Does octreotide hold promise for treatment of polycystic kidney disease?

One of the most frustrating things in clinical nephrology is to give a diagnosis of polycystic kidney disease (PKD) to a young patient, and follow that up by saying that they could progress to end stage renal disease requiring dialysis, and “there is not much I can offer to change that”.

Autosomal dominant PKD is the most prevalent monogenic disorder, and the average rate of GFR decline could be as much as 4.4 to 5.9 ml/min. Recently, the well-publicized TEMPO trial has shown a potential clinical application for tolvaptan in stemming the progression of PKD by slowing the growth of the total kidney volume and eGFR decline over a 3-year period.

Another agent that is being studied for a few years for a potential role in inhibiting cyst growth in PKD is octreotide, a long acting somatostatin analogue. This is an agent we in the nephrology universe have been using for some time for the treatment of hepatorenal syndrome. A randomized placebo controlled trial had first reported in 2005 that a 6-month treatment with somatostatin could slow cyst growth. Although we know that decline in kidney function in PKD follows cyst growth, the study stopped short of saying that slowing the cyst growth in this case would translate in to clinically meaningful renoprotection. A similar effect on liver volume has been reported as well.

A few months ago, we saw the results of the ALADIN trial published in the Lancet. This study had a longer follow-up period than the previous studies, and indicated a significantly lower kidney volume in patients treated with octreotide at 1-year follow-up, but not at 3-years.

Given the data we have so far, it appears that octreotide could have a potential role in the treatment of PKD. For some reason, it appears that octreotide slows growth in kidney volume over one year, but the effects become insignificant over the long term. Obviously, more comprehensive studies looking at long-term hard outcome data are needed. Another interesting thing would be to compare the data for octreotide vs. tolvaptan. Although both these agents have shown promise so far (in addition to other contenders like mTOR inhibitors), a major concern is cost. All other things being equal, octreotide could me a cheaper alternative than tolvaptan for what essentially could be a lifelong treatment. At my time of writing this, a ten-day course of 15 mg tolvaptan pills was priced at $3440.00, while a 100 mcg octreotide injection was priced at $11.93!

I can’t wait for the day when we will be able to offer our patients something more definitive for treatment of PKD, rather than the current bandaid regimen of ACE inhibitors, increased water intake, hand-holding, etc.

Posted by Veeraish Chauhan

Tolvaptan and the FDA - A patient's perspective

Over at the Atlantic this week, an article was published written by one of the people who took part in the early trials of tolvaptan for APKD. The article shows just how much hope people with this disorder were putting on this drug and the disappointment felt in the APKD community now that the FDA has rejected its use for this indication. Given the lack of new therapies that are available for renal diseases in general it is understandable that patients and their doctors are unhappy with this decision.

However, it should be said that there are substantial questions that remain to be answered about the use of this drug. The large trial published in the NEJM last year showed that tolvaptan reduced the rate of growth in kidney size while also leading to a slowdown in the rate of GFR decline. However, these are surrogate endpoints and we have been burned by surrogate endpoints in nephrology before (see Bardoxolone). Also, the majority of patients had good renal function at baseline. Not all patients with PCKD will develop ESRD and there is no indication at this time who should be treated with this drug and for how long. It should also be said that there was a high rate adverse events in the treatment group (primarily related to thirst and polyuria) and 23% of participants discontinued the drug. It is extremely expensive and it is important that there are clear guidelines for its use. As mentioned in this post, copeptin levels may be useful in determining who will respond to tolvaptan.

That said, it is always interesting and revealing to know the patient's point of view on this difficult issues.

New potential drug targets in ADPKD

Currently there is no good treatment for the most common inherited cause of ESRD, adult polycystic kidney disease. There have been a number of high profile trials in ADPKD in recent years. These trials have endeavored to show a reduction in cyst growth and GFR decline with everolimus, sirolimus) and most recently Tolvaptan (TEMPO). The longer (2years) and larger (433 patients) of the two mTOR inhibitor trials (everolimus) did show a significant reduction in cyst growth at one year but not in GFR reduction. The shorter sirolimus trial failed to show a reduction in cyst growth or GFR decline. The TEMPO trial was over 3 years, had 1445 patients and did show that the V2 antagonist Tolvaptan slowed GFR decline (reciprocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; p=0.001) and cyst growth, 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0). The jury is still out about the clinical applicability of these drugs and there have been criticisms. For example, tolvaptan is very expensive and would need to be used long term. In the mTOR inhibitor trials some argue doses could have been higher and the lack of hard end points speaks for itself.

However, all is not lost. A potential new drug target in ADPKD was reported by Rowe et al. in Nature Medicine last month. A good overview of the topic can also be found in the same issue.

Using MEF cells from pkd-/- and pkd+/+ mouse littermates they found that growth medium from the pkd-/- cells was more acidic and that the pkd-/- cells had a higher ATP content. To investigate which metabolic pathways might be causing this difference they used NMR spectroscopy and found lower glucose and higher lactate levels in the knock out cells. They then used a mitochondrial ATPase inhibitor to determine the source of higher ATP and found only wt cell had a reduction in ATP with this treatment.  Then the investigators did a real-time PCR analysis on the pkd-/- cells and found an upregulated glycolysis signature. They thus concluded that the pkd-/- cells rely on aerobic glycolysis for their energy demands. This is known as the Warburg effect described in cancer cells (Otto Warburg, a physician-scientist, received the Nobel Prize in Physiology or Medicine in 1931). To see if these in vitro findings translated into in vivo they used Ksp-Cre; Pkd1flox/− mice, which develop early and severe PKD and measured 13C-glucose or 13C-lactate using 13C-NMR. The findings were the same. The authors then used 2-deoxyglucose (2-DG) an analogue of glucose that is unmetabolised. They treated wt and pkd deficient mice this compound and found that the pkd deficient mice had a lower cyst index and lower 13C-glucose consumption as measured using 13C-NMR.

This interesting study proposes that the use of drugs targeting this pathway in combination with other drugs may reduce cystogenesis and progression of CKD in ADPKD. The authors do stress that their summary with regard to human treatments is speculative. In all I think the future is not so gloomy for ADPKD.

Posted by Andrew Malone

Aquaretics and PCKD

One of the big stories at the ASN this year was the announcement of the results of the TEMPO trial which were simultaneously published in NEJM. It has been known for some time that ADH is implicated in cyst growth in patients with polycystic kidney disease (PCKD) and that suppression of ADH release with high water intake or vasopressin receptor blockade reduces cyst growth in animal models. The TEMPO trial was a 3-year, multicenter controlled trial involving 1445 patients with PCKD who were randomized to receive tolvaptan (a V2-receptor antagonist) or placebo. The primary outcome was the rate of change in total kidney volume while the rate of CKD progression was a secondary outcome.

There was a lower rate of kidney growth in the tolvaptan group (2.8% per year vs. 5.5% per year) and a slower decline in renal function also. These are fantastic results and they should be celebrated, especially considering the disappointment surrounding bardoxolone. However, there are a couple of significant issues which should be considered. All of these patients had normal renal function at the time of entry into the study. The majority of these would progress very slowly to end stage and the cost of treatment with tolvaptan over this period of time would be enormous. Also, about 23% of the participants dropped out due to adverse effects (although, it should be said that 14% of the placebo group also dropped out). The most important side effect was liver toxicity.

So the question arises – who are the patients that will benefit most from vaptan treatment. As the accompanying editorial states – “the development of comprehensive criteria for aquaretic treatment and appropriate patient selection are needed”.

So maybe a recent series of papers from a group in Holland may help provide the answer. Vasopressin is difficult to measure in vivo because of its short half-life and tendency to bind to platelets. However, one of the components of its precursor, copeptin, is stable in plasma and can be used as a surrogate for the serum vasopressin concentration. Last year, this group published a paper which found that, in a group of 102 patients with PCKD, serum copeptin levels were associated with markers of disease severity such as kidney size, GFR and albuminuria. The group published two follow-up longitudinal studies (using historic samples from previous studies) in NDT and AJKD. In a group of 79 patients, higher baseline copeptin levels were associated with more rapid decline in renal function over 11 years follow-up. 8 of the 9 patients that started hemodialysis over the course of the study had copeptin levels above the median. It should be pointed out that baseline copeptin levels were higher in patients with lower GFR at the time of entry to the study and this could have biased the results.

The last paper looked back at 241 patients with normal baseline renal function who were included in a longitudinal study of cyst growth (and measured GFR!) In these patients, higher baseline copeptin levels were associated with a greater change in kidney volume over 8 years follow-up. After full covariate adjustment, there was a trend towards a greater decline in renal function in the higher copeptin group but this was not statistically significant. Again, however, patients with larger kidneys at baseline also had higher copeptin levels. Because of the size of the molecule, there may be some element of reduced clearance in patients with lower GFRs and this could explain some of the differential. Higher copeptin levels have also been noted in patients with other renal diseases so this is not entirely specific. This needs to be further studied.

Still, although not definitive, these studies provide some rationale for a potential means of stratifying patients with PCKD and certainly give a route for further investigation. It would be interesting, perhaps, to go back and measure baseline copeptin levels in the patients in the tolvaptan study to determine if there was a difference in response to therapy based on this promising biomarker.

Rapamycin and PCKD

A couple of years ago, it was noted that mTOR inhibitors slowed the growth of cysts in animal models of Polycystic Kidney Disease. Although the activity of mTOR is minimal in normal renal epithelial cells, in cyst epithelial cells, expression is markedly increased. At the time, there was understandably a lot of excitement about this and the potential for a role for rapamycin for treating patients with PCKD. (We got in on this ourselves and had two posts from Nate and Conall about this possible therapeutic pathway) Unfortunately, the clinical studies were not very impressive and the excitement has since faded somewhat. One of the reasons put forward for why it was ineffective was that the doses were inadequate. The dose of rapamycin needed to suppress cyst growth in mice was far higher than was tolerable for humans. Anyone who has used rapamycin in transplant recipients knows about the side-effect profile which prevents many people from taking the drug,

An article was just published in JASN which raises the possibility that rapamycin could be used in higher doses than previously thought possible. The folate receptor is selectively expressed on cancer cells and renal epithelial cells. As a result, there has been some work done on combining drugs with folate to increase the specificity of drug delivery, particularly chemotherapeutic agents and thus limiting toxicity. The beauty of this is that folic acid is taken up into most cells by an alternative pathway and this pathway is not available to conjugated folate. In this study, the authors conjugated rapamycin to folate and gave it to mice with PKD. They showed that it was effective both at reducing expression of downstream targets of mTOR and slowing cyst growth. This suggests that the combined compound could be given in large doses to humans with PKD and offer targeted therapy with less chance of significant extra-renal side effects.

Photo from the University of Indiana website

Cell Polarity and Cystic Diseases

There was an interesting article and accompanying editorial in JASN this month about the role of polarity in the development of cystic renal diseases. The maintenance of epithelial cell polarity is vital for the normal functioning of the renal tubules and the usual interpretation of this is the way in which a cell is organized into basolateral and luminal compartments (e.g. in intercalated cells, there is a luminal H+ ATPase and a basolateral anion exchanger and it is this polarity that facilitates acid excretion). In a similar way, mislocalization of the Na-K-ATPase has been noted in patients with ADPKD and is a putative mechanism for cyst formation.

However, there is another facet to polarity which appears to be just as important – planar polarity – this is the correct orientation of cells and specialized structures within cells along the plane of the epithelial sheet. Much research is continuing into the genes responsible for the development and maintenance of polarity. One of the means by which a loss of planar polarity may induce the formation of cysts is through the loss or dysfunction of primary cilia.

The authors in JASN found that both a gain and loss of function mutation in ErbB4 led to a loss of cell polarity. Members of this receptor family have been shown to be responsible for the development of polarity in neurons and in certain cancers.

Take one glass of water, three times a day...

As mentioned previously by Nate, there is some evidence that lowering urine osmolarity below that of the serum can reduce the rate of growth of cysts in PCKD and thus preserve renal function. The rationale for this is that ADH stimulates cAMP production in the collecting duct and that this is required for cyst growth. Therefore, if you can reduce ADH secretion, you might be able to delay progression of the disease.

One potential therapeutic option is the use of vaptans. ADH receptor-antagonists have been used in the treatment of SIADH and heart failure and theoretically, they could be of some benefit in patients with PCKD. However,these medications are not cheap and I wonder how you could ensure that the patients drink enough water so as not to become hypernatremic.

A paper was published in CJASN this month that suggests a more physiological means of decreasing ADH secretion. The study included 8 patients with PCKD who had 24 hour collections to determine their mean daily excretion of osmoles as well as their urine volume and osmolarity. At the beginning of the study, the average urine Osm was 496 with a total volume of 1.5L. The aim of the study was to decrease the urine osmolarity to less than 285, thus making it hypo-osmolar and theoretically reducing ADH secretion.

Assuming that total urine osmoles would not vary much from day to day on a normal diet, the authors used the formula:

(Total urinary solutes/285) – baseline urine volume = V

to determine the amount of excess water each subject would have to drink to reduce the urine osmolarity to 285 or below.

On average, the subjects managed to increase their urine volumes to about 2.3L daily at the end of the study. The mean urine Osm decreased to 325 and 5/8 patients achieved the target of 285 or lower.

Although this by no means proves that it is an effective therapy for PCKD, the paper shows that urine Osm can be safely reduced in a targeted way without the use of medications.

Revealed: my "covert" project with Nate a.k.a TRP channels in the kidney

Nate Hellman’s bench was three benches down from my lab. Nate and I trained together as clinical fellows. He and I had also brainstormed on research projects involving TRP channels and kidney disease. TRP channels are my research area of interest. It therefore seems appropriate to discuss some aspects of what Nate and I jokingly referred to as our “covert” project in my first blog posting.

What are TRP channels? And why do they matter in terms of kidney health and disease?

TRP stands for Transient Receptor Potential, a large family of non-selective cationic channels with diverse tissue distribution and diverse cellular functions. They were initially discovered in Drosophila (fruit fly) photoreceptors where they mediate fly vision. Some refer to them as “the last bastion of ion channels” since there is still much we do not understand about their role in health and disease. There are a few TRP subfamilies, indicated by letters which are there for various historical reasons (a discussion for another day – just take my word for it for now, or refer to a review by Ramsey et al., Annu Rev Physiol. 2006;68:619-47), but there are the TRPCs, the TRPVs, the TRPMs, the TRPPs, the TRPMLs and the TRPAs.

A few fun facts:
- TRP channels (TRPV1) are responsible for the hot taste of chili peppers in your mouth.
- TRP channels (TRPM8) also give you the cold sensation of menthol.

But how are TRP channels pertinent to your kidneys? It turns out that they are actually involved in many aspects of kidney physiology and disease (called “channelopathies”):

We’ll start from my favorite: Proteinuric kidney disease. Mutations in TRPC6 were found in a number of families with adult onset Focal Segmental Glomerulosclerosis. Many of us are now actively involved in research to identify the precise mechanisms by which disease occurs in these patients, but deleterious effects due to channel mutations in glomerular podocytes are strongly suspected.

Another channel, TRPV5, mediates vitamin D dependent calcium uptake in tubular epithelial cells. The absence of TRPV5 channels (at least in mice) causes renal calcium wasting and bone loss.

Perhaps more intriguingly, mutations in TRPM6 have been implicated in human hypomagnesemia with secondary hypocalcemia (HGH) as this channel is involved in renal magnesium uptake.

And rather famously, of course, polycystic kidney disease (ADPKD) emerges due to mutations in two slightly more distant relatives in the TRP family, the polycystins, known as TRPP1 and TRPP2.

This of course brings us full circle back to Nate and his research, which was focused on cystic disease, and specifically cystic kidney disease.

As this is my first time blogging, please let me know what you think, your comments and suggestions are welcome!

Polycystic Kidney Disease, mTOR and Sirolimus

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the gradual enlargement of multiple fluid filled cysts in both kidneys, which compress and destroy normal adjacent nephrons, typically resulting in ESRD by the fifth decade of life. Management has traditionally been limited to the treatment of the complications of hypertension and renal failure; however, several promising new therapies are on the horizon, such as nonpeptide vasopressin 2 receptor antagonists, inhibitors of the receptors for EGF and vascular endothelial growth factor (VEGF), and inhibitors of cmyc expression. All of which have been shown to inhibit disease progression in experimental models of PKD.

The mTOR inhibitor Sirolimus (Rapamycin) is another promising potential therapy, having also been shown to slow cyst development in rat models. Interestingly, it also slows the increase in size of native polycystic kidneys in human renal transplant recipients. It is currently the subject of three clinical trails underway in the US and Europe. Mechanistically, the cytoplasmic tail of wild-type Polycystin 1 normally interacts with, and inhibits, mTOR; loss of function of Polycystin 1, as seen in ADPKD, results in marked activation of mTOR within the epithelial cells of renal cysts. Sirolimus is believed to exert its effect via this mechanism. As mutations in PKD1, which encodes PC1, account for 85% of cases of ADPKD, Sirolimus has the potential to ameriorate the condition of the vast majority of APCKD patients.

A role for polycystins as blood pressure sensors?

One of the hallmarks of autosomal dominant polycystic kidney disease (ADPKD) is hypertension. True, most patients with advanced kidney disease get hypertension anyways--but often the degree of hypertension in ADPKD patients seems to be especially high. Is there something about the function of the polycystin proteins which explains the high blood pressure?

A recent article by Sharif-Naeini et al in this month's issue of Cell claims a pressure-sensing role for the polycystins. ADPKD is caused by mutations in two genes, PKD1 and PKD2, which encode for membrane proteins termed TRPP1 and TRPP2, respectively. It appears these genes function via regulating local calcium fluxes in and out of the cell. Although most efforts to understand TRPP1 and TRPP2 function have focused on renal tubular epithelial cells (since that's where cysts come from), a variety of extra-renal phenotypes are also observed. In this paper, the authors generated mice deficient in TRPP1 or TRPP2 ONLY in smooth muscle cells. Importantly, they found that the balance of TRPP1 and TRPP2 levels was critical for the ability of arterial smooth muscle to maintain appropriate blood pressure. These results imply that function of the polycystins may be different depending on cell type, and suggest a possible mechanism by which ADPKD patients may be especially prone to the development of abnormalities in blood pressure regulation.

Renal Cilia Length Increases with ATN

Get your flu shots, everyone!  Renal Fellow Network recently had to take an H1N1-sponsored weekend off, and I strongly suggest getting the vaccine if available to you; this bug is no fun at all. 

I've written about the ciliary hypothesis of cystic kidney disease before, and it is one of my personal research interests:  defects in renal primary cilia are the common pathogenesis of renal cyst formation. Despite large advantages in understanding cystic kidney diseases, however, there remains one really large, looming question:  what exactly does the cilia do in normal physiology?  Some studies suggest that the cilium is a rigid antennae, functioning to sense urine flow, but it is still not clear how this connects with the pathogenesis of cystic kidney disease. 

One potential clue to cilia function has come from recent studies which demonstrate that the cilia grows longer in response to kidney injury.  Previously, these results have been limited to animal studies; a recent article in JASN by Verghese et al however illustrates that cilia lengthening occurs in human kidneys subjected to ATN!  Their study design was fairly clever:  they performed cilia staining on serial biopsies of donor kidneys at the time of harvest (prior to any ATN changes having taken place) and then at 6-days post-transplant (after which ATN-like changes were present).  They found a striking doubling in average cilia length following ATN (compare the image on the right to the one on the left; the cilia is the green thread-like structure sticking into the lumen of the tubule).  

Why is cilia length increasing?  Is it simply an abnormal reaction to tubular injury?  Or could increasing the length of the cilium somehow be an adaptive response which aids in the recovery of nephron function?  The answer is not clear from this study alone, but understanding this phenomenon could turn out to be an important step forward in figuring out the precise role of renal cilia.

Tuberous Sclerosis Complex and the Kidney

Tuberous sclerosis complex (TSC) is a rare genetic disease, caused by mutations within one of two genes (TSC1 or TSC2) which is named for the formation of hard tumors ("tubers") within a variety of tissues, including the CNS, kidneys, eyes, heart, lungs and skin. Often, dermatologic clues can be essential to making a diagnosis; common examples include facial angiofibromas (a rash of reddish spots appearing on the nose and cheeks in a butterfly distribution), "ash leaf spots" (hypopigmented macules), ungual or subungual fibromas, Shagreen patches (areas of thick, leathery skin, often found at the nape of the neck), and cafe au lait spots.

Most patients with tuberous sclerosis have some renal lesion, though fortunately it is usually not severe. There are a wide range of renal manifestation of TSC, many of which are detailed in this 2006 Kidney International review by Rakowski et al. About 80% of patients have renal angiomyolipomas, an abnormal collection of blood vessels, smooth muscle, and fat cells; these are best identified on CT as fat-containing lesions. They are felt to pose little to no risk of evolving into anything malignant, though they are at risk for bleeding (and sometimes even catastrophic bleeding). In addition to angiomyolipomas, up to 45% of TSC patients get cysts. Rarely, TSC and ADPKD can occurs simultaneously, as the TSC1 gene and PKD1 gene are located near one another and may be deleted in some instances. Finally, about 1-2% of TSC patients will develop renal cell carcinoma. This can be tricky to diagnose (especially given the high likelihood of angiomyolipomas or simple cysts). Individuals with TSC who get kidney failure and enjoy a transplant generally do well, though the current recommendation here is to perform a bilateral native nephrectomy at the time of transplant in the hopes of minimizing the cancer risk in the setting of immunosuppression.

Sensipar for APKD?

Following on the heels of studies showing a potentially beneficial effect for vasopressin receptor antagonists and rapamycin in the treatment of renal cystic disorders, an article in this month's JASN by Gattone et al suggests another class of commonly-used nephrology-related drug which may be of use: calcimimetics (such as cinacalcet, or sensipar).

The logic is as follows: The growth of cysts in PKD is thought to be driven by low intracellular calcium levels and elevated cAMP levels. The calcium sensing receptor (upon which cinacalcet acts) is activated by binding to serum ionized calcium, and results in a G-protein-mediated decrease in cAMP levels & increase in intracellular calcium concentration. The investigators therefore suggested that cinacalcet might be an effective way to reduce cyst growth in late PKD.

To test their hypothesis, they took a rat model of PKD (Cy/+) and treated them either with placebo or with the calcimimetic R-568, which is similar in function to cinacalcet. Interestingly, rats in the treatment group showed less advanced cyst formation and fibrosis at later time points, suggesting that their hypothesis may be correct. This study is somewhat unique in that it looks at fairly advanced stages of cystic kidney disease, whereas other animal studies have focused on a more prophylactic approach to cyst growth.

Cautious optimism for ADPKD patients--if I were a young guy with the PKD1 or PKD2 gene, I would seriously consider enrollment in one of the ongoing trials.

Rapamycin for ADPKD?

Another potentially useful drug to prevent cyst growth in autosomal dominant polycystic kidney disease comes from the interesting observation that kidney transplant patients with native ADPKD kidneys who were given an immunosuppressant regimen containing the drug rapamycin (sirolimus) displayed less cyst growth than those who did not receive rapamycin.

The molecular mechanism of rapamycin is already known: it inhibits a cell signaling pathway known as the mTOR pathway (mTor = "mammalian target of rapamycin"). In support of its usefulness in ADPKD, the epithelium lining cysts (arrow) shows intense staining with an antibody against phosphorylated (active) mTOR, while non-cystic tubules (depicted by the arrowhead) do not show mTOR activity, as shown in this 2006 PNAS paper by Shillingford et al.
We will obviously have to see how rapamycin does in clinical trials. One of the obvious caveats is that this is not a wholly benign medication as observed by many transplant nephrologists, and bear in mind that it would likely be a chronic medication taken to prevent the growth of cysts and resultant ESRD. In the meantime, an article in this month's Kidney International by Gattone et al successfully uses rapamycin to decrease cyst growth in a mouse model of nephronophthisis (the pcy mouse), providing further rationale for this approach.

Zebrafish Model of Cystic Kidney Disease

For the research component of my Nephrology fellowship, I've chosen an unorthodox route:  I am using the zebrafish as a model organism for the study of kidney disease.  

The zebrafish system has a number of advantages.  First, a single male/female pair can produce hundreds of eggs overnight, thus opening the door for great genetic studies.  It's akin to the fruit fly in this respect, but because the zebrafish is a vertebrate and the fruit fly is not, the zebrafish genome is much more similar to the human genome.  Zebrafish embryos are completely transparent, and thus you can watch their kidneys develop in real-time.  The early zebrafish kidney (called the pronephros) first appears within 24-48 hours, so experiments can be done with a rapidity unmatched in mice.  Furthermore, the zebrafish pronephros is much more simple than the mammalian kidney:  in fact, it consists of a single nephron!!  Despite this simplicity, the nephron contains discrete proximal, distal, and collecting duct domains which appear to be very similar to their mammalian counterparts.  

I'm presently using the zebrafish system as a model of cystic kidney disease.  For example, knocking down the genes for PKD1 and PKD2 (mutations in which result in ADPKD in humans) result in glomerular cyst formation within the single nephron of the zebrafish.  I am presently using this system in order to identify new genes which may be part of the PKD1/PKD2 pathway.  For instance,  here is an example of a gene I knocked down which interestingly results in dilatation of the pronephric ducts (shown by arrows) and cysts which form in the single glomerulus (arrowheads, looks kind of like a big bubble).