Bardoxolone - The Final Chapter - Part 2

One of the issues surrounding the study of bardoxolone in animal models was that, because of the way that it is metabolized in rats and mice, it is highly toxic when given for long periods. This specific toxicity is not present in humans. As a result, it was not possible to study the drug directly. An alternative was to study analogues of the drug. A group from Italy have just published the results of a study of an analogue of bardoxolone, RTA 405, in rats with type 2 diabetes. This study was accepted for publication before the termination of the beacon trial but raised some important concerns which are even more salient now.

RTA 405 caused significant weight loss and elevation of transaminases in treated rats. Also, proteinuria increased threefold. When this rat model is treated with ACEi, there is normally a decrease in proteinuria and renal damage. When the rats were treated with RTA 405 and an ACEi simultaneously, there was some reduction in proteinuria but not to baseline. The proteinuria was accompanied by evidence of severe glomerular and tubular damage.

It is possible that these results are due to a metabolite of RTA 405 which may not be present in humans and as a result, the findings are not necessarily generalizable to humans. However, these adverse effects are similar to those initially reported in the NEJM. The mechanism for the increased renal injury is uncertain at this time.

Previous posts on this topic are here, here, here, and here

New JAMA Reader

JAMA has a new platform called the JAMA Network Reader that you can use to get access to content from any of the JAMA journals (includes what were formerly called Archives of ...).  All the content (which includes the ability to download pdfs as well as viewing things through the reader) is free for a limited time.  Pretty slick.

Skin Lesions in Dialysis - Part 2

Phototoxic skin disorders in renal failure:

Patients with renal failure or ESRD secondary SLE can have a photosensitive skin rash.

For example:

Discoid Lupus Erythematosus (DLE); these lesions are thick and scaly, plug the hair follicles, appear usually on surfaces of the skin exposed to sun (but can occur in non-exposed areas), tend to scar, and usually do not itch.

Acute Cutaneous Lupus Erythematosus (ACLE); Confluent erythema and edema, erythematous macules and papules that eventually become confluent and occur in areas exposed to the sun and can be triggered by sun exposure.

Subacute Cutaneous Lupus Erythematosus (SCLE); is a nonscarring, non–atrophy-producing, photosensitive dermatosis. SCLE may also occur in Sjögren syndrome, associated with deficiency of the second component of complement (C2d) or it may be drug induced.

50% of all people with lupus experience sensitivity to sunlight and other sources of UV radiation. 

The following to disorders are very similar but have very different outcomes:

Porphyria Cutanea Tarda (PCT)

This is the most common porphyria. It is caused by the accumulation of uroporphyrinogens, which cause a phototoxic skin reaction and liver abnormalities. PCT is due to low uroporphyrinogen decarboxylase activity. Spontaneous PCT can be caused by alcohol, hepatitis C or HIV infection, hemochromatosis or estrogen excess. Iron overload is a well-recognized trigger for PCT and thus something to be wary of in dialysis patients. The pathogenesis of this disorder in dialysis patients may also be due to the fact that they cannot excrete porphyrin precursors in the urine. The incidence of PCT in hemodialysis patients is between 1.2 – 18%. Clinically patients have fragile skin, blisters, vesicles and bullae in sun exposed in especially the dorsum of the hands. Sclerodermoid changes can occur in any skin area. Other clinical manifestations include hypertrichosis, hyperpigmentation, dark urine and pruritis. Histologically PCT is characterized by subepidermal separation of the skin with little or no inflammation. On IF, IgG and C3 can be seen along the dermoepidermal junction. Diagnosis in dialysis patients is by looking at the fractional levels of plasma porphyrin precursors. Treatment includes avoiding sun exposure and regular phlebotomy. Higher doses of ESA are usually required to avoid anemia. Chloroquine has also been used for this disorder but with varying results.

Pseudoporphyria (PP)

This disorder is also known as bullous dermatosis of ESRD. It has exactly the same clinical and histopathological changes as PCT (except there are no sclerodermoid changes or hypertrichosis in PP). However, there are no biochemical abnormalities of heme metabolism or porphyrins. This distinguishes it from PCT. One must be aware, however, that plasma uroporphyrin is increased at baseline in dialysis patients. Its incidence in dialysis patients is the same as for PCT. PP is associated with UV exposure, diuretics, NSAIDS (naproxen), antibiotics, antifungals (voriconazole), retinoids, finasteride, imatinib and others. In ESRD patients free-radical injury due to reduced glutathione levels in plasma and red blood cells is thought to play a role in PP. Treatment includes removal of any offending drugs and N-acetylcysteine. Symptoms may take months to improve.

Posted by Andrew Malone

Concept Map of Hypokalemia

MDRD vs CKD-EPI in Transplantation

With the results of the eAJKD brackets posted by Gearoid, I thought this article might be pertinent to stimulate further the debate... This article just came out on Transplantation and is a well designed study in which the performance of the CKD-EPI equation is compared with the MDRD Study equation in 825 stable kidney transplant recipients.
GFR was measured by urinary clearance of inulin (n=488) and plasma clearance of 51Cr-EDTA (n=337).
The results showed that bias was significantly lower for MDRD Study equation compared with CKD-EPI creatinine to estimate the GFR. This superiority translated into a better accuracy (80% and 74% for the MDRD and CKD-EPI creatinine, respectively). The best performance of the MDRD Study equation was confirmed both in the subgroups of patients with mGFR below 60 mL/min/1.73 m2 and between 60 and 90 mL/min/1.73 m2. For mGFR above 90 mL/min/1.73 m2, there were no significant differences between the two equations in terms of performance.
The data also bring us back to the main concern about using creatinine and how poor of a marker it is for renal function. About 30% are misclassified in the CKD stages...  The battle is far from over...

eAJKD Brackets

These are my brackets for the eAJKD nephmadness. My winner is a number 10 seed coming out of left field. For me, the importance of the MDRD trial is that it highlighted the high prevalence of CKD in the general population, lead to the standardization of staging of CKD and raised the awareness of CKD among the non-nephrology population. Much of what we see in renal epidemiology in the last 15 years comes from the MDRD study and although the CKD-Epi equation is superseding the MDRD equation at least in research, it does not take away from the overall influence of this study.

Skin Lesions in Dialysis Patients - Part 1

Nephrology grand rounds in Duke University Medical Center this week inspired me to write this blog on a subject I now realise that I am weak on.  Patients on dialysis are a unique group in whom we see diseases that are either vanishingly rare or not seen in non-renal patients. This includes diseases of the skin. I will give an overview of some of these conditions. Markova et al, gives a good overview of most skin disorders peculiar to renal patients. This will be part of a series of posts on skin disorders in renal patients.

1)Skin disorders involving calcification in renal failure.

Calcium and phosphate deposition in the skin has been said to be a contributing factor to pruritus that is common in renal failure as well as in other skin disorders. Here are two contrasting calcium related skin disorders with very different outcomes.

Calciphylaxis. In this disorder calcification of the small vessels of the dermis and subcutaneous tissues occurs. This leads to vessel thrombosis, tissue infarction and skin necrosis. It occurs in 1-4% of dialysis patients. Risk factors include hyperparathyroidism, an elevated calcium-phosphate product (>70 mg²/dl²), diabetes mellitus, female sex, obesity, warfarin use, and protein C or S deficiency. 1-year survival after the diagnosis of calciphylaxis is about 50%. In calciphylaxis patients get very painful violaceous reticulated plaques that are well defined and deep. These lesions develop into deep non-healing ulcers that can become gangrenous. Sepsis is the most common cause of mortality. Treatment options include a low phosphorous diet, normalizing calcium and phosphate with non-calcium based phosphate binders and low-calcium dialysate. Sodium thiosulphate 25g VI over 30 minutes three treatments per weeks has been shown to improve lesions and should be continued for 2 months beyond the resolution of lesions.

Calcinosis cutis. This refers to calcium deposition in the skin and is a subtype of calcinosis, a condition describing calcification in vessels and organs. Patients with calcinosis cutis get painless flexural infiltrating plaques at periarticular sites. The size and number of plaques corrolate with degree of hyperphosphatemia. Unlike calciphylaxis this disorder does not cause skin necrosis.  Risk factors include low albumin, high phosphate, high alkaline phosphatase and morbid obesity. It occurs in about 1% of dialysis patients. There is no gold standard treatment but normalisation of calcium and phosphate can cause lesions to regress.

Posted by Andrew Malone

Concept Map of Hyperkalemia

#NephMadness

 

 Check out Nephrology Madness Sunday 3/17/13 on eAJKD. They are pitting the top advances in nephrology against each other. 

High Salt-Intake and Autoimmunity

The incidence of auto-immune diseases has dramatically increased in the past 50 years and the concern that environmental exposures have contributed to this increase is broadly suspected. However, it is very hard to pin-point to an individual factor. 

Very intriguing observations were just published at Nature linking a high-salt intake to increased auto-immunity. The authors demonstrate that a high-salt diet increased the severity of experimental autoimmune encephalomyelitis (*EAE) - a mouse model of multiple sclerosis . The authors proposed that high salt-intake induces serum glucocorticoid kinase 1 (SGK1), which than promotes IL-23R expression and enhances TH17 ** cell differentiation in vitro and in vivo. SGK1 has has been shown to govern Na transport and salt (NaCl) homeostasis in other cells. Mice lacking this kinase in their T cells have impaired expression of IL-17-family cytokines and of a receptor for another cytokine molecule, IL-23, which stabilizes the TH17 cell phenotype.

Though salt might not be the trigger of autoimmunity, the possibility that high-salt intake might exacerbate auto-immunity is very provoking and would encourage even more the emergent initiation of trials evaluating the efficacy of low salt-diet in the development of auto-immune diseases and other potential diseases related to inflammation, such as coronary heart disease. 

Based on recent computer-generated data suggesting all the potential benefits of lowering salt consumption, this discussion is very pertinent.  

Above the diagram from the Editorial of Nature discussing the findings and below some additional explanations about the mouse model and Th17 cells. One caveat is that effect of high sodium on human cells was only shown in vitro...

* EAE: Experimental autoimmune encephalomyelitis. An animal model of the human autoimmune disease multiple sclerosis. EAE is experimentally induced in animals by immunization with myelin or with peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

** TH17 cells (T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, IL-21 and IL-23, as well as the transcription factors RORgt (retinoic-acid-receptor-related orphan receptor-gt) and STAT3 (signal transducer and activator of transcription 3).

Insert sensationalist headline here...

A recent BMJ Minerva column alerted me to an interesting paper in the journal Transplantation. The authors used collaborative databases to compare overall and age-specific graft survival in first deceased donor transplants carried out in the US & Europe. They found that although there was broad similarity in 1-year graft survival, 5 and 10 year graft survival was considerably higher in Europe than in the US. The tendency towards worse graft survival in the US persisted across all ethnic groups and was largest for children and young adults. The gap between European and US survival was greater beyond 3 to 4 years post engraftment.

I am British and have only ever practiced in the UK NHS. I am therefore in no position to comment meaningfully on the following points made in the paper’s discussion section: "it is necessary to recall…the 3-year restriction in medication coverage for immunosuppression in the United States by Medicare…A policy change may contribute to improving graft survival and ultimately saving lives and also help to reduce health care spending." I imagine that other readers and contributors to this site may have informed and/or deeply held opinions.

Pathology Case of the Month

An elderly woman presented for evaluation to the rheumatology service with arthritis and neuropathy. She was hypertensive and had microscopic hematuria with dysmorphic red cells on microscopy. Her creatinine was 1.6 which had not changed in the previous year. She had no history of diabetes. Her serology was notable for a positive ANCA, elevated CRP and ANA 1:640. The sense was that despite the presence of the ANCA, the likelihood of a vasculitis was low due to the indolent course but she went on to have a renal biopsy.

A low power view of the renal cortex revealed an obvious nodular appearance of the glomeruli. The tubules were relatively well-preserved.

High-power view of the glomerulus was characteristic of nodular glomerulosclerosis. Notably, there was no evidence of any crescents and no thickening of the capillary loops.

 IF was completely negative

There were no medullary or BM inclusions on EM

Nodular glomerulosclerosis is classically associated with diabetes and this is the first diagnosis that came to the mind of the pathologist when the slides were processed. However, the patient had no history of diabetes. Alternative diagnoses include chronic MPGN and dysproteinemias. There was no evidence of either in this case. The final diagnosis was "Idiopathic Nodular Glomerulosclerosis". This is somewhat of a misnomer as these days, it is thought that IGN is directly related to smoking. The mechanism is uncertain but is suggested in the flow-chart below from an a review in JASN on the topic.

This is not a benign condition. In the largest case series to date of 23 patients with biopsy-proven IGN, 6 patients reached ESRD in a median of 26 months. Predictors of progression included not quitting smoking, lack of ACEi use and the degree of atrophy, fibrosis and arteriosclerosis on renal biopsy.

(Click on any image to enlarge)

New Opportunity for Future Nephrologists

The ASN has out together this video announcing a new initiative to attract trainees to nephrology early in their careers. This would involve sponsoring medical students to attend the week-long origins of renal physiology course in Bar Harbor, a free membership of the ASN with access to travel grants for the annual meeting and pairing the student with a nephrology mentor.

I think that this is a great idea and suggest that if you are an interested student, or know some potential recruits, pass this video on to them.