Monday, January 14, 2019

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.

Thursday, January 10, 2019

Topic Discussion: Secondary Oxalate Nephropathy

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

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
Gastric bypass
Jejunoileal bypass
Bariatric surgery of various types
Cystic fibrosis
Orlistat( weight loss drug)
Mycophenolate mofetil ( rare)
Clostridium difficile colitis
Averrhoa carambola
Vitamin C
Chaga mushroom
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?"

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