Is it Diabetic Nephropathy?


Yesterday, i saw a T2DM patient admitted with heavy proteinuria (10 grams), anasarca and slightly elevated serum creatinine (1.5 mg/dL). Digging into her history, T2DM was diagnosed 1.5 years ago. Still, it seems a bit older, as she had diabetic retinopathy six months after diagnosis, which was treated with Laser photo-coagulation. She has a positive family history of diabetes. All features seems complying with a diagnosis of diabetic nephropathy.

With further history checking, her edema started only two months ago, and was progressively deteriorating despite escalating doses of diuretics. On examination, she had ascites, +++ lower extremity edema. Her current investigations reveals significantly high ESR (150 first hour), progressively rising proteinuria (1.5, 5,then 10 gm over a 2 month period), HbA1C 6.2, and nothing else of significance. Her USS shows normal kidneys.

On admission, a suspicion of non-diabetic-kidney-disease (NDKD)
was raised given her progressive proteinuria and high ESR (see the previous discussion about uses of ESR in nephrology practice). A kidney biopsy and a non-contrast CAT scan of chest, abdomen and pelvis were done. CAT scan revealed an ovarian cystic lesion of suspicious nature. MRI of this lesion revealed an ovarian cancer and biopsy showed secondary membranous nephropathy (PLA2R negative in biopsy).

Kidney affection in patients with T2DM is classified into Diabetic kidney disease (DKD), Non-Diabetic kidney disease (NDKD), or combined NDKD over a DKD. In clinical practice, however, diagnostic kidney biopsy is rarely performed in patients with DM and usually, renal impairment and proteinuria are assigned to DKD. The prevalence of NDKD ranges from 33% to 72.5% among patients with T2DM. These numbers are usually inflated and biased by selection of biopsies in atypical presentations like our case. Nevertheless, it is crucial to have a clue when to suspect a NDKD and when to do a kidney biopsy for patients with DM. NDKD can be any of; IgA nephropathy, infection related GN, paraproteinemia, renovascular diseases, cholesterol emboli, ….etc.

Usually the presence of the following events, although not mandatory, raise the suspicion of NDKD; short duration of DM, rapid progression to overt proteinuria, absence of diabetic retinopathy, presence of macroscopic hematuria or RBC cast, and signs/symptoms of other systemic diseases.

In summary, having a low threshold to biopsy patients with T2DM, is advocated by some clinicians to detect NDKD alone and mixed cases of DKD and NDKD. Centers with this policy can better serve their patients and diagnose different diseases that would have been mistakenly labelled as DKD. Our case has a relatively straightforward queries, that were explained by investigations and biopsy. Other cases may need an expert eye and a high index of suspicion!

Mohamed Elrggal,
18 April 2019


Gum Arabic in CKD, a Friend or Foe ?!

Image by montemari from Pixabay

Arabic Gum (or Gum Acacia), is a natural product extracted from acacia species, predominantly Acacia senegal and Vachellia (Acacia) seyal. Arabic Gum (AG) is a complex mixture of glycoproteins and polysaccharides. It is soluble in water, used primarily in the food industry as a stabilizer, with EU E number E414. AG is rich in Calcium, Magnesium and Potassium. Upon ingestion it is fermented by colonic microorganisms into short chain fatty acids.

Properties and composition of GA

Many nephrologist in Egypt and the Middle East prescribe AG for patients with CKD. Some nephrologists are skeptical about its use due to weak evidence, and possible harm probably due to adulteration, others are against its use completely. Fake doctors deceive patients to stop their medications, sometimes their dialysis, to take herbs instead (including AG) which result in disasters.

My patients always ask me about the use of herbs and specifically about AG, i didn’t have a clear answer actually, i thought AG might not be harmful (beside the patient medications) to take as long as you are trusting who you buy it from. I thought to review the evidence about the use of AG in CKD patients to have a clear answer for my patients.

Many studies were performed on AG both in animals and humans. In healthy mice, AG:

  1. Increased 24-hour creatinine clearance.
  2. increased fecal Na and water excretion (Na and water binding capacity).
  3. Increased intestinal calcium absorption (increasing serum calcium) and urinary calcium and Mg excretion.
  4. subsequently, it significantly decreased 1,25 OH vit D level, and PTH (non-significantly).
  5. No effect on serum K level.

These effects, as evident, are beneficial for CKD patients. Furthermore, in rat model of adenine induced CKD and Streptozotocin-Induced Diabetes, concomitant AG ameliorated the adverse biochemical alterations effect of adenine, it even mitigated the histopathological changes induced by adenine and streptozotocin. AG was beneficial even in acute renal conditions including AKI and Gentamycin induced nephrotoxicity in rats. Beside, in diabetic mice, AG decreased glucosuria, hypertension and proteinuria. A possible explanation is that AG decrease the expression of intestinal SGLT1, which decrease glucose and Na absorption from the intestine, thereby decrease insulin level and obesity. Other extrarenal benefits of AG are summarized elsewhere.

For human studies, the theory was that colonic bacteria ferment dietary fiber, providing them with energy for growth and nitrogen incorporation, thus increasing nitrogen excretion in feces. In 16 CKD patients randomly assigned to either a supplement of a highly fermentable fiber, gum arabic (50 g/d), or a placebo (1 g pectin/d), AG increased fecal nitrogen excretion and decreased serum urea nitrogen after only 4 weeks of the study. AG was well tolerated and it didn’t affect the nitrogen balance significantly. In another randomized study in hemodialysis patients, AG managed to decrease serum urea, creatinine, uric acid and phosphorus while increasing serum calcium in comparison to the control group. More recently, AG was found to have anti-inflammatory and anti-oxidative properties in rats, and it reduced CRP levels in CKD patients, which is thought to be another mechanism for its nephroprotective effect. A possible blood pressure reducing effect using AG was also reported in a child on peritoneal dialysis.

Finally, AG demonstrated prebiotic properties. When applied in vitro, AG was capable of increasing Lactobacillus sp stool content (useful bacteria) with slight reduction in the counts of Clostridium perfringens. In healthy volunteers, AG established prebiotic functionality in a dose-dependent manner.

How can we apply these results to our practice? These animal and human studies might shed light that AG deserve a trial in CKD patients. Whether you accept it as a practice or not, but it has some basic and clinical research evidence, and these should not be abandoned all together. To summarize:

  1. It do decrease serum urea nitrogen levels by enhancing its fecal excretion. This can be used in CKD 5 patients refusing dialysis and preferring conservative management (palliative therapy).
  2. It increases serum calcium, calcium absorption, this can help correct hypocalcemia of CKD (and may be decrease PTH as well), could it worsen patients with calcium stone??
  3. It increase fecal water content, this can help anuric hemodialysis patients maintain or decrease their inter-dialytic-weight-gain (IDWG).

However, you should always monitor serum Calcium, Magnesium, 1,25 OH Vitamin D and PTH levels. Make sure patients trust the seller. And make sure that the patient will not stop his own medications and replace it with herbal ones.

Do you prescribe AG to your CKD patients? Share your experience…


Mohamed Elrggal

9 April 2019

Erythrocyte Sedimentation Rate, use in Nephrology?


During my residency, ESR was a common investigation requested during initial kidney patient assessment. A cut-off value around 100 mm/h was the one that draws nephrologists attention to search for a hidden cause for the patient’s kidney disease. During my fellowship, i learned some arguments against the common use of ESR, with its low sensitivity. This kept me skeptical about its use. Here, i am going to highlight a recent article published in JAMA evaluating the use of ESR through a case based scenario.

First of all, ESR measures the rate at which RBCs settle in the plasma of anti-coagulated blood in a standardized Westergren tube.

ESR is a measure of inflammation caused by infection, malignancy, or rheumatologic diseases. However, multiple non-inflammatory causes can affect the ESR including anemia, hypergammaglobulinemia, hypoalbuminemia (those increase ESR), polycythemia, leukocytosis, hyperbilirubinemia and hypercholesterolemia (can decrease ESR).

ESR has poor sensitivity and specificity in low cut-off values, however specificity and sensitivity increase as the cut-off increase, with specificity for hidden disease reaching more than 90% in some studies when using values greater than 100 mm/h.

Common causes of an ESR > 100 mm/h include:
1. Deep seated infections (osteomyelitis or endocarditis)
2. Connective tissue disorders
3. Malignancy

With all what was said in mind, we can conclude that ESR greater than 100 mm/h deserves diagnostic attention but is nonspecific and cannot by itself establish a diagnosis.

Mohamed Elrggal
23 March 2019

Available options to treat ADPKD in Egypt!

Yesterday, I saw a 40-year-old man with autosomal dominant polycystic kidney disease (ADPKD). He had a normal serum creatinine of 1 mg/dl. He was seen by another nephrologist who prescribed Sandostatin injections for life! The patient was seeking a second opinion regarding whether or not to take this drug ?!

FYI, Tolvaptan (Vasopressin antagonist) is not yet available in Egypt, and there is little we can do for patients with ADPKD (only blood pressure control using ACEi or ARBs). Thus, you can sense the frustration from nephrologists in the management of these patients in Egypt…

So, What is the role of Sandostatin in the management of ADPKD?
Is there any evidence for its use to slow down ADPKD progression? Subsequently, are we justified, in Egypt, to prescribe it with no other options available? And is it cost-effective to be used in a limited resource country like ours?

ADPKD is a progressive disease characterized by the sustained growth of fluid-filled cysts and the progressive enlargement of kidneys, often leading to the development of CKD and kidney failure in affected individuals. Cyclic adenosine monophosphate (cAMP) is usually involved in the mechanism of cyst development and growth. Baseline total kidney volume (TKV) and the rate of kidney growth has been validated as prognostic biomarkers for disease progression in ADPKD.

Octreotide (Sandostatin) is a Somatostatin analogue (this group also include Lanreotide but it is not available in Egypt) that inhibits adenyl cyclase (the enzyme that produces cAMP) when bound to the Somatostatin receptor, and thus should have an inhibitory effect on cyst formation and growth.
Many observational trials showed that Somatostatin analogues (Octreotide or Lanreotide) successfully slowed cyst growth. Also placebo controlled trials showed the same results. but these trials were small, short and not always adequately controlled.
Two well conducted trials, The ALADIN and DIPAK-1, examined the effect of Somatostatin analogues in ADPKD patients on TKV and GFR.

In ALADIN trial (Lancet 2013), Octreotide-LAR 40 mg IM injections every 28 days managed to slow the increase in TKV at 1 year (but not at 3 years!!) as compared to placebo in 79 patients with ADPKD and GFR > 40 ml/min. At one year, measured GFR using iohexol plasma clearance, was not different between both groups, however, mean GFR remained stable in the Octreotide-LAR group but continued to decline in the placebo group at three years.

In the DIPAK-1 trial (JAMA December 2018), Lanreotide, 120 mg subcutaneously once every 4 weeks in 309 ADPKD patients with eGFR of 30-60 ml/min, despite slowing the rate of TKV growth, did not slow the decline in kidney function (eGFR using cystatin-C) over 2.5 years of follow-up. For more details about the DIPAK-1 read this excellent NephJC blog.

With these perplexing results, and given the fact that Sandostatin-LAR 30 mg vial cost about 6800 LE which will be given monthly (about 81600 L.E/year).
Do you find it cost effective to use this medication in your ADPKD patients?
How would you answer this patient?
Do you actually prescribe Sandostatin for your ADPKD patients?
Share your thoughts and practice….

Mohamed Elrggal
21 March 2019

First Do No Harm!

Courtesy: Prof Wesam Ismail, Nephropathologist, Cairo, Egypt

We recently had a 28-year-old female with nephrotic range proteinuria since 2017, who has been treated with different immunosuppression protocols including MMF, CNIs, cyclophosphamide and steroids, with no improvement in her proteinuria for about two years!

On presentation, she had normal serum creatinine, nephrotic proteinuria 8 grams, fish eye appearance and low HDL level. The decision was to re-biopsy her kidneys, and she turned out to have Lecithin- Cholesterol Acyltransferase (LCAT) Deficiency (biopsy in the figure showing mesangial expansion by large foamy histiocytes with many intracapillary foam cells).

Unfortunately, there is no treatment for such a condition, and transplantation is the option in case of progression. Decision was to withdraw immunosuppression and to continue on ACEis only. The biopsy here saved the patients the risk of un-needed immunosuppression.

Today, I saw another patient, also treated from nephrotic proteinuria with immunosuppression since 4 years with no improvement in her proteinuria what so ever. I discussed the biopsy with her, steps, risks and benefits, and she accepted to do the biopsy!

So, Are we allowed to give immunosuppression without a diagnosis of an immune-mediated glomerulonephritis ?! Treasure rule number 1 in medicine: “First Do No Harm !”. Spending time with your patient educating him about the importance of the biopsy for the diagnosis and management of his/her case could make the decision easier for him/her. Remember that there are many diseases which can present with proteinuria and doesn’t require immunosuppression therapy (Alport syndrome or thin basement membrane disease, for example).

Finally, don’t rush to give the patient a treatment, think about your differential diagnosis, do your lab tests and always remember:
First Do No harm !

Mohamed Elrggal
18 March 2019

Pursuing an Onco-Nephrology career, Steps to take!

Photo by shy sol from Pexels

Onco-Nephrology is a rapidly evolving subspeciality that covers all areas of renal involvement in cancer patients. There are several areas of contact where nephrologists and oncologists should collaborate to provide the optimum care for patients afflicted with cancer and kidney diseases. Actually, there are 10 points of contact between the 2 specialty detailed brilliantly in this lovely article (Onco-nephrology: a decalogue) and they include:
1. AKI and CKD in cancer patients
2. Nephrotoxic effects of anticancer medications
3. Paraneoplastic kidney affection.
4. Renal cell carcinoma and management of nephrectomized patients (eventually developing CKD).
5. Renal replacement therapy and oncological treatments.
6. Post-transplant malignancy
7. Kidney transplant in cancer survivors
8. Pain management in cancer patients with concomitant kidney disease.
9. Management of contrast induced AKI.
10. Prophylaxis against nephrotoxic effects of certain anticancer therapies.

Persuading a career in onconephrology require spending effort to read and learn the basics of this science as well creating an infrastructure for an outpatient onconephrology clinic with specific basic requirements to function properly.

Many valuable resources are available online to read and learn about nephrooncology including:
1. Special issue in “Seminars in Nephrology” in 2010.
2. Special issue in “CJASN Moving points in Nephrolgoy” in 2012
3. Special issue in “Advances in CKD” in 2014.
4. and finally the master of all, is the ASN onconephrology curriculum published in 2016, consisting of 19 chapters covering most of the essential Onco-Nephrology topics.

Here are some essential requirements to establish a functioning outpatient onconephrology clinic (as detailed here):
1. A sufficient number of patients enrolled in the clinic (approximately 150 patients/year).
2. Availability of (electronic) medical records and shared database between the two specialties.
3. Referral to onconephrology in cases, for example, with AKI or progressive CKD that might impede active cancer therapy.
4. A multidisciplinary approach for patients in need for mutual discussion.
5. Involvement of nurses, postgraduates, trainees and fellows to support the development and maintenance of the clinic.
6. Enhancing clinical research in the field and developing practice guidelines for the management of different situations.
7. Monitoring patients outcomes and measuring performance indicators, then reflecting on these data to improve patients care and health outcomes.

Finally, we need more nephrologists to persuade this subspeciality due to the growing demand of cancer patients. This subspeciality will improve more and more with further developments and research efforts to become more and more evidence based.

Acknowledgement: Thanks to Prof Kenar Jhaveri for providing reference .

Mohamed Elrggal
13 March 2019

Catheter Related Blood Stream Infection, points to remember!

A recent article published online in cJASN, in the series of kidney case conference, discussed the issue of catheter related blood stream infection (CRBSI) and its management. CRBSI is a very common problem among hemodialysis (HD) patients associated with high morbidity and mortality. And we are still facing this problem frequently in our patients. I am going to highlight some points in the article to be stressed on:

  1. Catheter use at dialysis initiation:

Despite substantial efforts over the last 15 years to increase the proportion of patients starting dialysis with an arteriovenous fistula, 80% of patients with incident ESKD and 20% of patients with prevalent ESKD in the United States still use a central venous catheter (CVC) for vascular access. 

from the introduction of the article.

This data is coming from the last 2018 USRDS report, which you can see clearly from the figure below.

It seems like we are facing the same problem, the accurate timing of placing an AVF, the way of convincing patients to do AVF before requiring dialysis, the optimum time to initiate dialysis, all are common questions we still don’t have clear answers to it.
On the other hand, the increasing incidence of ESKD in elderly with high rate of primary maturation failure of AVF, led others to think the other way around in this age group, and should fistula be always first ?!

2. Diagnosis of CRBSI: Diagnosis requires paired blood cultures (peripheral and central) as recommended by IDSA guidelines. However, some authors challenged this recently, showing that central blood culture (from HD circuit or venous catheter hub) are more sensitive and enough.
Either ways, always always draw cultures before initiating antibiotics.

3. Empirical treatment:
Empirical antibiotic coverage of both Gram-positive and Gram-negative organisms should be initiated promptly after blood cultures have been obtained. An accepted choice is to use vancomycin and ceftazidime.
It has been a common practice in Egypt, to just give vancomycin in any case with suspected CRBSI !
Always collect your culture results, know your antibiogram and modify your treatment accordingly. In our center, we collected the results of all cultures for CRBSI cases for one year, and we found that 50% of organisms were gram negative!! MRSA represented 40% of the gram positive cases (results can be found here).

So, again, it is almost always important to draw blood cultures before initiating antibiotics, and to start with a combination covering both gram positive and gram negative organisms.

4. Modify treatment according to culture results:
In order to protect against resistance, if culture grew gram positive organism, stop ceftazidime, and if it grew any gram negative organisms, stop Vancomycin.
Continue the full recommended duration of antibiotic treatment; 2–3 weeks (4 weeks for S. aureus) for uncomplicated CRBSI.
Treatment of complicated CRBSI with sepsis, persistently positive blood cultures, or metastatic infection (e.g., endocarditis, septic arthritis, epidural abscess, or osteomyelitis) requires a longer course of antibiotics (6–8 weeks).

5. Catheter salvage or Catheter removal:
Catheter removal (or even wire exchange) is always better especially in complicated CRBSI. Catheter salvage may be an option in cases with only remaining access. In these cases, a complimentary antibiotic lock solution may be used to eradicate catheter biofilm and permit effective clearance of the organism while allowing for salvage of the CVC.

Finally, design your own unit protocol for diagnosis and management of CRBSI. Monitor your cultures results, modify your antibiotic treatment, monitor your patient outcomes and always aim for early AVF creation to avoid catheter related complications.

Mohamed E Elrggal
9 March 2019