Topic Discussion: What causes glomerulomegaly?

What causes glomerulomegaly?

Congenital cyanotic heart disease
Cor pulmonale
Obesity and Sleep apnea
Sickle cell disease
Polycythemia vera
Alcoholism
Hepatic steatosis
Cystic fibrosis

What is the most common physiological abnormality in all of the above

Hypoxemia! Perhaps a combination of metabolic demands of some of these illnesses, hypertrophy of the erythropoietin producing cells, passive congestion causes in the systemic circulation and increased viscosity all might be leading to glomerular damage and proteinuria as a result.

What does glomerulomegaly mean on pathology?

There is going to be focal and diffuse hypercellularity, segmental or global sclerosis, mesangial thickening
Vessels:- capillary congestion, hyalinization of afferent and efferent arterioles
Tubular atrophy
Interstitial Fibrosis

Reference: http://www.ncbi.nlm.nih.gov/pubmed/9402101

IN the NEWS: ESRD re-admissions: where do we stand and what can we do?

ESRD re-admissions are a major concern. A recent KI paper discusses what the nephrology literature has found regarding this very important issue. Unfortunately, no studies have tested interventions in how to avoid re-admissions for our dialysis patients.  The authors propose certain areas for research.

An interesting concept that is discussed in table 3 of the paper is the potential places where the factors might be of the risk and how we can target our research in those 5 areas.

1.       The patient related risk factors ( socio-demographics, social support .etc)

2.       Index hospitalization( the first hospitalization and how to void re-admissions related to that admission, med reconciliation, structured communication from inpatient to outpatient units)

3.       Nephrologist ( timing of first visit post discharge, extra weekly visit for the hospitalized patient, effect of targeted structured eval only addressing certain key variables such as dry weight, access, medications changes)

4.       Dialysis unit- coordination with inpatient dialysis unit and ER of the hospital

5.       Payment structure- effect of resource redistribution in different payer models

Check out the paper here.

In the News: Regenerative Medicine in Nephrology

Chronic kidney disease (CKD) is a major global public health problem.  In the US, about 11% of adults have CKD as of 2012, and CKD accounts for $41 billion in Medicare expenditures (17%).   When patients with CKD progress to end-stage renal disease (ESRD), the options for treatment are limited to dialysis and kidney transplantation.  Dialysis is associated with significant morbidity and mortality, and kidney transplantation is limited by the supply of organs as well as the need for patients to take immunosuppressive medications for the rest of their lives.  There is a need for new, innovative therapies to treat CKD and ESRD.  One promising approach is to rebuild or repair cells, tissues, or organs to restore proper function.  This exciting new area of medicine has been termed “Regenerative Medicine.” 

We have been working for the last seven years on developing strategies to differentiate human pluripotent stem cells, particularly human embryonic stem (ES) cells and human induced pluripotent stem (iPS) cells, into cells of the kidney lineage for the purposes of kidney regeneration and kidney disease modeling.  We believe that the successful derivation of functional kidney cells and structures from human pluripotent stem cells will have an enormous impact on a variety of clinical and translational applications, including kidney tissue bioengineering to replace lost kidney tissue, renal assist devices to treat acute and chronic kidney injury, drug toxicity screening, screening for novel therapeutic agents, and human kidney disease modeling.

Our primary goal was to develop a highly efficient, chemically defined method of differentiating human pluripotent stem cells into kidney tissue.  The normal kidney consists of approximately one million nephrons (the functional units of the kidney).  During normal kidney development, nephron progenitor cells (NPCs) give rise to nearly all the epithelial cells of nephrons.  Nephrons are highly complex structures with multiple segments, each of which performs a set of specific physiologic functions of the kidney such as salt and water regulation and waste product elimination.  While previous studies, including work from our own lab, have demonstrated the ability to generate NPCs from human pluripotent stem cells, efficiencies have been low.  Furthermore, while these NPCs have been able to differentiate into rudimentary structures of the nephron, none of the prior studies have demonstrated the ability to form a complete, mature nephron from NPCs.

We hypothesized that a much higher efficiency of NPC generation and formation of kidney units could be achieved by following nature’s normal differentiation pathway. We therefore set out to establish a differentiation protocol that would mimic the stages of nephron formation as closely as possible.  Our approach in recapitulating the steps of kidney development as precisely as possible resulted in a highly robust recipe for generation of kidney organoids. To our knowledge, this is the most efficient method for generating complex kidney structures from human pluripotent stem cells. The ability to do this using induced pluripotent stem cells, which are derived from skin or blood cells of patients, allows creation of kidney tissue without ethical concerns and allows the tissue to be “personalized”, that is, generated from a particular patient.  If in the future the tissue is re-implanted back into the patient, the immune response may then be very limited since the tissue will be recognized as self.

Finally, we tested our nephron organoids for the ability to model human kidney development and drug toxicity to the kidneys.  Kidney development is an important medical topic since it has been increasingly recognized that individuals can be born with fewer functional kidney units and these patients are plagued by an increased chance of hypertension and kidney disease in later life.  By altering the environment of the NPC-derived renal vesicles with drugs that are known to affect kidney development, we found that the proximal tubule structures are greatly affected. This finding indicated that the nephron organoids are usable for the study of human kidney development, for which no “ex vivo” models currently exist.  With this model system we have a tool to evaluate potential therapeutic agents.

In addition, we tested nephron organoids for drug toxicity.  The kidney organoids were treated with the nephrotoxicants gentamicin and cisplatin.  Both nephrotoxicants induced segment-specific injury to nephron structures within organoids in a pattern that is consistent with what is observed in the clinical setting.  Given the individual variation in drug sensitivity in humans, the generation of these nephron organoids from human iPSCs would enable drug testing in a patient-specific manner.

Kidneys are the most commonly transplanted organs, but demand far outweighs supply.  While the human kidney does have the capacity to repair itself after injury, it is not able to regenerate new nephrons, the individual functional units that make up the kidney. Human pluripotent stem cells are the only human cells we can grow in the laboratory with the potential to generate new functional kidney tissue. Previously, researchers have been able to differentiate pluripotent stem cells into heart, liver, pancreas, or nerve cells by adding certain chemicals, but it has been challenging to turn these stem cells into kidney. Using normal kidney development as a roadmap, we developed the most efficient method for converting human pluripotent stem cells into kidney stem cells that will give rise to nearly all the functional cells of the kidney. These kidney stem cells organize into mature kidney structures that resemble the structures found in a normal human kidney. This gives us hope that, one day, we might be able to create kidney tissues that could function in a human patient and would be 100% immunocompatible with that patient.

Check out the manuscript here.

Ryuji Morizane, MD, PhD

Postdoctoral fellow, Renal Division, Brigham and WOmen's Hospital

Albert Q. Lam, MD

Associate Physician, Renal Division, Brigham and Women's Hospital

Joseph V. Bonventre, MD, PhD

Chief, Renal Division, Brigham and Women's Hospital

Consult Rounds: Cancer Drug induced Thrombotic microangiopathies

Cancer Drug induced TMA come in 2 variants

1.       Type 1 TMA:- onset is delayed, usually 6-12 months after starting therapy

Cumulative dose related

Clinically, could be permanent and irreversible renal damage

Would avoid rechallenge

High incidence of acute mortality and may require dialysis even after stopping agent

Thrombi in both arteriole and glomerular capillary

Examples: Mitomycin C and gemcitabine induced

2.       Type 2 TMA:- onset is more acute and only at time of initiation of agent.

Not dose related

High likelihood of recovery

Some evidence of safe rechallenge

Thrombi in glomerular capillary mainly

Patient and kidney survival excellent

Examples:  anti VEGF and TKI agents induced

Ref: http://www.ncbi.nlm.nih.gov/pubmed/25943718

Topic Discussion: CLL and the kidney

Classically, it's well know that infiltrative disease is seen with CLL and the kidney leading to AKI.
What other diseases can you see with CLL and the kidney?

A recent paper by The Leung group at Mayo discusses the Mayo clinic experience of CLL and monocloncal B cell lymphocytosis patients that had a kidney biopsy.

Most common findings:
20% had MPGN
12% had infiltration of CLL
12% had TMA from chemotherapy -- classically related to pentostatin
10% had Minimal change disease

Other less commonly observed findings were AIN, AL lamda amyloidosis, light chain cast nephropathy, membranous GN and mesangial proliferative GN.

Other unrelated biopsy findings were diabetic nephropathy, obesity related FSGS, and HTN nephropathy.

Topic Discussion: Non Dilated Obstructive Uropathy

Anuric renal failure has very few causes. The top three are usually: hydronephrosis, hydronephrosis and hydronephrosis! But sometimes, it’s the sonogram and imaging that sways you away from the diagnosis. The sonogram reads- no hydronephrosis and or dilatation.  But clinically, the only thing that makes sense to you is obstruction? What do you do then?

Non dilated obstruction is not uncommon especially in patients with cancer that effects the retroperitoneal regions. There is so much cancer mass that there is no ROOM for the kidney to expand. But doesn’t mean that hydronephrosis is not present. The syndrome of non-dilated obstructive uropathy (NDOU) and AKI is well reported. However, the literature suggests that this syndrome is rare, accounting for less than 5% of cases of urinary obstruction.

One of the earlier studies had looked at a series of patients at a single center and found that most common cause of these type of situations were cancers ( likely RP related)- so prostate, colon, bladder, lymphomas and other series have found cervical cancer as well.  Antegrade urography had found the obstruction in all of the cases in that one series. 

The first ever case of this was described by Ormand in 1948 with someone with retroperitoneal fibrosis.

A more recent study from Mayo Clinic has a case series of 3 cases. Despite the absence of dilatation on renal imaging, strong suspicion for NDOU led to decompression procedures with prompt recovery of kidney function in all three patients - two required percutaneous nephrostomy tube placements and/or ureteric stents and one responded to simple Foley catheter drainage. Here is another case series summarizing the data.

Treatment is usually diagnostic.  Given the pathology and the cause of the obstruction being present after the ureteral stents are placed, they usually only temporize the treatment. Percutaneous nephrostomy is usually the best procedure in such situations. 

When one encounters such cases, Urology and IR help is critical in getting the right diagnosis and prompt treatment.