Asif Sharfuddin

Pathophysiology of ischemic acute kidney injury

Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.

Soluble Thrombomodulin Protects Ischemic Kidneys

Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.

The strength of donor-specific antibody is a more reliable predictor of antibody-mediated rejection than flow cytometry crossmatch analysis in desensitized kidney recipients.

Mujtaba MA, Goggins W, Lobashevsky A, Sharfuddin AA, Yaqub MS, Mishler DP, Brahmi Z, Higgins N, Milgrom MM, Diez A, Taber T. The strength of donor‐specific antibody is a more reliable predictor of antibody‐mediated rejection than flow cytometry crossmatch analysis in desensitized kidney recipients.
Clin Transplant 2011: 25: E96–E102.

Cell-Free DNA and Active Rejection in Kidney Allografts

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

Renal Relevant Radiology: Imaging in Kidney Transplantation

Kidney transplantation can be associated with various complications that vary from vascular complications to urologic disorders to immunologic adverse effects. In evaluating the recipient with graft dysfunction, clinicians can choose among several imaging modalities, including ultrasonography, nuclear medicine studies, computed tomography, and magnetic resonance imaging. This review discusses the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality. A kidney biopsy is often required as a gold standard for diagnostic purposes. However, because of the inherent risks of a kidney biopsy, noninvasive imaging in diagnosing causes of graft dysfunction is a highly desired tool used and needed by the transplant community. Because the diagnostic accuracy varies depending on the time course and nature of the transplant-related complication, this review also addresses the advantages and limitations of each modality. The recent advances in kidney transplant imaging techniques and their clinical implications are also discussed.

Approach to Acute Renal Failure With Multiple Myeloma: Role of Plasmapheresis

Abstract:  Multiple myeloma is commonly complicated by renal failure, which limits therapeutic options and aggravates the prognosis. In myeloma the most common cause of advanced renal failure is myeloma kidney, where light chains produced by tumor cells precipitate and impede kidney function. We suggest that plasma exchange is an appropriate intervention in advanced renal failure from multiple myeloma, and support this notion with two case reports. The two elderly individuals had advanced chronic and acute renal failure, and recovered after the removal of large quantities of light chains by existing membrane separation techniques. We also present an algorithm to approach renal failure and myeloma.

Risk factors for native kidney dysfunction in patients with abdominal multivisceral/small bowel transplantation

Kidney dysfunction is a recognized complication after non‐renal solid organ transplantation, particularly after intestinal transplant. In our study, we reviewed data on 33 multivisceral transplant (MVT)‐ and 15 isolated small bowel (ISB)‐transplant patients to determine risk factors for kidney dysfunction. Kidney function was estimated by modified diet in renal disease (MDRD) and Schwartz formula for adults and children, respectively. Acute kidney injury (AKI) was defined as an increase in the serum Cr (sCr) greater than twofold. Kidney function declined significantly at one yr after transplantation with 46% of subjects showing an estimated GFR (eGFR) <60 mL/min. Patients with an episode of AKI were more likely to have reduced eGFR than those without AKI (p < 0.025). In linear regression analyses, age, pre‐transplant sCr, eGFR at postoperative day (POD) 30, 90, 180, 270, and tacrolimus level at POD 7 showed significant correlation with one yr post‐transplant eGFR (p < 0.05). Pediatric patients and patients with MVT had lesser decline in kidney function compared with adults or patients with ISB. In conclusion, risk factors for post‐transplant kidney dysfunction in intestinal transplantation included age, pre‐transplant sCr, AKI episode, eGFR at POD 30, 90, 180, 270, and tacrolimus level at POD 7.

BK virus nephropathy in simultaneous pancreas kidney transplant: A potentially preventable cause of kidney allograft loss

More than half of the simultaneous pancreas kidney transplant (SPK) patients afflicted with BK virus nephropathy (BKVN) lose their kidney allograft. Fear of pancreatic rejection limits the ability to reduce immunosuppression; this may result in inadequate treatment of BKVN.

Imaging Evaluation of Kidney Transplant Recipients

Renal transplantation is nowadays accepted as the treatment of choice for patients with end-stage renal disease. However, despite progress in immunosuppression and surgical techniques, various complications still can occur. Complications vary from vascular disorders and urologic diseases to parenchymal and immunologically related complications. The clinician evaluating the recipient with graft dysfunction has the option of choosing among a variety of imaging modalities including ultrasonography, nuclear medicine, computed tomography, and magnetic resonance imaging to start or continue the diagnostic work-up. In this article, we discuss the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality.

Correlation between CT-based measured renal volumes and nuclear-renography-based split renal function in living kidney donors. Clinical diagnostic utility and practice patterns

Living donor evaluation involves imaging to determine the choice of kidney for nephrectomy. Our aim was to study the diagnostic accuracy and correlation between CT‐based volume measurements and split renal function (SRF) as measured by nuclear renography in potential living donors and its impact on kidney selection decision.