Topic Discussion: Krüppel-Like Factors and the Kidney

Krüppel-Like Factors are now creeping their ways in to the Nephrology world. What are they and why is this important for kidney disease- and specifically glomerular diseases? The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have been published that describe their basic biology and contribution to human diseases. KLFs are critical regulators of physiological systems that include the cardiovascular, digestive, respiratory, hematological, and immune systems and are involved in disorders such as obesity, cardiovascular disease, cancer, and inflammatory conditions.

When I pubmed this, you get over 4000 citations.  

Several studies have looked at these factors and their role in kidney disease and specifically podocytes. 

Few deserve some mention.

Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. A series of papers have looked at KLF15 and it is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. In one study in JASN  2016, the investigators showed that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS.  In a more recent JASN article, Tg26 mice model, inducing podocyte-specific KLF15 attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice.So it is possible that KLF15 might be important in podocyte protection and overexpression of this factor might help response of steroids. Both steroids and retinoic acid induces increase expression of this factor in certain patients.

In addition, KLF2 might have a similar protective effect but in endothelial cells and endothelial injury. KLF2 is down-regulated in glomerular endothelial cells of patients with diabetic kidney disease and that endothelial cell-specific reduction in KLF2 expression in experimental model of diabetic kidney disease exacerbates glomerular endothelial cell injury and accelerates the disease progression.   

KLF6 might be involved in mitochondrial injury protection in diabetic disease.

Another study showed human kidney biopsy specimens of RPGN showing reduced KLF4 expression with a concomitant increase in phos-STAT3 expression. This loss of KLF4 results in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. 

With the advent  of KLFs in the kidney world, perhaps we might have a potential way to help enhance our therapy in glomerular diseases.

Topic Discussion: Secondary Oxalate Nephropathy

Oxalate deposition in the kidney is rare but recently several case reports have highlighted this finding.

A recent KI reports paper summarized and did a systematic review of all published cases showing biopsy proven oxalate nephropathy.

In their systematic review, the most common presentation of oxalate nephropathy was acute kidney injury (35%), followed by acute on CKD (29%). Twenty-six percent of patients presented with kidney disease and stones, and 10% with CKD. In contrast, 20%–50% of patients with primary hyperoxaluria present with recurrent nephrolithiasis, and CKD or kidney failure. Proteinuria was the most common urinary finding (69%), followed by hematuria (32%). Urinary oxalate crystals were identified in only 26% of cases. 

What did the pathology show in most cases?  Kidney biopsy findings of acute tubular injury and interstitial infiltration were reported in 71% and 72% of patients, respectively, which suggested a cause role for the oxalate crystals. Majority of the patients had chronicity. Interestingly, glomerular changes were found in 59% of the biopsy specimens, which were mostly mesangial cellular proliferation; this might explain the high prevalence of proteinuria. There were no cases of crystal deposition in the glomeruli.
 

Renal replacement therapy is required in >50% of patients and most patients remain dialysis-dependent.  Monitoring the 24-hour urinary oxalate excretion rate might be a useful tool for prevention of oxalate nephropathy in high-risk patients.

Some of the causes the authors noted that could lead to secondary oxalate nephropathy were:

Pancreatic adenocarcinoma
Systemic sclerosis
Roux-en-Y bypass surgeries of various types
Hemicolectomy
Gastric bypass
Jejunoileal bypass
Bariatric surgery of various types
Cystic fibrosis
Orlistat( weight loss drug)
Octreotide
Mycophenolate mofetil ( rare)
Clostridium difficile colitis
Averrhoa carambola
Vitamin C
Peanuts
Tea
Rhubarb
Chaga mushroom
Piridoxylate

Crohn’s disease
Celiac disease
Absence of Oxalobacter formigenes colonization
Chronic pancreatitis
Small bowel resection
Diabetic gastroenteropathy

On twitter, I asked a question "
What determines why someone can develop oxalate nephropathy while someone else develops nephrolithiasis?"

7:54 AM - 8 Jan 2019

#askrenal @askrenal What determines why someone can develop oxalate nephropathy while someone else develops nephrolithiasis?

— Kenar Jhaveri (@kdjhaveri) January 8, 2019

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.