Wednesday, May 18, 2016

Recurrent kidney stones: causes and management

Patient is a 37-year-old female with cystic fibrosis, recurrent nephrolithiasis who presents to clinic with asymptomatic bilateral kidney stones (8mm on right; 2mm on left) on imaging.

 What type of stone and why cystic fibrosis (CF) is associated with kidney stones?
 Patients with CF are at increased risk of calcium oxalate stones. This is thought to be primarily due to enteric hyperoxaluria and hypocitraturia.
 Gut malabsorption can lead to hyperoxaluria. In malabsorption, there is an increase in free fatty acids (FFA), which bind to calcium and decrease the amount of calcium in the gut available to bind to oxalate. This leads to an increase in soluble oxalate which is absorbed in the gut (See Nezzal et al. NDT 2016 for an excellent discussion of enteric hyperoxaluria). Furthermore, chronic diarrhea from malabsorption leads to a chronic metabolic acidosis and hypocitraturia. In the urine, citrate is an inhibitor of the calcium oxalate complex. Higher urinary oxalate and less urinary citrate are associated with higher risk of stone formation.

 What is the diagnostic work-up recommended in the above patient? 
Initial evaluation of all patients with kidney stones, should include two 24-hour urine collections. Evaluating the urine composition provides crucial data for characterizing the patient’s risk of kidney stone formation (both formation of new stones and growth of existing stones). For this patient, she also had a noncontrast CT that again demonstrated a 8mm stone in the lower pole of the right kidney. She also had 2 small (2-3mm) stones on the left (See Curhan, et al. “Diagnosis and acute management of suspected nephrolithiasis in adults” Up to Date, for more in depth discussion).

 How to best manage this patient’s stones?
 For her existing calcium oxalate stones we need the help of our urology colleagues. Kidney stones less then 5mm are likely to pass on their own, without procedural intervention. For larger stones, discussion with the patient and urology is important. Options include medical expulsion therapy (MET), extracorporeal shock-wave lithotripsy (ESWL), ureteroscopy (URS), and percutaneous nephrolithotomy (PNL) (See also: AUA/EAU J Urol Vol 178, 2418-2434 2007 and prior blog). Our patient underwent urological evaluation and ureteroscopy to remove her 8mm stone.

 How can we prevent further stones formation? 
Our patient’s 24-hour urine revealed total volume of below 2 Liters, oxalate 44, and citrate 87. For her, we discussed increasing fluid intake to reach a goal of at least 2 L/day.  To lower her urinary oxalate we discussed multiple strategies, including reduction of dietary oxalate intake, increasing dietary calcium intake to the recommended daily allowance, and starting calcium supplementation with meals (to bind to oxalate in the gut and reduce oxalate absorption) [see also

We also started potassium citrate to increase urinary citrate (check this article for the updated AUA guidelines for the medical management of kidney stones). 

Megan Prochaska MD
Second year fellow BWH

Image from oxalate stone (

Tuesday, May 10, 2016

Renal Functional Reserve: Time for a Kidney stress test in clinical practice?

GFR varies under normal physiological conditions and during illnesses. A popular example is a low GFR in vegetarians and a higher GFR in consumers of large quantities of animal protein, even when they have a similar normal renal mass. It is not clear what the maximum GFR can be, but it can be approached with an acute animal protein load. One to two hours after an animal protein load, individuals with healthy kidneys will show a significant rise in their GFR independent of their baseline GFR. The difference between baseline and maximal (i.e. stress or peak) GFR is called the Renal Functional Reserve (RFR).

The maximum capacity of a functioning renal mass is not reflected by the baseline GFR of a given individual. Bellomo et al used an example of 4 different patients to explain this concept. Patients A (animal protein consumer) and B (vegetarian) have the same renal mass but different baseline GFRs owing to different basal protein in-takes levels. Patient A has a GFR of 120 ml/min that can be stimulated to 170 ml/min. Patient B has a baseline GFR of 65 ml/min that also can be stimulated to 170 ml/min. Therefore, the RFR in these two patients is different because they are using their GFR capacity at a different level. Patient C had a unilateral nephrectomy. His baseline GFR corresponds to his maximal GFR under unrestricted dietary conditions. If a moderate protein restriction is applied to his diet, his baseline GFR may decrease and some degree of RFR become evident. Patient D, who is a vegetarian who underwent unilateral nephrectomy, will have a lower baseline compared to patient C but a higher RFR. Therefore, in general, restoring some RFR requires a severe protein restriction, and hence baseline GFR does not always correspond to the extent of functioning renal mass unless we place it in the context of maximal capacity. Bellomo et al concluded the section about GFR by using a very interesting, possibly true, statement:

“In this regard GFR is not unlike a resting ECG for the kidney. When it is grossly abnormal, renal function is impaired, but when it is normal, a stress test is required.”

The GFR rises considerably during pregnancy. This physiological rise is multifactorial and is mainly attributed to increase in cardiac output and renal blood flow. It becomes apparent from the 1st month and peaks at 40% – 50% above baseline levels by the 4th or 5th month of pregnancy. This increase in GFR is referred to as renal hyperfiltration. The RFR is consumed as a part of adaptation to this physiological demand that occur during pregnancy. This was demonstrated by Ronco et al. They assessed GFR changes in pregnant women, with normal kidneys, before and after protein load. After acute protein load, all women had a significant increase in GFR. This rise was more in the first than in the last trimester. This finding explains, at least partially, renal hyperfiltration in pregnancy.

RFR allow for an increase in GFR during stressful conditions to ensure maintenance of adequate kidney function. When RFR is lost or fully utilized and the kidney insult continues, changes in baseline GFR and serum creatinine occur. After an AKI episode, creatinine and GFR may return to normal, displaying an apparent complete recovery of the kidney. Unfortunately, this recovery might be at the expense of reduction or loss of the RFR. In my opinion, without performing a kidney stress test to assess the RFR post-AKI, it will remain unclear whether the recovery from AKI was complete or was it just a biochemical recovery (reflected by creatinine level) at the expense of RFR utilization. Conceptually, recovering baseline GFR and creatinine level post-AKI without recovering the RFR should be labelled as new-onset CKD because it actually reflects an irreversible loss of nephrons/RFR. I have no evidence to support this, but I would hypothesize that these patients who lose their RFR post-AKI are the ones who were shown to progress to CKD in previous studies.

I think the following are potential benefits for using a kidney stress test/ checking RFR:
  1. Assessment of recovery post-AKI: It will help to detect patients who are likely to progress to CKD.
  2. Assessment of living kidney donors prior to donation: It is likely that a low RFR might increase the long-term risk of CKD during the post-donation period.
  3. To assess the risk of AKI in patients undergoing contrast studies and high-risk surgeries.
Of course robust studies are needed to assess the diagnostic and the prognostic utility of RFR and kidney stress test in the clinical setting.

Post by Mohammed Kaballo

Thursday, May 5, 2016

Obesity and CKD: How big is this?

How important is obesity to the field of nephrology? Perhaps obesity is the single strongest risk factor for CKD in the US and most of the developed world. While genetics are certainly important, obesity drives the diabetes epidemic and contributes significantly to the hypertensive burden in our population. But if obesity is this important, how can we best help our patients? Should nephrologists emphasize obesity along with our traditional targets (e.g. HbA1c < 7%, SBP < 130 or 140 mmHg, statin use, etc.)? Unfortunately, there is not a lot of data to guide us.

Attempting to look at obesity as a risk factor for CKD independent of diabetes or hypertension is challenging. However, there are a few studies that suggest an independent effect on CKD and its progression (Hsu, Cao). Whether or not “metabolically healthy” obese patients are at higher risk of CKD remains unclear (Hashimoto).

There are likely other mechanisms in obesity beyond diabetes and hypertension that are injurious to our beans (Rao). For example – increased abdominal pressure can activate RAAS and visceral fat itself can generate not just angiotensinogen but also inflammatory cytokines (such as leptin) which may stimulate renal fibrosis. Physiologic changes in obesity create glomerular hypertension, hyperfiltration, and glomerulomegaly. In a subset of these patients, for unclear reasons, overt glomerulosclerosis develops.

The effect of obesity on renal function was clearly reported in 1974 in four non-diabetic patients with severe obesity and nephrosis (Weisinger). The nephrosis and proteinuria resolved with significant weight loss during prolonged hospitalizations. Subsequent studies have also shown the resolution of glomerular hyperfiltration with weight loss.

The clinical and pathologic characteristics of obesity related glomerular damage have been described (Kambham). Notably, when compared to patients with idiopathic FSGS, obesity-related glomerulopathy demonstrates lower rates of true nephrotic syndrome as well as less, but certainly not insignificant, progression to ESRD. Importantly, clinical characteristics do not seem to differentiate between obesity-related glomerulomegaly with hyperfiltration and the development of obesity-related FSGS.

If obesity worsens renal function then how should we combat it? Data focusing on individual patient treatments in CKD is limited, with the majority of studies being small with short term follow-up. Weight loss is associated with a reduction in proteinuria but no clear change in GFR (Naveneethan). Bariatric surgery offers a therapy that can reliably produce significant weight loss, reduce or eliminate proteinuria, and improve diabetic and hypertensive control. Its effects on GFR however are hard to predict, especially given that creatinine often decreases post-surgery given the loss of lean body mass that parallels declines in adiposity. Likewise, the true risk of hyperoxaluria and worsened renal function in modern malabsorptive procedures is not well understood. The literature on bariatric surgery and diabetic nephropathy was recently reviewed here (Friedman).

Questions still remain.
  • How aggressive should we be regarding weight loss in our patients? 
  • Is it enough to recommend diet and exercise or should we advocate for weight loss programs? 
  • Should we prescribe medications such as orlistat or phentermine/topiramate? 
  • Should we refer patients for consideration of bariatric surgery? 
 Hopefully the coming decades will clarify these questions.

Robert Rope, Nephrology Fellow, Stanford

Wednesday, May 4, 2016

Emphysematous Pyelonephritis was asked to see 74 year old man with an acute on chronic kidney injury.  He had 2 days of generalised lower abdominal pain and vomiting but no urinary symptoms or fever.  His past history included advanced CKD, benign prostatic hypertrophy and a slow growing renal cell tumour under radiological surveillance.  His vital signs were normal and he had mildly raised inflammatory markers.  I ordered a CT KUB to exclude obstruction (it was a weekend and was no ultrasound service in the hospital).  To my surprise this came back as showing emphysematous pyelitis.  Interestingly there had been a hiss of air as he was catheterised for fluid balance monitoring – a fact I had dismissed at the time!

Emphysematous UTIs are gas forming infections of the urinary tract and can manifest as cystitis (gas within the bladder wall), pyelitis (gas within the collecting system) or pyelonephritis (gas within renal parenchyma or perinephric tissues).  It is a relatively rare condition and there is a dearth of literature describing incidence.  Diabetes and urinary tract obstruction are major risk factors, present in around 80% and 20% of patients respectively. Causative organisms are most commonly E. Coli and Klebsiella pneumoniae, with Candida being involved less frequently. Presentation is usually similar to acute severe pyelonephritis with fever, flank pain and vomiting. 50% of patients have an associated bacteraemia. Diagnosis is usually made by CT which shows the extent of gas within the urinary tract and any obstruction.
Treatment depends on the extent of infection.  It ranges from parenteral antibiotics alone for patients where gas is limited to the collecting system with no obstruction, to percutaneous drainage of purulent material and antibiotics if there is abscess formation or extension of gas into the perinephric space, to nephrectomy in patients with diffuse gas and extensive renal destruction.

In the above case, the urine sample was initially reported as ‘no significant bacteriuria’ but subsequently grew a resistant E. Coli >1,000 - <10,000 cfu/ml.  Urology felt that surgical intervention was not required as the renal parenchyma was not involved and he had no abscess formation.  The patient completed 2 weeks of ertapenem and his renal function returned to baseline.
I took several learning points away from this case:
  • As someone who spends a lot of time signing off patients’ results, I realise that ‘no significant bacteriuria’ is not the same as ‘no growth’, and in this case the difference was substantial.  The wording of how we report things and how we interpret that is crucial.
  • A high index of suspicion is required to diagnose emphysematous UTIs and the most appropriate imaging modality should be considered.  Ultrasound is generally the first line investigation for urinary obstruction in patients with acute kidney injury or febrile urinary tract infection due to high sensitivity for hydronephrosis, lack of ionising radiation and lower cost than CT. Ultrasound appearances in emphysematous UTIs can be difficult to interpret however: gas, calculi and calcifications are hard to distinguish and there is often variability in how they are reported. CT is able to precisely localise the presence of gas within the urinary tract and determine whether there is involvement of the renal parenchyma and perinephric tissues.  It can also identify any concomitant pathology or alternate diagnosis e.g. renal calculi.  CT is therefore preferable for diagnosis and subsequent severity staging.
  • Pneumaturia has been described as a presenting feature of emphysematous UTI.  Other causes include vesicovaginal or vesicoenteric fistulae, renal tumour infarction and recent instrumentation.  The unexpected air hiss when catheterising this gentleman was a warning of a more serious pathology and should prompt further investigation.

While the outcome of emphysematous pyelitis is better than that of pyelonephritis (which has a mortality of 18-70% depending on extent of involvement), it is still not a condition to be taken lightly. 
Post by Ailish Nimmo, Royal Infirmary of Edinburgh

Tuesday, May 3, 2016

Introducing Nephropoly



Dorey A. Glenn, Pediatric Nephrology Fellow, UNC

Monday, May 2, 2016

Washington University Nephrology Web Episode - Bone Mineral Metabolism

The complex interplay of calcium and phosphorus metabolism with intact PTH, vitamin D, and FGF-23 is one of the more difficult things to understand, and also one of the hardest concepts to teach to students, residents, and fellows. The May episode of the Washington University Nephrology Web Series helps you to understand this topic in 20 minutes, demonstrating normal physiology and then the abnormalities that develop in chronic kidney disease states. 

In case you missed our April episode, which was a renal pathology teaching series on amyloidosis, you can find it here.  Enjoy!