#NephMadness 2021: Primary Care Region

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Selection Committee Member: Clarissa Diamantidis @cjdiamantidis

Clarissa Diamantidis is an Associate Professor of Medicine at Duke University School of Medicine, and attending nephrologist at the Durham VA Medical Center in Durham, NC. She is an NIH-funded clinical investigator with research interests in renal epidemiology, patient-centered care, the intersection of primary care and nephrology, and health disparities. 


Writer: Racquel Holmes @RacquelbelleMD

Racquel Holmes is a 2nd year nephrology fellow at Duke University and a 2020-2021 AJKD Editorial Intern. Her academic interests include obstetric nephrology, health disparities and advocating for medical education and the benefits of clinician educator leadership.

Competitors for the Primary Care Region

Transplant Primary Care vs CKD Primary Care

GFR in CKD vs Proteinuria in CKD

37 million people in the US have CKD

There are 10,000 nephrologists in the US

So that works out to 3,700 CKD patients per nephrologist.

It is clear that chronic kidney disease (CKD) cannot be tackled by nephrologists alone. It takes a village to care for the CKD community. One area is kidney transplant patients. These patients typically get much of their care from dedicated tertiary care specialists in transplant medicine, but patients with a kidney transplant have other medical conditions and compelling needs for PCP. We cover the nuts and bolts of what a PCP needs to know in order to care and counsel these complex patients. But, standard CKD is a common morbidity in many patients that present to primary care, and unfortunately multiple barriers exist to primary care doctors taking optimal care of these patients including: unfamiliarity with some aspects of CKD care (meds, algorithms, standards of care, etc), time constraints, and fear of emotionally overwhelming patients. So here we will distill CKD care down to some practical, high-impact, evidence-based principles and procedures for primary care providers (PCP) to take care of their CKD patients in busy primary care practices with limited time for patient care visits.

The other match-up pits the two axes of the KDIGO (Kidney Disease: Improving Global Outcomes) CKD heat map, proteinuria and glomerular filtration rate, against each other. We will look at how they are measured, how they should be measured, and how we should think about them. 

Which concept will the Blue Ribbon Panel pick as being the most impactful for patients with kidney disease – primary care of the transplant patient or primary care of the patient with CKD? The other matchup pits glomerular filtration rate versus proteinuria assessment – this is sure to be a challenge.  

Transplant Primary Care vs CKD Primary Care

 

Transplant Primary Care

A kidney transplant is the best therapy for kidney failure and the number of people with kidney transplants keeps growing. Their transplant care is provided by specialized transplant teams but kidney transplant patients still need primary care and these providers need to understand the unique needs of these patients.

The success of kidney transplantation has resulted in more and more patients living longer and longer with transplanted kidneys. The improvements in transplantation means that when patients with kidney transplants die, it is most often with the transplanted kidney still working. Overall mortality for patients with a kidney transplant is falling; the 10-year mortality has improved 24% from 1996 to 2005. Importantly, the cause of death is typically not directly related to the transplant, with CV deaths being most common and infectious complications coming in third, just ahead of malignancy. Interestingly, while the 10-year mortality trends of CV and infectious deaths have fallen steadily, malignancy showed no similar improvement.

Based on data from Awan et al.

As mortality gets pushed further and further from the time of transplant and the causes of death move further and further away from graft failure and infection, the role of the PCP grows more important in the management of kidney transplants. To provide optimal care for this complex patient population, a co-management strategy between the transplant nephrologist and PCP is ideal. Thus, it is important for PCPs to have familiarity with and understanding of the particular needs of the patient with a kidney transplant. 

Visual abstract by Verner Venegas on Voora et al.

Immunosuppression

Patients with a kidney transplant require immunosuppression to prevent allograft rejection. This is true throughout the lifespan of the patient. Patients need immunosuppression beyond the first few months post transplant. The goal with immunosuppression is to give enough to prevent rejection but not too much in order to prevent medication-related adverse effects including transplant damage, infection, and malignancy. While PCPs do not manage immunosuppressive medications, they should be familiar with side effects and common drug-drug interactions that could possibly result in toxic over-immunosuppression — or low drug levels that could lead to rejection.

 

Drug Notable Possible Side Effects Common Drug-Drug Interactions
Calcineurin Inhibitors (cyclosporine and tacrolimus) (Farouk 2020) -Hypertension

-Glucose intolerance (tacro>cyclo)

-Hyperlipidemia

-Hyperuricemia

-Hyperkalemia

-Hypomagnesemia

-Infection

-Tremor (tacro>cyclo)

-Malignancy

-Gingival hyperplasia and hirsutism (cyclosporine)

-Alopecia (tacrolimus)

Decrease levels: Inducers of cyp3A4/5 such as rifampin, phenytoin, St. John’s Wort, nafcillin

Increase levels: Inhibitors of cyp3A4/5 such as grapefruit, ketoconazole, clarithromycin, amiodarone, diltiazem, verapamil

mTOR Inhibitors (everolimus and sirolimus) -Thrombocytopenia

-Leukopenia

-Hyperlipidemia

-Infection

-Interstitial pneumonitis

-Mouth ulcers

-Poor wound healing

-Lymphedema

Decrease levels: Inducers of cyp3A4/5 (see above for examples) 

Increase levels: Inhibitors of cyp3A4/5 (see above for examples) 

mycophenolate (mycophenolate mofetil and enteric coated mycophenolate sodium) -Diarrhea

-Anorexia, nausea, vomiting

-Bone marrow suppression

-Infection

-Malignancy

Decrease levels: antacids, mineral supplements, bile acid sequestrants, and proton pump inhibitors

Increase levels: rifampin, acyclovir, valacyclovir, and probenecid

azathioprine -Anorexia, nausea, vomiting

-Bone marrow suppression

-Infection

-Malignancy

Increase levels of toxic metabolites: allopurinol and febuxostat
prednisone -Weight gain

-Hyperglycemia

-Osteoporosis

-Cardiovascular disease

-Hypertension

belatacept -Post transplant lymphoproliferative disorder

Cardiovascular Disease

The primary cause of death in patients with a kidney transplant is CV disease. Kidney transplant recipients should be considered at high risk for CV disease and risk factors should be mitigated whenever possible.

Blood Pressure

Like any patient with CKD, patients with kidney transplants need careful blood pressure monitoring and intervention. Guidelines for blood pressure control in patients with a kidney transplant are no different than for other patients with CKD. Blood pressure should be treated to a goal of <130/<80 mm Hg. Additionally no clear guidance is provided on specific drugs to use or avoid in patients with a kidney transplant as no study has shown an advantage in graft or patient survival with any specific class or agent. For example Ibrahim et al randomized 150 kidney transplant recipients to losartan 100 mg or placebo for 5 years and there was no difference in graft or patient survival. Similarly, the Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) randomized 502 patients with a kidney transplant to candesartan or placebo for 21 months and despite showing statistically significant reductions in blood pressure (by 6.8/4.8 mm Hg) and proteinuria (relative decrease of 20-30% depending on how proteinuria was assessed) there was no improvement in the composite outcome of graft survival, CV events, or patient survival. So despite a lack of confirmatory studies, guidelines and common sense say we should control blood pressure in kidney transplant recipients as well as in patients with CKD

Lipids

The KDIGO Transplant guidelines don’t make any specific recommendations for lipid management in patients with kidney transplants, but suggest physicians simply use the KDIGO CKD lipid guidelines, which recommend statins for everyone over the age of 50 and to evaluate the 10-year CV risk of people under the age of 50 and treat them with statins if the risk is over 10%. A number of studies have looked at the efficacy of statins in patients with a kidney transplant. The Assessment of LEscol in Renal Transplantation (ALERT) study was a 2102-person randomized placebo-controlled trial of fluvastatin. After nearly 6 years of follow up there was no difference in the primary outcome of major adverse cardiac events. A 2014 Cochrane review showed similar lack of efficacy with all outcomes crossing the line of identity.

Lovastatin, simvastatin, and pitavastatin have potentially harmful drug-drug interactions with both cyclosporine and tacrolimus (as well as everolimus and sirolimus) so those combinations should be avoided. Atorvaststin should be combined with those agents only at doses of 10 mg or below.

Bone Health

Bone disease is common following kidney transplant and this results in real morbidity and mortality. Fortunately the risk of hip fracture following transplant is falling (HR 0.56 for hip fracture in 2010 compared to 1997). Changes in immunosuppressive and improved bone health prior to transplant are likely explanations. Transplant patients typically lose bone mineral density following transplant, but this is typically limited to the first year after transplant with stability following that. Still bone health is an important problem with nearly 1 in 4 kidney transplant patients having a fracture in the first 5 years after transplant.

Interventions to reduce risk have been studied but there are no clear winners. Patients should have vitamin D deficiency corrected, but data on reduced fractures is still absent. Bisphosphonates have a checkered past with some showing improved BMD and others failing to show that. Studies that have done bone biopsies have shown increased adynamic bone disease. Again a reduction in fractures has been difficult to demonstrate. Denosumab has shown promise in CKD and looks promising in kidney transplant but its role has not yet been fully defined. Currently the best advice is to treat a patient with kidney transplants like any patient at high risk for fractures.

Malignancy 

Malignancy is one of the three leading causes of death in patients with kidney transplants, along with infection and CV disease, and malignancy may become more likely as the life of the allograft increases due to increased exposure to immunosuppression. In an analysis of the United Network for Organ Sharing (UNOS) registry, it accounted for 14.5% of deaths 5-10 years after kidney transplant. Additionally, unlike CV causes of death, deaths due to malignancy have not improved over time. Malignancy was responsible for 1% of deaths in the 70s, 5% in the 80s, and 13% in the 90s. Common cancers (breast, prostate, colon, lung) occur at a rate of about twice the risk of the general population. Other cancers, especially virus-associated cancers like Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer occur at a rate of about 20 times the general population. The most common malignancy seen post kidney transplant is skin cancer and may occur at a rate close to 100 times the rate of the general population. Cancer screening recommendations for patients with kidney transplants were summarized by Wong et al. An important malignancy specific to the population is post-transplant lymphoproliferative disease (PTLD), which refers to a spectrum that ranges from benign cell proliferations to malignant lymphomas. Risk factors include immunosuppression intensity and Epstein-Barr virus infection. PTLD can present in a myriad of ways.

The most important cause of the increased cancers in the transplant population is immunosuppression. This association was clearly shown in a RCT of two different cyclosporine dosing strategies: standard dose (a trough target of 150-250 ng/ml) versus low dose (75-125 ng/ml). After 66 months, there was significantly increased malignancy in the standard-dose arm (p = 0.034). Similar findings have subsequently been repeatedly shown in multiple retrospective studies. Malignancy is an unfortunate side effect of immunosuppression intensification that follows episodes of acute rejection. Immunosuppression regimens are tailored to balance rejection prevention with prevention of malignancy and infection. 

The KDIGO transplant guidelines recommend that patients with a kidney transplant have an annual skin exam by a qualified health professional with “experience in diagnosing skin cancer.” For non-skin cancers, the KDIGO transplant guidelines follow close to those established for the general population but do recommend that the plan is individualized to the patient. Namely, that in those with reduced survival due to other comorbidities, screening may not be appropriate.

Fertility

Advanced kidney disease severely decreases fertility and one of the potential joys and benefits of transplantation is the restoration of fertility in women of child-bearing age who wish to become pregnant. Though fertility is often restored within months of a kidney transplant, pregnancies should be planned and considered high risk. Pregnant patients with a kidney transplant should be referred to specialists to monitor and assist with their pregnancy. Women wanting to get pregnant should discuss this with their transplant team. Immunosuppression and antihypertensive regimens need to be adjusted to protect the baby and mother.

Vaccines

Patients with kidney transplants are maintained on immunosuppression to prevent rejection, but this treatment leaves patients at increased risk of infectious complications. To counter this patients with a kidney transplant should get immunizations to prevent infection. Ideally these vaccines should be administered prior to transplantation. In general, patients about to get a kidney transplant should have all of their vaccines given at 2 weeks prior to transplantation, or 1-6 months after transplantation to allow the proper immune response to the vaccine. The early immunosuppression is the most intense and theoretically it could block the development of vaccine-induced immunity. 

Influenza

In a 5-year prospective trial of influenza infection in patients with solid organ transplants, receiving a vaccine in the same year of infection was associated with a lower likelihood of pneumonia and ICU admission. In patients with influenza A, receiving the vaccine was associated with lower viral loads. The influenza vaccine offers impressive protection to recipients of organ transplants and should be administered every year. If available, patients with kidney transplant should receive a high (60 µg) dose vaccine or standard dose with a booster injection 5 weeks later.

Pneumonia

Invasive pneumococcal pneumonia is a problem in transplant. In a 10-year prospective study, the rate of invasive pneumococcal pneumonia was 146 infections per 100,000 patient-years in patients with solid organ transplants, compared to 11.5 per 100,000 patient-years in the general population. 85% of infections in the solid organ transplant patients were serotypes contained in the 23-valent vaccine. There are two pneumonia vaccines and the American Transplant Society (ATS) recommends patients with transplants get both. They should get the 13-valent vaccine first followed by the 23-valent vaccine no less than 8 weeks later. 

Varicella Zoster

The original varicella zoster vaccine (LZV) was a live attenuated virus with marginal efficacy. The second-generation vaccine (RZV) is highly effective in immunocompetent adults and, as a recombinant vaccine, can be used after transplantation. Vink et al performed a phase 3 trial in 264 kidney transplant recipients. Four-fifths had both humoral cellular responses 1 year later. No safety signal was seen. RZV is recommended by ATS for kidney transplant recipients over age 50.

SARS-CoV-2

No patients with transplantations were included in the phase 3 trials of the two RNA vaccines now available for SARS-CoV-2, but many have subsequently been vaccinated following their emergency approval. There are no indications that the vaccines cause problems with the allograft or are less effective in patients with kidney transplants. Kidney News recently published guidelines on vaccination for kidney transplant recipients.

The benefits of vaccination outweigh any theoretical risks especially in countries where SARS-CoV-2 transmission continues at a high level.

Statement of the American Society of Transplantation, 2021

 

CKD Primary Care

37 million people in the US have CKD. That is 14% of the adult population. How can the best care be delivered for this many patients?

In 2013, KDIGO published the 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease. It is a beast of a guideline, spanning 147 pages (excluding references). The executive summary alone is 10 pages and contains 102 recommendations! The philosophy of the guideline seemed to be, let’s set a marker of where the state of CKD research is at this moment regardless of level of evidence. The guidelines are broad and unwieldy for a busy practitioner to juggle in the 15 minutes they have to see a patient with 3 concerns, 6 medications, and only an incidental diagnosis of CKD.

In the same year, the American College of Physicians (ACP) came out with a tidy 10-page (excluding references) guide to the care of patients with CKD. The ACP, as they typically do, limited themselves to strict evidence-based guidelines and left everything else out. The 10 pages describe 4 straightforward and evidence-based guidelines for the management of CKD stages 1-3, which represents the vast majority of people with CKD in the US:

  1. Only screen for CKD in people at risk for CKD. The ACP made waves by not recommending generalized, unselected screening for CKD. But when you look at the list of people they included as being at risk for CKD, it seems well thought out and will largely catch everyone of concern: diabetes, hypertension, old age, obesity, family history, African American, American Indian, or Hispanic ethnicity. They also advised testing anyone with symptoms of kidney disease. So while not a generalized screening program it does cast a pretty wide net.
  2. Patients already on an ACE inhibitor or ARB don’t need additional testing for proteinuria. The value of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been shown in dozens of randomized controlled trials, but one thing all the trials had in common was using the maximum tolerated dose. So, the ACP guidelines ignoring dose and pretending any ACE inhibitor or ARB dose is fine seems like an oversight, but is there value in serial proteinuria assessment? Is this something to burden primary care doctors with? How would one use that information? Assess for proteinuria once. Maximally suppress it with renin-angiotensin aldosterone system (RAAS) inhibition and a sodium-glucose cotransporter 2 (SGLT2) inhibitor and move on. The counterargument is that it is a reliable prognostic marker that should alert physicians to patients who will have faster CKD progression and will require earlier referral for transplantation, vascular access, and advanced nephrology care. Moreover, it could signal the need to entertain alternate or additional diagnosis (e.g., myeloma, minimal change, membranous).
  3. ACE inhibitors or ARB for patients with CKD and hypertension regardless of albuminuria. This seems like a simple recommendation but KDIGO currently recommends ACE inhibitors only for patients with diabetes and albuminuria over 30 mg/g or more than 300 mg/g if they don’t have diabetes. The ACP guidelines seem to be breaking their strict evidence-only rule for this guideline. But interpreted through the lens of making things simple and straightforward for busy practitioners this seems like a reasonable shortcut unlikely to cause harm. Additionally, while patients without proteinuria don’t get the kidney protection provided by RAAS inhibitors, RAAS inhibitors are still a first-line agent for managing hypertension and in the presence of CKD, people will likely need multiple classes of antihypertensives to get their blood pressure to goal. 
  4. In patients with CKD and elevated low-density lipoprotein (LDL) levels, the ACP guidelines recommend the use of statins. This again seems like a conservative recommendation but it is not in line with the more aggressive KDIGO lipid guidelines, which recommend statins for all patients with CKD over the age of 50 and in patients under 50 with diabetes, previous CV events or a 10-year risk of CV disease greater than 10%. Of note, the only study to show a benefit of lipid-lowering therapy in patients with CKD was SHARP, which not only treated patients with simvastatin but also with ezetimibe, compared to placebo.

And that’s it. Nothing about vitamin D, phosphorus, or PTH. Nothing about anemia. Nothing about vein preservation, special diets, or avoiding NSAIDs. Why? Because no one has done the proper studies to see if those matter in CKD 1-3. This cautious, outcome-based document came from the realization that when you make sweeping recommendations for people, even those at high risk of poor outcomes, without outcomes-based evidence even the best intentions can have unintended negative consequences. 

The most important gap in the ACP guideline is direction on when a PCP should refer to a specialist, but of course the comprehensive KDIGO guidelines has that covered. KDIGO makes recommendations on not only when to refer initially but how often to see patients. KDIGO recommends referral when patients meet any one of 9 possible targets. Primary care doctors should refer to a specialist when CKD patients have:

  1. Acute kidney injury (AKI)
  2. Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.72 m2
  3. Albuminuria over 300 mg/g (spot urine ratio of albumin [in mg] to creatinine [in g])
  4. Progression of CKD, defined as a 25% decrease in eGFR or advance in CKD stage (e.g., moving from CKD stage 3a to 3b)
  5. Unexplained RBC casts on urine microscopy
  6. Hypertension refractory to treatment or requiring 4 drugs
  7. Persistent abnormalities of serum potassium 
  8. Recurrent or extensive nephrolithiasis
  9. Hereditary kidney disease

And if 9 bullet points were not enough to keep in your head they also recommend referral when patients have a 1-year risk of kidney replacement therapy of 10-20%. While these guidelines do not suggest a specific risk calculator, KidneyFailureRisk.com is a well-validated calculator that is easy to use.

Visual abstract by Dominique Tomacruz on Potok et al.

Of note, many primary care doctors are dissatisfied with the co-management of CKD with nephrologists. Greer et al conducted focus groups in 4 cities to determine what was the source of this dissatisfaction. The major themes are listed below. 

PCP-perceived barriers to nephrology referral and co-management

  • Lack of timely adequate information exchange. Have a plan and be specific about who will execute, for how long and what to monitor.
  • Unclear delineation of roles and responsibilities.
  • Poor working relationships with nephrologists.
  • Patient lack of trust or an established relationship with nephrologists.

The ACP and KDIGO CKD guidelines follow two different philosophies. The ACP provides a floor. It says this is the minimum you should be doing for your patients with CKD. This is where we have a solid evidence base and it is irresponsible to do less than this. Going beyond this is going to require some homework and since rigorous placebo-controlled trials are absent, you may be causing harm despite the best of intentions and no matter how much the intervention makes sense. The KDIGO guidelines inform physicians across the broad landscape of clinical CKD care. It provides physicians a summary of where the science was (in 2013) and how best to incorporate it into patient care. Both of these strategies are valid and have value and physicians who take care of patients with CKD should spend time familiarizing themselves with both documents.

However where both of these guidelines fall down is the fact that they are old. CKD is a fast-moving field and advances are developing on multiple fronts. Both guidelines are almost a decade old. The ACP guidelines literally expired in 2018.

Our patients deserve consensus guidelines that are continuously updated rather than published and then put in a drawer for 10 years. The most glaring intervention that is MIA from the guidelines is last year’s NephMadness winner, SGLT2 inhibitors. These drugs are rewriting the dogma on CKD. Introduced less than a decade ago to little fanfare, they have been winning converts by demonstrating powerful kidney and heart protection in RCT after RCT. This was most recently and most convincingly shown in the landmark DAPA-CKD trial where these drugs finally shed their diabetes drug skin to shine as general purpose CKD medications.

Visual abstract originally for NephJC by Denisse Arellano on Heerspink et al.

GFR in CKD vs Proteinuria in CKD

 

GFR in CKD

Conventional wisdom (and the NKF) says that the glomerular filtration rate (GFR) is the best way to measure kidney function and is routinely used to assess the progression of kidney disease. That said, determining the GFR is not straightforward and has created much controversy.

Part of the problem is determining what the actual GFR is. The textbook method for measuring a GFR is infusing inulin (a substance which is freely filtered by the glomerulus and neither secreted or reabsorbed by the tubules) until there is a steady-state concentration in the blood and then measuring the inulin clearance. Strangely, this would need a 24-hour test to average out the circadian rhythm of GFR (you knew that GFR is roughly 20% higher during the day, right?). Additionally, as if you need an “additionally” after requiring patients to stay 24 hours for a GFR measurement, almost all clinical labs have lost the ability to even measure inulin. It is no longer listed on the College of American Pathologists proficiency testing menu. So with inulin clearance out of reach of everyone but dedicated research labs, the gold standard crown was passed to iohexol and iothalamate infusions. This is usually done by giving a bolus of either drug and then following serial urine or plasma levels and calculating the GFR from the rate of appearance (in urine) or rate of disappearance (from plasma). But even that is more difficult than one would think, as there is variability due to the specific measurement technique used:

Using HPLC to measure iohexol, we detected no significant difference between iohexol and iothalamate clearance, but as in the study by Seegmiller et al, using LC-MS/ MS–measured iohexol gave significantly lower iohexol versus iothalamate clearance. Thus, the method for measuring iohexol or iothalamate can influence results.

We cannot expect clinicians to be familiar with the vagaries of iohexol measurement and know how it influences estimates of GFR. This is a problem that can be solved by creating and adopting international standards for the measurement of GFR using exogenous markers, as was done for serum creatinine and is being done for urinary albumin.

Despite these shaky foundations, exogenous clearances are used as the gold standard and are the measuring stick we use to define accuracy among the clinically convenient methods to estimate GFR. They even get to carry the name measured GFR (mGFR) to signify their privileged position as Conveyer of Truth.

Nuclear imaging of the kidney using different tracers can also be used to determine function. Technetium-99m mercaptoacetyltriglycine (Tc99m-MAG3 or simply MAG3) scans can be used to determine renal blood flow. Tc99 DTPA diethylenetriaminepentacetate (Tc99 DTPA or simply DTPA) can be used to determine GFR. Nuclear imaging has the advantage of not only showing GFR and renal blood flow but showing where this is occuring, allowing physicians to localize kidney function to a specific kidney. How does DTPA stand up to other measures of kidney function? It is pretty good but in some studies it underestimates GFR while in others it over-estimated GFR

Finding ways to estimate kidney function from conventional blood tests has been a 50-year journey. Most of these attempts use creatinine. Since creatinine is produced at a steady rate, is freely filtered, and not reabsorbed, its plasma level is largely related to GFR. There are two important weaknesses of creatinine:

  1. It is secreted in the proximal tubule. This means that not all of the creatinine that reaches the urine does so by being filtered at the glomerulus. A small amount of creatinine is secreted in the proximal tubule. This small amount (5-10%) increases as GFR falls (it may reach 50% at very low GFRs), so that more and more of the creatinine that is cleared from the blood is not cleared by glomerular filtration but rather tubular secretion. This can be problematic when patients take medications that antagonize creatinine secretion (cimetidine and trimethoprim both do this). This can result in an increase in the serum creatinine due to the loss of tubular secretion that does not represent any change in GFR.
  2. Creatinine secretion is not the same in all adults. Determinants of endogenous creatinine production are likely multifactorial, and serum creatinine levels may be associated with muscle mass, liver function, physical activity levels, and diet. Thus, estimation of kidney function from the serum creatinine is a challenge. Below is a summary of equations that have been derived to estimate GFR.

1976 brought the first earliest widely adopted formula below to convert creatinine into a semblance of GFR, the Cockcroft-Gault equation (which, by the way, is the most cited nephrology paper of all time). Cockcroft-Gault is the only equation that attempts to estimate creatinine clearance (CrCl) rather than GFR. Creatinine clearance is in itself just an estimate of GFR, so now we’re talking about an estimate of an estimate.

The 534-person cohort of hospitalized veterans used to derive this formula was 96% men. The coefficient of 72 in the denominator comes from the average weight of the participants in the study. If the cohort was only 4% women how did the authors come up with the 0.85 adjustment for women? They made it up. From the discussion section:

Since creatinine is secreted in the proximal tubule, CrCl overestimates the GFR. This can clearly be seen in the data from the MDRD Study. Beware the Cockcroft-Gault – it will confidently smile while lying that the kidney function is fine, when it’s not. Based on Figure 2E from Levey et al.

Cockcroft-Gault became the coin of the realm for a quarter century until Levey and colleagues shook it up with the second most-cited paper in nephrology, the MDRD Study equation. Though the paper describes a 6-variable equation, it was only marginally more accurate than the widely adopted 4-variable equation that was never published in a peer-reviewed journal and only published in abstract form. A slight modification was published in 2006 to account for standardized creatinine measurements.

6-variable MDRD Study equation for GFR estimation.

4-variable MDRD Study equation for GFR estimation using standardized creatinine values.

This eGFR equation may be among the most important things to come out of the MDRD Study since the primary findings, that tight control of blood pressure and low protein diets did not preserve kidney function. As part of MDRD Study, 1685 patients had iothalamate GFRs measured, and every patient also had 24-hour urine for creatinine and urea clearance. Importantly, the MDRD was a study of patients with kidney disease, so the average GFR was 23 ml/min. Additionally, the patients included in the MDRD Study were not reflective of the patient population seen in the US. For example, only 12% (less than 200) of patients identified as Black, only 6% had diabetes, but almost a quarter of patients had polycystic kidney disease. Despite these mismatches, the MDRD Study equation was rapidly adopted as the standard way to estimate GFR, especially after being endorsed by the 2003 KDOQI guidelines defining CKD and its stages.

Soon after this, the MDRD Study equation was shown to successfully predict hospitalization, cardiovascular events, and total mortality. These findings remained significant after being controlled for age, sex, income, education, dialysis use, history of coronary heart disease, chronic heart failure, ischemic stroke or transient ischemic attack, prior peripheral arterial disease, diabetes mellitus, hypertension, dyslipidemia, cancer, an albumin level < 3.5 g/dL, dementia, cirrhosis or chronic liver disease, chronic lung disease, documented proteinuria, and prior hospitalizations.

Visual abstract by Priti Meena on Go et al.

While the Cockcroft-Gault equation overestimated kidney function, the MDRD Study equation had a problem of erroneously showing low GFRs in healthy people without kidney disease and low serum creatinines. With its origins coming from a study of people with kidney disease and rather advanced kidney disease at that, these biases are not surprising. This was most problematic in evaluating people for transplant donation, where apparently healthy people with normal creatinines would be flagged for additional work-up and evaluation due to abnormal MDRD Study equation–derived eGFRs.

Challenges with the MDRD Study equation led to the derivation of the CKD-EPI equation. The CKD-EPI equation used a much larger population to derive and validate the relationship between creatinine and GFR, 12,000 people from 26 studies, including almost 3,000 from individuals who identified or were identified by study personnel as African American. The equation is complex.

Both the MDRD Study and CKD-EPI eGFR equations included race as a biological variable — though race is a social construct. Black patients are 2-4 more likely than White individuals to experience kidney failure and are less likely to receive kidney transplants. Inclusion of a Black racial coefficient in these equations increases the calculated eGFR and thus impacts several clinical care spheres including delayed diagnosis of kidney disease and eligibility for kidney transplantation, further contributing to racial inequities. A recently published cohort study found that inclusion of the Black racial coefficient was associated with delayed achievement of a clinical threshold for kidney transplantation referral and eligibility. It should be noted that racial inequalities extend far beyond the equation, and the recent deliberations surrounding the Black racial coefficient have opened new opportunities to examine sociocontexual factors—including structural racism— that have long contributed to disparities and racialized kidney health.

Recently, medical students, physicians, and others from around the US have questioned the inclusion of the Black racial coefficient in eGFRs. As a result, several institutions have removed this coefficient and the ASN and NKF have convened a joint task force to examine the use of race to estimate GFR. Recommendations from this task force are expected to be released soon. 

An alternative approach to estimating GFR is the use of cystatin C, a 120–amino acid protein (not affected by muscle mass) that inhibits extracellular cysteine proteases and is produced by every nucleated cell in the body. Cystatin C is freely filtered at the glomerulus and then metabolized in the proximal tubule. Blood levels are inversely proportional to GFR, just like creatinine—so as GFR falls, cystatin C levels rise. GFR estimation equations that use cystatin C do not include a Black racial coefficient. Measurement of cystatin C levels may be more expensive and retail lab costs range from around $20 to $250, however an analysis for the National Health Service of the UK had a cost of only £3 per test.

The accuracy of cystatin C–based eGFR is roughly equivalent to demographic-adjusted serum creatinine equations. However, in terms of predicting outcomes, cystatin C–based eGFRs regularly outperform creatinine-based eGFRs. Menon et al looked at the MDRD Study cohort and found that cystatin C–based estimates of GFR did better at predicting CV outcomes and kidney failure outcomes than creatinine-based GFR estimates. Cystatin C also outperformed creatinine in looking at CV outcomes in the elderly. Shlipak et al later reviewed the clinical use of cystatin C.

Beyond creatinine and cystatin C–based eGFR are future technologies that allow real-time assessment of GFR. These technologies use low molecular weight fluorescent tracers that are injected into the bloodstream. The concentration of the tracers can be measured through the skin with dedicated devices. Since the tracer is only removed from circulation by filtration, the GFR can be calculated based on the attenuation of fluorescent signal over time. The future of GFR measurement is going to be really cool.
 

Proteinuria in CKD

When learning about the kidney, GFR gets all the glory. Proteinuria is barely talked about but the deeper you go down the rabbit hole of kidney disease the more important proteinuria becomes.

The first issue to establish is the difference between measuring proteinuria and albuminuria. Proteinuria is the oldest laboratory finding of kidney disease. The discovery of proteinuria is conventionally attributed to Richard Bright as he associated proteinuria, dropsy (edema), and kidney disease, complete with pathology specimens, but proteinuria had been repeatedly “discovered” prior to that in the middle ages and the 1800s. Even Hippocrates commented “when bubbles settle on the surface of the urine it indicates disease of the kidneys and that the complaint will be protracted.”

One of the fundamental truths about the glomerulus is that it prevents protein from being filtered so that the glomerular filtrate is protein free, and that one of the earliest reliable signs of kidney disease is the presence of protein in the urine. Of course nothing is that simple, and a fair amount of protein does leak through the great glomerular barrier, but the proximal tubule takes up filtered protein and though some is returned to circulation the great majority is metabolized. So when protein ends up in the urine, it represents a large enough failure of the glomerulus that not only did protein leak through, but so much did that it overwhelmed the proximal tubules ability to reabsorb and catabolize it. Only after that happens will protein end up in the urine. Reabsorbing protein is hypothesized to increase inflammation and promote fibrosis contributing to tubulointerstitial damage. So urinary albumin levels are a balance of albumin passing through the glomerular barrier and failure of the proximal tubule to reabsorb the protein.

Measuring albumin is preferred over protein in the urine because measuring proteinuria is not standardized. Moreover, the measurement of protein is typically performed by using a chemical assay (Bradford assay) whereas albumin is typically measured by enzyme-linked immunosorbent assay (ELISA) and thus is more specific. By focusing on a single target, assays of albuminuria are more reliable and comparable from institution to institution. However the current method, using immunoassays, is more expensive than standard methods for quantifying proteinuria. However, only urine protein measurements are routinely available in some institutions. Because of this, equations have been generated to convert proteinuria to albuminuria. This is not to be used when albuminuria assessments are readily available but rather to salvage old databases that recorded proteinuria and in health systems where albuminuria assessments are not available. That said, when working up a patient with CKD, assessing for urine protein rather than just albuminuria will reveal patients with other pathologic types of proteinuria (e.g., aminoaciduria in Fanconi syndrome, light chains in myeloma). In one study, 8% of patients with normal albuminuria had pathologic proteinuria.

The value of albuminuria over proteinuria was realized by two discoveries. The first was Parving finding low levels of albuminuria with antibody testing in hypertension in 1974. The immunoassay was able to detect low degrees of albuminuria that was invisible to earlier experiments using chemical methods. This previously undetectable albuminuria, ranging from 30 to 300 mg per day, was called microalbuminuria. 

The second discovery looked at type 2 diabetes. Mogenson assessed albuminuria using the same immunoassay and followed these patients for 9 years. He discovered that these low levels of albuminuria (30-300 mg/d) predicted subsequent development of frank proteinuria, classic diabetic nephropathy, and mortality.

β2-microglobulin is a tubular protein and the fact that it was not abnormal in hypertension localized the leak to the glomerulus. Based on Figure 3 in Parving et al.

These studies demonstrated that albuminuria, even at previously undetectable levels, was an early warning sign of structural changes in the kidney and a harbinger of future disease. The fact that this warning sign could be done inexpensively with a noninvasive test has interesting potential for public health and impactful health policy. An intriguing example of this was the PREVEND study. Here a request for a first morning urine was made to every adult in Groningen, Netherlands. Roughly half of the 80,000 residents provided a sample. This resulted in a treasure trove of information regarding the albuminuria:

  • In this general population, they found measurable albuminuria in 8-12% of people with hypertension and 5-7% in those without diabetes or hypertension.
  • They defined the association of albuminuria and GFR very early in the natural history of CKD, long before people are diagnosed with diabetes, hypertension, or CKD. They found a curious bimodal distribution with albuminuria associated with lower creatinine clearances (evidence of potential early, subclinical kidney damage) and higher-than-normal creatinine clearances (hyperfiltration).
  • The data showed that low degrees of urinary albumin (even in the normal range, <30 mg/d) were associated with subsequent risk of death, in both people with and without diabetes.

And most importantly, especially for this region, PREVEND showed that albuminuria was an important CV risk factor and added additional risk information beyond traditional Framingham risk factors, while GFR did not!

Visual abstract by Edgar Lerma on Smink et al.

Based on Figure 1 from Hillege et al.

So, albuminuria is associated with bad outcomes. And even at low, “high normal” levels it predicts bad things. Its utility as a risk factor for CV outcomes is useful in both directions. While many studies have shown rising albuminuria to be associated with bad outcomes, falling albuminuria during treatment with losartan was associated with a decrease in CV outcomes in the LIFE trial.

But why does a few milligrams of albumin in the urine predict future kidney failure and—even weirder—CV outcomes?

Is this a case of reverse causation with atherosclerosis actually the cause of the albuminuria? This does not seem to be the case. If this was the case there would be clear overlap between peripheral vascular disease (PVD) (a good measure of atherosclerotic burden) and albuminuria, and controlling for PVD would negate much of the CV risk predicted by albuminuria, and vice versa, controlling for albuminuria would negate the CV risk from PVD. This does not seem to be the case.

The most common explanation is that albuminuria represents a visible manifestation of generalized endothelial dysfunction. Consistent with this theory is finding that flow-mediated vasodilation is impaired in patients with albuminuria whether or not they had diabetes. This endothelial dysfunction may increase intraglomerular pressure and decrease the charge selectivity of the glomerular membrane leading to albuminuria. Just as the urinalysis is a liquid biopsy of the kidney, albuminuria is a way to measure the generalized health of the endothelium. It is not the loss of a few milligrams of albumin that is problematic; it is the fact that albuminuria indicates generalized endothelial dysfunction which ultimately leads to the bad CV and kidney outcomes.

COMMENTARY BY HOLLY KRAMER:
The 21st Century Battle Against Kidney Disease

– Executive Team Member for this region: Joel Topf, AJKDBlog Contributor. Follow him @kidney_boy.

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1 Comment on #NephMadness 2021: Primary Care Region

  1. Yoshinosuke Shimamura // March 10, 2021 at 10:03 pm // Reply

    This is one of the best reading materials about proteinuria and GFR. I recommended my interns and residents reading this article. Thank you for the great work!

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