Thursday, May 27, 2010

The kidney in sickle cell disease

Today, one of my colleagues presented an interesting case of sickle cell disease with microscopic hematuria, nephrotic range proteinuria and elevated serum creatinine. The renal manifestations of sickle cell disease are myriad. There is a nice review article published last year on this topic (Scheinman, Nature Reviews Nephrology 2009). Common renal manifestations of sickle cell disease include:
- Painless microscopic or gross hematuria as a result of RBC sickling in vasa recta in relatively hypoxic renal medulla. More severe ischemia due to vaso-occlusive phenomena in vasa recta can lead to renal papillary necrosis.
- Tubular function defects like hypoesthenuria/impaired concentrating ability (because of involvement of juxtamedually nephron collecting ducts), incomplete distal RTA with hyperkalemia (because of voltage defect), supranormal proximal tubular function in initial stages causing increased sodium & phosphrous reabsorption and increased creatinine/uric acid secretion (?? because of prostaglandins)
- Sickle cell glomerulopathy with nephrosis more common than nephritis. Most common pathological diagnosis is FSGS predominantly involving juxta medually nephrons that are perfused by vasa recta. Medullary fibrosis is prominent.
Other key points:
- Lower incidence of hypertension
- More prone to acute renal failure (In addition to usual causes, keep in mind the renal vein thrombosis and urinary tract obstruction from blood clots)
- Renal medullary carcinoma: rare but exclusive to sickle cell patients
- For ESRD, transplant outcomes are not as good as for other ESRD patients

Saturday, May 22, 2010

Genetic Kidney Diseases

There is an excellent review article on genetic kidney diseases published in Lancet last month (Hildebrandt Lancet April 2010). It has the comprehensive list of prominent single gene kidney disorders and polygenic risk alleles of common disorders.

Few general points to recap what we learned before:
- Diseases caused by recessive genes usually manifest early (prenatal, childhood or adolescence) and have complete penetrance. Ex: Congenital nephrotic syndrome, Nephronophthisis, Bartter's, Cystinuria etc.
- Diseases caused by dominant genes typically manifest late (adulthood), have variable expression and incomplete penetrance. Ex: ADPKD, Liddle's, Gordon's etc.
- In polygenic diseases, genotype-phenotype correlation is weak and usually only a relative risk can be assigned to a genetic change. Ex: MYH-9, ELMO1 etc.
A nice article indeed!

Friday, May 21, 2010

Size does matter for renal transplant outcomes

In an interesting study from France (Giral et al, JASN express May 20, 2010), effects of nephron underdosing on long term allograft function were studied. The novel marker used in the study was ratio of the weight of kidney before implantation (Kw) to the weight of recipient (Rw) i.e Kw/Rw. In a multicenter cohort of 1189 transplant recipients with mean follow up of 6.2 years, those with Kw/Rw < 2.3 g/kg had worse long term graft survival, more GFR decline, more proteinuria, more hypertension and more glomerulosclerosis than those with Kw/Rw > 2.3 g/kg. Low nephron mass (relative to recipient weight) with resultant chronic functional overload likely forms basis for the study findings. The main caveat of the study is absence of data on outcomes with transplantation of kidneys from pediatric donors. In an earlier study, outcomes of adults who undergo transplantation with pediatric kidneys were comparable to those from older donors (Zhang et al, cJASN, 2009). It would be interesting to see if current study findiings replicate in other studies.

Tuesday, May 18, 2010

Multiplicative risk of CKD and albuminuria


A metanalysis to assess the independent and combined association of low eGFR and albuminuria with mortality is just published in Lancet (CKD Prognosis Consortium, Lancet, May 2010). In this well-conducted study, data from about 1.2 million participants from 21 eligible studies were analyzed. Median follow up was about 8 years. It was found that mortality was lowest with eGFR between 105 and 75 ml/min, and rose exponentially as eGFR decreased with statistical significance for eGFR below 60 ml/min. In regards to albuminuria, the risk was linear with significance starting at albumin/creatinine ratio of 10 mg/g (which is well below the microalbuminuric range of 30-300) or more. Risk was multiplicative when both eGFR and albuminuria were plotted together. Authors propose to use both these measures for risk assessment and CKD staging.

Friday, May 14, 2010

Normoalbuminuric Diabetic Nephropathy


Recently, one of my colleagues gave an interesting talk on diabetic nephropathy without proteinuria. Traditionally, we are taught that diabetic nephropathy progresses along 5 stages: 1.Hyperfilitration, 2.Normoalubminuria, 3.Microalbuminuria, 4.Macroalbuminuria and 5.ESRD. GFR declines as patients progress from one stage to the next stage. However, according to a nice review article on diabetic nephropathy, (Jerums et al, Nature Rev Nephrol 2009), about 10-25% of patients follow 'normoalubminuric pathway' in which GFR continues to decline without worsening proteinuria. All studies excepting one quoted on this subject in the paper suffer from lack of renal biopsy to exclude other causes of low GFR such as nephrosclerosis. Caromori et al (Diabetes 2003, 52(4):1036-40) biopsied 105 type 1 diabetic patients without albuminuria and compared patients with low GFR with those with normal GFR. It was found that patients with low GFR had advanced diabetic glomerular lesions despite absence of albuminuria. These data indicate that a proportion of diabetic patients suffer decline in GFR with progressive glomerular lesions in the absence of worsening albuminuria. We have to keep this in mind in evaluation of diabetic patients in our CKD clinic.

Tuesday, May 11, 2010

Politics of drug coverage for transplantation

Currently, Medicare covers 80% cost of immunosuppressive medications up to 3 years after transplantation in those patients who are Medicare eligible because of ESRD. American Society of Transplantation (AST) and transplant community have been advocating for extending coverage beyond 3 years. However, despite showing evidence for long term benefit of incurring short term expense to extend coverage, this has not become a reality yet. Just published cJASN article by David Cohen and Barbara Murphy (immediate past president of AST) outlines the politics behind the exclusion of transplant drug coverage provision in the recent Affordable Health Care for Americans Act and how powerful lobby of mighty dialysis industry trumped the long overdue coverage for transplant recipients.

Sunday, May 9, 2010

Emerging role of FGF 23 in CKD-MBD


Just released article (Evenepoel et al, cJASN 2010) provides additional support for a new paradigm for the pathogenesis of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). In the old traditional paradigm of CKD-MBD, loss of functioning kidney mass in CKD causes low active vitamin D level which leads to increased PTH production either directly or indirectly via diminished GI calcium absorption. However, in our CKD practice, we often see hyperparathyroidism without low active vitamin D or hypocalcemia. According to new phosphate-centric paradigm, CKD causes a decrease in renal phosphate excretion which leads to increased Fibroblast Growth Factor 23 (FGF-23) from bone osteocytes. FGF-23 act on kidney to inhibit phosphate reabsorption and also suppress production of active vitamin D to lower GI absorption of phosphorous. FGF-23 overproduction due to mutations in FGF gene was originally described in Autosomal Dominant Hypophosphatemic Rickets (ADHR consortium, Nature Genetics 2000). Recently, there has been explosion of literature on FGF-23 in CKD including its potential role in increased mortality (Gutierrez et al, NEJM 2008), left ventricular hypertrophy (Gutierrez et al, Circulation 2009) and progression of CKD (Fliser et al, JASN 2007). However, causal relationship between excess FGF-23 and adverse outcomes, and the potential mechanisms remain to be proven.

Tuesday, May 4, 2010

Controversy over eponym 'Wegener's granulomatosis'

The eponym "Wegener's granulomatosis" was derived after Friedrich Wegener (1907-1990), the german pathologist who initially described the condition. In a recent JASN review article on ANCA disease (Falk and Jennette, JASN 2010), alleged Nazi connections of Wegener are brought to the attention of nephrology community. Although no definitive evidence was found regarding his involvement in Nazi crimes, he was reportedly an early member of Nazi party. The authors proposed to medical community studying vasculitis to agree on an alternative name for Wegener's granulamatosis. In 2007, American College of Chest Physicians (ACCP) did an eloborate review of available data (Rosen MJ, Chest 2007) and finally decided to rescind their Master Clinician Award given to Wegener in 1989.