CONSULT ROUNDS

We discussed a case of NSAID induced glomerular disease. NSAIDS are a group of drugs that can effect the kidney in many ways possible. Besides the hemodynamic causes of renal injury from NSAIDS, there has been a strong association with Acute interstitial Nephritis.
Another interesting association of NSAIDS is AIN with nephrotic syndrome ( usually seen with membranous or Minimal Change disease) and patients present with frank nephrotic syndrome and even lympadenopathy sometimes.
What is the time from use to disease, usually around 1-2 months for AIN, but could be months or years even. It's been reported that membranous can be on average 39 months after using NSAIDS.
The degree of proteinuria was independent on the amount of immune deposits in the glomeruli. So even if you have two -three immune deposits, you might have membranous Stage I or II but may behave clinically like Minimal Change Disease. The pathology finding is swelling and allergic reaction and activation of lymphocytes.
The most important clinical pearl is that the renal function in AIN and glomerular disease with NSAIDS was strongly associated with the tubular interstitial changes more  and inversely related to the amount of immune deposits in the glomeruli.

TOPIC DISCUSSION: Pseudopheochromocytoma

Pseudopheochromocytoma is a real disease. Dr. Sam Mann from Cornell has written a lot about this disease.  It causes paroxysmal Hypertension.  98% of people with paroxysmal hypertension do not have pheochromocytoma. The cause and management of paroxysmal hypertension remain a mystery, and the subject of remarkably few papers. Patients experience symptomatic blood pressure surges likely linked to sympathetic nervous system stimulation. A specific personality profile( likely of some abuse as a child) associated with this disorder suggests a psychological basis, attributable to repressed emotion related to prior emotional trauma or a repressive (nonemotional) coping style. Based on this understanding, three forms of intervention, alone or in combination, appear successful: antihypertensive therapy with agents directed at the sympathetically mediated blood pressure elevation (eg, combined α- and β-blockade or central α-agonists such as clonidine); psychopharmacologic interventions including anxiolytic and/or antidepressant agents; and psychological intervention, particularly reassurance and increased psychological awareness. An appropriately selected intervention can reduce or eliminate attacks in most patients. Look for this disease in your patients. Its more common than we think.

IN THE NEWS- HIF and Kidney Disease

A recent article in Kidney International talks about the hypoxia inducible factor or HIF and its relation to kidney diseases and anemia.  Based on recent basic science experiments done on AKI and podocytopathies, it has been found that there are different variants of HIF 1 Alpha and 2 Alpha respectively affecting different parts of the kidney.  This paper is one of first basic science papers to localize HIF 2Alpha.  Accumulation of HIF 2Alpha was observed in mainly endothelial and glomerular cells whereas HIF 1Alpha was more in the tubular epithelia. This was more speculative before but now its confirmed.  A large proportion of erythropoetin expressing cells also co expressed HIF 2Alpha.  No co relation with Hif1alpha was found.

Why is this important?  In hypoxic challenges, there is stimulus to produce HIFs and that might be a stimulus for EPO production as well.  Hif is a protein that has alpha and beta subunits,  In normoxemia, Hif Alpha is always synthesized.  However, steady state levels are low as Hif is rapidly ubiquitinated and degraded. This degradation happens via the action of hif with Von Hippel lindau protein (vhL).  In hypoxemia, this interaction is suppressed and you have increased Hif production leading to accumulation in the cells.
This leads to downstream effects of increased Epo and expression of different types of hifs in different parts of kidneys. Hif1 in tubular cells perhaps during AKI
Hif 2 in podocytes and endothelial cells perhaps in glomerular injury
Interestingly , another down stream protein to Hif is VEGF..
A lot of things might be falling into place soon!!
The picture on the left ( Univ of Adelaide courtesy) can explain a lot

B cell agents in Transplantation

A nice review in recent CJASN highlights the use of anti CD20 and other novel b cell agents in transplantation.
The paper actually reviews all of glomerular diseases and transplantation.
Few things about use of B cell agents in Transplantation
1. Use of Rituximab is increasing more and more with desensitizing protocols for ABOI and + DSA patients. Is it a combination of IVIG, Pheresis and Rituximab that really works or is one better than the other, no studies have confirmed that? Although IVIG alone has not been affective.  Hence, it might be an additive effect.
2. Use of anti CD20 in antibody mediated rejection has become an increasingly used agent.  This stems from a simple concept that antibodies are produced by B cells and hence depleting the B cells will deplete the production of antibodies.
3. Bortezomib, has been now used as well in refractory antibody mediated rejection and in biopsies that have enriched plasma cells.  Total IgG were unchanged in those patients treated, so we don't know if this is a one time effect and or long lasting and also there is potential increased risk for infectious complications.
I think we shall see more and more of these agents used for treating transplant patients in the future.
We have to be careful as there are Regulatory B cells and what we are doing to those B cell clones, we don't exactly know!

Clinical Transplantation: KDIGO Transplant Guidelines

The Feb 2010 issue of Kidney International has summarized the KDIGO clinical practice guidelines for kidney transplant recipients. Its a very brief and to the point summary to standardize transplant care all around the globe. Things we always talked about as transplant physicians and wondered were all discussed and laid down as what should be done and what is the grade of evidence behind it.
For induction, for instance, they recommend( Grade 1B) that an IL2 -RA be used as first line agent and antilymphocyte depleting agent to be used for all kidney transplant with immunologic risk( Grade 2B)
Also, interesting to note that there is Grade2B evidence and they suggest that in patients who are at low immunological risk and who receive induction therapy, corticosteroids could be discontinued during the first week after transplantation. Other concepts on BK treatment, Bone disease, CMV, Cancer and rejection. All are discussed. I think its a good start and an essential read for all of us.

IN THE NEWS- IGA Nephropathy Recent Meeting Report

Recent Kidney International Journal reviews the symposium held on IgA Nephropathy in Italy this last year. 
Few interesting points.
1. The presence of aberrantly glycosylated IgA1 in patients with this nephropathy was again confirmed. This usually happens at the GalNac site on the molecule of IgA.
2. This alteration alters the molecule and possibly could affect the binding to intrinsic mesangial glycoproteins and plasma proteins.
3. Using immortalized B cells from subjects with IgA nephropathy, and normal controls, investigators showed that the aberrant galactosylation in patients is nonrandomly distributed among the glycan residues and that the premature sialylation of the GalNac residues may interfere with the galactosylation of GalNac.  These led to autoantibodies to GalNac.  So, it seems that molecular mimicry from environmental agents maybe involved in the autoantibody response to the neo antigenic GalNac sites on the aberrant IgA.
4. RISK factors to predict IgA post transplant:- prior recurrence of disease and loss of graft from recurrence; rapidly progressive initial disease; use of zero mismatched donors; using a living related donor; lack of treatment with antilymphocyte or anti thymocyte as induction agents; and the presence of IgA deposits on transplant biopsy by zero hour of the transplant.

CONSULT ROUNDS

This week we discussed a case of malignant hypertension with acute renal failure and Thombotic microangiopathy secondary to the severe hypertension.  We discussed in detail Hypertensive Retinopathy. Here are some of the saliant features discussed on rounds. There are different stages of HTN related changes in the retina. The first stage leads to small degrees of arteriolar narrowing and an increase in arteriolar tone due to local autoregulatory mechanisms. As the stages progress, you get more and more narrowing and hyperplasia of the medial wall and sclerosis. Final stages lead to exudative changes leading to retinal ischemia and formation of cotton wool spots, hemorrhages and microaneurysms.  Swelling of the optic disc is the final sometimes noticed on physical exam finding of severe hypertensive urgency.  

How is this different from atheroscloertic changes in the retina? There are four stages and these can also be seen in HTN Retinopathy.  Stage 1 is defined as a broadening of the light reflex from the artery, with minimal or no arteriovenous compression (earliest sign of retinal artery atherosclerosis). Stage 2 is defined as changes similar to those in Stage 1, but more prominent. These narrowings are called AV nicking. In Stage 3, the arteries have a “copper wire” appearance, the arteriovenous compression is much greater, and serious atherosclerotic changes of the retinal arteries are present. In Stage 4, the arteries have a “silver wire” appearance, and the arteriovenous crossing changes are the most severe. Stage 4 is the most severe form of atherosclerosis of the retinal arteries. 
So as Nephrologist or Internists, Do we actively take the time to look at someone's eye? An ophthalmoscopic exam is the least we can do and we should all do that in our hypertensive and diabetic patients because as we do more of these exams, the better we get at picking up more clues and more educated and timely referrals to Ophthalmology. 
A nice review of the Hypertensive Retinopathy is in NEJM. The image to the right is courtesy of MDconsult

IN THE NEWS-NEW TREATMENT FOR TYPE II DIABETES - FROM THE KIDNEY!!!

A nice review in CJASN this month takes us on the concept of glucose transport in the proximal tubule and rest of the human body.  Four members of two glucose transport families SGLT1, SGLT2 , GLUT1 and GLUT2 are expressed in the kidney.  Mutations in SGLT-1 are associated with glucose-galactose malabsoprtion, SGLT-2 with familial renal glucosuria and GLUT-2 with Fanconi Bickel Syndrome.  They take this one step further in this review and propose a treatment for Type 2 Diabetes.
In Familial renal glucosuria, majority of patients don't have any problems except for glucose in their urine.  There is no hyperglycemia and no other signs of tubular damage.  The SGLT2 transporter allows glucose absorption in the S1 segment of the tubule.  A natural inhibitor of this transporter exists as well called phlorizin( root bark of the apple tree and causes glucosuria).  When this was given to partially pancreatectomized rats, the hyperglycemia corrected without changes in insulin secretion.  Now there is a potential drug in development called dapagliflozin , SGLT2 inhibitor. It has shown in a prolonged study of over 300 patients compared to metformin or placebo showing much more reduction in blood glucose, hemoglobin A1c with maximum urinary excretion of 70g.day.
This compound would obviously lead to a mild diuretic effect and hence even benefit for BP control.
A novel thought from out of the box thinking. Hopefully we won't see any other side effects and long term effects of these drugs.

Interestingly also, the other transporter is SGLT1 and it also absorbs galactose. No studies have been done of that linkage to recurrence FSGS or even FSGS. Since galatose potentially binding this "permeability" factor in FSGS, perhaps these patients have an underlying mutation in SGLT1 and cannot absorb galactose leading to the "freedom" for the permeability factor. Something to ponder on!!

A good read!!

CLINICAL CASE 2

CLINICAL CASE 2: FOXP3 Positive T regulatory cells have shown to protect kidney allografts from rejecting. The more you have of Tregs, the safer is your graft. What is the disorder of Foxp3 deficiency called?
1.Polyenteropathy syndrome 0 (0%)
2.Immune dysregulation, polyendocrinopathy, enteropathy X linked (IPEX) 4 (80%)
3.FoxP3 deficiency syndrome 1 (20%)
4.Absent regulatory immunity syndrome(ARIS)

The correct answer is 2, or IPEX syndrome. great work everyone. What is IPEX syndrome and why do we care? The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a rare disorder characterized by multiorgan autoimmunity, often results in death in infancy. The above image is from an allergy immunology blog of Cleveland Clinic. It summarizes the T cell deficiencies diseases.  The IPEX syndrome results from mutations in the forkhead box P3 (FOXP3) gene, which encodes a transcriptional repressor considered to be the master regulator of differentiation in CD4+ regulatory T (Treg) cells. A nice case was first described in NEJM issue in 2009.
A missense mutation abolishes the T regulatory function FOXP3 positive T cells. The systemic autoimmunity in these patients with the IPEX syndrome is probably the consequence of defective Treg-cell–mediated control of immune responses.
This is important in the transplant literature as recently FOXP3 positive T cells in biopsy samples and in the urine of kidney transplant recipients have some value. Consider them to me " policemen" cells and if they are in good quantity and around during the time of rejection, the outcome will be better as they can keep the "troublemaker" T cells, the cytotoxic ones in check. 
In a more broader senses, when we uses drugs that suppress T cells in general, are we also suppressing T regulatory cells that are good to have around? Perhaps!!
Another good reference for this in transplant patients is also in NEJM, link attached.

CONSULT ROUNDS

Yesterday we discussed a case of nephrocalcinosis
What is that and what are the main causes?
Nephrocalcinosis is a condition in which calcium levels in the kidneys are increased. Usually its associated with calcium phosphate stones and picked up usually on a AXR or CT scan.
We extensively discussed the different causes that could lead to the images of nephrocalcinosis
Briefly they are listed below:
Rule them out when you see Nephrocalcinosis
1. Primary Hyperparathyrodism ( most common cause)
2. Distal Renal Tubular Acidosis ( complete and incomplete) , this is because of hypercalcemia, hypercalciuria, metabolic acidosis, and reduced excretion of citrate in the presence of increased urinary pH. 
3. Granulomatous Diseases ( TB, Sarcoidosis, --> due to excessive conversion of 1,25 Vitamin D). So hypervitaminosis D can also lead to it and so can Milk Alkali Syndrome
4. Idiopathic hypercalciuria is the other kind or anything that can lead to increase calcium in the urine
5. Medullary Sponge Kidney
Other rare causes
Renal Papillary Necrosis from Analgesics
Severe Osteoporosis
Primary Hyperoxaluria
Dent's Disease
Parathyroid carcinoma
Barter's Syndrome
Liddle's Syndrome

TOPIC DISCUSSION: POST TRANSPLANT RECURRENCE FSGS

Recurrence in the allograft of FSGS is devastating both to the patient and the physicians taking care of such patients. The time frame is variable but its usually rapid and usually first signs of it might be minimal change on biopsy and not full blown FSGS.  Its thought to be secondary to a circulatory factor or the absence of normally present factor in plasma, each causing podocytopathy.

THINGS TO TAKE HOME:
1. Rule out viral causes:- HIV, parvovirus b19 infection , CMV, EBV and Hepatitis B and C but usually this is seen with collapsing glomerulopathy.
(usually seen with low immunoglobulin levels)
2. Rule out familial FSGS, usually mutations in ACTN4, NPHS2, TRPC6, and CD2AP, especially if donor was a living related person.
3. Drug induced--> classically sirolimus causing a both collapsing GN and a podocytopenic FSGS

TREATMENT options:
1. Plasmapheresis:- Initial studies showed transient benefit after several weeks.  Best results are consecutive treatements for 3 days for total of 9 treatments and then spacing them out. 1.5 Plasma volume is what is required.  How long to continue this treatment and how to space it out is anecdotal.  No randomized studies have been done with this treatment
2. IVIG:- might be an option if there is viral induced and there is hypogammaglobulinemia.
3. Plasmapheresis with Cytoxan:- 2 studies with some benefit noted. In my opinion, already on triple regimen for transplant, what is the benefit of Cytoxan?
4. Plasmapheresis with CNI:- some evidence but by default most patients are getting this anyway as they are post transplant, again case reports and series
5. Steroids:- keep higher dose post transplant:- case reports and series
6. Rituximab:- few case reports with variable success, only worked 50% of the time
7. Galactose:- some emerging data that IV form of this sugar and possible PO might be beneficial in treating resistant FSGS. No definite data yet.

IN THE NEWS --->LUPUS INDUCTION THERAPY( CLASS V)

A recent article in Kidney International pooled data from two large trials comparing induction treatment in Class V Lupus.  These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points.  A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. 

TOPIC DISCUSSION: Eculizumab and Kidney Transplantation? What is the future

Eculizimab is now starting to be used at some transplant centers for treatment of antibody mediated rejection.  What is that and why?  Eculizimab(Solaris) is a monoclonoal ab directed against the complement protein C5.  This antibody blocks the cleavage of C5 and halts the process of complement mediated cell destruction. It has been used effectively and FDA approved for paroxymal nocturnal hemoglobinuria. 

               In reviewing the literature for renal diseases, I found mice studies for many connective tissue diseases and nice JASN paper from 2007 in renal transplantation use. Mice with this drug given prior had zero rejection vs placebo. In 2009, Early results from a Mayo Clinic research study were presented at ATC 2009. Results showed that eculizumab prevents antibody-mediated kidney transplant rejection by inhibiting the immune system's activation of one of the body's important defense mechanisms -- the complement system. Antibody-mediated rejection is a major barrier to transplant in patients with antibodies against their living donors sometimes called "positive crossmatch kidney transplants."

            The benefit was mainly in high risk PRA and highly immunized patients. Increasingly recognized as a major problem, high levels of these antibodies delay transplantation, as evidenced by the approximately 7,000 people on the United Network for Organ Sharing (UNOS) kidney waiting list who are still looking for a match. Mayo Clinic has long been a leader in devising innovative approaches to help this challenging group of kidney patients, and these latest findings about eculizumab add to the expertise and options offered to patients.  This suggests a novel way to block antibody-mediated tissue injury. The Mayo team showed that eculizumab blocks the part of the immune system known as the complement system, which initiates tissue destruction. In this study, 10 positive crossmatch kidney transplant patients were treated with eculizumab. None of the treated patients developed antibody-mediated rejection compared to historical controls in which 60 percent with similar levels of antibody would have developed antibody-mediated rejection.  
    This is a big leap in transplantation but long term effects are unknown. How many doses to be given? How long does the effect last is unclear? And if on this drug, rejection occurs, will C4D be negative. Also, interesting findings like this take us back to diseases like lupus and perhaps its use in those diseases as a good induction agent.

IN THE NEWS- MPGN is really MGUS?

There is disappearance of idiopathic MPGN.  Recently the Mayo Clinic analyzed renal biopsies of patients with MPGN and the most important findings were association with a monoclonal gammopathy either later on or during the time of the diagnosis.  This is a potential precursor of Myeloma.  Also, in a recent review of renal allograft protocol biopsies in patients who had ESRD from MPGN, patients with MGUS had a higher incidence of MPGN recurrence compared to MPGN without monoclonal proteins.

This is important to consider when we get a diagnosis of MPGN back from the pathologist and checking serum free light chains and possibly have analysis of anti light chain antibodies to detect a possible MGUS in the biopsy specimen and a complete workup in serum and urine immunofixation before embarking to treatment.

We also recently published a case report of MPGN diagnosis and few months later the patient developed Celiac Sprue and treatment of sprue led to disappearance of the MPGN as well.

Secondary causes of MPGN are increasing and pattern recognition is important: four most important being:-
Immune complex diseases, viral diseases, paraproteins and thrombotic microangiopathies can mimic a MPGN pattern of injury on the kidney biopsy!!

IN THE NEWS- DETECTIVE NEPHRON

The latest issue of ASN Kidney News debuts my column called Detective Nephron. 
Its a different type of teaching tool using creative writing in a funny manner to teach a certain point in nephrology.
Any advice is appreciated to improve it and cases are welcomed as well.

CONSULT ROUNDS

Hypertension management, a mechanist approach
Managing BP is something we all learned in medical school and nephrologist have become front runners in HTN management now.  An understanding of risk factors and mechanisms is very essential. That is what we discussed on a difficult HTN case yesterday.

Key Points:
1. Choosing medications based on age, sex and race is an appropriate along with co morbidities. Its reasonably studied that certain medications work better in certain races and not in some.  Adding and choosing BP regimens based on what other diseases the patient has is also a good point
2. Mechanism approach of treating HTN is becoming more and more popular but doesn't have that much evidence basis for it. But it makes sense pathophysiologically. Three mechanism exists: RENIN mediated, CATECHOLAMINE mediated and finally VOLUME mediated.
Most of your medications fall in any of those categories and if identified by history, physical and lab evals, one can choose the right kind of medication for treating the HTN.

For more interests in this subject, please read the AJH 2001;14 by John Laragh.

TOPIC DISCUSSION: HIV and the KIDNEY

This is a wide topic but recently in ACKD, Dr. Novak and Dr. Szczech reviewed many aspects of the role of the nephrologists in the care of the HIV patient.

It starts with a general overview of the HIV illness and where we are now in terms of ART therapy.  A chapter on CKD screening in HIV is good as it outlines that the risk factors for CKD in HIV are : age, race, CKD family history, HIV disease state(CD4 count, HIV viral load), History of cocaine use, cigarette use, nephrotoxic medication use and comorbid conditions like Diabetes, HTN and Hep C co infection.
The pathogenesis of HIVAN is reviewed in detail about the Nef induced podocyte dedifferentiation and leading to proliferation.

An interesting chapter is on Gene interactions on HIVAN in the African American population.  There is an emerging concept of MYH9 Gene nephropathies in the AA population.  Polymorphisms in this gene has been associated with kidney diseases historically called Hypertensive nephroscloerosis in the AA population.
It might be the renal failure susceptibility gene independent of HIV infection in AA.  It has been associated with idiopathic FSGS as well. The authors postulate that established CKD risk factor, this gene susceptibility and a second unknown hit might be instigators for HIVAN in AA population. Very interesting.

Finally, the supplement concludes with non HIVAN related diseases in HIV patients.They link them based on groups. Group 1 is diseases which have causal links have been made with HIV infection and the nephropathy( HIV associated Immune complex GN, HIV associated IG A nephroapthy, HIV associated TMA)
Group 2 is indivudual cases and causal links to HIV infection ( Post infectious GN, Lupus like GN, MPGN, Cryoglobulinemia, Immunotactoid GN, Fibrillary GN).
Group 3 are kidney diseases in which causal links largely have not been made to the virus( Interstitial Nephritis, Minimal change, Membranous, Amyloidosis)

A must read!

CLINICAL CASE 1, RESULTS and EXPLANATION

CLINICAL CASE 1: A 23 YEAR OLD MALE WITH HEMATURIA FOR 2 YEARS, NOW WITH WORSENING RENAL FUNCTION AS WELL. THE PATIENT HAS PAST HISTORY OF RETINAL DRUSEN DIAGNOSED FEW MONTHS AGO. HIS C3 IS LOW AND C4 IS NORMAL, WHAT IS THE MOST LIKELY BIOPSY FINDING?
A. MPGN Type 1
b. LUPUS NEPHRITIS
C. Post INFECTIOUS, IGA type
D. DENSE DEPOSIT DISEASE
THE ANSWER IS DENSE DEPOSIT DISEASE:

THE EYE IS A WINDOW TO KIDNEY DISEASES IN MANY INSTANCES. SLE, WEGNENER'S GRANULOMATOSIS HAVE EYE INVOLVEMENTS AS WELL; RETINAL HEMORRHAGES AND NECROTIZING SCLERITIS RESPECTIVELY.

OTHER SYNDROMES THAT HAVE EYE AND KIDNEY INVOLVEMENT ARE ALPORT'S SYNDROME, SENIOR-LOKEN SYNDROME, CHARGE SYNDROME AND BARDET-MOON-BIEDL SYNDROME.  MOST RECENTLY, THERE HAS BEEN AN ASSOCIATION OF DENSE DEPOSIT DISEASE WITH DRUSEN LIKE DEPOSITS IN THE RETINAL PIGMENT EPITHELIUM IN THE FUNDUS. THE LESION IS SIMILAR TO THE AGE RELATED MACULAR DEGENERATION.  these characteristics lesions are also associated with partial lipodystrophy with low serum C3, often accompanied by a circulating c3 nephrtitic factor or abnormality of complement factor h.

I f you have a patient with MPGN II or DDD, or think of that in the differential, have a look at the eye or look for drusen, question the ophthalmologist? you might be surprised.

take a look at the recent NDT , the article by D’Souza and Short on The eye- a window on the kidney.