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welcome to week 4

This is the last week. of the rotation and we still have exciting topics to cover. If you are asking, yes, we are trying to cover all of glomerular disease in one day. This is insane and we realize it, but also know that even on the nephrology boards, this topic only comprises 10% of the exam. This area is rich in nuance, pathophysiology, and new data, but knowledge of ~1% of renal fellow-level glomerular knowledge (as well as a framework to learn now information on the subject) will put you ahead of most internal medicine residents. Lastly, we’ll talk about secondary hypertension. This subject loves to pop up on board exams, but it’s also good to know when to consider secondary hypertension and a good initial workup. Lastly, we are going to talk about outpatient CKD management. If you go into primary care, then you are our frontline defense against CKD progression and we look forward to working with you to take care of patients. If you go into nephrology, then knowing good CKD management is the next step in learning how to make a difference in people’s lives.

Table of Contents

  1. Glomerular Disease

  2. Evaluation and Management of Secondary Hypertension

  3. Outpatient CKD Management

Glomerular Disease

approach to glomerular disease

The kidney is a complex machine — and as with any complex machine has a variety of ways that it can break. We are going to talk about glomerular diseases, but first, let’s think about how we approach a malfunctioning kidney. 

Let’s say you are the parent of a teenager who just learned to drive. They call you and tell you that their car wasn’t able to make it home from school to the house. This is an incredibly vague situation (it’s vague in the same way that someone having “kidney disease” is vague). To figure out the issue, you may start asking a series of questions like:

  1. Did the car start?

  2. Did any lights actually turn on, or is the battery just dead?

  3. Did your car make it part of the way home and then die or did it start in the first place?

  4. Is the gas tank empty?

  5. Are there four wheels on the car?

After an intuitive series of questions, you can likely narrow down the problem to a few different causes and find a solution.

The kidneys maintain homeostasis and when homeostasis is compromised, we are alerted to a potential problem with the kidneys. There are three main ways a kidney can break — something happening before the kidney, something after the kidney, or something happening within the kidney itself. Drilling down further, when something is happening within the kidney itself, one of three “compartments” can be affected. These three compartments are the microscopic vasculature, the interstitial compartment, and the glomerulus. We are going to focus on glomerular disease, but some quick examples of pathophysiology of the other two compartments are a thrombotic microangiopathy affecting the vasculature or acute interstitial nephritis affecting the interstitial compartment. 

Glomerular disease is an understandably intimidating topic. Even the terminology is challenging. Some of the terms we use to describe glomerular disease are umbrella terms. Additionally, some diseases have multiple names. Sure, glomerular disease can be an endless deep hole of pathophysiology, cytokines, clinical trials, and immunosuppression, but it can be so much more simple. The following is a good approach to a basic understanding of glomerular disease. 

Let’s say you have a patient with an elevated creatinine and hematuria (with dysmorphic RBCs). You are asked what the possible glomerular disease is. This can appear difficult because there are multiple possibilities and it’s hard to make a good differential diagnosis unless you take care of these type of patients all the time. It’s confusing, but it doesn’t have to be this way. Shifting gears, let’s think about the next bacterial pneumonia you admit — they have a left lower lobe opacity on the CXR and are being admitted to the hospital from a home setting. You get the recommended testing and start them on empiric therapy for community-acquired pneumonia. They respond to treatment, get better, and everyone is happy. It doesn’t feel that complex and this is despite the fact that you have absolutely no clue what actual bacteria caused their pneumonia. It probably was S pneumonia, but it could have also been H influenze, M catarrhalis, M pneumoniae, ect. They got better and so you actually don’t really care which bacteria caused it because you did the following: diagnosed their clinical phenotype, considered, but ruled out things the patient does not have (differential diagnoses for dyspnea such as heart failure, pulmonary embolism, ect), did the recommended workup, and treated them as recommended. 

The same comfort in the fact of uncertainty can be applied to glomerular disease. First we define the clinical phenotype which is either nephrotic or nephritic syndrome. Nephrotic syndrome is defined as the combination of nephrotic range proteinuria (at least 3.5 grams of daily proteinuria) along with hypoalbuminemia, lower extremity edema, and hyperlipidemia. Nephritic syndrome is just when you have dysmorphic RBCs in the urine, although worsening kidney function, some proteinuria, and HTN can occur. When you’ve decided if the patient has nephritic or nephrotic syndrome, then congratulate yourself because you’ve defined the clinical phenotype. Next, make a differential diagnosis and consider non-glomerular etiologies that could explain their presentation. This will help you avoid confirmation bias. The workup part for glomerular disease is easy. In general, you have to have a kidney biopsy to properly diagnose glomerular disease and in your mind, this is where the buck stops… suspect glomerular disorders, rule out alternative diagnoses, and get a kidney biopsy to diagnose it. 

Sure, we get serological testing on the patients. If you are in the position of working up glomerular disease, then you are either a nephrologist or working alongside one. We’ll forego the details of glomerular testing for patient-specific discussions. Lastly, you treat the patient according to their specific condition. This is a can of worms we are not going to open at this point in time since the sky is the limit for information abundance in this area. Just enjoy reading your heart out on the next glomerular patient and that will be a quality learning experience. 

So in short, that’s the process of glomerular disease evaluation. The only last things we will try to do is make a short list and a few buzz phrases or presentations to associate with each condition. 

Nephrotic Syndrome differential diagnosis

If your patient has nephrotic syndrome, consider the etiologies noted below. As a disclaimer, FSGS is only a pattern of disease seen on a kidney biopsy, not a specific disease etiology. Overall, if the following is your differential diagnosis, you are well-prepared mentally to diagnose your patient. 

  1. Diabetic kidney disease

  2. FSGS

  3. Membranous nephropathy

  4. Lupus nephritis (class V)

  5. Amyloidosis

  6. Minimal change disease


Nephritic Syndrome differential diagnosis

The following are the diseases you should be considering if your patient has nephritic syndrome. As with FSGS, please note that MPGN is also just a pattern on a kidney biopsy and not a specific disease. 

  1. IgA Nephropathy

  2. ANCA Vasculitis

  3. Lupus nephritis

  4. Anti-GBM disease

  5. Infection-related glomerulonephritis

  6. Alport syndrome

  7. Thin basement membrane disease

And now, some buzzwords or buzz presentations to think about for each disease:


Nephrotic Syndrome Buzz phrases

Diabetic kidney disease

  • Consider this in patients with a history of uncontrolled diabetes. The association between diabetic retinopathy and diabetic kidney disease is less firm with type 2 diabetes as compared to type 1 diabetes. It’s tricky to diagnose nephrotic syndrome in diabetics, but consider autoimmune causes of nephrotic syndrome in a well-controlled diabetic who all of a sudden develop rip-roaring nephrotic syndrome out of the blue. 

FSGS

  • More common in African Americans due to the higher incidence of APOL1 risk variants in this group. FSGS is associated with HIV. Do note that people can get FSGS after years of severely uncontrolled hypertension. 

Membranous nephropathy

  • Consider this in older patients. If you do get a patient with biopsy-proven membranous nephropathy, a big consideration is if it is primary (due to an autoimmune cause only), or if it is secondary to another cause such as cancer. If you are presenting a patient with membranous nephropathy to an attending, be sure to have information on age-appropriate cancer screening available. 

Lupus nephritis

  • Lupus is known for causing every presentation under the sun. It can cause pure nephrotic syndrome and this is referred to as class V lupus nephritis. Lupus nephritis is more common in young women. 

Amyloidosis

  • Most of the time, when we think of amyloidosis, we are thinking of it in association with multiple myeloma. In nephrotic syndrome in patients over the age of 50, always look for clinical signs of myeloma. 

Minimal change disease

  • This is much more common in children, but can happen in adults. We bump minimal change disease higher on our differential diagnosis if a patient with nephrotic syndrome develops an abrupt onset of lower extremity edema and nephrotic syndrome. 

Nephritic Syndrome Buzz phrases

IgA nephropathy

  • This is the most common cause of nephritic syndrome. Always keep it high on your differential diagnosis in this setting. 

ANCA Vasculitis

  • This is a relatively common cause of nephritic syndrome. Always keep it high on your differential. Note that people can have mononeuropathies with this, along with recurrent sinus “infections.” If you have a patient with nephritic syndrome, look at their skin because vasculitis lesions can commonly be seen in these people. Also note that ANCA vasculitis is one cause of pulmonary renal syndrome, so consider it if your patient has hemoptysis and kidney failure. 

Lupus nephritis

  • Always keep this in your differential, but higher on the list in young women. 

Anti-GBM disease

  • This is one of most aggressive nephritis disorders, so place it higher on your differential during rapidly progressive glomerulonephritis. It also causes hemoptysis in pulmonary renal syndrome. 

Infection-related glomerulonephritis

  • We first learned this condition in med school as post-streptococcal glomerulonephritis, but many types of infections can be associated with glomerulonephritis. 

Alport syndrome

  • Honestly, by the time you see an adult patient with this, they will already tell you that they have Alport syndrome considering that it is an inherited disease. Always ask about a family history and consider it if there is an unknown etiology for hearing loss in a glomerulonephritis patient. 

Thin basement membrane disease

  • This is not an autoimmune disease, but likely a carrier phenotype of Alport syndrome which causes thin glomerular basement membranes. Typically it causes acanthocytes to be present in the urine, but is typically not associated with a significant decline in kidney function. 

Quiz Questions

  1. What are the characteristics of nephritic and nephrotic syndrome?

  2. Name four causes of nephritic syndrome. 

  3. Name four causes of nephrotic syndrome. 

  4. What blood disorder is usually associated with amyloidosis?

  5. What nephrotic syndrome is known for having an abrupt onset of edema and proteinuria?

Evaluation and management of secondary hypertension

Secondary hypertension should always be on your radar, especially when you encounter someone who has had long standing, difficult to control blood pressure, someone who was diagnosed with early onset hypertension, or someone who has had relatively good blood pressure control, which then all of a sudden spikes. Workup for secondary hypertension does not have to be scary. The more you screen for it, the more you are going to diagnose. Trust me, it’s out there -- except. Except for pheochromocytoma. You are probably never going to diagnose that, but should recognize that it exists. 

Renal Artery Stenosis

The most common type of secondary hypertension is renovascular hypertension or renal artery stenosis (RAS). Your most at-risk population in this category are going to be older persons with a history of hypertension, hyperlipidemia, and who often have peripheral artery disease and a history of smoking. However, you should also be aware that renovascular hypertension can be present in young females with a history of fibromuscular dysplasia (familial history, wide blood pressure variability, and smoking should raise red flags here). The three most common presentations of severe RAS are drug resistant hypertension, ischemic nephropathy, and flash pulmonary edema. Before testing for RAS, you need to decide which patients are likely to have a beneficial clinical response to revascularization (hint...it’s usually younger people). Diagnostic work up includes three types: noninvasive functional imaging or doppler, CT or MRA, and invasive digital subtraction angiography. When patients have normal renal function, game on! You can pick which test you think is most appropriate. For patients with altered renal function, a risk assessment for potential contrast induced kidney injury should be performed.  Of note, the gold standard for assessing severity of RAS is the invasive digital subtraction angiography. However, doppler ultrasonography with measurement of resistive index can not only diagnose RAS but can ascertain the likelihood that a patient will respond to revascularization (so pick this test!). RAS first line treatment should be an ACE or ARB but watch out for an inappropriate rise in serum creatinine after initiating treatment. Understand that often revascularization poses a larger threat to the patient than the actual stenosis and that outcomes are typically the same with intensive medication therapy. 

Primary aldosteronism

Primary hyperaldosteronism is our next topic. This type of secondary hypertension is gaining lots of attention in the world of hypertension research. It was once thought to be a binary diagnosis. Kinda like pregnancy. You either have it or you don’t. What we now know is that primary hyperaldosteronism is a disease of progression. It often goes undiagnosed because the hallmark signs have always been hypertension in the setting of low potassium and metabolic alkalosis. Now we understand that people with this problem exist on a spectrum and that our previous diagnostic techniques are not as great as we thought. The idea that measuring aldosterone and renin and calculating a ratio that proves or disproves a diagnosis is quickly becoming obsolete and often results in muddy waters filled with effects of RAAS inhibitors, diuretics, and even antidepressants. Unfortunately, we don’t have a better option at this point. So the better strategy is to ensure proper specimen collection and look at the values individually. If the renin is low and the aldosterone is high, repeat the test again. If the second set of tests give similar results, then perhaps proceed with confirmatory testing. This is of course assuming that your patient is potentially willing to undergo adrenalectomy. If not, suppressive therapy in the form of a mineralocorticoid antagonist is your new best friend. 

Now for real world application! When you are covering a night shift or admissions and receive a phone call from the nurse to report a “critically high” blood pressure, what do you do? Here are a few things to consider to not only make your life easier, but also some tips and interventions that will impress your colleagues:

  1. Look at the blood pressure trend. Is this a singular event or has the blood pressure been inappropriately elevated for a significant amount of time?

  2. Ensure that a quality blood pressure has been taken (appropriate cuff placement, cuff size, patient body position)

  3. Evaluate for outside influences (are they vomiting, having pain, panic attack, etc.) and treat those appropriately

  4. What antihypertensives have they received in the last 24 hours? Is there room for adding additional first line therapies or increasing to at least a moderate dose of current medications? 

  5. Consider lab values - particularly potassium. If it is low - add replacement.

  6. Consider secondary hypertension labs and evaluation: Labs should include a renin activity, aldosterone, and plasma metanephrines, and possibly cortisol levels if something like Cushing’s is suspected. Note: if potassium levels are low, the potassium should be replaced and values should be normal prior to checking renin/aldosterone.

  7. Consider evaluation for renovascular hypertension with a renal doppler study

  8. Pro tip: there are specific times and appropriate cases for using direct vasodilators (i.e, hydralazine) and alpha-blockers (clonidine). Most likely there is another alternative that is more appropriate and will provide better long term blood pressure control in comparison to these medications. These classes of drugs come with significant risk and have an unpleasant side effect profile, not to mention they are very short acting. Please avoid using these as much as possible. 

Outpatient CKD Management

Outpatient CKD clinic is where nephrologists spend a lot of time. It’s also the arena that we can make some of the most lasting changes in our patient’s health and outcomes. More importantly is the knowledge of primary care physicians for CKD management since they are our first line defense against CKD progression. To cover this topic, read the CKD management writeup here.

Quiz Questions

  1. What are the eGFR and albuminuria stages of CKD?

  2. Give 3 ways you could treat mild hyperkalemia of 5.4mmol/L in an outpatient patient with diabetic kidney disease with and eGFR of 32mL/min and a bicarbonate level of 21mmol/L on lisinopril 20mg daily (on only one BP med) with a blood pressure of 142/89mmHg.

  3. Name 3 phosphorous binders.

  4. What is the goal blood pressure we use for the majority of our patients?