In the NEWS: PD-1 inhibitors and ATN, not AIN

Check point inhibitors have been associated with kidney injury. The incidence of check point inhibitor associated renal injury varies widely in the literature. The most common kidney biopsy observed has been acute interstitial nephritis and in a few rare cases- podocytopathies. 

In a recent study from France, the authors report on the incidence of pembrolizumab associated kidney toxicity in a French single-center nephrology referral center and report that renal adverse events occur in 1.77% of patients. A renal biopsy was performed in all 12 patients and acute tubular injury was the most common lesion noted. The most common glomerular pathology in this case series was minimal change disease. In this study, surprisingly, acute tubular injury was the most commonly observed pattern of injury on histology. This is in contrast with other reports that identified acute tubulo-interstitial nephritis as the dominant form of renal injury associated with immunotherapy treatment. A possible explanation is the low threshold to perform a kidney biopsy in this study. 

About half of their patients had ATN. Those patients had more frequently cardiovascular risk factors and marked histological vascular lesions and are more frequently men than AIN patients. Two of them received platinum but at least 1 year before pembrolizumab was introduced. No known mechanism is postulated for the ATN related to pembrolizumab.

This is an important study as this highlights the varied degree of renal toxicities seen with these agents. AIN will respond to steroids and ATN won’t. A kidney biopsy will be important to distinguish that. Empiric steroid treatment by oncologist should not be the gold standard but should be based on kidney biopsies performed and or a nephrology consultation. 

Besides AIN and podocytopathies, it appears that PD-1 inhibitors also can cause ATN.

Topic Discussion: Lenalidomide and the Transplanted Kidney

Lenalidomide has multiple immunomodulatory effects that provide antitumor properties and has been used in treatment of myeloma and AL amyloidosis. Recently, several cases have been reported of acute allograft rejection in patients who got this agent with a renal transplant.

Activation of the immune system by lenalidomide has been shown to result in immune-mediated complications. In a retrospective analysis, Montefusco et al discovered a 4-fold increased risk for the development of autoimmune disease following the administration of lenalidomide for the treatment of multiple myeloma, most of which occurred in the first 3 to 5 weeks after initiating therapy.

Meyers et al had reported the first case of rejection in a patient after heart-kidney transplantation with stable immunosuppression following lenalidomide administration. Since then two additional cases are reported in the renal transplant population both in the recent years.

The two cases are listed below

The AJKD case report

Transplantation Proceedings case report

Why does this happen? The authors of most articles postulate that lenalidomide might activate T cells by directly inducing tyrosine phosphorylation of CD28, an essential T-cell−signaling protein in the costimulatory pathway. Direct activation of this pathway allows for T-cell activation in the presence of CTLA4 immunoglobulin blockade, increased secretion of interferon γ and IL-2, and stimulation of cytotoxic CD8-positive and CD4-positive helper cells.

In addition to CTLA-4 antagonist and PD1 and PDL1 inhibitors that activate the immune system and cause transplant rejection, we will have to add Lenalidomide to the list as well.

In the News: Nephrologists take care of the most complex patients

As a nephrologist, I always wondered , “ too many med reconciliations, so many co morbidities and I feel like I am taking care of so many complex patients.”  A study from Canada confirmed my assumption. This study was a population-based retrospective cohort study of 2 597 127 residents of the Canadian province of Alberta aged 18 years and older with at least 1 physician visit between April 1, 2014 and March 31, 2015. Data were analyzed in September 2018. When types of physician were ranked according to patient complexity across all 9 markers, the order from most to least complex was nephrologist, infectious disease specialist, neurologist, pulmonologist, hematologist, rheumatologist, gastroenterologist, cardiologist, general internist, endocrinologist, allergist/immunologist, dermatologist, and family physician.

This study had some interesting findings:

1.      They used 2 different methods of sensitivity analysis making their discovery a strong finding, which were consistent with both methods

2.      In terms of mean number of comorbid conditions a specialists deals with, Nephrologists were the highest followed by Infectious diseases

3.      Nephrologists took care of sick patients with mental conditions as well- not a surprise to most of us ( followed by ID and Neurology in the lead)

4.      We also dealt with patients that were prescribed the most medications( not just by us but by all physicians they see). I can attest to that as doing a med recon on most takes a lot of time as there are many medications. As a result, med discrepancies are not uncommon in our patients

5.      Most patients referred to renal also had a higher mean of seeing other physicians, a close second to ID

6.      Mean number of days spent in hospital, we were also on top with ID, this is part of the fact that many have co morbid conditions such as CAD, CHF and access infections and so forth

7.      Strikingly, we also had the patients with the highest mortality( significantly higher than other fields)

What is more important is not where we stand in the ranking but that there is such a wide variation of types of complexities of patients all fields are seeing and taking care of. As authors suggest, this impacts education and health policy.

Should residents applying for ID and Nephrology be involved in learning about complex disease models? Is this perhaps a major reason why residents are scared to go into these fields? Complexity and curiosity drove me to Nephrology but for some – might scare them.

In addition, the reimbursement in the US doesn’t reflect complexity of the patient. There is no question that patient complexity requires time (including the time required to communicate with the multiple other doctors), expertise, and resources to optimize management. However, reimbursement of physicians and facilities in North America is most commonly based on

fee-for-service compensation. The complexity of medical decision making is addressed by assessing the number of diagnoses and management options that are considered, the medical risks, and the amount of data to be reviewed. Adjusting payments to encourage physicians to spend more time and resources caring for patients at highest risk of complications makes sense from a health care payer perspective. This is important in Nephrology as there is declining interest in this field and changes in reimbursement might help change that trend.

As ESRD and transplant physician, internal medicine is part of our core and most often, we are in charge of the medical management of these individuals. Due to the fact that we take care of the most complex patients, most nephrologists are good leaders. Leading the dialysis unit, dealing with multiple physicians, and communicating with all types of doctors makes us ideal in leading an administration. Hence, many Nephrologists also take on administrative roles and fit well in them. A recent ACKD series of articles highlight these non-traditional roles of the Nephrologist.

Nephrologists are in a very crossroads of a complex field in medicine, with high regards from many fields of medicine. We should take pride in this and allow for an ongoing dialogue with the payers that complexity takes time and dealing with complex sick patients is equally as hard as doing an interventional procedure.

Concept Map: Pathophysiology Breakdown of TMA

Consult Rounds: Adipsic Hypernatremia

When one encounters really high Na levels- 170-200meq/L range, adipsic hypernatremia should be in the differential; especially if they are asymptomatic. The key question to ask is “ are you thirsty?” Once called essential hypernatremia, this disorder is now called adipsic diabetes insipidus or central diabetes insipidus with deficient thirst or easier to call them adipsic hypernatremia. The most common reasons for these are lesions that affect the thirst center in the brain- craniopharyngiomas, CNS sarcoidosis, germinomas and clipping or rupture aneurysms of the anterior communicating artery of the circle of Willis. 

Tight regulation of water balance is accomplished via the thirst mechanism and ADH. Both are crucial to maintaining a remarkably narrow range of plasma osmolarity of 282–298 mOsm/kg. Osmoregulation of ADH is mediated by osmoreceptors located in the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus. These osmoreceptors are extremely sensitive to changes in osmotic pressure. For example, an increase in osmolarity of 1 to 2 percent increases ADH secretion. However, ADH secretion alone is not adequate to prevent dehydration, and an intact thirst mechanism is vital for water homeostasis. Thirst is regulated by hypothalamic osmoreceptors that are sensitive to changes in effective osmotic pressure of body fluids. The osmotic threshold at which the thirst mechanism is activated begins approximately 5–10 mOsm higher than the threshold for ADH release. These two systems work together to maintain plasma osmolality. With both systems intact, hypernatremia is a rare development, but can occur in patients who have lost their ability to maintain or increase free water intake, for example hospitalized patients and particularly the geriatric population. 

There are four variants of adipsic hypernatremia. Type A adipsia is characterized by an upward setting of the osmotic threshold for both thirst and vasopressin release, sometimes called essential hypernatremia. Type B adipsia is characterized by subnormal thirst and vasopressin responses to osmotic stimuli. This is due to partial destruction of the osmoreceptors. Complete destruction of these receptors is classified as type C adipsia, and these patients have complete absence of ADH release and a lack of thirst mechanism. Type D is an extremely rare form that manifests as only a thirst mechanism failure with an intact ADH production.

In all patients with adipsic hypernatremia, a careful neurologic and radiologic evaluation should be performed, looking for a possible treatable disease (such as a benign tumor) that might restore osmoreceptor function. 

Forced drinking to make patients eunatremic is the treatment—that is, scheduled water drinking because there is no thirst mechanism, with some desmopressin if need be—is usually what helps. Surgical correction of the cause will be helpful in cases where it is possible. 

An old case of detective nephron that discusses this in a fun way at ASN Kidney News.

In the NEWS: A new paradigm in calciphylaxis

A recent small report from the MGH group found that apixaban can be used in ESRD HD patients with calciphylaxis who require anticoagulation.  It is well know that warfarin is a risk factor for calciphylaxis. Most of the patients on HD that require anticoagulation are on warfarin. Given the risk of calciphylaxis, the concept of changing over to a factor Xa inhibitor was used in this study to see if that be used for replacement of warfarin.  It was a retrospective study at a single center and they found 20 patients who were on dialysis who were on apixaban following a diagnosis of calciphylaxis.  27% of the drug is renally excreted and hence not a bad choice for an ESRD patient. 

There are although no trials of this agent on ESRD on dialysis and specifically not in calciphylaxis patients. A large retrospective trial did show that use of apixaban compared to warfarin was associated with less bleeding in ESRD patients and less stroke risk and mortality with 5mg BID dosing.

While the study really highlighted that the switch from warfarin to apixaban  was ok and there were no significant bleeding and clotting episodes, there were some additional surprise findings. What was surprising to me was that the majority of the patient got better with their calciphylaxis part. The cohort that got apixiban had a lower mortality compared to the established published rates of patients with calciphylaxis not on apixiban.

Have the investigators just stumbled upon a potential treatment for this deadly disease? Given calciphylaxis has a component of TMA and having them on an anticoagulant that doesn’t inhibit vitamin K might be beneficial.  The question remains that would you start apixiban in someone with calciphylaxis who was not on anticoagulation?

Topic Discussion: Diagnosis of Pheochromocytoma in a Dialysis patient

Dialysis patients have ups and downs of blood pressure and a diagnosis of pheochromocytoma(PH) is always challenging. Screening for PH is always a tough challenge in non CKD/ESRD patients. It is even more challenging in ESRD patients. Many medications can interfere with measurements of catecholamine levels. Tricyclic antidepressants interfere most frequently with the interpretation of plasma fractionated metanephrines and 24-hour urinary catecholamines and metabolites.  Most of these should be tapered and discontinued at least two weeks before any hormonal assessments. 

In general, the approach to diagnosis is initial biochemical testing based upon the index of suspicion that the patient has a PH. If there is a low index of suspicion, a 24-hour urinary fractionated catecholamines and metanephrines; if there is a high index of suspicion, a plasma metanephrine level should be done. The endocrine society clinical practice guideline suggests initial biochemical testing using 24-hour urinary fractionated metanephrines or plasma fractionated metanephrines (drawn supine with an indwelling cannula for 30 minutes). However, many times the measurement of plasma fractionated metanephrines is not done under these conditions, and the test is associated with a high false-positive rate.

Biochemical tests in renal disease might not be valid. In patients without PH who are receiving dialysis, plasma norepinephrine and dopamine concentrations are increased threefold and twofold above the upper limit of normal, respectively. When patients with CKD have plasma norepinephrine concentrations more than threefold above the upper normal limit or epinephrine concentrations greater than the upper normal limit, PH should be suspected. It is hard to distinguish PH just with plasma metanephrines in ESRD and CKD patients. Studies done have shown mixed results. Most ESRD patients are anuric and hence urinary studies are not available. A new biomarker has been recently discovered in the world of PH- Plasma methoxytyramine. This is still not used in routine practice and data on ESRD-CKD is not available to my knowledge. 

What about the imaging studies?

CT dedicated to the adrenals or MRI of the abdomen and pelvis is usually performed first. Either test is a reasonable first test as both detect almost all sporadic symptomatic tumors because most are 3 cm or larger in diameter. If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of PH, think of a perhaps a different diagnosis. If it is still considered likely, then iodine-123 (123-I) iobenguane (also known as metaiodobenzylguanidine [MIBG]) scintigraphy may be done. MIBG is a compound resembling norepinephrine that is taken up by adrenergic tissue. Normal adrenal glands take up MIBG, and the uptake may be asymmetric. One prior paper showed perhaps a false positive scan in ESRD. No newer studies have shown this. No specific studies have looked at MIBG scans in ESRD patients except one case series from Japan.

Finally, FDG-PET scan is more sensitive than 123-I MIBG and CT/MRI for detection of metastatic disease. A scan called 68-Ga DOTATATE PET — Gallium 68 (68-Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)-positron emission tomography (68-Ga DOTATATE PET) is proving to be more sensitive in some patients than 123-I MIBG, CT/MRI, or FDG-PET for detection of metastatic disease. 

So what does one do finally for a CKD-ESRD patient?

If the plasma metanephrines are threefold the upper limit of normal and there is an abnormal CT scan or MRI localizing a lesion in one of the adrenals( depending on contrast load), a MIBG scan is reasonable. If that is positive, there is a good chance that it is a PH. Surgery decision should not be based solely on MIBG scan alone. A PET scan or a TATE scan might be required to confirm the diagnosis in the grey zone of CKD-ESRD and diagnosis of a PH.