Complement-Mediated Thrombotic Microangiopathy with 10 Years of Stable Renal Function After a Year-Long Treatment with Eculizumab with Coincidental Polycystic Kidney Disease.

BACKGROUND Complement-mediated thrombotic microangiopathy (cTMA), is a genetic disease that results when an unchecked alternative complement pathway is triggered by an external factor, resulting in endothelial cell injury with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, though other organ systems may be involved. CASE REPORT A 5-year-old girl presented with non-bloody diarrhea, hemolysis, renal failure, and thrombocytopenia. She was negative for Shiga toxin. She was diagnosed with cTMA, and this diagnosis was confirmed later by a mutation in the complement factor H (CFH) gene. The patient was started on eculizumab 8 weeks after onset of symptoms. A month later, she was able to stop hemodialysis. Eculizumab was given for a year, and then, because of clinical remission, was stopped. At the time of stopping hemodialysis, serum creatinine was 2.07 mg/dL; at the end of eculizumab therapy, it was 1.23 mg/dL. Now, 10 years later, it is 1.10 mg/dL. Glomerular filtration rate by Schwartz equation was 52 mL/min/1.73 m² after eculizumab and 60 mL/min/1.73 m² currently. The cTMA lab parameters normalized after 2 doses of eculizumab and have remained normal for 10 years. Two years ago, on routine ultrasound, renal cysts were noted. Recent genetic testing re-confirmed the CFH mutation and additionally showed a polycystic kidney disease (PKD1) mutation. Notably, there is no family history of either. Currently, the patient has mild proteinuria. CONCLUSIONS Instead of lifelong eculizumab treatment, we successfully managed the patient's condition with a year of eculizumab and intensive followup on sixty occasions over a decade. This approach can work if there are no relapses. Genetic tests revealed mutations for cTMA and autosomal dominant polycystic kidney disease (ADPKD)/PKD1 in the same patient. These have not been reported before, to the best of our knowledge.

Uric Acid Control in Advanced Chronic Kidney Disease in a Southeastern US Urban Cohort.

OBJECTIVES: Uric acid (UA) control may be insufficient in chronic kidney disease (CKD) patients in the current era. It is unclear, however, whether this is the result of environmental effects, patient anthropometrics or insufficient dosing of medical therapy (allopurinol). METHODS: We have collected data on multiple clinical and laboratory parameters of 114 CKD clinic patients attending the nephrology clinic of the University of Mississippi Medical Center with an estimated glomerular filtration rate <45 mL · min-1 · 1.73 m2. We assessed the correlates of UA levels and the allopurinol doses along with achieved serum UA and urine pH. RESULTS: The cohort consisted of middle-aged to elderly patients with a mean (± standard deviation) age of 62.1 (11.6) years; 45.6% were female, 68.4% were African American and 47.4% had a history of gout. The mean UA level was 7.7 (2.49) mg/dL (range 3.1-16), allopurinol dose was 192 (99) mg/day (range 50-450) and estimated glomerular filtration rate was 23.8 (11.3) mL · min-1 · 1.73 m2. While the overall serum bicarbonate level was 25 (3.2) mEq/L, urine pH was <6 in 60.5% of the cohort. Significant univariate correlates of the administered doses of allopurinol were weight (r 0.317, P = 0.001), body mass index (BMI; r 0.313, P = 0.001), and female sex (r -0.198; P = 0.035). Achieved UA levels correlated directly with BMI (r 0.201, r = 0.036) but inversely with the allopurinol dose (r -0.196; P = 0.036). During logistic regression analysis with stepwise selection, only weight (ß 0.313, P = 0.001) and sex (ß -0.190, P = 0.039) proved to be predictive of the allopurinol dose; as for the achieved UA level, only BMI (ß 0.271, P = 0.006) and the allopurinol dose (ß -0.258; P = 0.009) had a significant effect. CONCLUSIONS: In patients with advanced CKD, conventional dosing recommendations for allopurinol are unlikely to suffice in reaching target serum UA goals. In our cohort, larger-than-usual allopurinol doses were well tolerated.

Targeted surgical parathyroidectomy in end-stage renal disease patients and long-term metabolic control: A single-center experience in the current era.

BACKGROUND: The long-term results of surgical parathyroidectomy (PTX) in end-stage renal disease (ESRD) patients are less well known in the modern era of newer activated vitamin-D analogs, calcimimetics and intraoperative monitoring of parathyroid hormone (PTH). METHODS: We performed a retrospective chart review of all ESRD patients undergoing PTX at the University of Mississippi Medical Center between January 2005 and August 2011, with follow-up data as available up to 4 years. All PTXs were performed with intraoperative second-generation PTH monitoring and targeted gland size reduction. RESULTS: The cohort (N = 37) was relatively young with a mean (±SD) age of 48.4 ± 13.9. 94.6% of the subjects were African American and 59.5% female. Preoperatively, 45.9% received cinacalcet (CNC) at a mean dose of 63.5 ± 20.9 mg. The size of the largest removed glands measured 1.7 ± 0.8 cm and almost all (94.6%) glands had hyperplasia on histology. The mean length of inpatient stay was 5.5 ± 2.4 days. Preoperative calcium/phosphorus measured 9.6 ± 1.2/6.6 ± 1.7 mg/dL with PTH concentrations of 1589 ± 827 pg/mL. Postoperative PTH values measured 145.4 ± 119.2 pg/mL. Preoperative PTH strongly correlated (P < 0.0001) with both alkaline phosphatase (ALP) levels (r: 0.596) and the number of inpatient days (r: 0.545), but not with CNC administration. Independent predictors for the duration of hospitalization were preoperative ALP (beta 0.469; P = 0.001) and age (beta -0.401; P = 0.005) (R2 0.45); for postoperative hypocalcemia, age (beta: -0.321; P = 0.006) and preoperative PTH (beta: 0.431; P = 0.036) were significant in linear regression models with stepwise selection. CONCLUSION: Gland-sparing PTX achieved acceptable control of ESRD-associated hyperparathyroidism in most patients from a socioeconomically challenged, underserved population of the United States.

Peritoneal Dialysis in Class 2-3 Obesity-A Single-Center Experience.

Extreme obesity may hamper successful peritoneal dialysis (PD) delivery. Among our PD patients, we have identified 15 markedly obese (class 2-3 obesity: body mass index [BMI] ≥35kg/m2) and 20 lean (BMI: 20-25kg/m2) dialysis patients and reviewed multiple clinical, laboratory and dialysis-related parameters. Extreme outliers of obesity (BMI > 40; 6 subjects) received detailed review. Although weight (P < 0.0001) and BMI (P < 0.0001) differed significantly, weekly Kt/V (obese versus lean: 2.05 ± 0.51 versus 2 ± 0.36), creatinine clearance (86.8 ± 44.8 versus 70 ± 30.4L/1.73m2) or residual renal functions were not statistically different. Total daily PD exchange volumes were similar (11.2 ± 2.5L versus 10.4 ± 2.5L, P = 0.378). Serum albumin, calcium, phosphorus, hemoglobin and parathyroid hormone levels did not differ, either. Analogous results have been obtained for extremely obese subjects (BMI 44.3 ± 4.2kg/m2; range: 40.2-51.6). Our study shows only limited effect of class ≥2 obesity for successful PD in this predominantly African American cohort.

Clinical Utility of Potassium-Sparing Diuretics to Maintain Normal Serum Potassium in Peritoneal Dialysis Patients.

♦ BACKGROUND: Hypokalemia is a vexing problem in end-stage renal disease patients on peritoneal dialysis (PD), and oral potassium supplements (OPS) have limited palatability. Potassium-sparing diuretics (KSD) (spironolactone, amiloride) may be effective in these patients. ♦ METHODS: We performed a cross-sectional review of 75 current or past (vintage > 6 months) PD patients with regard to serum potassium (K+), OPS, and KSD utilization. We reviewed charts for multiple clinical and laboratory variables, including dialysis adequacy, residual renal function, nutritional status and co-existing medical therapy. ♦ RESULTS: The cohort was middle-aged with a mean age of 49.2 years (standard deviation [SD] = 14.7) and overweight with a body mass index of 29.5 (6.7) kg/m2. Of all the participants, 57.3% were female, 73.3% African-American, and 48% diabetic with an overall PD vintage of 28.2 (24.3) months at the time of enrollment. Weekly Kt/V was 2.12 (0.43), creatinine clearance was 73.5 (33.6) L/week/1.73 m2 with total daily exchange volume of 10.8 (2.7) L. Residual urine output (RUO) measured at 440 (494) mL (anuric 30.6%). Three-month averaged serum K+ measured at 4 (0.5) mmol/L with 36% of the participants receiving K+ supplements (median: 20 [0;20] mmol/day) and 41.3% KSD (spironolactone dose: 25 - 200 mg/day; amiloride dose: 5 - 10 mg/day). Serum K+ correlated positively with weekly Kt/V (r = 0.239; p = 0.039), PD vintage (r = 0.272; p = 0.018) but not with PD modality, daily exchange volume, RUO, or KSD use. However, KSD use was associated with decreased use of OPS (r = -0.646; p < 0.0001). ♦ CONCLUSIONS: Potassium-sparing diuretics were effective in this cohort of PD patients and decreased the need for OPS utilization.

Successful Peritoneal Dialysis in Large-Weight Subjects: Clinical Features and Comparisons with Normal-Weight Subjects.

Peritoneal dialysis (PD) obviates the need for temporary vascular access in end-stage renal disease; however, extremely heavy weight has been viewed as a relative contraindication to PD.We performed a cross-sectional review of multiple clinical and laboratory variables for 75 current or past PD patients (vintage > 6 months), comparing dialysis adequacy parameters for those with a large body weight (>100 kg, LWS group) and with a normal body weight (<75 kg, NWS group).In the LWS group (n = 17), mean weight was 117.2 ± 15.7 kg, and mean body mass index (BMI) was 37.2 ± 6.3 kg/m2; in the NWS group (n = 33), mean weight was 63.2 ± 9.2 kg, and mean BMI was 25.3 ± 4.5 kg/m2. Despite the marked differences in weight and BMI between the groups (both p < 0.0001), achieved Kt/V was adequate, although marginally less, in large subjects (1.96 ± 0.29 for the LWS group vs. 2.22 ± 0.47 for the NWS group, p = 0.022), and weekly global creatinine clearance was significantly better in the LWS group (92.5 ± 43.5 L/1.73 m2 vs. 62.2 ± 27.5 L/1.73 m2, p = 0.016). The total daily exchange volume was approximately 30% higher in the LWS group (12.8 ± 2.5 L vs. 9.9 ± 2.2 L, p < 0.0001). Residual creatinine clearance (p = 0.224) and residual urine output (p = 0.125) were similar and did not seem to influence the results. Compared with their LWS counterparts, members of the NWS group were more likely to have higher iron saturation (p = 0.053) and serum ferritin (p = 0.004), but lower achieved hemoglobin (p = 0.055).Successful PD is feasible in larger-weight individuals; however, given the retrospective nature of the present study, prospective trials are needed to confirm that observation.

Rescue of renal function in a 3-year-old girl with Goodpasture's syndrome with a brief review of literature.

Goodpasture's syndrome has been documented in only a handful of children under the age of four. We describe a 3-year-old girl presenting with anaemia and renal failure whose kidney biopsy showed anti-glomerular basement membrane (GBM) disease. She was treated aggressively with pulse steroids, plasmapheresis and monthly infusions of cyclophosphamide. After months of aggressive immunosuppression, her renal function normalized, and her anti-GBM antibody disappeared. A year after the onset, she underwent a second kidney biopsy for persistent proteinuria and hypertension that surprisingly showed focal sclerosing glomerulonephritis, an unreported finding at this age. The biopsy showed deposition of antibody on the GBM despite the fact that anti-GBM antibody had normalized in the serum 5 months earlier. Mycophenolate mofetil was added to the immunosuppression at that point. At her 3-year follow-up, creatinine clearance was 88.4 mL/min/1.73 m(2), proteinuria was 408 mg/day and blood pressure was controlled with enalapril 0.2 mg/kg/day. She has not had a relapse or abnormal anti-GBM antibody for 30 months, but her renal prognosis remains guarded. To our knowledge, this is the youngest patient to have a successful rescue of renal function after isolated Goodpasture's syndrome.

Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits.

Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli.

Regulation of Na+/H+ exchanger-NHE3 by angiotensin-II in OKP cells.

Previous studies have shown that circulating Angiotensin II (A-II) increases renal Na+ reabsorption via elevated Na+/H+ exchanger isoform 3 (NHE3) activity. We hypothesized that prolonged exposure to A-II leads to an increased expression of renal NHE3 by a transcriptionally mediated mechanism. To test this hypothesis, we utilized the proximal tubule-like OKP cell line to evaluate the effects of 16-h treatment with A-II on NHE3 activity and gene expression. A-II significantly stimulated NHE3-mediated, S-3226-sensitive Na+/H+ exchange. Inhibition of transcription with actinomycin D abolished the stimulatory effect of A-II on NHE3-mediated pH recovery in acid-loaded OKP cells. This prolonged exposure to A-II was also found to elevate endogenous NHE3 mRNA (by 40%)-an effect also abolished by inhibition of gene transcription. To evaluate the molecular mechanism by which A-II regulates NHE3 expression, the activity of NHE3 promoter driven reporter gene was analyzed in transient transfection assays. In transfected OKP cells, rat NHE3 promoter activity was significantly stimulated by A-II treatment, and preliminary mapping indicated that the A-II responsive element(s) is present between 149 and 548 bp upstream of the transcription initiation site in the NHE3 gene promoter. We conclude that a transcriptional mechanism is at least partially responsible for the chronic effects of A-II treatment on renal NHE3 activity.

Effects of angiotensin II on NaPi-IIa co-transporter expression and activity in rat renal cortex.

The kidney plays a major role in reabsorption of phosphate with the majority occurring in the proximal tubule (PT). The type IIa sodium-phosphate co-transporter (NaPi-IIa) is the main player in PT. The purpose of current study was to determine the effect of angiotensin II (A-II) on membrane expression of NaPi-IIa in the rat renal cortex. A-II (500 ng/kg/min) was chronically infused into the Sprague-Dawley rats by miniosmotic pump for 7 days. The arterial pressure and circulating plasma A-II level along with urine output were markedly increased in A-II rats. There was diuresis but no natriuresis. The phosphate excretion increased sevenfold on day 4 and 5.7-fold on day 7. There was no change in Na-dependent Pi uptake in brush-border membrane (BBM) vesicles between A-II-treated group and control on day 4, however, there was a 43% increase on day 7. Western blot analysis of NaPi-IIa protein abundance showed a parallel pattern: no change after 4 days of treatment and a 48% increase after 7 days of treatment. However, Northern blot analysis of cortical RNA showed no change in NaPi-IIa mRNA abundance on day 7. A-II stimulation of Na/Pi co-transport activity is a result of increases in the expression of BBM NaPi-IIa protein level and that stimulation is most likely mediated by posttranscriptional mechanisms.

Kimura disease with advanced renal damage with anti-tubular basement membrane antibody.

Kimura disease (KD) is an autoimmune eosinophilic granulomatous disorder with generalized lymphadenopathy. A handful of pediatric patients with renal disease have been described, none of whom have been African-American (AA). We present an AA boy with KD and nephrotic syndrome (NS). Two months after stopping steroids, fever, asthma, eczema, and proteinuria recurred. His NS did not relapse but his platelet count decreased to 51,000/microl (x10(6)/l). On restarting prednisone, his platelet count normalized. A kidney biopsy revealed 23 of 37 glomeruli obsolescent and advanced damage with over 50% of cortical tissue replaced by interstitial fibrosis and chronic inflammation. Glomerular immunofluorescence was largely negative; very intense linear anti-tubular basement membrane (TBM) deposits of IgA, IgG, C3, and C4 were noted. At present, 36 months from onset, serum creatinine is 1.2 mg/dl (106 micromol/l). We present a 4-year-old AA boy with KD, NS, relapsing thrombocytopenia, and renal damage with anti-TBM antibody.

Effect of angiotensin-II on renal Na+/H+ exchanger-NHE3 and NHE2.

The purpose of the present study was to determine the effect of angiotensin II (A-II) on membrane expression of Na+/H+ exchange isoforms NHE3 and NHE2 in the rat renal cortex. A-II (500 ng/kg per min) was chronically infused into the Sprague-Dawley rats by miniosmotic pump for 7 days. Arterial pressure and circulating plasma A-II level were significantly increased in A-II rats as compared to control rats. pH-dependent uptake of 22Na+ study in the presence of 50 microM HOE-694 revealed that Na+ uptake mediated by NHE3 was increased approximately 88% in the brush border membrane from renal cortex of A-II-treated rats. Western blotting showed that A-II increased NHE3 immunoreactive protein levels in the brush border membrane of the proximal tubules by 31%. Northern blotting revealed that A-II increased NHE3 mRNA abundance in the renal cortex by 42%. A-II treatment did not alter brush border NHE2 protein abundance in the renal proximal tubules. In conclusion, chronic A-II treatment increases NHE3-mediated Na+ uptake by stimulating NHE3 mRNA and protein content.

Intravenous cyclophosphamide--resistant systemic lupus erythematosus in Arizona.

Systemic lupus erythematosus (SLE) tends to be severe and to have a variable response in childhood. We undertook this retrospective study to assess response rates and outcome in 14 children with SLE. Mean age at onset was 12.8+/-3.1 years. Ten patients were female and 4 were male, and 12 patients (86%) were Hispanic. Creatinine clearance prior to therapy was 104+/-36 ml/min. All had hematuria and proteinuria with a protein/creatinine ratio of 3.9+/-4.8. WHO classification of renal biopsies revealed class IV in 64%, class III in 21%, and class V in 14%. Patients were treated with 6-monthly pulses of intravenous cyclophosphamide (IVCY) followed by longer-duration pulses. The mean duration of follow-up was 3.7+/-3.3 years. Of the 14 patients, 3 (21%) achieved systemic remission but all relapsed subsequently; 7 of 14 achieved renal remission, although 6 relapsed. Six (42%) had adverse outcomes, defined by death, dialysis, or need for bone marrow transplant. All 6 had failed 6 months of IVCY, suggesting that patients who demonstrate resistance to initial IVCY therapy have an unfavorable outcome and a high likelihood of complications. In summary, we report a poor response to standard therapeutic protocols with higher relapse rates, as well as significant adverse outcomes.

Hyponatremic hypertensive syndrome (HHS) in an 18-month old-child presenting as malignant hypertension: a case report.

BACKGROUND: The combination of hyponatremia and renovascular hypertension is called hyponatremic hypertensive syndrome (HHS). Malignant hypertension as a presentation has been reported in adults with HHS but is rare in children. CASE PRESENTATION: An eighteen month-old male presented with drowsiness, sudden onset status epilepticus and blood pressure of 210/160. The electrolytes on admission revealed sodium of 120 mEq/L and potassium of 2.1 mEq/L. The peripheral renin activity (PRA) was 172 ng/ml/min (normal 3-11 ng/ml/min) and serum aldosterone level was 91 ng/dl (normal 4 to 16 ng/dl). Patient underwent angioplasty with no success, followed by surgical correction. Two years since the diagnosis, the blood pressure is controlled with labetolol and amlodipine (at less than sixth of the pre-operative dosages). The PRA is 2.4 ng/ml/min and aldosterone 15.5 ng/dl. The child not only had three renal arteries on left but all of them were stenosed which to best of our knowledge has not been described. CONCLUSION: As uncommon as HHS with malignant hypertension may be in adults it is under-reported in children and purpose of the case report is to raise its awareness.

Managing Henoch-Schonlein purpura in children with fish oil and ACE inhibitor therapy.

BACKGROUND: Henoch-Schonlein purpura (HSP) is a vasculitic syndrome with palpable purpura and renal involvement. The treatment for HSP with persistent renal disease remains controversial. The kidney biopsy in HSP shows IgA deposits and fish-oil therapy has proven to be promising in halting the progression of IgA nephropathy. METHODS: Five children with biopsy-proven HSP with repeated episodes of haematuria and proteinuria were treated with fish oil (1 g orally twice daily). In three of the five patients an angiotensin-converting enzyme inhibitor (ACEI) was added for hypertension. RESULTS: The mean duration of follow up after starting fish-oil therapy was 49.2 weeks. The protein excretion rate prior to starting fish oil was 1041 mg/day and on the last follow-up visit the rate had decreased to 104 mg/day (P <0.05). The average blood pressure (BP) prior to therapy was 135/82. On the last follow-up visit the average BP off ACEI had decreased to 100/54 (P <0.05). After a year of follow up serum creatinine and glomerular filtration rates have remained stable at 51.2 micromol/L and 128 mL/min/1.73 m2, respectively. CONCLUSION: This is the first report of abatement of HSP with fish oil and ACEI in children. There is a need for randomized prospective trials to confirm this observation.

Acute myelo-monocytic infiltrate of the lower esophagus in a 4-year-old renal transplant recipient.

BACKGROUND: Acute myeloid leukemia after solid organ transplantation is a rare phenomenon. Few achieve remission; most succumb to relapse and infection. METHODS: A 4-year-old male renal transplant recipient on triple immunosuppression had culture-negative high spiking fever, persistent leukopenia, anemia and severe gastritis. Upper endoscopy showed 2 ulcerating masses in the lower esophagus. RESULTS: Esophageal biopsy showed a highly atypical myelo-monocytic infiltrate. A blastic population of cells featuring convoluted nuclear envelopes with an open chromatin pattern and abundant cytoplasm were filling the submucosa and infiltrating into the muscularis propria. Extensive investigation including bone marrow aspiration showed no spread. Drastic reduction of immunosuppression except 4-mg/d (0.22 mg/kg/d) prednisone for 2 to 3 weeks led to resolution of the leukemic process proven on repeat biopsy. The patient still is in remission 2 years later. CONCLUSION: This case provides evidence that early diagnosis and aggressive reduction of immunosuppression may remit a posttransplant locally invasive acute myelo-monocytic infiltrative process.

Nephropathic cystinosis associated with cardiomyopathy: a 27-year clinical follow-up.

BACKGROUND: Nephropathic cystinosis is an autosomal recessive disease resulting from intracellular accumulation of cystine leading to multiple organ failure. CASE REPORT: We describe the clinical course of a patient managed from the age of six until his death at the age of 33 years. He underwent multiple surgery, including two renal transplants, developed transplant renal artery stenosis that was managed medically, and progressive heart failure at the age of 33 years. His death from a ruptured pseudoaneurysm associated with a restrictive cardiomyopathy is noteworthy. A limited cardiac autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell, along with 1000-fold higher tissue cystine content of the left ventricular myocardium compared to patients without cystinosis, suggesting the possibility of direct cystine mediated metabolic injury.