 1-hour alteplase dwell prior to dialysis. You decide to:
a. Ask the nurse to reposition the patient and try to reverse the dialysis ports b. Refer the patient for CVC exchange c. Order a three-hour alteplase dwell d. Order ultrasound vein mapping and surgical consultation for AVF placement
Case 3 suggests the presence of a fibrin sheath, which can begin to form as soon as 24 hours following placement of the catheter. A fibrin sheath is composed of fibrinogen, lipoproteins, albumin, and coagulation factors. It has been found in up to 70% of catheters being exchanged for malfunction. The best choice for this patient, who has failed to improve following tPA dwell, is referral for CVC exchange with possible angioplasty and/or stripping of the fibrin sheath (choice b).
Case 4: You have a patient with a history of two failed right upper extremity AVFs and who is currently dialyzing through a left subclavian vein CVC. She had a new AVF placed in the left upper arm 6 weeks ago. Based on a recent ultrasound, the AVF is mature, but it is too deep and needs to be superficialized before it can be used. She has been complaining of left arm pain and swelling during her last few dialysis sessions. You are concerned for:
a. Left upper extremity AVF stenosis b. Left upper extremity deep vein thrombosis c. Central vein stenosis d. Right upper extremity deep vein thrombosis
Angiography is the preferred method for diagnosis. Patients with central vein stenosis may be asymptomatic and do not always require catheter removal unless problems develop. Angioplasty (with or without stenting) is the treatment of choice, followed by surgery for recurrent vein stenosis where angioplasty has failed.
General bedside management for non-infectious catheter complications includes repositioning the patient, forceful flushing of saline through the catheter, tPA dwell prior to dialysis, or obtaining a chest x-ray to rule out catheter kinks or malpositioning. If conservative measures fail to improve catheter function, the patient should quickly be referred to an interventional radiologist or nephrologist for further evaluation.